PMID: 28752777
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Anti-EGFR monoclonal antibody panitumumab for the treatment of patients with metastatic colorectal cancer : an overview of current practice and future perspectives .
1 INTRODUCTION :
2 Targeted agents alone or in combination with chemotherapy are current standard of treatment for metastatic colorectal cancer ( mCRC ) .
3 Panitumumab is a fully human monoclonal antibody which inhibits the epidermal growth factor receptor ( EGFR ) .
4 It is currently approved in combination with chemotherapy in first - and second - line and as a monotherapy in chemorefractory patients .
5 ✓ RAS gene mutations confer resistance to anti-EGFR agents ; thus , panitumumab is restricted to the treatment of RAS wild-type ( WT ) tumors .
6 Areas covered : This review explores the available data on panitumumab and presents new perspectives on predictive markers of anti-EGFR efficacy including primary tumor sidedness and BRAF mutations .
7 Other details covered include panitumumab's mechanism of action , pharmacokinetics , pharmacodynamics and safety aspects of the therapy as well as mechanisms of secondary resistance and future prospects of treatment in different settings .
8 Expert opinion : Panitumumab has significantly added to the treatment armamentarium for RAS WT mCRC .
9 The effort spent in identifying predictive biomarkers of panitumumab efficacy has been of pivotal importance to development of the molecular selection of patients with mCRC .
10 Primary and secondary resistance , however , still represent important issues .
11   Novel strategies to overcome those issues are currently underway with promising results which highlight the potential use of panitumumab in combination with other targeted agents in the future .



PMID: 28749408
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Role of ASCT2 (SLC1A5) in KRAS-Mutated Colorectal Cancer .
1 Mutation in the KRAS gene induces prominent metabolic changes .
2 We have recently reported that KRAS mutations in colorectal cancer ( CRC ) cause alterations in amino acid metabolism .
3 However , it remains to be investigated which amino acid transporter can be regulated by mutated KRAS in CRC .
4 Here , we performed a screening of amino acid transporters using quantitative reverse-transcription polymerase chain reaction ( RT-PCR ) and then identified that ASCT2 (SLC1A5) was up-regulated through KRAS signaling .
5 Next , immunohistochemical analysis of 93 primary CRC specimens revealed that there was a significant correlation between KRAS mutational status and ASCT2 expression .
6 In addition , the expression level of ASCT2 was significantly associated with tumor depth and vascular invasion in KRAS-mutant CRC .
7 Notably , significant growth suppression and elevated apoptosis were observed in KRAS-mutant CRC cells upon SLC1A5-knockdown .
8 ASCT2 is generally known to be a glutamine transporter .
9 Interestingly , SLC1A5-knockdown exhibited a more suppressive effect on cell growth than glutamine depletion .
10 Furthermore , SLC1A5-knockdown also resulted in the suppression of cell migration .
11 These results indicated that ASCT2 (SLC1A5) could be a novel therapeutic target against KRAS-mutant CRC .



PMID: 28748988
(Patient)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 [ Characterization of patients with sporadic colorectal cancer following the new Consensus Molecular Subtypes ( CMS ) ] .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is an heterogeneous disease .
3 Three carcinogenic pathways determine its molecular profile : microsatellite instability ( MSI ) , chromosomal instability ( CIN ) and CpG island methylator phenotype ( CIMP ) .
4 Based on the new molecular classification , four consensus CRC molecular subtypes ( CMS ) are established , which are related to clinical , pathological and biological characteristics of the tumor .
5 AIM :
6 To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways .
7 MATERIAL AND METHODS :
8 Prospective analytical study of 53 patients with a mean age of 70 years ( 55% males ) with CRC , operated at a private clinic , without neoadjuvant treatment .
9 From normal and tumor tissue DNA of each patient , CIN , MSI and CIMP were analyzed .
10 Combining these variables , tumors were classified as CMS1/MSI-immune , CMS2/canonical , CMS3/metabolic and CMS4/mesenchymal .
11 RESULTS :
12 ✓ CMS1 tumors ( 19% ) were located in the right colon , were in early stages , had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene . RO-ASS-GM
13 CMS2 tumors ( 31% ) were located in the left colon , had moderate differentiation , absence of vascular invasion , lymphatic and mucin .
14 CMS3 tumors ( 29% ) were also left-sided , with absence of vascular and lymphatic invasion , and 29% had an activating mutation of the KRAS oncogene .
15 CMS4 tumors ( 21% ) showed advanced stages and presence of metastases .
16 CONCLUSIONS :
17 This new molecular classification contributes to understanding the heterogeneity of tumors .
18 It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma , opening the door to personalized medicine .



PMID: 28747102
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Irinotecan-induced muscle twitching from a possible drug interaction : A case report .
1 We report the case of a 50-year-old human immunodeficiency virus-positive patient with stage IV KRAS-mutated colorectal cancer who experienced visible muscle twitching in the right lateral triceps brachii from irinotecan administration for which typical supportive care measures were unsuccessful , including the administration of atropine and slowing down the infusion rate .
2 The patient was able to tolerate this reaction and received 20 cycles of irinotecan-based chemotherapy despite experiencing the muscle twitching with every cycle at the same onset , duration , and severity .
3 It is possible that competitive metabolism by concomitant medications metabolized by CYP3A4 or UGT1A1 was responsible for this event .
4 Due to ethical concerns , we were unable to formally assess the drug interaction by discontinuing the suspected interacting medications and re-initiating them to evaluate the effects .
5 A formal pharmacokinetic study may be warranted to better elucidate these potential drug interactions .



PMID: 28747067
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 RAS mutation prevalence among patients with metastatic colorectal cancer : a meta-analysis of real-world data .
1 AIM :
2 A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer .
3 This noninterventional , observational research project estimated RAS mutation prevalence from real-world sources .
4 MATERIALS & ; METHODS : Aggregate RAS mutation data were collected from 12 sources in three regions .
5 Each source was analyzed separately ; pooled prevalence estimates were then derived from meta-analyses .
6 RESULTS :
7 Μ The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% ( 95% CI : 38.8-48.5% ) ; ranging from 33.7% ( 95% CI : 28.4-39.3% ) to 54.1% ( 95% CI : 51.7-56.5% ) between sources .
8 CONCLUSION :
9 The RAS mutation prevalence estimates varied among sources .
10 The reasons for this are not clear and highlight the need for further research .



PMID: 28746977
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer .
1 INTRODUCTION :
2 The biological importance of tumour-associated stroma is increasingly apparent , yet clinical utility remains ill-defined .
3 In stage-II / Dukes B colorectal cancer ( CRC ) , clinical biomarkers are urgently required to direct therapeutic options .
4 We report here prognostic/predictive analyses , and molecular associations , of stromal morphometric quantification in the Quick and Simple and Reliable ( QUASAR ) trial of CRC MATERIALS AND METHODS : Relative proportions of tumour epithelium ( PoT ) or stroma ( PoS ) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 ( 91% stage II ) CRC patients between adjuvant fluorouracil/folinic acid ( FUFA ) chemotherapy and observation .
5 The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses RESULTS : High tumour stroma ( >/ = 50% ) was associated with increased recurrence risk : 31.3% ( 143/457 ) recurrence for >/ = 50% versus 21.9% ( 294/1,343 ) if <50% [Rate ratio ( RR ) =1.62 ; 95%CI 1.30-2.02 , p<0.0001 ) ] .
6 For stromal proportions of >/ = 65% , 40% ( 46/115 ) of patients had recurrent disease within 10 years .
7 The adverse prognostic effect of high stroma was independent of established prognostic variables , and maintained in stage II / Dukes B patients ( RR = 162 ; 95%CI = 126-208 ; p = 00002 ) .
8 KRAS mutation in the presence of high stroma augmented recurrence risk ( RR = 293 ; 95%CI = 187-459 ; p = 00005 ) .
9   Stromal morphometry did not predict response to FUFA chemotherapy DISCUSSION : Simple digital morphometry applied to a single representative H& ; E section identifies CRC patients with over 50% higher risk of disease recurrence .
10 This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner .
11 Further prospective validation is warranted .
12 This article is protected by copyright .
13 All rights reserved .



PMID: 28746882
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution .
1 Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers .
2 However , the particular pathways that should be targeted to optimize therapeutic responses are unclear .
3 Using CRISPR/Cas9 , we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK , ERK , and PI3K .
4 By performing 70 screens in models of KRAS mutant colorectal , lung , ovarian , and pancreas cancers , we uncovered universal and tissue -specific sensitizing combinations involving inhibitors of cell cycle , metabolism , growth signaling , chromatin regulation , and transcription .
5   Furthermore , these screens revealed secondary genetic modifiers of sensitivity , yielding a SRC inhibitor -based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers ( CRCs ) with clinical potential .
6 Surprisingly , acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment , but by targeting signaling feedback or apoptotic priming , it is possible to construct three - drug combinations that greatly delay its emergence .



PMID: 28740573
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Telomere length regulation through epidermal growth factor receptor signaling in cancer .
1 Length of the telomere ( TL ) , a structure at the tip of chromosome that protects and ensures stability , is determined by multi - protein complexes such as telosome/shelterin and telomerase .
2 Earlier studies from our laboratory show that longer TL has potential to be positive predictive biomarker of clinical outcome to anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody therapy in patients with KRAS WT metastatic colorectal cancer .
3 Although there is extensive literature suggesting the role of shelterin and telomerase , not much literature exists that describes the role of EGFR and KRAS pathway in regulating TL .
4 This detailed review focuses on an insight into various components , including proteins , enzymes and transcription factors , interlinking between EGFR pathways and telomerase that regulate TL .



PMID: 28736627
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Current state of immunotherapy for non-small cell lung cancer .
1 Small , spontaneously ruptured gastrointestinal stromal tumor in the small intestine causing hemoperitoneum : A case report .



PMID: 28735067
(Patient)  
Terms: phase III
Sent# Symbols Sentence Mnemonics
0 Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first - line FOLFIRI/bevacizumab : An Italian Group for the Study of Gastrointestinal Cancer phase III , randomised trial comparing two sequences of therapy in colorectal metastatic patients .
1 INTRODUCTION :
2 The optimal treatment strategy for RAS wild type ( WT ) mCRC is controversial .
3 Our phase III study investigated the effect of introducing earlier ( second - line ) or later ( third - line ) cetuximab in patients progressed after FOLFIRI/bevacizumab first - line .
4 PATIENTS AND METHODS :
5 mCRC patients progressing after FOLFIRI/bevacizumab first - line were randomised to receive second - line irinotecan/cetuximab followed by third - line FOLFOX-4 ( arm A ) or the reverse sequence ( arm B ) .
6 Primary end-point was progression-free survival ( PFS ) .
7 RESULTS :
8 About 54 and 56 patients were randomised in arm A and in arm B , respectively .
9 After a median follow-up of 37.5 months , 100 PFS events were recorded .
10 ✓ Median PFS was 9.9 months in arm A and 11.3 months in arm B ( Hazard ratio [HR] 1.04 , 95% confidence interval [CI] : 0.69-1.56 , p = 0.854 ) , while median overall survival was 12.3 months in arm A and 18.6 months in arm B ( HR 0.84 , 95% CI : 0.55-1.28 ; p = 0.411 ) . GE-ASS-RO
11 No overall difference in side-effects were observed between the two treatment arms .
12 CONCLUSIONS :
13 This trial did not meet the primary end-point ( PFS ) .
14 Like other preclinical and clinical evidences , our study seems to suggest a reduced activity of cetuximab after a first - line bevacizumab-based therapy .



PMID: 28722262
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF p.V600E-specific immunohistochemical assessment in colorectal cancer endoscopy biopsies is consistent with the mutational profiling .
1 The assessment of BRAF p.V600E mutational status has already become an essential part of the diagnostic routine in colorectal cancer ( CRC ) .
2 Indeed , on one side , the BRAF mutational status is regarded as being a key molecular marker to definitely decide the most proper therapeutic options in a selected cohort of patients .
3 On the other , it is used to exclude a suspicious of Lynch Syndrome in case of MLH1 absence in deficient mismatch repair ( dMMR ) tumors [1] .
4 This article is protected by copyright .
5 All rights reserved .



PMID: 28712102
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Precision Medicine in Metastatic Colorectal Cancer : Relevant Carcinogenic Pathways and Targets-PART 2 : Approaches Beyond First - Line Therapy , and Novel Biologic Agents Under Investigation .
1 A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second - line and higher treatment settings .
2 While not approved by the US Food and Drug Administration ( FDA ) in the first - line setting , the vascular endothelial growth factor ( VEGF ) -targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second - line setting , as is continuation of first - line bevacizumab .
3 Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor ( EGFR )- directed therapies , and other novel biomarkers ( BRAF , HER2 , and mismatch repair deficiency ) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies .
4 Maintenance therapy for patients with stable disease following first - line therapy is a unique clinical situation that warrants special attention .
5   Immunotherapy has thus far been ineffective for patients with mismatch repair-proficient tumors , but novel combination strategies are being studied to break through this treatment barrier .
6   Finally , several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer .



PMID: 28712098
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Precision Medicine in Metastatic Colorectal Cancer : Relevant Carcinogenic Pathways and Targets-PART 1 : Biologic Therapies Targeting the Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor .
1 The survival of patients with metastatic colorectal cancer has improved dramatically in recent years , with overall survival exceeding 3 years in large randomized clinical trials .
2 There are now several treatment options for patients with metastatic colorectal cancer .
3 In addition to chemotherapy backbones utilizing fluoropyrimidine , oxaliplatin , and irinotecan combinations , biologic agents that target specific oncogenic pathways have contributed to the improved survival observed in this patient population .
4 This class of medications includes epidermal growth factor receptor ( EGFR )- targeted drugs ( cetuximab and panitumumab ) and vascular endothelial growth factor ( VEGF )- targeted therapies ( bevacizumab , ramucirumab , ziv-aflibercept , and regorafenib ) .
5 Bevacizumab remains the only VEGF-targeted agent approved by the US Food and Drug Administration in the first - line metastatic setting .
6 EGFR -directed treatment should be restricted to patients with extended RAS and BRAF wild-type tumors .
7 Tumor sidedness may be a more powerful prognostic and predictive biomarker than tumor mutational profile .
8   Patients with left-sided primary tumors derive greater benefit from EGFR-targeted therapies whereas patients with right-sided primary tumors benefit more from bevacizumab .
9   Herein we review drugs that target the EGFR and VEGF pathways , focusing on patient selection , drug toxicities , and how to choose agents for first - line therapy .



PMID: 28711984
(Patient)  
Terms: Retrospective
Sent# Symbols Sentence Mnemonics
0 Clarithromycin co-administration does not increase irinotecan ( CPT-11 ) toxicity in colorectal cancer patients .
1 PURPOSE :
2 Irinotecan ( CPT-11 ) is used to treat advanced colorectal cancer .
3 The drug is activated by carboxylesterases and rendered inactive by CYP3A4 .
4 Recently , the efficacy of combining CPT-11 and anti-epidermal growth factor receptor ( EGFR ) agents was confirmed in patients with KRAS wild-type metastatic colorectal cancer .
5 Clarithromycin ( CAM ) is a strong CYP3A inhibitor often used to prevent rash associated with anti-EGFR therapy .
6 The objective of this study was to evaluate the risk of increased neutropenia and diarrhea in combining CPT-11 and CAM .
7 METHODS :
8 Retrospective analyses were conducted at Osaka National Hospital ( Osaka , Japan ) on the records of colorectal cancer patients treated with a CPT-11-containing regimen between November 2006 and January 2014 .
9 The incidence of neutropenia and diarrhea was compared between patients who received CPT-11 and CAM and patients who received CPT-11 without CAM .
10 RESULTS :
11 One-hundred and twenty-eight patients were included in this study , of whom 21 were concomitantly treated with CAM and 107 were not .
12 There was no difference in the incidence of grade 3-4 neutropenia between the CAM co-administration group ( 10% ) and the non-CAM group ( 16% ) [Odds ratio : 0.56 ( 95% confidence interval : 0.12-2.62 ) , p = 0.45] .
13 No difference in the incidence of grade 3-4 diarrhea was found between the CAM co-administration group ( 0% ) and the non-CAM group ( 4% ) ( p = 037 ) .
14 CONCLUSIONS :
15 This study did not identify an increase in CPT-11 toxicity by co-administration with CAM .



PMID: 28709170
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Leptomeningeal carcinomatosis as a rare metastatic spreading of BRAF-mutated microsatellite stable colon cancer ] .
1 Leptomeningeal carcinomatosis is a rare but serious complication of solid tumors such as melanoma , breast and lung cancer , as well as gastrointestinal carcinomas .
2 Its clinical manifestation is highly variable , presenting as radicular pain with or without neurological deficits , as well as with headaches and hallucinatory irritation symptoms .
3 Leptomeningeal carcinomatosis is often misdiagnosed , which delays treatment .
4 Here we report a rare case of a patient with BRAF-mutated microsatellite stable colon carcinoma with lymphatic and skeletal metastases , who developed neurological symptoms one month after the initial diagnosis of malignancy .
5 Based on the cytological detection of tumor cells in the cerebrospinal fluid , a leptomeningeal carcinomatosis was diagnosed , despite normal findings on MRI .
6 Intrathecal chemotherapy with methotrexate , combined with intensive systemic immunochemotherapy , resulted in a good partial remission of the underlying malignant disease .
7   However , approximately 8 months after the start of therapy , the patient developed progressive leptomeningeal carcinomatosis and died a few weeks later .



PMID: 28708579
(Patient)  
Terms: meta-analysis, retrospective studies
Sent# Symbols Sentence Mnemonics
0 The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status : a systematic review and meta-analysis .
1 OBJECTIVE :
2 To assess the prognostic role of primary tumor location along with Kras status in metastatic colorectal cancer ( mCRCs ) treated with cetuximab .
3 MATERIALS AND METHODS :
4 Databases of EMBASE , Pubmed , the Cochrane library , China National Knowledge Infrastructure and other databases from inception to July 2016 were searched .
5 Randomized controlled trial ( RCT ) and/or retrospective studies of influence of primary tumor location on efficacy of cetuximab in patients with mCRC were identified .
6 The primary endpoint was progression-free survival ( PFS ) , and the secondary endpoints were overall survival ( OS ) , overall response rate ( ORR ) and disease control rate ( DCR ) .
7 RESULTS :
8 Ten studies including 2977 cases were finally included .
9 The results of meta-analysis were in favor of cetuximab to patients with left-sided colorectal cancer in terms of OS ( HR = 0.52 , 95% CI : 0.40-0.66 ; p <0.01 ) , PFS ( HR = 0.64 , 95% CI : 0.58-0.70 ; p <0.01 ) , and ORR ( OR = 2.17 , 95% CI : 1.57-2.99 ; p <0.01 ) .
10   Patients with right-sided CRC gained less benefit from cetuximab in terms of OS ( HR = 1.89 , 95% CI : 1.43-2.50 ; p <0.01 ) , compared with left-sided CRC .
11 ✓ Regarding Kras status , left-sided mCRC with wild type Kras had better PFS ( HR = 0.61 , 95% CI : 0.51-0.74 ; p <0.01 ) and OS ( HR = 0.49 , 95% CI : 0.35-0.69 ; p <0.01 ) than right-sided cases when treated with cetuximab . GM-ASS-RO, RO-ASS-GM
12 We also found that cetuximab was both significantly effective in different treatment lines and regions when comparing by primary tumor locations ( p <001 ) .
13 CONCLUSIONS :
14 ✓ mCRC Patients with left-sided , wild type Kras have a better prognosis than those with right-sided diseases when treated with cetuximab . RO-ASS-GM
15 The clinical application of cetuximab should be determined by the primary tumor location and molecular gene mutation status .



PMID: 28708207
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Variations in transrenal DNA and comparison with plasma DNA as a diagnostic marker for colorectal cancer .
1 BACKGROUND :
2 Transrenal DNA can potentially be useful in the disease management of colorectal cancer ( CRC ) and has potential diagnostic utility .
3 Our study aimed to conduct preoperative and postoperative analysis of KRAS-positive patients , using transrenal DNA compared with plasma DNA .
4 This is critically needed for disease diagnostics and treatment response monitoring .
5 METHODS :
6 CRC patients at different stages of the disease and with different molecular profiles were recruited for serial time-point analysis .
7 Preoperative and postoperative urine specimens were extracted and compared with tumor tissues and plasma DNA .
8 RESULTS :
9 Our analysis demonstrated that transrenal DNA offered comparable sensitivity and specificity to plasma DNA analysis .
10 Collection of transrenal DNA , being noninvasive , is an attractive assay and easily allows serial monitoring of the disease .
11 Results from preoperative detection showed a close correlation to tumor tissue profiling and demonstrated close associations to the disease .
12 ✓ We also observed significant decreases in mutant KRAS DNA concentration after surgery , which confirmed transrenal DNA's sensitivity to treatment response .
13 CONCLUSIONS :
14 The use of transrenal DNA offers a possible alternative method of disease profiling , detection and tracking .
15 Our study is one of the first to systematically analyze a relatively large number of different CRC patients using transrenal DNA .
16 The positive correlation with disease demonstrates the assay's viability in the clinical setting , and our method further opens up the possibility to use transrenal DNA for clinical intervention investigations .



PMID: 28708103
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment .
1 The use of targeted agents in the treatment of metastatic colorectal cancer ( CRC ) has improved patient outcomes .
2 Anti-epidermal growth factor receptor ( anti-EGFR ) agents ( cetuximab and panitumumab ) and antiangiogenic molecules ( bevacizumab , regorafeninb , ramucirumab , and aflibercept ) have been successfully integrated into clinical practice .
3 Other drugs have been designed to target additional deregulated pathways in CRC , such as MAPK ( mitogen-activated protein kinase ) /PI3K-AKT ( phosphatidylinositol-3-kinase-AKT serine/threonine kinase ) /mTOR ( mammalian target of rapamycin ) , HER-2 and 3 ( human epidermal growth factor receptor -2 and -3 ) , and BRAF .
4 A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance .
5 Μ Pharmacogenomic research has demonstrated its value in this field , highlighting some tumor mutations that could discriminate responders from non-responders .
6 The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents ; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice .
7 The introduction of immunotherapy has paved the way for a new generation of predictive markers , including genome -wide assessment of the tumor landscape .
8 Furthermore , the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine , rendering precision medicine available to every patient .



PMID: 28698359
(Cell)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 EGFR Down-regulation After anti-EGFR Therapy Predicts the Anti-tumor Effect in Colorectal Cancer .
1 Anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody ( mAb ) is reported to induce EGFR internalization in colorectal cancer ( CRC ) cells .
2 However , the biological relevance of EGFR internalization with anti-EGFR mAb is unknown .
3 Therefore , the relevance of EGFR downregulation with anti-EGFR mAb to anti-tumor activity in CRC cells was investigated .
4 Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry , and its growth-inhibitory effects were measured by trypan blue-exclusion , in 10 RAS , BRAF wild-type CRC cell lines , but there was no significant correlation between EGFR number and its growth-inhibitory effect .
5 However , a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines .
6 Treatment with TGF-alpha , a ligand for EGFR , induced EGFR internalization in CRC cells , but most EGFRs subsequently recycled to the cell surface , consistent with previous studies .
7 While cetuximab treatment induced EGFR internalization , most receptors subsequently translocated into the late endosome , leading to lysosomal degradation , as revealed by immunoblotting and double immunofluorescence .
8 Cetuximab-sensitive CRC cells showed greater EGFR internalization , stronger cell growth inhibition , and more augmented apoptotic signals than non-sensitive cells .
9   Immunohistochemistry ( IHC ) for EGFR , performed using an EGFR pharmDxkit ( mouse anti-human EGFR mAb clone 2-18C9 ) , in clinical specimens before and after anti-EGFR mAb therapy in 13 CRC patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy .
10 IMPLICATIONS :
11 This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes , which is an important determinant of the efficacy of anti-EGFR mAb treatment for CRC .



PMID: 28697193
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The value of 18FDG PET/CT parameters , hematological parameters and tumor markers in predicting KRAS oncogene mutation in colorectal cancer .
1 OBJECTIVE :
2 In this study we investigated the predictive value of maximum standardized uptake value ( SUVmax ) , metabolic tumor volume ( MTV ) , total lesion glycolysis ( TLG ) , neutrophils/lymphocytes ratio ( NLR ) , platelets/lymphocytes ratio ( PLR ) , carcinoembryonic antigen ( CEA ) and carbohydrate antigen ( CA 19-9 ) in the prediction of KRAS gene mutation which plays an important role in the choice of treatment in colorectal cancer patients .
3 SUBJECTS AND METHODS :
4 Μ A total of 55 cases with untreated colorectal cancer who had undergone both PET/CT examinations for initial staging and also mutation analysis of KRAS oncogene were studied .
5 Μ Fluorine-18-FDG PET/CT parameters ( SUVmax , MTV , TLG ) , hematological parameters ( NLR , PLR ) , and tumor markers ( CEA , CA 19-9 ) were recorded and the relationship between these parameters and KRAS oncogene mutation was evaluated using receiver operating characteristics ( ROC ) analysis and multiple logistic regression analysis .
6 RESULTS :
7 Μ In 20 cases mutations in the KRAS gene were detected , while in 35 cases mutations were not observed ( wild-type ) .
8 ROC analysis revealed that SUVmax , MTV , TLG , NLR , PLR , and CA 19-9 could not predict mutations in KRAS oncogene ( P = 0600 , 0263 , 0214 , 0057 , 0104 , 0189 , respectively ) although CEA value showed signi . .
9 cant difference ( P = 0031 ) but without high value of the area under the curve ( 0676 ) .
10 Multivariate logistic regression analysis also did not show significant association between KRAS gene mutations and SUVmax , MTV , TLG , NLR , PLR , CEA , CA 19-9 values .
11 CONCLUSION :
12 Μ We observed that in patients with colorectal cancers , we cannot predict KRAS gene mutations using PET/CT parameters ( SUVmax , MTV , TLG ) , hematological parameters ( NLR , PLR ) or tumor marker CA 19-9 .
13 We detected a significant but not very strong association only between CEA and KRAS mutations .



PMID: 28695301
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer : a meta-analysis .
1 This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer ( mCRC ) .
2 Seventeen randomized clinical trials were included , all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC .
3 Hazard and odds ratios were pooled using a random effect model , weighted according to cohort size .
4 Pooled data of six first - and two second - line studies demonstrated a significantly improved ORR ( OR 162 , CI 127-204 ; OR 478 , CI 339-675 , respectively ) and PFS ( HR 079 , CI 067-094 ; HR 080 , CI 071-091 , respectively ) with the addition of anti-EGFR mAb to chemotherapy , while OS remained similar .
5 Two third - line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS ( HR 044 , CI 035-052 ; HR 055 , CI 041-074 ) .
6 Addition of anti-EGFR versus anti-VEGF mAb to first - line chemotherapy was evaluated in three studies ; ORR and PFS were comparable , while OS was improved ( HR 08 , CI 065-097 ) .
7 The influence of the chemotherapy backbone on anti-EGFR mAb efficacy , evaluated with meta-regression , indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens , but comparable PFS and OS .
8 Reported toxicity ( >/ = 3 grade ) increased ~20% in all treatment lines with the addition of anti-EGFR mAb .
9   Anti-EGFR treatment significantly improves response and survival outcome of patients with (K) RAS wild-type mCRC , regardless of treatment line or chemotherapeutic backbone .
10   Saving anti-EGFR mAb as third - line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy .
11 Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation .



PMID: 28694923
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular genetic changes in benign colorectal tumors synchronous with microsatellite unstable carcinomas do not support a field defect .
1 BACKGROUND :
2 A colorectal cancer may develop through a particular molecular genetic pathway , raising the question of whether the particular molecular changes are random , or are unique to the particular segment of colon .
3 We wanted to determine whether molecular changes found within a colorectal cancer might also be detected in separate adenomas and polyps removed from the same area of colon at surgery .
4 Microsatellite instability was chosen as a marker for a pathway of colon carcinogenesis .
5 METHODS :
6 We studied a total of 46 primary colorectal cancers with microsatellite instability and 77 synchronous adenomas and polyps .
7 All tumors were evaluated for microsatellite instability , BRAF and KRAS mutations , and methylation using standard polymerase chain reaction based methods .
8 RESULTS :
9 Forty-nine benign tumors did not follow a pathway similar to that of their 31 synchronous primary cancers .
10 For two distinct subsets of the microsatellite unstable colorectal cancers , those with acquired methylation and BRAF mutation , and those without methylation suggestive of an underlying germ line mutation , the molecular changes in the majority of their synchronous benign tumors were different from the colorectal cancer .
11 CONCLUSIONS :
12 These differences suggest a stochastic process within the colon regarding the particular molecular carcinogenic pathways followed by the synchronous tumors , rather than a 'field defect' within the colon segments .
13 Variability in molecular findings was present for colorectal cancers arising from acquired methylation , as well as those cancers suggestive of a germ line origin .



PMID: 28693799
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The current value of determining the mismatch repair status of colorectal cancer : A rationale for routine testing .
1 Colorectal Cancer ( CRC ) is the third most prevalent cancer in men and women .
2 Up to 15% of CRCs display microsatellite instability ( MSI ) .
3 MSI is reflective of a deficient mismatch repair ( MMR ) system and is most commonly caused by hypermethylation of the MLH1 promoter .
4 However , it may also be due to autosomal dominant constitutional mutations in DNA MMR , termed Lynch Syndrome .
5 MSI may be diagnosed via polymerase chain reaction ( PCR ) or alternatively , immunohistochemistry ( IHC ) can identify MMR deficiency ( dMMR ) .
6 Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing .
7 The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing .
8 Aside from screening for Lynch syndrome , MMR testing is important because of its prognostic and therapeutic implications .
9 Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable ( MSS ) CRCs .
10 For example , response to conventional chemotherapy has been reported to be less in MSI tumours .
11 More recently , MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy .
12 This provides a rationale for routine testing for MSI or dMMR in CRC .



PMID: 28692881
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Detection of KRAS Exon 2 Mutations in Circulating Tumor Cells Isolated by the ISET System from Patients with RAS Wild Type Metastatic Colorectal Cancer .
1 INTRODUCTION :
2 The presence of KRAS mutations in patients with metastatic colorectal cancer ( mCRC ) predicts poor response to agents targeting the EGFR .
3 Even in patients with RAS wild type ( WT ) tumors , resistance eventually develops due to multiple mechanisms , including the expansion of previously undetected KRAS mutated clones .
4 Μ In this feasibility study , we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells ( CTCs ) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells ( ISET ) system .
5 METHODS :
6 CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first - line therapy initiation , at first imaging assessment and on disease progression .
7 CTCs were enumerated using hematoxylin & ; eosin and CD45 double stain on a single membrane spot .
8 Μ DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction ( qPCR ) assay .
9 RESULTS :
10 Fifteen patients were enrolled and 28 blood samples were analyzed .
11 In 9 ( 60% ) patients , atleast one sample was positive for the presence of a KRAS exon 2 mutation .
12 Μ In 11 out of 28 samples ( 392% ) with detectable CTCs a KRAS mutation was detected ; the corresponding percentages for baseline and on progression samples were 27% and 37.5% , respectively .
13 Μ The most commonly detected mutations were G13D and G12C ( n = 3 ) .
14 The presence of KRAS mutated CTCs at baseline was not prognostic for either PFS ( P = 950 ) or OS ( P = 383 ) .
15 CTC kinetics did not follow tumor response patterns .
16 CONCLUSION :
17 Μ The results demonstrate that using a qPCR-based assay , KRAS exon 2 mutations could be detected in CTCs captured by the ISET system from patients with RAS WT primary tumors .
18 However , the clinical relevance of these CTCs remains to be determined in future studies .



PMID: 28685354
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A Multicenter Phase 2 Study on the Feasibility and Efficacy of Neoadjuvant Chemotherapy Without Radiotherapy for Locally Advanced Rectal Cancer .
1 BACKGROUND :
2 This prospective multicenter phase 2 study aimed to evaluate the feasibility and efficacy of neoadjuvant chemotherapy ( NAC ) without radiotherapy for locally advanced rectal cancer ( LARC ) .
3 METHODS :
4 Patients with LARC ( cStage II and III ) were included in the study .
5 Those with cT4b tumor were excluded .
6 Six cycles of modified FOLFOX6 ( mFOLFOX6 ) plus either bevacizumab or cetuximab , depending on KRAS status , were administered before surgery .
7 The primary end point of the study was the R0 resection rate .
8 The secondary end points were adverse effect , rate of NAC completion , postoperative complications , and pathologic complete response ( pCR ) rate .
9 RESULTS :
10 The study enrolled 60 patients from eight institutions .
11 For the study , mFOLFOX6 was administered with cetuximab to 40 patients who had wild-type KRAS and with bevacizumab to 20 patients who had KRAS mutations .
12 The completion rate for NAC was 88.4% .
13 Sphincter-preserving surgery was performed for 43 patients and abdominoperineal resection for 17 patients .
14 The median operation time was 335 min , and the median blood loss was 40 g .
15 The R0 resection rate was 98.3% , and the pCR rate was 16.7% .
16 The overall postoperative complication rate ( >/ = grade 2 ) was 21.7% .
17 The complications included anastomotic leakage ( 116% ) , surgical - site infection ( 67% ) , and urinary dysfunction ( 33% ) .
18 The patients with wild-type KRAS did not differ significantly from those with KRAS mutations in terms of response rate , postoperative complication rate , and pCR rate .
19 CONCLUSION :
20 The findings show that NAC is a feasible and promising treatment option for LARC ( This study is registered with UMIN-CTR , UMIN000005654 ) .



PMID: 28685087
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody .
1 Molecular heterogeneity between primary tumors ( PTs ) and synchronous resected liver metastasis in colorectal cancer ( CRC ) has potential relevance in treatment strategies .
2 Next-generation sequencing ( NGS ) may be able to increase the chances of identifying multiple molecular driver alterations , calling for therapy .
3 The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with rat Kirsten sarcoma 2 viral oncogene homolog ( KRAS ) exon 2 wild-type metastatic (m) CRC who underwent chemotherapy ( CT ) featuring an anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody .
4 Genomic analysis was performed on 54 lesions from 7 patients with mCRC .
5 For each patient , a PT biopsy or a surgical specimen was obtained prior to CT , and the PT and all liver metastases resected following CT were analyzed .
6 DNA libraries were generated using the Ion AmpliSeq Colon and Lung Cancer Panel , assessing the most frequent somatic mutations in 22 genes involved in colon tumorigenesis , and sequencing was performed on an Ion Personal Genome Machine system .
7 A partial response was achieved in all the patients , with a median progression free survival time of 11 months ( range , 3-21 months ) .
8 All the patients were subjected to surgical liver metastasis resection .
9 The median overall survival time was 31 months ( range , 4-46 months ) .
10 Molecular analysis of the genes correlated with the target therapy , suggesting significant intratumor heterogeneity , as revealed by the different mutational landscape of certain PTs and synchronous resected liver metastases following systemic therapy when compared with the PT prior to treatment .
11 In particular , the loss and acquisition of mutations in KRAS , neuroblastoma RAS viral oncogene homolog ( NRAS ) , tumor protein p53 ( TP53 ) , the p110alpha catalytic subunit of phosphoinositide 3-kinase ( PIK3CA ) , F-box/WD repeat-containing protein 7 ( FBXW7 ) and phosphatase and tensin homolog ( PTEN ) were observed .
12 In addition , one patient developed a mucinous pattern following systemic CT .
13 Taken together , the results of the present study demonstrated that intratumor heterogeneity is likely to affect the response to therapy , and to drive acquired resistance to targeted agents .
14   The preliminary data also suggest a potential role for NGS in the evaluation of biological drug resistance , affecting future sequential treatment strategies .



PMID: 28680740
(None)  
Terms: , mice, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Haploinsufficient tumor suppressor genes .
1 Haploinsufficiency of tumor suppressor genes ( TSGs ) indicates that the reduced levels of proteins in cells that lack one allele of the genomic locus results in the inability of the cell to execute normal cellular functions contributing to tumor development .
2 Representative cases of haploinsufficient TSGs are p27Kip1 , p53 , DMP1 , NF1 , and PTEN .
3 Tumor development is significantly accelerated in both mice with homozygous and heterozygous gene deletion , with expression of the wild type allele in the latter .
4 Newly characterized TSGs such as AML1 , EGR1 , TGFbetaR1/2 , and SMAD4 have also shown haploid insufficiency for tumor suppression .
5 This phenotype has typically been demonstrated in gene knockout mouse models , but analyses of human samples have been conducted in some cases .
6 Recent studies suggest collaboration of multiple haploinsufficient TSGs in 5q - , 7q - , and 8q - syndromes , which is called compound haploinsufficiency .
7 Although ARF is a classical TSG , it also belongs to this category since Arf+/- accelerates tumor development when both alleles for Ink4a are inactivated .
8 Haploid insufficiency of Arf was also reported in myeloid leukemogenesis in the presence of inv ( 16 ) .
9 In case of p53 , p53+/- cells achieve only ~25% of p53 mRNA and protein levels as compared to those in wild type , which could explain the mechanism .
10 TGFbetaR1+/- collaborates with ApcMin+/- in colorectal cancer development ; TGFbetaR2+/- and Smad4+/- collaborates with K-Ras mutation in pancreatic ductal adenocarcinomagenesis , demonstrating the synergism of haploinsufficient TSGs and other oncogenic events .
11 These TSGs can be targets for activation therapy in cancer since they retain a functional allele even in tumor cells .



PMID: 28678173
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular and Clinicopathological Differences by Age at the Diagnosis of Colorectal Cancer .
1 Fighting cancer drug resistance : Opportunities and challenges for mutation-specific EGFR inhibitors .



PMID: 28671043
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogene mutation profile predicts tumor regression and survival in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy and radical surgery .
1 Tumor response to preoperative chemoradiotherapy and postoperative survival differs among patients with locally advanced rectal cancer .
2 Μ The objective was to find correlations of mutated oncogenes and clinical outcomes in locally advanced rectal cancer .
3 A total of 70 patients with preoperative preoperative chemoradiotherapy followed by radical surgery at a single cancer center between 2006 and 2012 were enrolled .
4 Pretreatment tumor biopsy samples were assayed for 238 mutation hotspots harboring 19 oncogenes by time-of-flight mass spectrometry and OncoCarta Array .
5 Μ Oncogene mutations were found in 48.6% of patients ( 34/70 ) .
6 Μ KRAS was the most frequent driver mutation , found in 35.7% of patients ( 25/70 ) , followed by PIK3CA ( 143% ) , NRAS ( 57% ) , FLT3 ( 29% ) , and BRAF ( 14% ) .
7 Μ Multiple gene mutations were observed in eight patients ( 114% ) .
8 Tumors with KRAS mutations responded poorly to preoperative chemoradiotherapy ( p = 0044 ) .
9 ✓ Patients with oncogene mutations had worse 3-year disease-free survival than those without mutations ( 672% versus 942% , p = 0010 ) . GM-ASS-RO, RO-ASS-GM
10 ✓ Patients with KRAS or RAS mutations had lower 3-year disease-free survival ( 68% versus 883% , p = 0016 ; 655% versus 923% , p = 0004 , respectively ) and 3-year overall survival ( 88% versus 954% , p = 0020 ; 897% versus 949% , p = 0036 , respectively ) than those without KRAS or RAS mutations . GM-ASS-RO, GE-ASS-RO, RO-ASS-GM
11 Oncogene mutation status affected tumor response to treatment and long-term survival in locally advanced rectal cancer .



PMID: 28669023
(Patient)  
Terms: Phase I/II, phase I/II, retrospective, retrospective study
Sent# Symbols Sentence Mnemonics
0 Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility : A Single-Institution Experience .
1 BACKGROUND :
2 Patients with metastatic colorectal cancer ( mCRC ) refractory to standard therapies have a poor prognosis .
3 In this setting , recruitment into clinical trials is warranted , and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value .
4 OBJECTIVE :
5 We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drugs .
6 PATIENTS AND METHODS :
7 From June 2011 to May 2016 , 2044 patients with mCRC underwent molecular screening .
8 Eighty patients ( 39% ) were enrolled in ad hoc studies ; the median age was 60 years ( range 36-86 ) and the median number of previous treatment lines was five ( range 2-8 ) .
9 Molecular characteristics exploited within these studies were MGMT promoter hypermethylation ( 487% ) , HER2 amplification ( 288% ) , BRAF V600E mutation ( 20% ) , and novel gene fusions involving ALK or NTRK ( 25% ) .
10 RESULTS :
11 One patient ( 1% ) had RECIST ( Response Evaluation Criteria In Solid Tumors ) complete response ( CR ) , 13 patients ( 165% ) experienced a partial response ( PR ) , and 28 ( 35% ) stable disease ( SD ) .
12 Median progression-free survival ( PFS ) was 2.8 months ( range 263-383 ) , with 24% of patients displaying PFS >5 months .
13 Median growth modulation index ( GMI ) was 0.85 ( range 0-1561 ) and 32.5% of patients had GMI >1.33 .
14 ✓ Μ KRAS exon 2 mutations were found in 38.5% of patients , and among the 78 patients with known KRAS status , those with wild-type tumors had longer PFS than those with mutated tumors ( 3.80 [95% CI 280-503] vs. 2.13 months [95% CI 177-287] , respectively , p = 0.001 ) . GM-ASS-RO, RO-ASS-GE
15 ✓ Median overall survival ( OS ) was 7.83 months ( range 717-933 ) for all patients , and patients with KRAS wild-type tumors had longer OS than those with mutated tumors ( 7.83 [95% CI 733-1080] vs. 7.18 months [95% CI 563-933] , respectively , p = 0.06 ) . GE-ASS-RO
16 CONCLUSIONS :
17 This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention .
18 Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment .



PMID: 28668886
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 An Alpha- kinase 2 Gene Variant Disrupts Filamentous Actin Localization in the Surface Cells of Colorectal Cancer Spheroids .
1 BACKGROUND/AIM :
2 Alpha-kinase 2 ( ALPK2 ) , suggested to be a novel tumour-suppressor gene down-regulated by oncogenic KRAS , plays a pivotal role in luminal apoptosis in normal colonic crypts .
3 The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer .
4 MATERIALS AND METHODS :
5 Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases ( 1,446 cases with cancer and 897 cases without cancer ) were screened using HumanExome BeadChip arrays .
6 To address the functional effect of a missense ALPK2 variant , a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type ( wt ) ALPK2 ( HCT116-wtALPK2 ) or amino acid -substituted ( sub ) ALPK2 ( HCT116-subALPK2 ) .
7 RESULTS :
8 Μ We identified that one of the ALPK2 germline variants , rs55674018 ( pQ1853E ) , was significantly associated with the presence of cancer ( adjusted odds ratio ( OR ) =4.39 ; 95% confidence interval ( CI ) =1.31-14.78 , p = 0.001 ) .
9 The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain .
10 Notably , the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids .
11 Furthermore , luminal apoptosis and cell aggregation were promoted by wtALPK2 , but not by subALPK2 in 3D culture .
12 CONCLUSION :
13 The p.Q1853E variant of ALPK2 , which had been accumulating in the Japanese population , induced a metastatic phenotype by disrupting ALPK2 function .



PMID: 28668883
(Cell)  
Terms: , rat, mice
Sent# Symbols Sentence Mnemonics
0 Apremilast Induces Apoptosis of Human Colorectal Cancer Cells with Mutant KRAS .
1 BACKGROUND/AIM :
2 We previously reported the crucial roles of oncogenic rat Kirsten sarcoma viral oncogene homologue ( KRAS ) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 ( PDE4B2 ) expression in human colorectal cancer ( CRC ) HCT116 cells in a three-dimensional culture (3DC) .
3 Here , we evaluated the effects of apremilast , a selective PDE4 inhibitor , on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type ( wt ) PDE4B2 ( HKe3-wtPDE4B2 ) , mutant ( mt ) PDE4B2 ( kinase dead ) ( HKe3-wtKRAS ) , wtKRAS ( HKe3-wtKRAS ) and mtKRAS ( HKe3-mtKRAS ) .
4 MATERIALS AND METHODS : Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy or western blot in HKe3-wtPDE4B2 , HKe3-mtPDE4B2 , HKe3-wtKRAS and mtKRAS cells treated with or without apremilast in 3DC .
5 Tumourigenicity was assessed in nude mice assay using these cells .
6 RESULTS :
7 Apremilast did not inhibit the proliferation of HKe3-wtPDE4B2 cells or HKe3-mtKRAS in two-dimensional cultures , whereas the number of apoptotic HKe3-wtPDE4B2 cells and HKe3-mtKRAS cells increased after apremilast treatment in 3DC , leading to formation of a luminal cavity .
8 Tumour growth in nude mice was dramatically reduced by intraperitoneal injection of apremilast .
9 Μ Notably , a decreased level of caspase-1 expression was observed in HKe3-wtPDE4B2 and HKe3-mtKRAS cells .
10 CONCLUSION :
11 Apremilast induces tumour regression in nude mice , possibly by inducing caspase-1 expression .



PMID: 28668881
(None)  
Terms: this review, rat
Sent# Symbols Sentence Mnemonics
0 Clinicopathological and Corresponding Genetic Features of Colorectal Signet Ring Cell Carcinoma .
1 Europe and the United States have high morbidity rates of colorectal cancer , it being the third most common new cancer among both men and women each year .
2 Colorectal cancer morbidity is also high in Japan .
3 Advances in surgery , chemotherapy , and molecular targeted drugs have extended the prognosis of colorectal cancer , although the effects of these treatments remain poor in some patients .
4 Colorectal cancer almost always presents as differentiated adenocarcinoma , although one tissue type , signet-ring cell carcinoma , occurs rarely .
5 Overall , colorectal signet-ring cell carcinoma is very infrequent among cases of colorectal cancer , however , its prognosis is reported as being extremely poor .
6 Several reports have addressed its clinicopathological and typical genetic characteristics , such as mutation of viral oncogene Kirsten rat sarcoma ( KRAS ) gene , but there have been few comprehensive investigations of its characteristics and genetic background .
7 In this review , we examine features of colorectal signet-ring cell carcinoma by summarizing its clinical and genetic characteristics .



PMID: 28665451
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Discordance in RAS mutations between primary colon tumor and metastases : a real event or a matter of methodology ?
1 Genetic Testing in Pancreatic Ductal Adenocarcinoma : Implications for Prevention and Treatment .



PMID: 28659148
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PLX8394 , a new generation BRAF inhibitor , selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation .
1 BRAF inhibitors ( BRAFi ) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma , but can lead to paradoxical activation of the mitogen -activated protein kinase ( MAPK ) signalling pathway .
2 This can result in the promotion of precancerous lesions and secondary neoplasms , mainly ( but not exclusively ) associated with pre-existing mutations in RAS genes .
3   We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF wt /KRAS G12D-metastatic colorectal cancer ( CRC ) , whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib ( GSK2118436 ) .
4   We used tissue from the resected CRC metastasis to derive a cell line , LM-COL-1 , which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment .
5 Novel BRAF inhibitors ( PLX8394 and PLX7904 ) , dubbed as "paradox breakers" , were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation .
6 In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling .



PMID: 28656305
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cetuximab promotes SN38 sensitivity via suppression of heat shock protein 27 in colorectal cancer cells with wild-type RAS .
1 Combination treatment with cetuximab and CPT-11 produces beneficial and synergistic effects in wild-type RAS metastatic colorectal cancer ( mCRC ) patients .
2 However , the mechanism underlying this synergism is not yet understood .
3 We examined whether cetuximab had a synergistic effect with CPT-11 and its active metabolite , SN38 , and examined the molecular mechanism of the synergism between cetuximab and SN38 in CRC cells with various mutational status .
4 We hypothesized that cetuximab promotes sensitivity to SN38 via suppression of heat shock protein 27 ( HSP27 ) , a protein involved in multidrug resistance through blocking the Janus kinase ( JAK ) /signal transducer and activator of transcription ( STAT ) signaling pathway , which is associated with chemosensitivity .
5 Four human CRC cell lines with different RAS and BRAF mutational status were used .
6 Expression levels of HSP27 protein correlated with SN38 sensitivity in these cell lines ( R = 0841 , p = 0159 ) .
7 Exposure to cetuximab and various concentration of AG490 , an inhibitor of JAK2 , STAT3 and HSP27 protein levels , except in the KRAS G12V mutant line , SW620 .
8 A synergistic effect of cetuximab in combination with SN38 was observed in RAS and BRAF wild-type cells ( here , Caco2 ) , but not in the three other RAS - or BRAF-mutated cell lines .
9 These results indicate that cetuximab may promote sensitivity to SN38 via suppression of HSP27 through blocking the JAK/STAT pathway in Caco2 cells .
10 The mutational status of numerous downstream effectors , such as RAS and BRAF , is important in mono - or combination therapy with cetuximab .
11 In conclusion , cetuximab may promote SN38 sensitivity via suppression of HSP27 , through blocking the JAK/STAT signaling pathway , and shows synergistic effects when combined with SN38 in wild-type RAS CRC cells .



PMID: 28655712
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF-inhibitor associated MEK Mutations Increase RAF -dependent and -independent Enzymatic Activity .
1 Alterations in MEK1/2 occur in cancers , both in the treatment naive state and following targeted therapies , most notably BRAF and MEK inhibitors in BRAF-V600E mutant melanoma and colorectal cancer .
2 Efforts were undertaken to understand the effects of these mutations , based upon protein structural location , and MEK1/2 activity .
3 Two categories of MEK1/2 alterations were evaluated , those associated with either the allosteric pocket or helix-A .
4 ✓ Clinically , MEK1/2 alterations of the allosteric pocket are rare and we demonstrate that they confer resistance to MEK inhibitors , whilst retaining sensitivity to BRAF inhibition .
5 Most mutations described in patients fall within , or are associated with , helix-A .
6 ✓ Mutations in this region reduce sensitivity to both BRAF and MEK inhibition and display elevated phospho-ERK1/2 levels , independent from increases in phospho-MEK1/2 .
7 Biochemical experiments with a representative helix-A variant , MEK1-Q56P , reveal both increased catalytic efficiency of the activated enzyme , and phosphorylation -independent activity relative to wild-type MEK1 .
8 Consistent with these findings , MEK1/2 alterations in helix A retain sensitivity to downstream antagonism via pharmacologic inhibition of ERK1/2 .
9 This work highlights the importance of classifying mutations based on structural and phenotypic consequences , both in terms of pathway signaling output and response to pharmacological inhibition .
10 IMPLICATIONS : This study suggests that alternate modes of target inhibition , such as ERK inhibition , will be required to effectively treat tumors harboring these MEK1/2 resistance alleles .



PMID: 28654634
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer .
1 Dietary Patterns and Risk of Colorectal Cancer : Analysis by Tumor Location and Molecular Subtypes .



PMID: 28654140
(Patient)  
Terms: meta-analysis, rat
Sent# Symbols Sentence Mnemonics
0 Epidermal growth factor receptor ( EGFR ) inhibitors for metastatic colorectal cancer .
1 BACKGROUND :
2 Epidermal growth factor receptor ( EGFR ) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer , whether used as single agents or in combination with chemotherapy .
3 Clear benefit has been shown in trials of EGFR monoclonal antibodies ( EGFR MAb ) but not EGFR tyrosine kinase inhibitors ( EGFR TKI ) .
4 However , there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity .
5 OBJECTIVES :
6 To determine the efficacy , safety profile , and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone , in combination with chemotherapy , or with other biological agents .
7 The primary outcome of interest was progression-free survival ; secondary outcomes included overall survival , tumour response rate , quality of life , and adverse events .
8 SEARCH METHODS :
9 We searched the Cochrane Central Register of Controlled Trials ( CENTRAL ) , the Cochrane Library , Issue 9 , 2016 ; Ovid MEDLINE ( from 1950 ) ; and Ovid Embase ( from 1974 ) on 9 September 2016 ; and ClinicalTrials .
10 gov and the LONGTOKEN on 14 March 2017 .
11 We also searched proceedings from the major oncology conferences ESMO , ASCO , and ASCO GI from 2012 to December 2016 .
12 We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed .
13 SELECTION CRITERIA :
14 We included randomised controlled trials on participants with metastatic colorectal cancer comparing : 1 ) the combination of EGFR MAb and 'standard therapy' ( whether chemotherapy or best supportive care ) to standard therapy alone , 2 ) the combination of EGFR TKI and standard therapy to standard therapy alone , 3 ) the combination of EGFR inhibitor ( whether MAb or TKI ) and standard therapy to another EGFR inhibitor ( or the same inhibitor with a different dosing regimen ) and standard therapy , or 4 ) the combination of EGFR inhibitor ( whether MAb or TKI ) , anti-angiogenic therapy , and standard therapy to anti-angiogenic therapy and standard therapy alone .
15 DATA COLLECTION AND ANALYSIS :
16 We used standard methodological procedures defined by Cochrane .
17 Summary statistics for the endpoints used hazard ratios ( HR ) with 95% confidence intervals ( CI ) for overall survival and progression-free survival , and odds ratios ( OR ) for response rate ( RR ) and toxicity .
18 Subgroup analyses were performed by rat Kirsten sarcoma viral oncogene homolog ( KRAS ) and neuroblastoma RAS viral ( V-Ras ) oncogene homolog ( NRAS ) status - firstly by status of KRAS exon 2 testing ( mutant or wild type ) and also by status of extended KRAS/NRAS testing ( any mutation present or wild type ) .
19 MAIN RESULTS :
20 We identified 33 randomised controlled trials for analysis ( 15,025 participants ) , including trials of both EGFR MAb and EGFR TKI .
21 Looking across studies , significant risk of bias was present , particularly with regard to the risk of selection bias ( 15/33 unclear risk , 1/33 high risk ) , performance bias ( 9/33 unclear risk , 9/33 high risk ) , and detection bias ( 7/33 unclear risk , 11/33 high risk ) .
22 The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival ( HR 070 , 95% CI 060 to 082 ; high-quality evidence ) , overall survival ( HR 088 , 95% CI 080 to 098 ; high-quality evidence ) , and response rate ( OR 241 , 95% CI 170 to 341 ; high-quality evidence ) .
23 We noted evidence of significant statistical heterogeneity in all three of these analyses ( progression-free survival : I2 = 76% ; overall survival : I2 = 40% ; and response rate : I2 = 77% ) , likely due to pooling of studies investigating EGFR MAb use in different lines of therapy .
24 Rates of overall grade 3 to 4 toxicity , diarrhoea , and rash were increased ( moderate-quality evidence for all three outcomes ) , but there was no evidence for increased rates of neutropenia .
25 For the extended RAS wild-type population ( no mutations in KRAS or NRAS ) , addition of EGFR MAb improved progression-free survival ( HR 060 , 95% CI 048 to 075 ; moderate-quality evidence ) and overall survival ( HR 077 , 95% CI 067 to 088 ; high-quality evidence ) .
26 Response rate was also improved ( OR 428 , 95% CI 261 to 703 ; moderate-quality evidence ) .
27 We noted significant statistical heterogeneity in the progression-free survival analysis ( I2 = 61% ) , likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies .
28 We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab , in progression-free survival ( HR 102 , 95% CI 093 to 112 ; high quality evidence ) or overall survival ( HR 084 , 95% CI 070 to 101 ; moderate-quality evidence ) .
29 We noted significant statistical heterogeneity in the overall survival analysis ( I2 = 51% ) , likely due to the pooling of first - line and second - line studies .
30 The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets ( meta-analysis not performed ) .
31   The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival ( HR 104 , 95% CI 083 to 129 ; very low quality evidence ) , overall survival ( HR 100 , 95% CI 069 to 147 ; low-quality evidence ) , or response rate ( OR 120 , 95% CI 067 to 212 ; very low-quality evidence ) but increased toxicity ( OR 257 , 95% CI 145 to 457 ; low-quality evidence ) .
32 We noted significant between-study heterogeneity in most analyses .
33 Scant information on quality of life was reported in the identified studies .
34 AUTHORS' CONCLUSIONS :
35 The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival ( moderate - to high-quality evidence ) , overall survival ( high-quality evidence ) , and tumour response rate ( moderate - to high-quality evidence ) , but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer ( moderate-quality evidence ) .
36 The addition of EGFR TKI to standard therapy does not improve clinical outcomes .
37 EGFR MAb combined with bevacizumab is of no clinical value ( very low-quality evidence ) .
38 Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data .



PMID: 28653203
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS screening in colorectal cancer : a comprehensive analysis of the results from the UK NEQAS colorectal cancer external quality assurance schemes ( 2009-2016 ) .
1 Evidence strongly indicates that extended RAS testing should be undertaken in mCRC patients , prior to prescribing anti-EGFR therapies .
2 With more laboratories implementing testing , the requirement for External Quality Assurance schemes increases , thus ensuring high standards of molecular analysis .
3 Data was analysed from 15 United Kingdom National External Quality Assessment Service ( UK NEQAS ) for Molecular Genetics Colorectal cancer external quality assurance ( EQA ) schemes , delivered between 2009 and 2016 .
4 Laboratories were provided annually with nine colorectal tumour samples for genotyping .
5 Information on methodology and extent of testing coverage was requested , and scores given for genotyping , interpretation and clerical accuracy .
6 There has been a sixfold increase in laboratory participation ( 18 in 2009 to 108 in 2016 ) .
7 For RAS genotyping , fewer laboratories now use Roche cobas(R) , pyrosequencing and Sanger sequencing , with more moving to next generation sequencing ( NGS ) .
8 Μ NGS is the most commonly employed technology for BRAF and PIK3CA mutation screening .
9 KRAS genotyping errors were seen in
10 NRAS genotyping errors peaked at 25.6% in the first 2015-2016 scheme but subsequently dropped to below 5% .
11 Interpretation and clerical accuracy scores have been consistently good throughout .
12 Within this EQA scheme , we have observed that the quality of molecular analysis for colorectal cancer has continued to improve , despite changes in the required targets , the volume of testing and the technologies employed .
13 It is reassuring to know that laboratories clearly recognise the importance of participating in EQA schemes .



PMID: 28652417
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas .
1 K-ras oncogene is a key factor in colorectal cancer .
2 Based on published and our data we propose that K-ras could be the oncogene responsible for the inactivation of the tumor-suppressor gene APC , currently considered as the initial step in colorectal tumorigenesis .
3 K-ras fulfills the criteria of the oncogene -induced DNA damage model , as it can provoke well-established causes for inactivating tumor-suppressors , i.e . DNA double - strand breaks ( causing allele deletion ) and ROS production ( responsible for point mutation ) .
4 The model we propose is a variation of the currently existing model and hypothesizes that , in a subgroup of colorectal carcinomas , K-ras mutation may precede APC inactivation , representing the earliest driving force and , probably , an early biomarker of colorectal carcinogenesis .
5 Μ This observation is clinically useful , since it may modify the preventive colorectal cancer strategy , restricting numerically patients undergoing colonoscopies to those bearing K-ras mutation in their colorectum , either in benign polyps or the normal accompanying mucosa .



PMID: 28651158
(Patient)  
Terms: Prospective, prospective, phase III study, NCT02364024
Sent# Symbols Sentence Mnemonics
0 Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX .
1 BACKGROUND :
2 The prognostic value of lymphocyte infiltration ( LI ) of colorectal carcinoma ( CC ) has been demonstrated by several groups .
3 However , no validated test is currently available for clinical practice .
4 We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use .
5 PATIENTS AND METHODS :
6 According to National Institutes of Health criteria , we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study .
7 Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI ( #NCT02364024 ) .
8 Associations of LI with patient recurrence and survival were analysed , and multivariable models were adjusted for treatment and relevant factors .
9 Automated testing of LI was performed on virtual slides without access to clinical data .
10 RESULTS :
11 Among the 1220 CC patients enrolled , LI was high , low and not evaluable in 241 ( 198% ) , 790 ( 648% ) and 189 ( 155% ) , respectively .
12 Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI , respectively ( p = 002 ) .
13 Patients with high LI also had better disease free survival ( DFS ) and overall survival ( OS ) .
14 Tumour stage , grade , RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS .
15 Μ Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair ( MMR ) proficient patients , and in patients without RAS mutation , but not in MMR deficient and RAS mutated patients .
16 CONCLUSION :
17 Although this is the first validation with high level of evidence ( IIB ) of the prognostic value of a LI test in colon cancers , it still needs to be confirmed in independent series of colon cancer patients .



PMID: 28649886
(Patient)  
Terms: phase III
Sent# Symbols Sentence Mnemonics
0 Epidermal growth factor inhibitors in first - line for metastatic colorectal cancer with ras wild-type : a perspective based on pharmacological costs .
1 INTRODUCTION :
2 In light of the relevant expenses of pharmacological interventions it might be interesting to make a balance between the cost of the new drugs administered , such as EGFRIs ( cetuximab and panitunumab ) and the added value represented by the improvement of the clinical parameters of interest such as progression free survival ( PFS ) .
3 Areas covered : The analysis was conducted to assess the effect of front - line chemotherapy on the PFS , separately , on each arm of the evaluated trials .
4 Only phase III randomized controlled trials ( RCTs ) were considered .
5 We calculated the pharmacological costs necessary to get the benefit in PFS , for each trial .
6 We have subsequently applied the LONGTOKEN to the above phase III RCTs .
7 Our analysis evaluated 9 phase III RCTs , including 7199 patients .
8 ESMO-MCBS reached high scores ( grade 4 ) for the CRYSTAL and PRIME trials .
9 The combination of FOLFOX and panitunumab is associated with low difference per month-PFS gained ( 15 8219 euro ) instead of FOLFIRI plus cetuximab ( 21 8546 euro ) in KRAS wild-type patients .
10 Expert commentary : Our data demonstrate a huge difference in cost per month of PFS gained in modern front - line treatments in mCRC with RAS wild-type .



PMID: 28649441
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical responses to ERK inhibition in BRAFV600E-mutant colorectal cancer predicted using a computational model .
1 Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma .



PMID: 28647837
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Targeting metabolic reprogramming in KRAS-driven cancers .
1 Μ Mutations of KRAS are found in a variety of human malignancies , including in pancreatic cancer , colorectal cancer , and non-small cell lung cancer at high frequency .
2 To date , no effective treatments that target mutant variants of KRAS have been introduced into clinical practice .
3 In recent years , a number of studies have shown that the oncogene KRAS plays a critical role in controlling cancer metabolism by orchestrating multiple metabolic changes .
4 One of the metabolic hallmarks of malignant tumor cells is their dependency on aerobic glycolysis , known as the Warburg effect .
5 The role of KRAS signaling in the regulation of aerobic glycolysis has been reported in several types of cancer .
6 KRAS-driven cancers are characterized by altered metabolic pathways involving enhanced nutrients uptake , enhanced glycolysis , enhanced glutaminolysis , and elevated synthesis of fatty acids and nucleotides .
7 However , Just how mutated KRAS can coordinate the metabolic shift to promote tumor growth and whether specific metabolic pathways are essential for the tumorigenesis of KRAS-driven cancers are questions which remain to be answered .
8 In this context , the aim of this review is to summarize current data on KRAS-related metabolic alterations in cancer cells .
9 Given that cancer cells rely on changes in metabolism to support their growth and survival , the targeting of metabolic processes may be a potential strategy for treating KRAS-driven cancers .



PMID: 28646840
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad .
1 INTRODUCTION :
2 Lynch Syndrome ( LS ) is a genetically inherited autosomal disorder that increases the risk of many types of cancer , especially colorectal cancer ( CRC ) .
3 Identifying these subjects improves morbidity and mortality .
4 We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad , Iran .
5 METHODS :
6 In this retrospective study , we screened 322 patients with CRC between 2013 and 2016 in Mashhad , Iran .
7 CRCs were screened based on Amsterdam II criteria , revised Bethesda guideline , and universal strategy .
8 Information regarding the clinical criteria was obtained by interviewing the patients or , their families .
9 Tumors were screened by pathologists with IHC staining of four Mismatch repair ( MMR ) proteins ( MLH1 , MSH2 , MSH6 , and PMS2 ) .
10 Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs .
11 RESULTS :
12 Of 322 CRCs , 33 cases were found to be deficient-MMR ; 22 of these had concurrent loss of MLH1 and PMS2 , followed by concurrent loss of MSH2 and MSH6 in 8 CRCs .
13 Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation , 4 of which were recognized as a positive BRAF mutation .
14 Μ Finally , 29 CRCs were found as being positive screen for LS .
15 Μ Poor sensitivity ( 2174% ) was found for the Amsterdam II criteria and a poor positive predictive value ( 1539% ) for the revised Bethesda .
16 CONCLUSION :
17 Application of clinical criteria may not be effective enough to identify LS and atleast 2 - antibody panel ( PMS2 , MSH6 ) should be conducted for newly diagnosed CRCs .



PMID: 28646407
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Associations of red and processed meat intake with major molecular pathological features of colorectal cancer .
1 Red and processed meat is an established risk factor for colorectal cancer ( CRC ) .
2 However , exact mechanisms to explain the associations remain unclear .
3 Few studies have investigated the association with CRC by molecular tumor features , which could provide relevant information on associated molecular pathways .
4 In this population-based case-control study from Germany ( DACHS ) , 2449 cases and 2479 controls provided information on risk factors of CRC and completed a food frequency questionnaire .
5 Multivariable logistic regression was used to estimate odds ratios ( ORs ) and 95% confidence intervals ( CI ) for the associations between meat intake and risk of CRC by molecular pathologic features and specific subtypes .
6 Red and processed meat intake was associated with increased risk of colorectal ( >1 time/day versus
7 Among the single molecular tumor features investigated , the results were similar for associations of red and processed meat with CRC risk by microsatellite instability , CpG island methylator phenotype , BRAF , oestrogen receptor -beta and p53 status .
8 Red and processed meat intake was associated less strongly with risk of KRAS-mutated CRC ( OR >1 time/day versus KRAS-wildtype CRC ( OR 182 , 95% CI 142-234 ; p heterogeneity 004 ) .
9 These results support an association between red and processed meat and CRC risk similar for subsites of CRC and most of the investigated major molecular pathological features .
10 Potential differences were observed in more specific subtype analyses .
11 Further large studies are needed to confirm these results and to help further elucidate potential underlying mechanisms .



PMID: 28646291
(Cell)  
Terms: clinical trial, rat
Sent# Symbols Sentence Mnemonics
0 Application of open-access databases to determine functional connectivity between resveratrol-binding protein QR2 and colorectal carcinoma .
1 Colorectal cancer ( CRC ) is a major cause of cancer-associated deaths worldwide .
2 Recently , oral administration of resveratrol ( trans-3,5,4'-trihydroxystilbene ) has been reported to significantly reduce tumor proliferation in colorectal cancer patients , however , with little specific information on functional connections .
3 The pathogenesis and development of colorectal cancer is a multistep process that can be categorized using three phenotypic pathways , respectively , chromosome instability ( CIN ) , microsatellite instability ( MSI ) , and CpG island methylator ( CIMP ) .
4 Μ Targets of resveratrol , including a high-affinity binding protein , quinone reductase 2 ( QR2 ) , have been identified with little information on disease association .
5 We hypothesize that the relationship between resveratrol and different CRC etiologies might be gleaned using publicly available databases .
6 A web-based microarray gene expression data-mining platform , Oncomine , was selected and used to determine whether QR2 may serve as a mechanistic and functional biotarget within the various CRC etiologies .
7 We found that QR2 messenger RNA ( mRNA ) is overexpressed in CRC characterized by CIN , particularly in cells showing a positive rat KRAS ( Kirsten sarcoma viral oncogene homolog ) mutation , as well as by the MSI but not the CIMP phenotype .
8 Μ Mining of Oncomine revealed an excellent correlation between QR2 mRNA expression and certain CRC etiologies .
9 Two resveratrol-associated genes , adenomatous polyposis coli ( APC ) and TP53 , found in CRC were further mined , using cBio portal and Colorectal Cancer Atlas which predicted a mechanistic link to exist between resveratrol-->QR2/TP53-->CIN .
10   Multiple web-based data mining can provide valuable insights which may lead to hypotheses serving to guide clinical trials and design of therapies for enhanced disease prognosis and patient survival .
11 This approach resembles a BioGPS , a capability for mining web-based databases that can elucidate the potential links between compounds to provide correlations of these interactions with specific diseases .



PMID: 28645942
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Agminated melanocytic nevus status post dabrafenib therapy for metastatic melanoma .
1 Purpose : The majority of genomic alterations causing intratumoral heterogeneity ( ITH ) in colorectal cancer ( CRC ) are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone .
2 We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations , thus challenging the prevailing monoclonal monocryptal model .

Experimental design : High-depth next-generation sequencing and SNP arrays were performed in whole lesion extracts of 37 FAP colorectal adenomas .

3 Also , ultra-sensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies ( n = 59 ) and crypts ( n = 591 ) from 18 adenomas and 7 carcinomas and adjacent normal tissues.

Results : Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole lesion extracts from adenomas and subsequently confirmed to belong to multiple clones .

4 Μ Ultra-sensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas , whereas abundant wild-type APC crypts were detected in adenomas .
5 KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas .
6 Μ Non-random heterogeneity among crypts was also observed.

Conclusions : The striking degree of non-random intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis .



PMID: 28644145
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal carcinoma with osseous metaplasia .
1 Osseous metaplasia ( OM ) is rarely observed in colorectal cancer ( incidence <04% in rectal cancer ) , where it has a non-specific clinical presentation and unknown pathogenesis .
2 Here , we report three cases of colorectal carcinoma with OM and propose a new hypothesis .
3 All three patients ( two males and one female ) were Chinese and had different sites of colorectal carcinoma with OM : rectum , sigmoid colon , and appendix .
4 The pathologic diagnoses were serrated adenocarcinoma ; moderately to poorly differentiated adenocarcinoma with micropapillary carcinoma and cribriform comedo-type adenocarcinoma ; and mucinous adenocarcinoma , respectively .
5 Clinical follow-up showed that one patient died 5 months after surgery , but the others are alive after 68 months and 53 months .
6 Immunohistochemistry revealed that CD44 , MAPK , MDM2 , OPN and PEDF were expressed by both tumor cells and stromal cells , while P53 was expressed only by tumor cells .
7 Μ KRAS/NRAS/BRAF genotyping revealed different KRAS mutations in each of the three cases , but the NRAS and BRAF exons were all wild-type .
8 These findings suggest OM has no relation with NRAS and BRAF mutation , and it is uncertain whether there is a relationship between ossification and KRAS mutation .
9 OPN , MAPK , MDM2 , P53 , PEDF and CD44 may act as osteogenic factors in colorectal cancer with OM .



PMID: 28639239
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Significant Improvement in Detecting BRAF , KRAS , and EGFR Mutations Using Next-Generation Sequencing as Compared with FDA-Cleared Kits .
1 INTRODUCTION :
2 Μ We compared mutations detected in EGFR , KRAS , and BRAF genes using next-generation sequencing ( NGS ) and confirmed by Sanger sequencing with mutations that could be detected by FDA-cleared testing kits .
3 METHODS :
4 Paraffin-embedded tissue from 822 patients was tested for mutations in EGFR , KRAS , and BRAF by NGS .
5 Sanger sequencing of hot spots was used with locked nucleic acid to increase sensitivity for specific hot-spot mutations .
6 This included 442 ( 54% ) lung cancers , 168 ( 20% ) colorectal cancers , 29 ( 4% ) brain tumors , 33 ( 4% ) melanomas , 14 ( 2% ) thyroid cancers , and 16% others ( pancreas , head and neck , and cancer of unknown origin ) .
7 Results were compared with the approved list of detectable mutations in FDA kits for EGFR , KRAS , and BRAF .
8 RESULTS :
9 Of the 101 patients with EGFR abnormalities as detected by NGS , only 58 ( 57% ) were detectable by cobas v2 and only 35 ( 35% ) by therascreen .
10 Μ Therefore , 42 and 65% , respectively , more mutations were detected by NGS , including two patients with EGFR amplification .
11 Μ Of the 117 patients with BRAF mutation detected by NGS , 62 ( 53% ) mutations were within codon 600 , detectable by commercial kits , but 55 ( 47% ) of the mutations were outside codon V600 , detected by NGS only .
12 Μ Of the 321 patients with mutations in KRAS detected by NGS , 284 ( 885% ) had mutations detectable by therascreen and 300 ( 935% ) had mutations detectable by cobas .
13 Μ Therefore , 11.5 and 6.5% additional KRAS mutations were detected by NGS , respectively .
14 CONCLUSION :
15 NGS provides significantly more comprehensive testing for mutations as compared with FDA-cleared kits currently available commercially .



PMID: 28638266
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Nuclear Expression of GS28 Protein : A Novel Biomarker that Predicts Prognosis in Colorectal Cancers .
1 Aims : GS28 ( Golgi SNARE protein , 28kDa ) , a member of the LONGTOKEN protein family , plays a critical role in mammalian endoplasmic reticulum ( ER )- Golgi or intra-Golgi vesicle transport .
2 To date , few researches on the GS28 protein in human cancer tissues have been reported .
3 In this study , we assessed the prognostic value of GS28 in patients with colorectal cancer ( CRC ) .
4 Methods and results : We screened for GS28 expression using immunohistochemistry in 230 surgical CRC specimens .
5 The CRCs were right-sided and left-sided in 28.3% ( 65/230 ) and 71.3% ( 164/230 ) of patients , respectively .
6 GS28 staining results were available in 214 cases .
7 Among these , there were 26 nuclear predominant cases and 188 non-nuclear predominant cases .
8 Stromal GS28 expression was noted in 152 cases of CRC .
9 GS28 nuclear predominant immunoreactivity was significantly associated with advanced tumour stage ( p = 0045 ) and marginally associated with perineural invasion ( p = 0064 ) .
10 Decreased GS28 expression in the stromal cells was significantly associated with lymph node metastasis ( N stage ; p = 0036 ) .
11 GS28 expression was not associated with epidermal growth factor receptor ( EGFR ) immunohistochemical positivity or KRAS mutation status .
12 Investigation of the prognostic value of GS28 with Kaplan-Meier analysis revealed a correlation with overall survival ( p = 0004 ) .
13 ✓ Cases with GS28 nuclear predominant expression had significantly poorer overall survival than those with a non-nuclear predominant pattern . RO-ASS-GE
14 ✓ Conclusions : Taken together , these results indicate that GS28 nuclear predominant expression could serve as a prognostic marker for CRC and may help in identifying aggressive forms of CRC . GE-MRK-DS



PMID: 28636636
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 SensiScreen(R) KRAS exon 2-sensitive simplex and multiplex real-time PCR-based assays for detection of KRAS exon 2 mutations .
1 Activating mutations in codon 12 and codon 13 of the rat KRAS ( Kirsten sarcoma viral oncogene homolog ) gene are implicated in the development of several human cancer types and influence their clinical evaluation , treatment and prognosis .
2 Numerous different methods for KRAS genotyping are currently available displaying a wide range of sensitivities , time to answer and requirements for laboratory equipment and user skills .
3 Here we present SensiScreen(R) KRAS exon 2 simplex and multiplex CE IVD assays , that use a novel real-time PCR-based method for KRAS mutation detection based on PentaBase's proprietary DNA analogue technology and designed to work on standard real-time PCR instruments .
4 By means of the included BaseBlocker technology , we show that SensiScreen(R) specifically amplifies the mutated alleles of interest with no or highly subdued amplification of the wild type allele .
5 Furthermore , serial dilutions of mutant DNA in a wild type background demonstrate that all SensiScreen(R) assays display a limit of detection that falls within the range of 0.25-1% .
6 Μ Finally , in three different colorectal cancer patient populations , SensiScreen(R) assays confirmed the KRAS genotype previously determined by commonly used methods for KRAS mutation testing , and notably , in two of the populations , SensiScreen(R) identified additional mutant positive cases not detected by common methods .



PMID: 28636540
(Patient)  
Terms: NCT01772004
Sent# Symbols Sentence Mnemonics
0 Implementation and utilization of the molecular tumor board to guide precision medicine .
1 BACKGROUND :
2 Avelumab , a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma , has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial .
3 In this dose-expansion cohort of that trial , we assess avelumab treatment in a cohort of patients with advanced , platinum-treated non-small-cell lung cancer ( NSCLC ) .
4 METHODS :
5 In this dose-expansion cohort of a multicentre , open-label , phase 1 study , patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA .
6 Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology , measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 ( RECIST v11 ) , tumour biopsy or archival sample for biomarker assessment , and Eastern Cooperative Oncology Group performance status 0 or 1 , among other criteria .
7 Patient selection was not based on PD-L1 expression or expression of other biomarkers , including EGFR or KRAS mutation or ALK translocation status .
8 Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity .
9 The primary objective was to assess safety and tolerability .
10 This trial is registered with ClinicalTrials .
11 gov , number NCT01772004 ; enrolment in this cohort is closed and the trial is ongoing .
12 FINDINGS :
13 Between Sept 10 , 2013 , and June 24 , 2014 , 184 patients were enrolled and initiated treatment with avelumab .
14 Median follow-up duration was 8.8 months ( IQR 72-119 ) .
15 The most common treatment-related adverse events of any grade were fatigue ( 46 [25%] of 184 patients ) , infusion-related reaction ( 38 [21%] ) , and nausea ( 23 [13%] ) .
16   Grade 3 or worse treatment-related adverse events occurred in 23 ( 13% ) of 184 patients ; the most common ( occurring in more than two patients ) were infusion-related reaction ( four [2%] patients ) and increased lipase level ( three [2%] ) .
17   16 ( 9% ) of 184 patients had a serious adverse event related to treatment with avelumab , with infusion-related reaction ( in four [2%] patients ) and dyspnoea ( in two [1%] ) occurring in more than one patient .
18 Serious adverse events irrespective of cause occurred in 80 ( 44% ) of 184 patients .
19 Those occurring in more than five patients ( >/ = 3% ) were dyspnoea ( ten patients [5%] ) , pneumonia ( nine [5%] ) , and chronic obstructive pulmonary disease ( six [3%] ) .
20   Immune-related treatment-related events occurred in 22 patients ( 12% ) .
21 Of 184 patients , 22 ( 12% [95% CI 8-18] ) achieved a confirmed objective response , including one complete response and 21 partial responses. 70 ( 38% ) had stable disease .
22 Overall , 92 ( 50% ) of 184 patients achieved disease control ( they had a confirmed response or stable disease as their best overall response ) .
23 One patient was initially thought to have died from grade 5 radiation pneumonitis during the study ; however , this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression .
24   INTERPRETATION : Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC , providing a rationale for further studies of avelumab in this disease setting .
25 FUNDING : Merck KGaA and Pfizer .



PMID: 28633089
(None)  
Terms: phase II trial, Orthotopic Xenograft
Sent# Symbols Sentence Mnemonics
0 First - line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases : A randomised , phase II trial ( PLANET-TTD ) .
1 Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft ( PDOX ) Nude Mouse Model .



PMID: 28632865
(None)  
Terms: Clinical Trial, This review
Sent# Symbols Sentence Mnemonics
0 Effect of First - Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer : A Randomized Clinical Trial .
1 Molecular profiling and the discovery of drugs that target specific activating mutations have allowed the personalization of treatment for non-small cell lung cancer ( NSCLC ) .
2 The epithelial growth factor receptor ( EGFR ) is frequently over-expressed and/or aberrantly activated in different cancers , including NSCLC .
3 The most common activating mutations of EGFR in NSCLC fall within the tyrosine kinase -binding domain .
4 Three oral EGFR tyrosine kinase inhibitors ( TKIs ) have been approved by the U .
5 S .
6 Food and Drug Administration ( FDA ) for first - line use in patients with EGFR mutation-positive NSCLC ( exon 19 deletions or exon 21 [L858R] substitution mutations ) , as detected by an FDA-approved test .
7 However , disease progression is common and is often the result of secondary mutations , of which the EGFR T790M mutation is the most prevalent .
8   Few options were available upon progression until the introduction of osimertinib , a kinase inhibitor that targets the T790M mutation , which was recently approved for use in patients with metastatic EGFR T790M mutation-positive NSCLC , as detected by an FDA-approved test , who progressed on or after EGFR TKI therapy .
9   With the introduction of osimertinib , outcomes can now be improved in select patients .
10 Therefore , performing a biopsy at progression to determine the underlying molecular cause of the acquired resistance is important for the enabling of individualized options that may provide the greatest opportunity for improved outcomes .
11 This review discusses the latest updates in molecular testing at progression and outlines treatment options for this difficult-to-treat population .
12 THE ONCOLOGIST :
13 2017 ; 22 : 3-11 IMPLICATIONS FOR PRACTICE :
14   Although the epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors ( TKIs )- gefitinib , erlotinib , and afatinib-have changed the treatment paradigm for non-small cell lung cancer among those with EGFR mutation positive disease , most patients experience progression after approximately 12 months of treatment .
15 Until recently , options were limited for patients who progressed , but improvements in molecular profiling and the approval of osimertinib , which targets the resistance mutation T790M , afford the opportunity for improved outcomes in many patients with this mutation .
16   This article explains the options available after progression on initial EGFR TKI therapy and the importance of molecular testing at progression in making treatment decisions .



PMID: 28632725
(Patient)  
Terms: retrospective, prospective
Sent# Symbols Sentence Mnemonics
0 The role of primary tumour sidedness , EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab .
1 BACKGROUND :
2 The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer ( CRC ) patients , particularly during treatment with anti-epidermal growth factor receptor ( EGFR ) therapy .
3 However , an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting .
4 METHODS :
5 We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type ( WT ) metastatic CRC patients treated with second-third - line irinotecan/cetuximab were analysed for EGFR gene copy number ( GCN ) and promoter methylation .
6 Study objective was to evaluate the correlation of tumour sidedness , EGFR promoter methylation and EGFR GCN with clinical outcome .
7 Median follow-up duration was 14.3 months .
8 RESULTS :
9 Eighty-eight patients were included in the study , 27.3% had right-sided CRC , 72.7% had left-sided CRC ; 36.4% had EGFR GCN<2.12 tumour , 63.6% had EGFR GCN2.12 tumour ; 50% had EGFR promoter -methylated tumour .
10 Right-sided colorectal cancer ( RSCRC ) were associated with reduced overall response rate ( ORR ) ( 4.2% for RSCRC versus 35.9% for left sided colorectal cancer ( LSCRC ) , P = 0.0030 ) , shorter progression-free survival ( PFS ) ( 30 versus 675 months , P<00001 ) and shorter overall survival ( OS ) ( 8 versus 136 months , P<00001 ) .
11 EGFR GCN<2.12 tumours were associated with reduced ORR ( 62% for EGFR GCN<212 versus 393% for EGFR GCN212 tumours , P = 00009 ) , shorter PFS ( 35 versus 65 months , P = 00006 ) and shorter OS ( 85 versus 140 months , P<00001 ) .
12 Epidermal growth factor receptor -methylated tumours were associated with reduced ORR ( 91% for methylated versus 455% for unmethylated , P = 00001 ) , shorter PFS ( 3 versus 767 months , P<00001 ) and shorter OS ( 8 versus 17 months , P<00001 ) .
13 At multivariate analysis , EGFR GCN and EGFR promoter methylation maintained their independent role for ORR ( respectively P = 00082 and 00025 ) , PFS ( respectively P = 00048 and<00001 ) and OS ( respectively P = 00001 and<00001 ) .
14 CONCLUSIONS :
15 In our study , an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy .
16 However , these data need to be validated with future prospective and translational studies .



PMID: 28626084
(Patient)  
Terms: clinical trial, retrospective
Sent# Symbols Sentence Mnemonics
0 Optimization of RAS/BRAF mutational analysis confirms improvement in patient selection for clinical benefit to anti-EGFR treatment in metastatic colorectal cancer .
1 In metastatic colorectal cancer ( mCRC ) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds .
2 We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR ( dPCR ) .
3 Tumor samples from 583 mCRC patients treated with anti-EGFR ( n = 255 ) or bevacizumab ( n = 328 ) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas(R) , therascreen(R) and dPCR .
4 We evaluated concordance between techniques using Cohen's kappa index .
5 Response rate , progression-free survival ( PFS ) and overall survival ( OS ) were correlated to the mutational status and the mutant allele fraction ( MAF ) .
6 Concordance between techniques was high when analyzing RAS and BRAF ( Cohen's kappa index around 075 ) .
7 We observed an inverse correlation between MAF and response in the anti-EGFR cohort ( p<0001 ) .
8 Μ Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value .
9 PFS and OS were significantly longer in RAS/BRAF wild-type patients , independently of the technique .
10 However , the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario ( HR = 1.53 ; CI 95% [112-209] for PFS , and HR = 1.9 ; CI 95% [133-272] for OS ) .
11 Μ Although the rate of mutations observed among techniques is different , RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy .
12 Additionally , dPCR with a threshold of 1% outperformed the other platforms .



PMID: 28625649
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Delay of treatment change after objective progression on first - line erlotinib in epidermal growth factor receptor -mutant lung cancer .
1 Axillary lymph nodes ( axLN ) are a rare site of nodal metastases in patients with lung cancer .
2 BRAF mutated lung cancer is a genetically distinct subtype that occurs in 2-5% of non-small cell lung carcinomas ( NSCLC ) .
3 A recent study identified a highly unusual pattern of metastatic spread to axLN in patients with BRAF mutated colorectal cancer ( CRC ) .
4 The purpose of the study is to assess the incidence of axLN metastases in BRAF mutated NSCLC .
5 Baseline computed tomography ( CT ) imaging at diagnosis and all follow up CTs of patients with BRAF mutated NSCLC treated at our institution were retrospectively reviewed by two radiologists for evidence of axLN metastases .
6 Positron emission tomography ( PET ) /CT was reviewed when available .
7 A control group of patients with non-BRAF mutated NSCLC was assessed .
8 Three criteria were used for the diagnosis of a metastatic node ; pathologic confirmation , radiologic size greater >/ = 1.5cm in short axis diameter or fluorodeoxyglucose avidity on PET/CT and radiologic size >/ = 1.0cm in short axis diameter .
9 Μ Forty-six patients with BRAF mutated NSCLC and CT images on the institutional PACS were identified. 7 ( 15% ) patients with BRAF mutated NSCLC had axLN metastases using the proposed diagnostic criteria .
10 One patient had a pathologic proven axLN metastasis , 3 had axLNs measuring >/ = 1.5cm in short axis , and 3 had nodes which were FDG avid on PET/CT and measured >/ = 1.0cm in short axis .
11 By comparison , 1 of 46 ( 2% ) control patients with non-BRAF mutated NSCLC had axLN metastases .
12 Previous series have reported the prevalence of axLN metastases in patients with NSCLC as 0.61-0.75% .
13 Μ We have found a higher incidence of axLN metastases in BRAF mutated NSCLC patients than described in non-BRAF mutated NSCLC patients .
14 Examination of the axilla should be a routine part of physical examination in this genetically distinct subgroup of lung cancer patients .



PMID: 28623901
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarker correlation network in colorectal carcinoma by tumor anatomic location .
1 BACKGROUND :
2 Colorectal carcinoma evolves through a multitude of molecular events including somatic mutations , epigenetic alterations , and aberrant protein expression , influenced by host immune reactions .
3 One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network .
4 Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process .
5 Due to embryological , physiological , and microbial differences , proximal and distal colorectal cancers have distinct sets of molecular pathological signatures .
6 Given these differences , we hypothesized that a biomarker correlation network might vary by tumor location .
7 RESULTS :
8 We performed network analyses of 54 biomarkers , including major mutational events , microsatellite instability ( MSI ) , epigenetic features , protein expression status , and immune reactions using data from 1380 colorectal cancer cases : 690 cases with proximal colon cancer and 690 cases with distal colorectal cancer matched by age and sex .
9 Edges were defined by statistically significant correlations between biomarkers using Spearman correlation analyses .
10 We found that the proximal colon cancer network formed a denser network ( total number of edges , n = 173 ) than the distal colorectal cancer network ( n = 95 ) ( P <00001 in permutation tests ) .
11 The value of the average clustering coefficient was 0.50 in the proximal colon cancer network and 0.30 in the distal colorectal cancer network , indicating the greater clustering tendency of the proximal colon cancer network .
12 In particular , MSI was a key hub , highly connected with other biomarkers in proximal colon cancer , but not in distal colorectal cancer .
13 Among patients with non-MSI-high cancer , BRAF mutation status emerged as a distinct marker with higher connectivity in the network of proximal colon cancer , but not in distal colorectal cancer .
14 CONCLUSION :
15 In proximal colon cancer , tumor biomarkers tended to be correlated with each other , and MSI and BRAF mutation functioned as key molecular characteristics during the carcinogenesis .
16 Our findings highlight the importance of considering multiple correlated pathways for therapeutic targets especially in proximal colon cancer .



PMID: 28622298
(None)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 TGFbeta pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis .
1 Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells ( ISCs ) and tumour-initiating cells .
2 However , little is known of the processes that regulate this plasticity .
3 Our previous work has shown that activating mutations of Kras or the NF-kappaB pathway can drive dedifferentiation of intestinal cells lacking Apc .
4 To investigate this process further , we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis .
5 Μ Remarkably , no clear differences were observed in the tumours ; however , during dedifferentiation in vitro we found a marked upregulation of TGFbeta signalling , a pathway commonly mutated in colorectal cancer ( CRC ) .
6 Genetic inactivation of TGFbeta type 1 receptor ( Tgfbr1/Alk5 ) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis .
7 Mechanistically this is associated with a marked activation of MAPK signalling .
8 Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition .
9 Taken together , we show that tumours arising in differentiated compartments will be exposed to different suppressive signals , for example , TGFbeta and blockade of these makes tumourigenesis more efficient from this compartment .
10 Cell Death and Differentiation advance online publication , 16 June 2017 ; doi : 10.1038/cdd.2017.92 .



PMID: 28621683
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Genomic analysis of exceptional responder to regorafenib in treatment-refractory metastatic rectal cancer : a case report and review of the literature .
1 We present the case of a 53-year-old male with metastatic rectal cancer who was treatment resistant to FOLFOX and FOLFOXIRI .
2 Due to a rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutation , regorafenib was given in the third line setting .
3 Surprisingly , the patient had a prolonged partial response that lasted 27 months .
4 Μ Mutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for this unusual event .
5 A poorly characterized but nontransforming mutation in Fms-like tyrosine kinase 4 ( FLT4 ) was present in the tumor .
6 Μ Prior to and at the time of clinical progression , we found amplification of fibroblast growth factor receptor 1 ( FGFR1 ) and epidermal growth factor receptor ( EGFR ) , loss of the FLT4 mutation , and gain of KIT proto-oncogene receptor tyrosine kinase ( KIT ) G961S suggesting potential roles in acquired resistance .



PMID: 28618430
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low-frequency mutations in the KRAS gene .
1 PTEN loss in circulating tumour cells correlates with PTEN loss in fresh tumour tissue from castration-resistant prostate cancer patients .



PMID: 28617917
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic Profiling of Small-Bowel Adenocarcinoma .
1 Importance : Small-bowel adenocarcinomas ( SBAs ) are rare cancers with a significantly lower incidence , later stage at diagnosis , and worse overall survival than other intestinal-derived cancers .
2 To date , comprehensive genomic analysis of SBA is lacking .
3 Μ Objective : To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations .
4 Design , Setting , and Participants : Prospective analysis was performed of clinical samples from patients with SBA ( n = 317 ) , colorectal cancer ( n = 6353 ) , and gastric carcinoma ( n = 889 ) collected between August 24 , 2012 , and February 3 , 2016 , using hybrid-capture-based genomic profiling , at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions .
5 Results : Of the 7559 patients included in analysis , 4138 ( 547% ) were male ; the median age was 56 ( range , 12-101 ) years .
6 Μ The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer ( APC : 26.8% [85 of 317] versus 75.9% [4823 of 6353] , P <.001 ; and CDKN2A : 14.5% [46 of 317] versus 2.6% [165 of 6353] , P <.001 ) or gastric carcinoma ( KRAS : 53.6% [170 of 317] versus 14.2% [126 of 889] , P <.001 ; APC : 26.8% [85 of 317] versus 7.8% [69 of 889] , P <.001 ; and SMAD4 : 17.4% [55 of 317] versus 5.2% [46 of 889] , P <.001 ) .
7 BRAF was mutated in 7.6% ( 484 of 6353 ) of colorectal cancer and 9.1% ( 29 of 317 ) of SBA samples , but V600E mutations were much less common in SBA , representing only 10.3% ( 3 of 29 ) of BRAF-mutated cases .
8 The ERBB2/HER2 point mutations ( 8.2% [26 of 317] ) , microsatellite instability ( 7.6% [13 of 170] ) , and high tumor mutational burden ( 9.5% [30 of 317] ) were all enriched in SBA .
9 Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma , as well as in inflammatory bowel disease-associated SBAs .
10 Targetable alterations in several additional genes , including PIK3CA and MEK1 , and receptor tyrosine kinase fusions , were also identified in all 3 series .
11 Conclusions and Relevance : This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma .
12 The distinct genomic differences establish SBA as a molecularly unique intestinal cancer .
13   Μ In addition , genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases ( 91% ) , and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy .



PMID: 28617623
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival .
1 Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer ( CRC ) .
2 However , the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) in relation to survival is unclear .
3 Patients and Methods In all , 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States , Canada , and Australia .
4 Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up.Survival outcomes were completed through linkage to national death registries .
5 BRAF - and KRAS-mutation status , microsatellite instability , and CpG island methylator phenotype were also evaluated .
6 Cox proportional hazards regression was used to estimate hazard ratios ( HRs ) and 95% CIs for overall survival ( OS ) and CRC-specific survival .
7 Results After a median of 10.8 years of follow-up since diagnosis , 381 deaths ( 100 as a result of CRC ) were observed .
8 Compared with nonusers , postdiagnostic aspirin-only users had more favorable OS ( HR , 075 ; 95% CI , 059 to 095 ) and CRC-specific survival ( HR , 044 ; 95% CI , 025 to 071 ) , especially among those who initiated aspirin use ( OS : HR , 0.64 ; 95% CI , 0.47 to 0.86 ; CRC-specific survival : HR , 0.40 ; 95% CI , 0.20 to 0.80 ) .
9 The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = 01 ) .
10 Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors ( HR , 060 ; 95% CI , 046 to 080 ) but not among those with KRAS-mutant tumors ( HR , 124 ; 95% CI , 078 to 196 ) .
11 Conclusion Among long-term CRC survivors , regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors .



PMID: 28616082
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prevalence of pks-positive Escherichia coli in Japanese patients with or without colorectal cancer .
1 BACKGROUND :
2 Recent studies show that some Escherichia coli strains possessing a gene cluster named the pks island might have a causative role in the development of human colorectal cancer ( CRC ) .
3 In several reports from Europe , they are found more prevalently in colon tissue specimens derived from CRC patients compared to those from controls .
4 In this study we sought to clarify the difference in pks prevalence between CRC patients and non-CRC controls in the Japanese population , by using non-invasive sample collection technique during colonoscopy .
5 METHODS :
6 Colonic lavage samples were collected during diagnostic colonoscopy , and bacterial DNA within each sample was extracted .
7 Fecal DNA samples were then examined for pks island genes using conventional qualitative PCR and real-time quantitative PCR .
8 In some patients biopsy samples were also collected in the same session of colonoscopy , and the correlation between the pks status of the colonic lavage sample and the biopsy sample of the same patients was evaluated .
9 RESULTS :
10 Twelve out of thirteen patients ( 92% ) showed the same pks status by colonic lavage sample and biopsy sample , suggesting the usefulness of colonic lavage samples as a surrogate for biopsy samples .
11 A total of 98 colonic lavage samples were collected , which included 35 from CRC patients , 37 from adenoma patients , and 26 from controls .
12 Μ The pks-positive bacterial DNA was detected in 43 , 51 , and 46% of colonic lavage samples from CRC , adenoma , and control patients , respectively , and there was no significant difference among diseases .
13 Μ Real-time quantitative PCR showed no significant difference in the relative concentrations of pks-positive bacterial DNA among diseases .
14 Age , gender , location of CRC , CRC staging , or k-ras gene status was not associated with pks prevalence .
15 CONCLUSIONS :
16 Although the method of collecting fecal DNA from colonic lavage samples was safe and technically feasible , factors other than pks-positive bacteria appear to play more important roles in CRC development in this cohort .



PMID: 28612017
(None)  
Terms: retrospective, retrospective studies
Sent# Symbols Sentence Mnemonics
0 Treatment Options in Colorectal Liver Metastases : Hepatic Arterial Infusion .
1 BACKGROUND :
2 The liver is the most common site for metastases from colorectal cancer ( CRC ) with the majority of these patients having unresectable disease .
3 METHODS :
4 This is a retrospective review of studies using hepatic arterial infusion ( HAI ) therapy to treat liver metastasis from CRC .
5 A PubMed search of randomized controlled trials and retrospective studies from 2006 to present was conducted using the search terms 'hepatic arterial infusion ( HAI ) therapy' , 'colorectal cancer' , and 'treatment of liver metastases' .
6 RESULTS :
7 The first randomized studies comparing HAI to systemic therapy with 5-fluorouracil/leucovorin produced significantly higher response rates of 41 versus 14% .
8 Systemic therapy has improved with the addition of irinotecan and oxaliplatin ; however , the responses with HAI and these modern agents have also increased , with responses as high as 80% .
9 ✓ For patients with wild-type KRAS , HAI and systemic therapy produced a median survival of 68 months . GM-REG-RO
10 In patients with refractory disease , response rates are in the 30% range with a median survival of 20 months .
11   Adjuvant HAI after liver resection has shown an increase of hepatic disease-free survival and overall disease-free survival when compared to systemic therapy alone in three of four randomized trials .
12 A recent update of the adjuvant trials after liver resection at Memorial Sloan Kettering Cancer Center has shown a 5-year survival of 78% .
13 CONCLUSION :
14 HAI therapy has a role in treating hepatic metastases from CRC in both the resectable and unresectable setting .



PMID: 28611337
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 ✓ BRAF mutation is associated with poor clinicopathological outcomes in colorectal cancer : A meta-analysis . GM-ASS-RO
1 BACKGROUND :
2 Oncoprotein genes are over-represented in statically defined , low mutation-frequency fractions of cancer genome atlas ( TCGA ) datasets , consistent with a higher driver mutation density .
3 MATERIALS AND METHODS :
4 We developed a "continuously variable fraction" ( CVF ) approach to defining high and low mutation-frequency groups .
5 RESULTS AND CONCLUSION :
6 Using the CVF approach , an oncoprotein set was shown to be associated with a TCGA , low mutation-frequency group in nine distinct cancer types , versus six , for statically defined sets ; and a tumor-suppressor set was over-represented in the low mutation-frequency group in seven cancer types , notably including BRCA .
7 Μ The CVF approach identified single-mutation driver candidates , such as BRAF V600E in the thyroid cancer dataset .
8 The CVF approach allowed investigation of cytoskeletal protein -related coding regions ( CPCRs ) , leading to the conclusion that mutation of CPCRs occurs at a statistically significant , higher density in low mutation-frequency groups .
9 Supporting online material for this article can be found at www .
10 universityseminarassociates .
11 com/Supporting online material for scholarly pubs .



PMID: 28611205
(None)  
Terms: PDX, xenograft, mouse
Sent# Symbols Sentence Mnemonics
0 Mouse PDX Trial Suggests Synergy of concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS mutations .
1   Purpose : It is to evaluate the anti-tumor efficacy of cetuximab in combination with LSN3074753 , an analogue of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer ( CRC ) patient derived xenograft ( PDX ) models.
Experimental Design : 79 well characterized CRC PDX models were employed to conduct a single mouse per treatment group ( n = 1 ) trial.
Results : Consistent with clinical results , cetuximab was efficacious in wild type KRAS and BRAF PDX models , with an overall response rate ( ORR ) of 6.3% and disease control rate ( DCR ) of 20.3% .
2 Μ LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations .
3 However , the combination treatment displayed the enhanced antitumor activity with DCR of 35.4% .
4 Μ Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity , and were significantly associated with synergistic effect with a p value of 0.01 compared with cetuximab alone .
5 In 12 models with BRAF mutations , the combination therapy resulted in a DCR of 41.7% , whereas either monotherapy had a DCR of 8.3% .
6 Among 44 KRAS mutation models , cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4% , respectively , and the combination therapy increased DCR to 34.1% .
7 Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.
Conclusions : MAPK and EGFR pathway activations are two major molecular hallmarks of CRC .
8 This mouse PDX trial recapitulated clinical results of cetuximab .
9 Concurrent EGFR and RAF inhibition demonstrated synergistic anti-tumor activity for CRC PDX models with a KRAS or BRAF mutation .



PMID: 28608265
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel .
1 We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer ( CRC ) in Israel .
2 Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study .
3 The primary screening method was immunohistochemical staining for mismatch-repair proteins ( MLH1 , MSH2 , MSH6 , and PMS2 ) .
4 For subjects with abnormal immunohistochemical staining , we performed microsatellite instability ( MSI ) analyses , and for tumors with a loss of MLH1 expression we also performed BRAF testing .
5 In MSI high cases we searched further for germline mutations .
6 Μ Of the 24 patients enrolled , four subjects ( 167% ) had MSI high tumors : one subject was found to harbor a biallelic PMS2 mutation , one subject had Lynch syndrome ( LS ) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type/normal MLH1 sequence .
7 Ten patients ( 417% ) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC .
8 Μ In conclusion , in this cohort of 24 consecutive Arab Bedouins with CRC , one patient was found to harbor a constitutional mismatch repair deficiency , one patient had LS with MSH6 mutation , and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype .



PMID: 28600626
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mucosa-associated microbiota signature in colorectal cancer .
1 Significant Prognostic Features and Patterns of Somatic TP53 Mutations in Human Cancers .



PMID: 28600477
(Cell)  
Terms: in vivo, in vitro, mice, transgenic mice
Sent# Symbols Sentence Mnemonics
0 Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies : a major breakthrough for K-RAS mutated colorectal cancer treatment .
1 PURPOSE :
2

Patients with metastatic colorectal cancer ( CRC ) suffer from disease relapse mainly due to cancer stem cells ( CSC ) .

3 Interestingly , they have an increased level of blood progastrin , a tumor-promoting peptide essential for the self-renewal of colon CSCs , which is also a direct b-catenin/Tcf4 target gene .
4 In this study we aimed to develop a novel targeted therapy to neutralize secreted progastrin in order to inhibit Wnt signaling , CSCs and reduce relapses.

Experimental Design :

Antibodies ( monoclonal and humanized ) directed against progastrin were produced and selected for target specificity and affinity .

5 After validation of their effectiveness on survival of CRC cell lines harboring B-RAF or K-RAS mutations , their efficacy was assessed in vitro and in vivo , alone or concomitantly with chemotherapy , on CSCs self-renewal capacity , tumor recurrence and Wnt signaling.

Results :

We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo , either alone or in combination with chemotherapy .

6 Furthermore , migration and invasion of CRC cells are diminished ; chemosensitivity is prolonged in SW620 and HT29 cells and post-treatment relapse is significantly delayed in T84 cells , xenografted nude mice .
7   Finally , we show that the Wnt signaling activity in vitro is decreased , and , in transgenic mice developing Wnt-driven intestinal neoplasia , the tumor burden is alleviated , with an amplification of cell differentiation in the remaining tumors.

Conclusions :

All together , these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS mutated colorectal patients , for which there is a crucial unmet medical need .



PMID: 28599473
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer in cases of multiple primary cancers : Clinical features of 59 cases and point mutation analyses .
1 The present study aimed to investigate the occurrence and clinical features of cases of multiple primary cancers including colorectal cancer ( MPCC ) .
2 The medical records of patients with colorectal cancer ( CRC ) who underwent surgery at the Third Xiangya Hospital of Central South University ( Changsha , China ) between August 2007 and August 2014 were retrospectively analyzed .
3 Μ Patients with MPCCs were identified and mutation analyses were performed on colon specimens .
4 The results revealed that among 1,311 patients with CRC , 59 had MPCC ( including 35 cases of >/ = 1 CRC with >/ = 1 other cancer type , and 24 cases with multiple CRCs and no other primary cancers ) .
5 Foci occurred on the right side of the colon ( n = 32 ) , in the rectum ( n = 28 ) , and on the left side of the colon ( n = 24 ) .
6 MPCCs were synchronous in 24 patients , metachronous in 32 patients , and both in 3 patients .
7 Age of onset and presence of polyps were identified as significantly different between MPCC and CRC overall ( P<005 ) ; however , sex or adenoma incidence were not observed to differ significantly between groups .
8 Mutation incidence rates in 26 specimens were 11.54% for KRAS proto-oncogene GTPase ( KRAS ) G13D , 3.85% for KRAS Q61R and 3.85% B-Raf proto - oncogene serine/threonine kinase V600E .
9 Mutations of exon 21 of the epithelial growth factor receptor gene , including L858R and L861Q , and of KRAS G12V were not detected .
10 In conclusion , the likelihood of occurrence of MPCC is closely associated with the age of onset and the presence of polyps .
11 Routine examination of multiple systems is necessary for patients with CRC to avoid missed diagnosis and misdiagnosis .
12 Further study is required to demonstrate the molecular mechanism of CRC in cases of multiple primary cancers .



PMID: 28598398
(Patient)  
Terms: prospective, phase III
Sent# Symbols Sentence Mnemonics
0 Right - vs . Left-Sided Metastatic Colorectal Cancer : Differences in Tumor Biology and Bevacizumab Efficacy .
1 There is evidence of a different response to treatment with regard to the primary tumor localization ( right-sided or left-sided ) in patients with metastatic colorectal cancer ( mCRC ) .
2 We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter "Italian Trial in Advanced Colorectal Cancer ( ITACa ) " , randomized to receive first - line chemotherapy ( CT ) or CT plus bevacizumab ( CT + B ) .
3 RAS and BRAF mutations ; baseline expression levels of circulating vascular endothelial growth factor ( VEGF ) , endothelial nitric oxide synthase ( eNOS ) , cyclooxygenase-2 ( COX2 ) , ephrin type-B receptor 4 ( EPHB4 ) , hypoxia-inducible factor 1-alpha ( HIF-1alpha ) , lactate dehydrogenase ( LDH ) , and high-sensitivity C reactive protein ( hs-CRP ) ; and inflammatory indexes such as the neutrophil-to-lymphocyte ratio , platelet-lymphocyte rate and systemic immune-inflammation index were evaluated .
4 Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group ( 126 vs. 90 months , respectively , p = 0017 ) .
5 Baseline inflammatory indexes were significantly higher in left-sided tumors , whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors .
6 Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC , which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors .



PMID: 28595137
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Health-related quality of life in patients with metastatic colorectal cancer , association with systemic inflammatory response and RAS and BRAF mutation status .
1 BACKGROUND :
2 The aim of this study was to evaluate the effect of cetuximab on health-related quality of life ( HRQoL ) in the NORDIC-VII trial on metastatic colorectal cancer ( mCRC ) , and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers .
3 PATIENT AND METHODS :
4 HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 ( QLQ-C30 ) at baseline , after every fourth cycle of chemotherapy , and at the end of treatment .
5 HRQoL during 12 cycles of chemotherapy was evaluated over time , compared between treatment arms , and assessed for association with tumour mutation status and inflammatory markers .
6 RESULTS :
7   QLQ-C30 was completed by 512 patients ( 90% ) before start of treatment .
8 HRQoL variables were well balanced across treatment arms at baseline , and no statistically significant differences during treatment were seen .
9 Patients with BRAF-mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS-mutated or RAS/BRAF wild-type tumours .
10 Patients with high serum interleukin-6 ( IL-6 ) or C-reactive protein ( CRP ) had markedly impaired HRQoL compared to patients with normal levels .
11 There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4 .
12 CONCLUSION :
13   The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients .
14 Patients with BRAF-mutated tumours have both a worse prognosis and a poor HRQoL .
15   The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment .



PMID: 28583095
(Patient)  
Terms: retrospective, prospective
Sent# Symbols Sentence Mnemonics
0 The prognostic significance of KRAS and BRAF mutation status in Korean colorectal cancer patients .
1 BACKGROUND :
2 BRAF and KRAS mutations are well-established biomarkers in anti-EGFR therapy .
3 However , the prognostic significance of these mutations is still being examined .
4 We determined the prognostic value of BRAF and KRAS mutations in Korean colorectal cancer ( CRC ) patients .
5 METHODS :
6 From July 2010 to September 2013 , 1096 patients who underwent surgery for CRC at Seoul St .
7 Mary's Hospital were included in the analysis .
8 Resected specimens were examined for BRAF , KRAS , and microsatellite instability ( MSI ) status .
9 All data were reviewed retrospectively .
10 RESULTS :
11 Among 1096 patients , 401 ( 367% ) had KRAS mutations and 44 ( 40% ) had BRAF mutations .
12 Of 83 patients , 77 ( 928% ) had microsatellite stable ( MSS ) or MSI low ( MSI-L ) status while 6 ( 72% ) patients had MSI high ( MSI-H ) status .
13 ✓ Μ Patients with BRAF mutation demonstrated a worse disease-free survival ( DFS , HR 1990 , CI 1080-3660 , P = 002 ) and overall survival ( OS , HR 3470 , CI 1900-6330 , P <00001 ) . GM-ASS-RO
14 Regarding KRAS status , no significant difference was noted in DFS ( P = 00548 ) or OS ( P = 0107 ) .
15 Comparing the MSS/MSI-L and MSI-H groups there were no significant differences in either DFS ( P = 0294 ) or OS ( P = 0557 ) .
16 CONCLUSIONS :
17 BRAF mutation , rather than KRAS , was a significant prognostic factor in Korean CRC patients at both early and advanced stages .
18 The subgroup analysis for MSI did not show significant differences in clinical outcome .
19 BRAF should be included in future larger prospective biomarker studies on CRC .



PMID: 28580315
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Coexistence of KRAS and BRAF Mutations in Colorectal Cancer : A Case Report Supporting The Concept of Tumoral Heterogeneity .
1 The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor ( EGFR )- targeted therapy resistance of colorectal carcinomas .
2 The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers ( CRCs ) with the prevalence of less than 0.001% of the cases .
3 In patients with KRAS-mutant tumors , BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor .
4 The current report demonstrates a case with advanced adenocarcinoma of the colon showing the coexistence of KRAS and BRAF mutations and may have profound clinical implications for disease progression and therapeutic responses .



PMID: 28579802
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and KRAS mutation .
1 The KRAS gene mutation is involved in several types of tumors .
2 However , the potential role of the KRAS mutation in human primary and paired metastatic colorectal cancer ( CRC ) among different nationalities is poorly understood .
3 In the present study , we assessed the relationship between KRAS mutation status and overall survival ( OS ) and disease-free survival ( DFS ) in 230 patients with primary and paired metastatic CRC .
4 The KRAS mutation rate in primary CRC tissue was 43.0% ( 99/230 ) , which was higher than in paired metastatic CRC , which was 31.9% ( 23/72 ; P<0001 ) .
5 Clinicopathologically , the KRAS gene mutation rate was higher in tumors that had infiltrated more deeply ( T3 , T4 ) and in lymph node ( LN ) metastases (N1/N2) ( P = 0029 and P = 0010 , respectively ) .
6 The KRAS gene status did not differ between the Han and Uyghur nationalities in both primary and metastatic CRC .
7 In 72 paired cases , the KRAS mutation rate in primary CRC was significantly higher than in metastatic CRC ( P<0001 ) and in metastatic CRC that had infiltrated more deeply ( T3 , T4 ) ( P = 0034 ) .
8 In the metastatic cases , the KRAS gene mutation rate was higher in patients aged over 65 years ( P = 0035 ) .
9 ✓ Specifically , KRAS mutation was correlated with a poorer OS and DFS ( P = 0004 and P = 0029 , respectively ) . GM-ASS-RO
10 ✓ In our study , 35 patients with wild-type KRAS who received cetuximab targeted therapy had a better DFS than patients with mutant KRAS ( P = 0029 ) . GM-ASS-RO
11 The results of the current study demonstrate that the KRAS status is significantly associated with infiltrating LN metastases and the TNM stage in primary CRC .
12 ✓ In addition , the results show that the KRAS mutation is significantly more common in primary tumors than in paired metastatic CRC , and the KRAS mutation is correlated with a shorter OS and DFS , as patients with wild-type KRAS who received cetuximab experienced a longer DFS . GM-ASS-RO



PMID: 28576867
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ALK-rearranged pulmonary adenocarcinoma in Thai Patients : From diagnosis to treatment efficacy .
1 CXCR3 , a G - protein coupled chemokine receptor , has been found to be overexpressed in many tumors and act as an independent prognostic marker .
2 However , it is still unclear whether CXCR3 is involved in gastric cancer progression .
3 In this study , we found that CXCR3 was markedly expressed in gastric cancer cells and tissues .
4 ✓ High CXCR3 expression correlated with advanced tumor stage , vascular invasion , lymph node metastasis and poor survival of gastric cancer patients . GE-ASS-RO
5 Activation of CXCR3 by one of its ligands CXCL10 promoted the invasion and migration of gastric cancer BGC-823 and MGC-803 cells , and increased the secretion and activities of MMP-2 and MMP-9 .
6 However , the effects of CXCL10 on gastric cancer cells were attenuated by CXCR3 siRNA transfection .
7 Furthermore , overexpression of CXCR3 enhanced CXCL10 -mediated cell invasion and migration of gastric cancer MKN28 cells .
8 In addition , CXCR3 time-dependently induced activation of AKT .
9 PI3K/AKT pathway was required for CXCR3 -mediated gastric cancer cell invasion , migration and MMP-2/9 production .
10 Together , our findings suggest that CXCL10/CXCR3 axis promotes gastric cancer cell invasion and migration by upregulating MMP-2 and MMP-9 production via PI3K/AKT pathway .
11   Thus , CXCR3 could be a potential target for the gastric cancer treatment .



PMID: 28576857
(None)  
Terms: meta-analyses, rat
Sent# Symbols Sentence Mnemonics
0 ✓ BRAF Mutations as Predictive Biomarker for Response to Anti-EGFR Monoclonal Antibodies . GM-MRK-RO
1 Recently , the American Society of Clinical Oncology ( ASCO ) and the European Society for Medical Oncology ( ESMO ) recommended that patients with epidermal growth factor receptor ( EGFR ) -expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies ( mAbs ) cetuximab and panitumumab only in absence of Rat-Sarcoma ( RAS ) mutations .
2 Μ In addition to the previously established biomarker rat Kirsten sarcoma viral oncogene homolog ( KRAS ) exon 2 , cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog ( NRAS ) exons 2 , 3 , and 4 mutations are found unlikely to benefit from anti-EGFR treatment .
3 In line with the resistance of RAS mutated ( mt ) tumors , treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway .
4 However , BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient .
5 This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs .
6 Μ Based on a review of literature , eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs .
7 After discussing the quality and quantity of available evidence , we conclude that evidence is stronger than suggested by ESMO and ASCO .
8 Additionally , we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker .
9 We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response .
10 IMPLICATIONS FOR PRACTICE :
11 In metastatic colorectal cancer ( mCRC ) , therapy with anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations .
12 Cumulative evidence shows that patients with BRAF mutations , who comprise 10% of the mCRC population , do not benefit from anti-EGFR - antibody treatment .
13 Although guidelines state that evidence for BRAF as a predictive marker is insufficient , we highlight that the quality and quantity of evidence is higher than suggested .
14   We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected .



PMID: 28576843
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting BRAF-Mutant Colorectal Cancer : Progress in Combination Strategies .
1 INTRODUCTION :
2 Nodular thyroid disease is one of the most frequently diagnosed pathologies of the adult population in iodine-deficient regions .
3 Approximately 30% of thyroid aspirates are classified as nondiagnostic/unsatisfactory or indeterminate .
4 However , patients with indeterminate cytology still undergo surgery .
5 The object of this study was to determine the diagnostic value of re-examining the BRAF V600E mutation in papillary thyroid carcinoma patients .
6 MATERIAL AND METHODS :
7 All patients underwent ultrasound guided fine-needle aspiration of a thyroid nodule .
8 They were assigned to one of the four groups ( indeterminate or positive for malignant cells ) of the Bethesda System for Reporting Thyroid Cytopathology .
9 Genetic investigation of the BRAF V600E mutation was performed for all of the fine-needle aspiration cytology specimens .
10 All of the patients underwent surgery .
11 Subsequently , histological investigation of the removed tissues was performed .
12 Additional analysis of the BRAF V600E mutation from the histology specimen was then performed for the initially BRAF-negative cases .
13 RESULTS :
14 Two hundred and fourteen patients were involved in the study .
15 One hundred and six ( 4953% ) patients were diagnosed with thyroid cancer .
16 Of these 106 patients , 95 ( 8962% ) patients were diagnosed with papillary thyroid cancer .
17 The BRAF V600E mutation was positive in 62 ( 6526% ) and negative in 33 ( 3474% ) histologically confirmed papillary thyroid cancer cases .
18 After the genetic investigation , a total of 74 ( 7789% ) papillary thyroid cancer cases were positive for the BRAF V600E mutation and 21 ( 2211% ) were negative .
19 CONCLUSIONS :
20 ✓ Repeated examination of the BRAF V600E mutation status in the fine-needle aspiration may potentially increase the sensitivity of papillary thyroid cancer diagnostics .



PMID: 28576751
(Cell)  
Terms: clinical trial, in vivo
Sent# Symbols Sentence Mnemonics
0 Targeting of super - enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway .
1 Bromodomain and extra-terminal ( BET ) inhibitors suppress super - enhancers and show cytotoxicity against multiple types of tumors .
2   However , early clinical trials with BET inhibitors showed severe hematopoietic toxicities , highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential .
3 Here , we identified colon cancer-specific super - enhancers that were associated with multiple oncogenic pathways , including the mitogen -activated protein kinase ( MAPK ) signaling pathway .
4 Among the 14 colon cancer cell lines tested , their sensitivity to JQ1 , a BET inhibitor , was not correlated with c-MYC expression .
5 Three of four BRAFV600E-mutant cell lines were sensitive .
6 Addition of JQ1 to vemurafenib , a specific mutant BRAF inhibitor , suppressed cell growth by arresting cell cycle progression and inducing apoptosis in the BRAFV600E-mutant cells .
7 Mechanistically , the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1 .
8 Further , the addition of JQ1 to a BRAF inhibitor enhanced the in vivo anti-tumor effect .
9   Thus , this study indicates the therapeutic potential of targeting of super - enhancers and mutant BRAF in patients with BRAFV600E-mutant colorectal cancer .



PMID: 28573495
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers .
1 The WNT signaling pathway is commonly altered during colorectal cancer development .
2 The E3 ubiquitin ligase , RNF43 , negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor .
3 RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable ( MSI ) colorectal cancers .
4 This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome .
5 Μ The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes ( MLH1 , MSH6 , MSH2 , PMS2 ) , or ( ii ) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins , was BRAF wild type at V600E , were under 60 years of age at diagnosis , and demonstrated no promoter region methylation for MLH1 in tumor DNA .
6 A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry ( ACCFR ) were sequenced for the most common truncating mutation hotspots ( X117 and X659 ) .
7 Μ RNF43 mutations were found in 9 of 24 ( 375% ) Lynch syndrome colorectal cancers .
8 Μ The majority of mutations were frameshift deletions in the G659 G7 repeat tract ( 29% ) ; 2 cancers ( 2/24 , 8% ) from the one patient harbored frameshift mutations at codon R117 ( C6 repeat tract ) within exon 3 .
9 Μ In the ACCFR validation cohort , RNF43 hotspot mutations were identified in 19/44 ( 432% ) of samples , which was not significantly different to the initial series .
10 The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers .
11 These findings identify further genetic differences between sporadic and hereditary colorectal cancers .
12 Μ This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation , whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation , decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome .



PMID: 28570994
(Patient)  
Terms: Retrospective
Sent# Symbols Sentence Mnemonics
0 CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma .
1 AIM :
2 The aim is to assess the BRAF gene mutations in patients with posterior uveal melanoma .
3 MATERIAL AND METHODS :
4 Retrospective analysis of the group of patients with malignant melanoma of the uvea , who were indicated to enucleation between 1.1 2015 to 1.3.2016 .
5 Μ We analyzed stage of uveal melanoma , volume , cell type and BRAF gene mutations .
6 RESULTS :
7 In clinical study of 20 patients after enucleation due to uveal melanoma at the Department of Ophthalmology in Bratislava , patient age was ranged from 22 to 89 years with a median of 62 years .
8   In 14 patients ( 70 % ) enucleation was the primary treatment and in 6 patients ( 30 % ) enucleation was after irradiation ( brachytherapy , Leksell gama knife , linear accelerator ) .
9 In 17 cases ( 85 % ) the mutation of the BRAF gene was negative and in 3 cases the sample was not assessable for the BRAF mutation .
10 CONCLUSION :
11 Μ BRAF gene mutation is confirmed by several studies found in malignant melanoma of the skin .
12 The histopathology findings in our group did not confirmed our theory , that since the uveal melanoma itself has the similar origin as skin melanoma , should also contain a BRAF mutation .
13 ✓ Key words : malignant melanoma of the uvea , mutation of the BRAF gene , chromosomal abnormalities as a prognostic factor . GN-MRK-RO



PMID: 28569041
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer .
1 The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction .
2 Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab .
3 We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer ( mCRC ) patients receiving cetuximab-based chemotherapy .
4 Six single nucleotide polymorphisms ( SNPs ) in TLR7 , TLR9 , IRF5 and IRF7 were tested for the association with RR , PFS , and OS in KRAS-wild type mCRC patients .
5 Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set ( FIRE3-Cet , n = 244 ) or a control set ( FIRE3-Bev , n = 246 ) , respectively .
6 Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set ( JACCRO , n = 76 ) .
7 Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing .
8 ✓ In the discovery cohort , patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants ( median 100 vs. 118 months , HR 139 , p = 0092 ) . GM-ASS-RO, RO-ASS-GM
9 ✓ This preliminary association was confirmed in the validation cohort , and those with the G/G genotype showed a PFS benefit compared with others ( univariate : 9.1 vs. 11.6 months , HR 2.04 , p = 0.005 , multivariate : HR 2.02 , 95% CI : 1.14-3.55 , p = 0.015 ) . GM-ASS-RO, RO-ASS-GM
10 This association was not observed in the control cohort .
11 ✓ Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients . GM-REG-RO



PMID: 28567185
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lung Cancer Onset in Wild Type Mice Following Bone Marrow Reconstitution with kras ( v12 ) Cells .
1 AIM :
2 To identify whether CpG island methylator phenotype ( CIMP ) is predictive of response to neoadjuvant chemoradiotherapy ( NACRT ) and outcomes in rectal cancer .
3 METHODS :
4 Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified .
5 Pre-treatment tumour biopsies were analysed for CIMP status ( high , intermediate or low ) using methylation specific PCR .
6 KRAS and BRAF status were also determined using pyrosequencing analysis .
7 Clinical information was extracted from case records and cancer services databases .
8 Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen .
9 The relationship between these molecular features , response to NACRT and oncological outcomes were analysed .
10 RESULTS :
11 There were 160 patients analysed with a median follow-up time of 46.4 mo .
12 Μ Twenty-one ( 13% ) patients demonstrated high levels of CIMP methylation ( CIMP-H ) and this was significantly associated with increased risk of extramural vascular invasion ( EMVI ) compared with CIMP-L [8/21 ( 38% ) versus 15/99 ( 15% ) , P = 0.028] .
13 CIMP status was not related to tumour regression after radiotherapy or survival , however EMVI was significantly associated with adverse survival ( P <0001 ) .
14 Intermediate CIMP status was significantly associated with KRAS mutation ( P = 001 ) .
15   There were 14 ( 9% ) patients with a pathological complete response ( pCR ) compared to 116 ( 73% ) patients having no or minimal regression after neoadjuvant chemoradiotherapy .
16 Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression , although this was not statistically significant ( P = 026 ) .
17 Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed , EMVI positivity was associated with poor overall survival , advanced "T" stage and CIMP-H but not nodal status , age , sex , KRAS mutation status and presence of local or systemic recurrence .
18 CONCLUSION :
19 We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination .



PMID: 28561063
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Selective analysis of cancer - cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer .
1 Stromal content heavily impacts the transcriptional classification of colorectal cancer ( CRC ) , with clinical and biological implications .
2 Lineage -dependent stromal transcriptional components could therefore dominate over more subtle expression traits inherent to cancer cells .
3 Since in patient-derived xenografts ( PDXs ) stromal cells of the human tumour are substituted by murine counterparts , here we deploy human-specific expression profiling of CRC PDXs to assess cancer - cell intrinsic transcriptional features .
4 Through this approach , we identify five CRC intrinsic subtypes ( CRIS ) endowed with distinctive molecular , functional and phenotypic peculiarities : (i) CRIS-A : mucinous , glycolytic , enriched for microsatellite instability or KRAS mutations ; ( ii ) CRIS-B : TGF-beta pathway activity , epithelial-mesenchymal transition , poor prognosis ; ( iii ) CRIS-C : elevated EGFR signalling , sensitivity to EGFR inhibitors ; ( iv ) CRIS-D : WNT activation , IGF2 gene overexpression and amplification ; and (v) CRIS-E : Paneth cell -like phenotype , TP53 mutations .
5 CRIS subtypes successfully categorize independent sets of primary and metastatic CRCs , with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances .



PMID: 28560458
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells .
1 Patients with wild-type KRAS metastatic colorectal cancer ( mCRC ) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies .
2 Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR -directed antibody cetuximab .
3 Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab , we uncovered an unexpected mechanism of resistance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis .
4 Parental NRAS+/+ cells , but not NRASQ61K/+ cells , activated the ephrin receptor ephA1 in response to cetuximab treatment .
5 Moreover , whereas cetuximab treatment significantly downregulated EPHA2 gene expression in NRAS+/+ cells , EPHA2 expression in NRASQ61K/+ cells was refractory to cetuximab .
6 Remarkably , pharmacologically mimicked ephrin-A1 engagement to ephA2 converted NRAS-mutant into RAS wild-type mCRC cells in terms of cetuximab efficacy .
7 Accordingly , activation of the ephA2 receptor by bioactive recombinant human ephrin-A1/Fc-fusion protein suppressed the cetuximab-unresponsive hyperactivation of MAPK and AKT and fully restored cetuximab activity in NRAS-mutant colorectal cells .
8 Collectively , these findings reveal that the clinical benefit of cetuximab in mCRC might necessarily involve the suppression of the ligandless oncogenic signaling of the ephA2 receptor .
9   Hence , ligand -dependent tumor suppressor signaling using therapeutic ephA2 agonists might offer new therapeutic opportunities to clinically widen the use of cetuximab in NRAS-mutated and/or ephA2 -dependent mCRC tumors .



PMID: 28560069
(Cell)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 The identification and validation of Trichosstatin A as a potential inhibitor of colon tumorigenesis and colon cancer stem-like cells .
1 Colon cancer is one of the most prevalent cancer types in developed countries .
2 Metastasis and drug resistance are two contributing factors to the high mortality rate .
3 Accumulating evidence suggest that cancer stem-like cells ( CSCs ) represents as a major contributor to these malignant features .
4 Here , we identified and isolated colon cancer stem-like cells using side-population ( SP ) method from human colon cancer cell lines .
5 SP colon cells demonstrate cancer stem-like cell properties including enhanced sphere-forming ability and resistance towards fluorouracil ( 5-FU ) .
6 The CSC properties were associated with the increased expression level of major oncogenic and stem cell markers including beta-catenin , NF-kB , Akt/mTOR , KRAS and c-Myc .
7 Μ Trichostatin A ( TSA ) , an antifungal antibiotic also a HDAC inhibitor , was found to function not only to decrease the expression of oncogenic markers but also the colon CSC properties .
8 Importantly , TSA and 5-FU combined treatment synergistically suppressed colon cancer viability .
9 Finally , in vivo results demonstrated that TSA alone and in combination with 5-FU effectively suppressed colon tumorigenesis .
10   Collectively , this study provides preclinical evidence that TSA may function as a potential colon cancer therapeutic agent by targeting CSC and overcoming 5-FU resistance .



PMID: 28559118
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor regression grades , K-RAS mutational profile and c-MET in colorectal liver metastases .
1 INTRODUCTION :
2 Recently TRG , necrosis grade and the rate of viable cancer cells of colorectal liver metastases were correlated with the response to chemotherapy treatments , whereas K-RAS mutations and c-MET over-expression were correlated with the prognosis .
3 METHODS :
4 58 resection specimens were assessed for regression grades .
5 Patients undergone neo-adjuvant treatments were compared to patients who underwent therapy exclusively adjuvantly .
6 We investigated the K-RAS mutational profile , the c-MET over-expression along with patients' survivals curves .
7 RESULTS :
8   Patients undergone neo-adjuvant treatment presented significant higher fibrosis rates and lower rates of viable cells. 36.7% of the patients had a K-RAS mutation and the 26.7% presented c-MET over-expression , but these features did not correlate with patients' clinical/pathological data .
9 Survival analysis documented that K-RAS WT patients presenting c-MET over-expression had worse outcomes .
10 CONCLUSION :
11   Fibrosis and the rate of viable cells significantly correlate with the response to chemotherapy treatments .
12 c-MET is a promising marker in K-RAS WT patients .



PMID: 28551618
(Cell)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines .
1 BACKGROUND :
2 Preclinical evidence demonstrates that mitogen -activated protein kinase kinase ( MEK ) /extracellular signal-regulated kinase ( ERK ) pathway inhibition increases sensitivity to 5-fluorouracil ( 5-FU ) in colorectal cancer ( CRC ) cell lines and xenografts .
3 Here , we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma ( KRAS ) and proto - oncogene B-rapidly accelerated fibrosarcoma ( BRAF ) mutation , that are common in CRC and often lead to resistance to chemotherapy .
4 MATERIALS AND METHODS :
5 Wild-type and mutant KRAS/BRAF human CRC cell lines were treated with escalating doses of 5-FU or trifluridine with MEK162 ( MEK1/2 inhibitor ) for 72 h .
6 Cell viability was assessed by 3 - ( 4, 5-dimethylthiazol-2-yl ) -2, 5-diphenyltetrazolium bromide assay and synergism expressed by the combination index was calculated using CalcuSyn .
7 RESULTS :
8 Evidence of synergistic antitumor activity was observed for the majority of human CRC cell lines treated with MEK162 plus 5-FU ( 4/6 ) or trifluridine ( 7/9 ) .
9 Synergism was greater in KRAS - or BRAF-mutant cell lines compared to wild-type KRAS/BRAF CRC cell lines .
10 CONCLUSION :
11 The combination of MEK inhibition and trifluridine is worthwhile advancing in clinical development , particularly for treatment-refractory KRAS - or BRAF-mutated metastatic CRC .



PMID: 28551386
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Influence of mucinous and necrotic tissue in colorectal cancer samples on KRAS mutation analysis .
1 Evaluation of the RAS mutation status is necessary for patients with advanced colorectal cancer to predict the response to anti-EGFR therapy .
2 In routine diagnostics , FFPE tissue samples are tested by sequencing ( amplicon-based NGS and Sanger ) to obtain the RAS status of the patient .
3 Samples that are collected after chemotherapy occasionally contain necrotic tissue .
4 Furthermore , colorectal cancer tissue sometimes has mucinous components .
5 This may pose a challenge to molecular analysis because mucinous tumor samples often contain only few tumor cells compared to solid tumor samples .
6 Μ Therefore , the aim of this study was to explore if mucin or necrosis affect mutation analysis and if mucinous tumor samples contain enough tumor cells for reliable mutation detection .
7 To this end , we analyzed KRAS status in 10 samples showing mucin production and 10 samples with necrosis .
8 In all 20 samples the tissue areas with the highest amount of mucin or necrosis were used for re-evaluation .
9 These results show no differences with those obtained during routine diagnostics , where analysis of mucinous or necrotic areas was tried to avoid .
10 Μ Our study thus shows that mucin and necrosis have no influence on KRAS mutation analysis .
11 Μ Furthermore we were able to demonstrate that mucinous adenocarcinoma contains enough tumor cells for a valid mutation analysis .
12 In addition , we also observed only minor differences in KRAS status results when comparing Sanger sequencing with NGS .
13 Μ Both methods detected the KRAS mutation in 19 of 20 tested samples , even for mutated samples with low allele -frequencies .



PMID: 28551381
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer .
1 8-Oxoguanine , a common mutagenic DNA lesion , generates G : C>T : A transversions via mispairing with adenine during DNA replication .
2 When operating normally , the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine .
3 Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer ( CRC ) in MUTYH-Associated Polyposis (MAP) syndrome .
4 Here , we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours .
5 The excess G : C>T : A transversion mutations in MAP CRCs exhibits a novel mutational signature , termed Signature 36 , with a strong sequence dependence .
6 The MUTYH mutational signature reflecting persistent 8-oxoG : A mismatches occurs frequently in the APC , KRAS , PIK3CA , FAT4 , TP53 , FAT1 , AMER1 , KDM6A , SMAD4 and SMAD2 genes that are associated with CRC .
7 The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs .



PMID: 28548125
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Next-generation sequencing-based molecular characterization of primary urinary bladder adenocarcinoma .
1 Primary bladder adenocarcinoma is a rare and aggressive tumor with poor clinical outcomes and no standard of care therapy .
2 Molecular biology of this tumor is unknown due to the lack of comprehensive molecular profiling studies .
3 Μ The study aimed to identify genomic alterations of clinical and therapeutic significance using next-generation sequencing and compare genomic profile of primary bladder adenocarcinoma with that of high-grade urothelial carcinoma and colorectal adenocarcinoma .
4 A cohort of 15 well-characterized primary bladder adenocarcinoma was subjected to targeted next-generation sequencing for the identification of mutations and copy-number changes in 51 cancer-related genes .
5 Genomic profiles of 25 HGUCs and 25 colorectal adenocarcinomas using next-generation sequencing of 50 genes were compared with primary bladder adenocarcinoma .
6 Genomic profiles were visualized using JavaScript library D3 .
7 js .
8 A striking finding was the distinct lack of genomic alterations across the 51 genes assessed in mucinous subtype of primary bladder adenocarcinoma .
9 Μ Eleven of 15 primary bladder adenocarcinoma harbored atleast one genomic alteration in TP53 , KRAS , PIK3CA , CTNNB1 , APC , TERT , FBXW7 , IDH2 and RB1 , many of which are novel findings and of potential therapeutic significance .
10 CTNNB1 and APC mutations were restricted to enteric subtype only .
11 Μ While genomic alterations of primary bladder adenocarcinoma showed substantial overlap with colorectal adenocarcinoma , FGFR3 and HRAS mutations and APC , CTNNB1 and IDH2 alterations were mutually exclusive between primary bladder adenocarcinoma and high-grade urothelial carcinoma .
12 These alterations affecting the MAP kinase , PI3K/Akt , Wnt , IDH ( metabolic ) and Tp53/Rb1 signaling pathways may provide the opportunity for defining targeted therapeutic approaches .
13 Modern Pathology advance online publication , 26 May 2017 ; doi : 10.1038/modpathol.2017.33 .



PMID: 28548123
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype .
1 We have previously shown that commonly expressed miRNAs influenced tumor molecular phenotype in colorectal cancer .
2 Μ We hypothesize that infrequently expressed miRNAs , when showing higher levels of expression , help to define tumor molecular phenotype .
3 In this study , we examine 304 miRNAs expressed in atleast 30 individuals , but in <50% of the population and with a mean level of expression above 1.0 relative florescent unit .
4 We examine associations in 1893 individuals who have the tumor molecular phenotype data as well as miRNA expression levels for both carcinoma and normal colorectal tissue .
5 We compare miRNAs uniquely associated with tumor molecular phenotype to the RNAseq data to identify genes associated with these miRNAs .
6 Μ This information is used to further identify unique pathways associated with tumor molecular phenotypes of TP53-mutated , KRAS-mutated , CpG island methylator phenotype and microsatellite instability tumors .
7 Thirty-seven miRNAs were uniquely associated with TP53-mutated tumors ; 30 of these miRNAs had higher level of expression in TP53-mutated tumors , while seven had lower levels of expression .
8 Of the 34 miRNAs associated with CpG island methylator phenotype-high tumors , 16 were more likely to have a CpG island methylator phenotype-high tumor and 19 were less likely to be CpG island methylator phenotype-high .
9 For microsatellite instability , 13 of the 22 infrequently expressed miRNAs were significantly less likely to be expressed in microsatellite unstable tumors .
10 KRAS-mutated tumors were not associated with any miRNAs after adjustment for multiple comparisons .
11 Of the dysregulated miRNAs , 17 were more likely to be TP53-mutated tumors while simultaneously being less likely to be CpG island methylator phenotype-high and/or microsatellite instability tumors .
12 Genes regulated by these miRNAs were involved in numerous functions and pathways that influence cancer risk and progression .
13 In summary , some infrequently expressed miRNAs , when expressed at higher levels , appear to have significant biological meaning in terms of tumor molecular phenotype and gene expression profiles .
14 Modern Pathology advance online publication , 26 May 2017 ; doi : 10.1038/modpathol.2017.38 .



PMID: 28544821
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Predictive model for high-frequency microsatellite instability in colorectal cancer patients over 50 years of age .
1 Microsatellite instability ( MSI ) is an important biomarker for screening for Lynch syndrome , and also of response to immune checkpoint inhibitors .
2 The aim of this study is to create a predictive model to determine which elderly patients with colorectal cancer ( CRC ) should undergo MSI and/or immunohistochemistry testing on the basis of clinicopathological data .
3 Μ We analyzed a test cohort of CRC patients aged >/ = 50 years ( n = 2219 ) by multivariate logistic regression analyses to identify predictors of high-frequency MSI ( MSI-H ) .
4 The created prediction model was validated in an external cohort ( n = 992 ) .
5 The frequency of MSI-H was 5.5% among CRC patients aged >/= 50 years .
6 The following five predictors of MSI-H were identified in the test cohort : female ( 1 point ) , mucinous component ( 2 points ) , tumor size >/= 60 mm ( 2 points ) , location in proximal colon ( 3 points ) , and BRAF mutation ( 6 points ) .
7 The area under curve ( AUC ) in the receiver-operating characteristic ( ROC ) analysis of this prediction model was 0.832 ( 95% confidence interval : 0.790-0.874 ) .
8 The sensitivity and specificity were 74.4% and 77.7% , respectively , for a cut-off score of 4 points .
9 The receiver-operating characteristic curve of the validation cohort also showed an AUC of 0.856 ( 95% CI : 0.806-0.905 ) .
10   This prediction model is useful to select elderly CRC patients who should undergo MSI testing , and who may benefit from treatment with 5-FU-based adjuvant chemotherapy and cancer immunotherapy .



PMID: 28542846
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers .
1 The prognostic value of CpG island methylator phenotype ( CIMP ) in colorectal cancer remains unsettled .
2 We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series .
3 CIMP status was determined by analyzing the 5-markers CAGNA1G , IGF2 , NEUROG1 , RUNX3 and SOCS1 by quantitative methylation specific PCR ( qMSP ) .
4 The effect of CIMP on time to recurrence ( TTR ) and overall survival ( OS ) were determined by uni - and multivariate analyses .
5 Μ Subgroup analyses were conducted according to MSI and BRAF mutation status , disease stage , and also age at time of diagnosis ( <60 , 60-74 , >/ = 75 years ) .
6 Μ Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors ( multivariate hazard ratio [95% CI] 1.86 [131-263] and 1.89 [134-265] , respectively ) .
7 In stratified analyses , CIMP tumors showed significantly worse outcome among patients with microsatellite stable ( MSS , P <0001 ) , and MSS BRAF mutated tumors ( P <0001 ) , a finding that persisted in patients with stage II , III or IV disease , and that remained significant in multivariate analysis ( P <001 ) .
8 Consistent results were found for all three age groups .
9 To conclude , CIMP is significantly associated with inferior outcome for colorectal cancer patients , and can stratify the poor prognostic patients with MSS BRAF mutated tumors .



PMID: 28540987
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lack of Aberrant Methylation in an Adjacent Area of Left-Sided Colorectal Cancer .
1 PURPOSE :
2 The molecular nature and the rate-limiting step of epigenetic field defects in the evolution of left-sided colorectal cancer ( LCA ) remain uncertain .
3 MATERIALS AND METHODS :
4 The methylation status of 27 candidate field defect markers , six classic CpG island methylator phenotype ( CIMP ) markers , and LINE-1 were determined in LCA and adjacent normal mucosas ( ADJs ) from 33 LCA patients and in left normal colorectal mucosa ( LNM ) from 33 age - and sex-matched controls .
5 Μ Hotspot mutation analyses in KRAS codons 12 and 13 and BRAF V600E were performed by genomic PCR and pyrosequencing using DNA extracted from endoscopically biopsied tissues .
6 RESULTS :
7 Among the 27 candidate genes tested , we confirmed 15 differentially methylated genes in cancer ( 15 DMGs ; ER , SFRP1 , MYOD1 , MGMT , CD8a , SPOCK2 , ABHD9 , BNIP3 , IGFBP3 , WIF1 , MAL , GDNF , ALX4 , DOK5 , and SLC16A12 ) in comparison to ADJ samples .
8 We further compared the methylation status of 15 DMGs of ADJs to LNM and found only methylation levels of SLC16A12 in ADJs of LCA patients to be significantly higher than that in LNM ( 173% vs. 115% , p = 0002 ) .
9 Μ Based on the CIMP , no significant differences in methylation levels of the 15 DMGs were found between ADJs in CIMP positive LCA cases and those without CIMP .
10 Μ In mutation analyses , no mutation was found in ADJs , while significant KRAS mutations ( 6/33 , 18% ) were noted in LCA samples .
11 CONCLUSION :
12 Epigenetic field defect marked by aberrant methylation is uncommon in normal-appearing ADJs of LCA , indicating the critical rate-limiting change of methylation is likely to occur with morphological alterations in the evolution of LCA .



PMID: 28536339
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case Report on a Successful Resection after FOLFIRI plus Cetuximab Therapy for Unresectable Colorectal Cancer with Multiple Liver Metastases ] .
1 The patient was a 66-year-old woman with a history of right breast cancer 20 years prior .
2 Her chief complaint was hematochezia , and she was diagnosed as having rectal cancer .
3 She underwent laparoscopic high anterior resection .
4 We made a diagnosis of moderately differentiated adenocarcinoma , type 2 , 25x20 mm , pMP , pN0 , Stage I , KRAS being wild-type .
5 Multiple liver metastases were detected 6 months after the surgery .
6 Tumor contacted with grison .
7 The tumor was not completely resected as evidenced by the small liver remnant volume .
8   Conversion therapy was administered , and the patient received 6 courses of FOLFIRI plus cetuximab therapy .
9 Alopecia and grade 1 eruption were observed as adverse effects of the chemotherapy .
10 The tumor size was reduced , and we resected the tumor by performing right lobectomy and partial hepatectomy .
11 At 1 year 3 months after surgery , no recurrence was observed .



PMID: 28536078
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes .
1 BRAF , one of the key factors in mitogen -activated protein kinase ( MAPK ) signaling pathway , plays an important role in cell functions including growth and proliferation .
2 Inhibition of BRAF represents a promising antitumor strategy .
3 Dabrafenib , a type I inhibitor of BRAF interrupting RAF/MEK interaction , has been approved by FDA as a single agent or combined with MEK inhibitor trametinib for the treatment of patients with BRAF V600E mutation-positive advanced melanoma .
4 In the present study , we investigated the feasibility of combined treatment with dabrafenib and sorafenib , type I and type II BRAF inhibitor respectively , on colorectal cancer cells with BRAF V600E mutation .
5 Unexpectedly , sorafenib significantly antagonized the inhibition effect of dabrafenib on the proliferation of colorectal cancer HT-29 and Colo205 cells .
6 Μ The antagonism relied on co-existence of wild-type and mutant (V600E) BRAF , for no antagonism was observed in tumor cells expressing homozygous wild-type or mutant (V600E) BRAF .
7 BRAF , but not CRAF , was required for this antagonism .
8 Moreover , we found that sorafenib reversed dabrafenib inhibition of AKT in HT-29 cells , and phosphatidylinositol-3-kinase ( PI3K ) inhibitor GDC0941 significantly restored this antagonistic effect when combined with dabrafenib and sorafenib , indicating that AKT is critically involved in this antagonism .
9 Collectively , we found that significant antagonism was observed when dabrafenib was combined with sorafenib in colorectal cancer cells harboring heterozygous genotype of BRAF and AKT is critically involved in this antagonism .
10 We suggest that BRAF inhibitor dabrafenib and sorafenib should not be combined in clinic .



PMID: 28533659
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF inhibitor treatment of melanoma causing colonic polyps : An alternative hypothesis .
1 Colonic polyps may arise from BRAF inhibitor treatment of melanoma , possibly due to paradoxical activation of the mitogen -activated protein ( MAP )- kinase pathway .
2 Μ In an alternative evidence based scenario , tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment , in the absence of mutations of MAPK genes .
3 A minority of colorectal cancers develop by an alternative "serrated polyp pathway" .
4 This article postulates a novel hypothesis , that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps .
5 Serrated polyps are characterized by a CpG island methylation phenotype , MLH1 silencing and cellular senescence .
6 They also have BRAF mutations .
7 The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF : C-RAF heterodimers .



PMID: 28533490
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Is FOLFOXIRI alone or combined with targeted therapy administered as first - line treatment a reasonable choice for most patients with mCRC? Systematic review and network meta-analysis .
1 Whether the intensive administration of folinic acid , 5-fluorouracil , oxaliplatin and irinotecan ( FOLFOXIRI ) alone or combined with target therapy as first - line treatment could improve the prognosis of metastatic colorectal cancer ( mCRC ) patients is controversial .
2 PubMed , the Cochrane Collaboration Central Register of Controlled Clinical Trials , Cochrane Systematic Reviews , ClinicalTrials .
3 gov , the databases of conferences were queried to identify RCTs evaluating the efficacies and toxicities of intensive therapies used for first - line treatment of mCRC patients .
4 The search included articles dated from the inception of these resources until March 31 , 2017 .
5 We estimated HRs for OS and PFS and RRs for ORR , the R0 resection rate , and toxicities .
6 Ten RCTs comprising 2,506 patients were included in this network meta-analysis .
7   The PFS of patients administered FOLFOXIRI plus target therapy experienced prolonged PFS and OS and improved ORRs compared with FOLFOX/FOLFIRI plus target therapy ( PFS : HR 0.71 , 95% CI 0.59-0.86 ; OS : HR 0.81 , 95% CI 0.69-0.94 ; ORR : RR 1.66 , 95% CI 0.96-2.88 ; R0 resection rate : RR 2.66 , 95% CI 1.86-3.82 ) .
8   There were no significant differences between PFS , OS , ORRs , or R0 resection rates and toxicities of patients administered FOLFOXIRI and FOLFOX/FOLFIRI plus target therapy .
9 Further , FOLFOXIRI plus target therapy did not increase toxicities compared with FOLFOX/FOLFIRI plus target therapy .
10   FOLFOXIRI plus target therapy when administered as first - line treatment of patients with mCRC is the best choice and did not increase toxicities .
11 The patients with RAS/BRAF mutations could benefit from FOLFOXIRI plus Bev .
12 FOLFOXIRI is as effective as FOLFOX/FOLFIRI plus target therapy .



PMID: 28531891
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dual Inhibition of EGFR and VEGF in Heavily Pretreated Patients with Metastatic Colorectal Cancer .
1 OBJECTIVE :
2 The aim of this study was to evaluate the efficacy and safety of combining irinotecan , bevacizumab , and cetuximab/panitumumab as a 4th - line treatment in patients with metastatic colorectal cancer .
3 METHODS :
4 All patients had KRAS wild-type metastatic colorectal cancer and had previously received fluoropyrimidine , oxaliplatin , irinotecan , and cetuximab/panitumumab in a 1st , 2nd , and 3rd line setting .
5 Most patients had previously received bevacizumab as well .
6 All patients had progressed within 3 months after the last given treatment before starting the triple combination therapy every second week .
7 RESULTS :
8 Sixty-three patients were evaluated .
9 The triple combination therapy was well tolerated .
10 The median progression-free survival was 6.1 months , and the median overall survival was 11.9 months .
11 Four patients ( 6% ) obtained a partial response , and 40 ( 63% ) had stable disease .
12 CONCLUSION :
13 The combination of irinotecan , bevacizumab , and cetuximab/panitumumab is safe and shows a toxicity profile corresponding to what is expected from the agents alone .
14 The results indicate that the combination in the 4th line may result in a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer .



PMID: 28531253
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Gender-related prognostic value and genomic pattern of intra-tumor heterogeneity ( ITH ) in colorectal cancer .
1 Intra-tumor heterogeneity ( ITH ) is crucial in tumorigenesis and resistance to target therapy .
2 Here , we used mutant -allele tumor heterogeneity ( MATH ) to measure ITH based on next-generation sequencing data and high MATH was proven as an independent risk prognostic factor in male CRC patients in both a training set of 284 colorectal cancer ( CRC ) patients with from The Cancer Genome Atlas ( TCGA ) and a validating set of 187 CRC patients from International Cancer Genome Consortium ( ICGC ) .
3 Μ Further , the genomic pattern according to MATH demonstrated that mutation rates of TP53 , IRF5 and KRAS were independently associated with MATH , and the latter two were only significant in male patients .
4 As MATH increased , the fraction of somatic copy number alteration ( SCNA ) elevated .
5 Moreover , more SCNA events was independently associated with MATH in male than in female .
6 WNT pathway , TGF-beta pathway and DNA repair deficiency was enriched in high MATH group and the latter two showed up only in male patients .
7 In summary , we reveal the gender-related prognostic value of MATH and relevant genomic pattern in CRC .
8 Potential mechanisms are provided and it remains to be proven whether they are drivers of subclone formation and ITH .
9 Taking MATH into consideration in clinical trial might contribute to better therapeutic strategies in CRC with researches added on in the future .



PMID: 28528980
(Cell)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Phospholipase C delta1 negatively regulates autophagy in colorectal cancer cells .
1 Colorectal cancer ( CRC ) is one of the leading causes of cancer-related death worldwide .
2 Μ rat Kirsten sarcoma viral oncogene homolog ( KRAS ) is frequently mutated in CRC , and KRAS mutations promote cell motility , growth , and survival .
3 Μ We previously revealed that the expression of phospholipase C ( PLC ) delta1 , one of the most basal PLCs , is down-regulated in colon adenocarcinoma , and that the KRAS signaling pathway suppresses PLCdelta1 expression .
4 Μ Although recent studies revealed that KRAS mutations activate autophagy in cancer cells , a relation between PLCdelta1 and autophagy remains unclear .
5 Here , we found that PLCdelta1 overexpression suppresses the formation of autophagosomes , which are key structures of autophagy , whereas endogenous PLCdelta1 knockdown increases autophagosome formation in CRC cells .
6 We also showed that PLCdelta1 overexpression promotes cell death under nutrient deprivation .
7 Furthermore , PLCdelta1 overexpression suppresses the autophagy induced by the anti-cancer drug oxaliplatin and promotes cell death under oxaliplatin treatment .
8   These data suggest that PLCdelta1 negatively regulates autophagy , and PLCdelta1 suppression contributes to the tolerance of CRC cells harboring KRAS mutations to nutrient deprivation and anti-cancer drug treatment .



PMID: 28524162
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia .
1 BACKGROUND :
2 Long-standing ulcerative colitis ( UC ) leading to colorectal cancer ( CRC ) is one of the most serious and life-threatening consequences acknowledged globally .
3 Μ Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma .
4 METHODS :
5 Μ Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma ( UCHR ) was performed to identify somatic driver mutations , which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia .
6 Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma .
7 RESULTS :
8 Μ Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects .
9 In addition to TP53 ( 17% ) and KRAS ( 22% ) mutations , recurrent mutations in APC ( 33% ) , ACVR2A ( 61% ) , ARID1A ( 44% ) , RAF1 ( 39% ) and MTOR ( 61% ) were observed in UCHR subjects .
10 Μ In addition , APC , FGFR3 , FGFR2 and PIK3CA driver mutations were identified in UCHR subjects .
11 Recurrent mutations in ARID1A ( 44% ) , SMARCA4 ( 17% ) , MLL2 ( 44% ) , MLL3 ( 67% ) , SETD2 ( 17% ) and TET2 ( 50% ) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects .
12 CONCLUSIONS :
13 Μ Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia .



PMID: 28524155
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Statin use , candidate mevalonate pathway biomarkers , and colon cancer survival in a population-based cohort study .
1 BACKGROUND :
2 Statin use after colorectal cancer diagnosis may improve survival but evidence from observational studies is conflicting .
3 The anti-cancer effect of statins may be restricted to certain molecular subgroups .
4 In this population-based cohort study , the interaction between p53 and 3-hydroxy-3-methylglutaryl coenzyme-A reductase ( HMGCR ) expression , KRAS mutations , and the association between statin use and colon cancer survival was assessed .
5 METHODS :
6 The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008 .
7 Statin use was determined through clinical note review .
8 Tissue blocks were retrieved to determine immunohistochemical expression of p53 and HMGCR in tissue microarrays and the presence of KRAS mutations in extracted DNA .
9 Cox proportional hazards models were used to calculate hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) for colorectal cancer-specific and overall survival .
10 RESULTS :
11 Statin use was not associated with improved cancer-specific survival in this cohort ( HR = 091 , 95% CI 064-128 ) .
12 Statin use was also not associated with improved survival when the analyses were stratified by tumour p53 ( wild-type HR = 131 , 95% CI 067-256 versus aberrant HR = 080 , 95% CI 052-124 ) , HMGCR ( HMGCR-high HR = 069 , 95% CI 040-118 versus HMGCR-low HR = 110 , 95% CI 066-184 ) , and KRAS ( wild-type HR = 073 , 95% CI 044-119 versus mutant HR = 121 , 95% CI 070-221 ) status .
13 CONCLUSIONS :
14   Statin use was not associated with improved survival either independently or when stratified by potential mevalonate pathway biomarkers in this population-based cohort of colon cancer patients .



PMID: 28523274
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification of "BRAF-Positive" Cases Based on Whole-Slide Image Analysis .
1 A key requirement for precision medicine is the accurate identification of patients that would respond to a specific treatment or those that represent a high-risk group , and a plethora of molecular biomarkers have been proposed for this purpose during the last decade .
2 Their application in clinical settings , however , is not always straightforward due to relatively high costs of some tests , limited availability of the biological material and time , and procedural constraints .
3 Hence , there is an increasing interest in constructing tissue -based surrogate biomarkers that could be applied with minimal overhead directly to histopathology images and which could be used for guiding the selection of eventual further molecular tests .
4 In the context of colorectal cancer , we present a method for constructing a surrogate biomarker that is able to predict with high accuracy whether a sample belongs to the "BRAF-positive" group , a high-risk group comprising V600E BRAF mutants and BRAF-mutant-like tumors .
5 Our model is trained to mimic the predictions of a 64 - gene signature , the current definition of BRAF-positive group , thus effectively identifying histopathology image features that can be linked to a molecular score .
6 Since the only required input is the routine histopathology image , the model can easily be integrated in the diagnostic workflow .



PMID: 28521461
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 KRAS and BRAF mutations in serum exosomes from patients with colorectal cancer in a Chinese population .
1 The efficacy of epidermal growth factor receptor - targeted therapy is significantly associated with rat Kirsten sarcoma viral oncogene homolog ( KRAS ) and B-raf serine/threonine kinase proto - oncogene (BRAF) mutation in patients with colorectal cancer ( CRC ) , for which the standard gene testing is currently performed using tumor tissue DNA .
2 The aim of the present study was to compare the presence of KRAS and BRAF mutations in the serum exosome and primary tumor tissue from patients with CRC .
3 Genomic DNA were extracted from the tumor tissues of 35 patients with histologically-confirmed CRC and exosomal mRNA were obtained from peripheral blood , which were collected from the corresponding patients prior to surgery .
4 Three mutations in the KRAS gene ( codons 12 , 13 and 61 ) and a mutation in the BRAF gene ( codon 600 ) were detected using a polymerase chain reaction-based sequencing method and their presence were compared between tumor tissues and the matched serum exosomes .
5 The KRAS mutation rates in tumor tissues and the matched serum exosomes were 57.6 and 42.4% , respectively , which was not significantly different ( P = 0063 ) .
6 The detection rate of the BRAF mutation was 24.2 and 18.2% in tumor tissues and the matched serum exosomes , respectively , and there was no significant difference ( P = 0500 ) .
7 The patients with CRC that had a KRAS mutation of codon 12 in exon 2 in their tumor tissues and serum exosomes were significantly older compared with those without this mutation ( tumor tissue , P = 0002 ; serum exosome , P = 0022 ) .
8 The sensitivity of KRAS and BRAF mutation detection using exosomal mRNA was 73.7 and 75% , respectively .
9 Μ The specificity of the detected mutations exhibited an efficiency of 100% , and the total consistency rate was 94.9 and 93.9% for KRAS and BRAF mutations , respectively .
10 These results suggested that serum exosomal mRNA may be used as a novel source for the rapid and non-invasive genotyping of patients with CRC .



PMID: 28513830
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) develops through the alteration of several critical pathways .
3 This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC .
4 METHODS :
5 Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC ( WNT , P53 , RTK-RAS , phosphatidylinositol-4,5-bisphosphate 3 - kinase [PI3K] , and transforming growth factor beta [TGF-beta] ) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy .
6 Μ The associations between critical pathway mutations and relapse-free survival ( RFS ) and overall survival were analyzed .
7 The associations were further analyzed according to the tumor location .
8 RESULTS :
9 The mutation rates for the WNT , P53 , RTK-RAS , PI3K , and TGF-beta pathways were 84.5% , 69.0% , 60.7% , 30.0% , and 28.9% , respectively .
10 A mutation in the PI3K pathway was associated with longer RFS ( adjusted hazard ratio [HR] , 0.59 ; 95% confidence interval [CI] , 0.36-0.99 ) , whereas a mutation in the RTK-RAS pathway was associated with shorter RFS ( adjusted HR , 160 ; 95% CI , 101-252 ) .
11 Μ Proximal tumors showed a higher mutation rate than distal tumors , and the mutation profile was different according to the tumor location .
12 The mutation rates of rat Kirsten sarcoma viral oncogene homolog ( KRAS ) , LONGTOKEN , and B-Raf proto - oncogene serine/threonine kinase (BRAF) were higher in proximal tumors , and the mutation rates of adenomatous polyposis coli ( APC ) , tumor protein 53 ( TP53 ) , and neuroblastoma RAS viral oncogene homolog ( NRAS ) were higher in distal tumors .
13 The better RFS with the PI3K pathway mutation was significant only for proximal tumors , and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors .
14 CONCLUSIONS :
15 ✓ A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy , and an RTK-RAS pathway mutation was associated with worse RFS . GM-ASS-RO
16 The significance of the prognostic impact differed according to the tumor location .
17 Cancer 2017 .
18 (c) 2017 American Cancer Society .



PMID: 28512242
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer .
1 Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy .
2 Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized , prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes .
3 Μ Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing , the STAR fusion gene detection pipeline , and GATK RNA-seq variant calling .
4 We considered gene fusions to be pathogenically relevant when recurrent , producing divergent gene expression ( outlier analysis ) , or as functionally important ( e.g. , kinase fusions ) .
5 Overall , 2.5% of all specimens were defined as harboring a relevant gene fusion ( kinase fusions 18% ) .
6 Novel configurations of BRAF , NTRK3 , and RET gene fusions resulting from chromosomal translocations were identified .
7 Μ An R-spondin fusion was found in only one tumor ( 035% ) , much less than an earlier reported frequency of 10% in colorectal cancers .
8 Μ We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS , a constitutively active RAS protein normally expressed only in embryonic stem cells .
9 This USP9X-ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling .
10 Μ Oncogenic fusions were identified only in lymph node-negative tumors that lacked BRAF or KRAS mutations .
11   In summary , we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy .
12 Cancer Res ; 77 ( 14 ) ; 3814-22 .
13 (c) 2017 AACR .



PMID: 28512021
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Statin Use After Diagnosis of Colon Cancer and Patient Survival .
1 BACKGROUND & ; AIMS : Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer .
2 Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein ( BMP ) signaling pathway in colorectal cancer cells .
3 We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer , and whether their effects were associated with changes in KRAS or the BMP signaling pathways .
4 METHODS :
5 Data were derived from the PHARMO database network ( Netherlands ) and linked to patients diagnosed with colon cancer from 2002 through 2007 , listed in the Eindhoven Cancer Registry .
6 We obtained information on causes of death from statistics Netherlands .
7 We constructed a tissue microarray of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008 .
8 Survival was analyzed with statin user status after diagnosis as a time -dependent covariate .
9 Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival .
10 Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4 , BMPR1A , BMPR1B , and BMPR2 proteins .
11 Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A , BMPR1B , or BMPR2 .
12 Μ DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS .
13 The primary outcome measures were overall mortality and cancer-specific mortality .
14 RESULTS :
15 In this cohort , 21.0% of the patients ( 210/999 ) were defined as statin users after diagnosis of colon cancer .
16 Statin use after diagnosis was significantly associated with reduced risk of death from any cause ( adjusted relative risk [RR] , 0.67 ; 95% confidence interval [CI] , 0.51-0.87 ; P = .003 ) and death from cancer ( adjusted RR , 066 ; 95% CI , 049-089 ; P = 007 ) .
17 Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling ( adjusted RR , 039 ; 95% CI , 022-068 ; P = 001 ) , but not for patients whose tumors did not have BMP signaling ( adjusted RR , 081 ; 95% CI , 055-121 ; P = 106 ; P <0001 for the interaction ) .
18 Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations ( adjusted RR , 081 ; 95% CI , 056-118 ; P = 273 ) or whose tumors did have KRAS mutations ( adjusted RR , 059 ; 95% CI 035-103 ; P = 062 ; P = 90 for the interaction ) .
19 CONCLUSIONS :
20 In an analysis of 999 patients with a diagnosis of colon cancer , we associated statin with reduced risk of death from any cause or from cancer .
21 The benefit of statin use is greater for patients whose tumors have intact BMP signaling , independent of KRAS mutation status .
22 Randomized controlled trials are required to confirm these results .



PMID: 28507204
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA .
1 ALK rearrangements have been observed in 0.05%-2.5% of patients with colorectal cancers ( CRCs ) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS , NRAS , or BRAF alterations .
2 Here we present the case of a patient with metastatic CRC who was treatment naive at the time of molecular testing .
3 Μ Initial ALK immunohistochemistry ( IHC ) staining was negative , but parallel genomic profiling of both circulating tumor DNA ( ctDNA ) and tissue using similar hybrid capture-based assays each identified an identical STRN-ALK fusion .
4 Subsequent ALK IHC staining of the same specimens was positive , suggesting that the initial result was a false negative .
5 Μ This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay .
6 KEY POINTS :
7 Current guidelines for colorectal cancer ( CRC ) only recommend genomic assessment of KRAS , NRAS , BRAF , and microsatellite instability ( MSI ) status .
8 ALK rearrangements are rare in CRC , but patients with activating ALK fusions have responded to targeted therapiesALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue , and this methodology may be informative in cases where immunohistochemistry ( IHC ) or other standard testing is negative .



PMID: 28504299
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 What We Know About Stage II and III Colon Cancer : It's Still Not Enough .
1 The introduction of oxaliplatin as adjuvant treatment for stage III colon cancer in 2004 has been the last practice changing progress in adjuvant treatment for patients with early colon cancer .
2 Since then , many prognostic and predictive biomarkers have been studied , but only DNA mismatch repair status has been validated as having an important prognostic value .
3 Accordingly , TNM and clinical-pathological patterns , such as pT4 lesions and lymph node sampling <12 nodes , are the main factors that guide physicians' choice regarding adjuvant treatment .
4 More recently , many biomarkers showed promising results : POLE , ErbB2 , CDX2 , SMAD4 , BRAF and KRAS .
5 In addition to these , immune-contexture , molecular classification , and gene signatures could become new ways to better classify colon cancer patients with more discriminatory power than TNM .
6 The aim of this review is to report the state-of-the-art of prognostic and predictive factors in the adjuvant setting and which of these could modify clinical practice and maybe replace TNM classification .



PMID: 28501592
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Endoscopic and molecular characterization of colorectal sessile serrated adenoma/polyps with cytologic dysplasia .
1 BACKGROUND AND AIMS :
2 Sessile serrated adenoma/polyps ( SSA/Ps ) , which are precursor lesions of colorectal cancer ( CRC ) with BRAF mutation and the CpG island methylator phenotype ( CIMP ) , develop cytologic dysplasia ( CD ) during the progression of colorectal tumorigenesis .
3 In the present study we aimed to clarify the endoscopic and molecular signatures of SSA/Ps , with and without CD .
4 METHODS :
5 A series of 208 serrated lesions , including 41 hyperplastic polyps , 90 SSA/Ps , 33 SSA/Ps with CD , and 44 traditional serrated adenomas , were observed and resected using magnifying endoscopy .
6 BRAF and KRAS mutations and methylation of CIMP markers ( MINT1 , MINT2 , MINT12 , MINT31 , and p16 ) were analyzed through pyrosequencing .
7 Molecular alterations were then compared with endoscopic and pathologic characteristics .
8 RESULTS :
9 Among SSA/Ps without CD , the Type II-Open pit pattern ( Type II-O ) , BRAF mutation , and CIMP were tightly associated with a proximal colon location .
10 SSA/Ps in the distal colon infrequently exhibited Type II-O and CIMP .
11 Μ By contrast , most SSA/Ps with CD showed Type II-O plus adenomatous pit patterns ( Type III or IV ) , BRAF mutation , and CIMP , irrespective of their locations .
12 CONCLUSIONS :
13 Our results suggest that the Type II-O plus III/IV pit pattern is a common feature of SSA/Ps with CD in both the proximal and distal colon and that this pit pattern is a hallmark of serrated lesions at high risk of developing into CRCs .



PMID: 28488528
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Future perspectives of circulating tumor DNA in colorectal cancer .
1 Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance .
2 However , there are major challenges with this technique , including the need for serial sampling to monitor treatment resistance , which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity .
3 These challenges highlight the need for more effective methods for obtaining Tumor samples .
4 Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive , real-time picture of the tumor burden in an individual patient .
5 Indeed , liquid biopsy has the potential to revolutionize cancer management .
6 Here , we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer , including screening , diagnosis , detection of minimal residual disease after surgery , detection of recurrence , prognosis , predicting treatment response , monitoring tumor burden or response during treatment , and tracking resistance .
7   We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA , both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance .
8 The future integration of liquid biopsy into clinical practice is discussed , together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely .



PMID: 28486948
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Associating transcriptional modules with colon cancer survival through weighted gene co-expression network analysis .
1 BACKGROUND :
2 Colon cancer ( CC ) is a heterogeneous disease influenced by complex gene networks .
3 As such , the relationship between networks and CC should be elucidated to obtain further insights into tumour biology .
4 RESULTS :
5 Μ Weighted gene co-expression network analysis , a powerful technique used to extract co-expressed gene networks from mRNA expressions , was conducted to identify 11 co-regulated modules in a discovery dataset with 461 patients .
6 A transcriptional module enriched in cell cycle processes was correlated with the recurrence-free survival of the CC patients in the discovery ( HR = 059 ; 95% CI = 042-081 ) and validation ( HR = 051 ; 95% CI = 025-105 ) datasets .
7 The prognostic potential of the hub gene Centromere Protein-A ( CENPA ) was also identified and the upregulation of this gene was associated with good survival .
8 Another cell cycle phase-related gene module was correlated with the survival of the patients with a KRAS mutation CC subtype .
9 Μ The downregulation of several genes , including those found in this co-expression module , such as cyclin-dependent kinase 1 ( CDK1 ) , was associated with poor survival .
10 CONCLUSION :
11   Network-based approaches may facilitate the discovery of biomarkers for the prognosis of a subset of patients with stage II or III CC , these approaches may also help direct personalised therapies .



PMID: 28486044
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer .
1 Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer ( CRC ) .
2 Μ Expanded mutational testing , such as next-generation sequencing ( NGS ) , often identifies mutations with unclear clinical or prognostic implications .
3 One such example is BRAF mutations that occur outside of codon 600 ( non-V600 BRAF mutations ) .
4 Methods We conducted this multicenter , retrospective cohort study to characterize the clinical , pathologic , and survival implications of non-V600 BRAF mutations in metastatic CRC .
5 Μ We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories .
6 Results A total of 9,643 patients with metastatic CRC underwent NGS testing .
7 Μ We identified 208 patients with non-V600 BRAF mutations , which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified .
8 Μ Cancers with non-V600 BRAF mutations , compared with cancers with V600E BRAF ( V600E BRAF ) mutations , were found in patients who were significantly younger ( 58 v 68 years , respectively ) , fewer female patients ( 46% v 65% , respectively ) , and patients who had fewer high-grade tumors ( 13% v 64% , respectively ) or right-sided primary tumors ( 36% v 81% , respectively ) .
9 ✓ Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC ( 607 v 114 v 430 months , respectively ; P <001 ) . RO-ASS-GM
10 ✓ In multivariable analysis , non-V600 BRAF mutation was independently associated with improved overall survival ( hazard ratio , 018 ; P <001 ) . GM-ASS-RO
11 Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis .



PMID: 28476018
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Local recurrences at the anastomotic area are clonally related to the primary tumor in sporadic colorectal carcinoma .
1 Disease flare after gefitinib discontinuation .



PMID: 28473715
(None)  
Terms: ex-vivo
Sent# Symbols Sentence Mnemonics
0 Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2 .
1 KRAS mutation status can distinguish between metastatic colorectal carcinoma ( mCRC ) patients who may benefit from therapies that target the epidermal growth factor receptor ( EGFR ) , such as cetuximab .
2 However , patients whose tumors harbor mutant KRAS ( codons 12/13 , 61 and 146 ) are often excluded from EGFR-targeted regimens , while other patients with wild type KRAS will sometimes respond favorably to these same drugs .
3 These conflicting observations suggest that a more robust approach to individualize therapy may enable greater frequency of positive clinical outcome for mCRC patients .
4 Here , we utilized alive tumor tissues in ex-vivo platform termed CANscript , which preserves the native tumor heterogeneity , in order to interrogate the antitumor effects of EGFR-targeted drugs in mCRC ( n = 40 ) .
5 We demonstrated that , irrespective of KRAS status , cetuximab did not induce an antitumor response in a majority of patient tumors .
6 Μ In the subset of non-responsive tumors , data showed that expression levels of EGFR ligands contributed to a mechanism of resistance .
7 Transcriptomic and phosphoproteomic profiling revealed deregulation of multiple pathways , significantly the Notch and Erbb2 .
8 Targeting these nodes concurrently resulted in antitumor efficacy in a majority of cetuximab-resistant tumors .
9 These findings highlight the importance of integrating molecular profile and functional testing tools for optimization of alternate strategies in resistant population .



PMID: 28470797
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Screening for mismatch repair deficiency in colorectal cancer : data from three academic medical centers .
1 Reflex immunohistochemistry ( rIHC ) for mismatch repair ( MMR ) protein expression can be used as a screening tool to detect Lynch Syndrome ( LS ) .
2 Increasingly the mismatch repair-deficient ( dMMR ) phenotype has therapeutic implications .
3 We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres ( CCs ) .
4 CRC databases were analyzed from January 2005-December 2013 .
5 CC1 performs IHC upon physician request , CC2 implemented rIHC in November 2008 , and CC3 has been performing rIHC since 2004 .
6 The number of eligible patients referred to clinical genetic services ( CGS ) , and the number of LS patients per center was determined. 3906 patients were included over a 9-year period .
7 dMMR CRCs were found in 32/153 ( 21% ) of patients at CC1 and 55/536 ( 10% ) at CC2 , accounting for 3% and 5% of the CRC population , respectively .
8 At CC3 , 182/1737 patients ( 10% ) had dMMR CRCs ( P <0001 ) .
9 Additional testing for the BRAF V600E mutation , was performed in 49 patients at CC3 prior to CGS referral , of which 29 were positive and considered sporadic CRC .
10 Referrals to CGS were made in 66% , 33% , and 30% of eligible patients at CC1 , CC2 , and CC3 , respectively .
11 LS accounted for CRC in eight patients ( 08% ) at CC1 , eight patients ( 07% ) at CC2 , and 20 patients ( 12% ) at CC3 .
12 Cascade testing of patients with dMMR CRC was not completed in 56% .
13 Universal screening increases the detection of dMMR tumors and LS kindreds .
14 Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients .



PMID: 28468827
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HMG-CoA synthase 1 is a synthetic lethal partner of BRAFV600E in human cancers .
1 Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years .
2 Although many human cancers share similar metabolic alterations , it remains unclear whether oncogene -specific metabolic alterations are required for tumor development .
3 Using an RNAi-based screen targeting the majority of the known metabolic proteins , we recently found that oncogenic BRAFV600E up-regulates HMG-CoA lyase ( HMGCL ) , which converts HMG-CoA to acetyl-CoA and a ketone body , acetoacetate , that selectively enhances BRAFV600E -dependent MEK1 activation in human cancer .
4 Here , we identified HMG-CoA synthase 1 ( HMGCS1 ) , the upstream ketogenic enzyme of HMGCL , as an additional "synthetic lethal" partner of BRAFV600E Although HMGCS1 expression did not correlate with BRAFV600E mutation in human melanoma cells , HMGCS1 was selectively important for proliferation of BRAFV600E-positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants , and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAFV600E melanoma cells .
5 Moreover , cytosolic HMGCS1 that co-localized with HMGCL and BRAFV600E was more important than the mitochondrial HMGCS2 isoform in BRAFV600E-expressing cancer cells in terms of acetoacetate production .
6 Interestingly , HMGCL knockdown did not affect HMGCS1 expression levels , whereas HMGCS1 knockdown caused a compensating increase in HMGCL protein level because of attenuated protein degradation .
7 However , this increase did not reverse the reduced ketogenesis in HMGCS1 knockdown cells .
8 Mechanistically , HMGCS1 inhibition decreased intracellular acetoacetate levels , leading to reduced BRAFV600E-MEK1 binding and consequent MEK1 activation .
9 We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAFV600E-positive human cancers .



PMID: 28459822
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Feasibility of multiplexed gene mutation detection in plasma samples of colorectal cancer patients by mass spectrometric genotyping .
1 Μ Mutation analysis of circulating tumor DNA ( ctDNA ) has recently been introduced as a noninvasive tumor monitoring method .
2 Μ In this study , we tested the mass spectrometric-based MassARRAY platform for multiplexed gene mutation analysis of plasma samples from colorectal cancer ( CRC ) patients .
3 A total of 160 patients , who underwent curative resection of either primary or metastatic CRC harboring KRAS mutations between 2005 and 2012 , were included .
4 Circulating DNA was isolated from plasma was analyzed on the MassARRAY platform with or without selective amplification of mutant DNA fragments .
5 Μ Tumor-specific KRAS mutations were detected in 39.6% ( 42/106 ) of patients with distant metastasis , and in 5.6% ( 3/54 ) of patients without distant metastasis .
6 ✓ Selective amplification of the mutant allele increased sensitivity to 58.5% ( 62/106 ) for patients with distant metastasis , and 16.7% ( 9/54 ) for patients without distant metastasis .
7 These mutation detection rates were no less than those of droplet digital polymerase chain reaction .
8 ✓ Among patients with distant metastasis , detectable plasma KRAS mutations correlated with larger primary tumors and shorter overall survival rate ( P = 0014 and P = 0003 , respectively ) . GM-ASS-RO
9 Μ In addition , activating PIK3CA mutations were detected together with KRAS mutations in two plasma samples .
10 Taken together , massARRAY platform is a cost-effective , multigene mutation profiling technique for ctDNA with reasonable sensitivity and specificity .



PMID: 28459468
(Patient)  
Terms: xenograft, in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer .
1 Therapeutic strategies against KRAS mutant colorectal cancers are developed using cell line models , which do not accurately represent the transcriptome driven by oncogenic KRAS in tumors .
2 We sought to identify a KRAS-associated gene signature from colorectal tumors to develop a precise treatment strategy .
3 Integrative analysis of quantitative KRAS mutation detection and matched gene expression profiling in 55 CRC bulk tumors was carried out to define a gene signature enriched in CRC tumors with high KRAS mutation .
4 The KRAS-associated gene signature identified exhibits functional enrichment in cell cycle and mitosis processes , and includes mitotic transcription factor , FOXM1 .
5 Combination treatment of CDK4/6 inhibitor Palbociclib and MEK inhibitor PD0325901 was tested in KRAS-mutant , BRAF-mutant CRC , normal colon epithelial lines and xenografts models to determine their efficacy and toxicity and to monitor the changes in the gene signature .
6 Inhibiting CDK4/6 , an upstream regulator of FOXM1 , and MEK synergistically depleted FOXM1 and KRAS-associated gene signature , suggesting that CDK4/6 and MEK regulate the KRAS gene signature .
7 The combined inhibition of CDK4/6 and MEK elicited a robust therapeutic response in KRAS -dependent and BRAF-mutant CRC , both in vitro and in vivo and this correlated with downregulation of the KRAS-associated gene signature .
8 Our preclinical study demonstrated the efficacy of Palbociclib and PD0325901 combinatorial treatment selectively in KRAS -dependent and BRAF-mutant CRC but not in normal colon epithelial cells .
9 The KRAS-associated gene signature could facilitate the identification of responsive metastatic CRC to this therapeutic strategy in clinical settings .
10 Oncogene advance online publication , 1 May 2017 ; doi : 10.1038/onc.2017.120 .



PMID: 28459462
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genome -wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia .
1 Colorectal cancer ( CRC ) is characterized by genome -wide alterations to DNA methylation that influence gene expression and genomic stability .
2 Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development .
3 In this study , we have combined laser-capture microdissection with reduced representation bisulfite sequencing to identify cancer-associated DNA methylation changes in human aberrant crypt foci ( ACF ) , the earliest putative precursor to CRC .
4 Using this approach , methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation , as well as matched samples of normal mucosa .
5 Of 811 differentially methylated regions ( DMRs ) identified in ACF , 537 ( 66% ) were hypermethylated and 274 ( 34% ) were hypomethylated .
6 DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated .
7 Furthermore , gene ontology analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development , including homeobox genes and targets of the Polycomb repressive complex 2 .
8 Consistent with their role in the earliest stages of colonic neoplasia , 75% of the loci harboring methylation changes in ACF were also altered in CRC samples , though the magnitude of change at these sites was lesser in ACF .
9 Although aberrant promoter methylation was associated with altered gene expression in CRC , this was not the case in ACF , suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia .
10 Altogether , these data demonstrate that DNA methylation changes , including significant hypermethylation , occur more frequently in early colonic neoplasia than previously believed , and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk .
11 Oncogene advance online publication , 1 May 2017 ; doi : 10.1038/onc.2017.130 .



PMID: 28459449
(None)  
Terms: In vivo, in vivo, mice, orthotopic organoid transplantation in mice, mouse, orthotopic transplantation model
Sent# Symbols Sentence Mnemonics
0 In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis .
1 In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice .
2 Here we describe approaches to model colorectal cancer ( CRC ) and metastasis , which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations .
3 Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids .
4 ApcDelta/Delta ; KrasG12D/+ ; Trp53Delta/Delta (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver .
5 Finally , we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas .
6 These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis .



PMID: 28455994
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular profiling of colorectal pulmonary metastases and primary tumours : implications for targeted treatment .
1 This study aimed to molecularly characterise colorectal pulmonary metastases ( PM ) and investigate whether their molecular profiles were concordant with those of the primary tumour .
2 Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent >/= 1 pulmonary metastasectomies for colorectal cancer between 1997-2012 .
3 Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes .
4 The 5-year progression-free and overall survival rates for the 81 patients in this study were 32% ( 95% CI 22-42% ) and 77% ( 95% CI 66-85% ) respectively .
5 Fifty-four patients had samples available from >/= 1 PM , and sequencing data were successfully obtained from 33 PM from 24 patients .
6 Μ The most frequently mutated genes were APC ( 71% ) , KRAS ( 58% ) and TP53 ( 46% ) .
7 Seventy-three percent of the 15 patients with matched primary and PM samples and 6 of the 7 patients ( 86% ) with data from >/= 2 PM had concordant molecular profiles .
8 The concordance for KRAS and NRAS was 100% .
9 At our institutions , patients with resectable colorectal PM had a favourable prognosis .
10 Μ RAS mutations were commonly detected in PM and the molecular profiles of colorectal PM were highly concordant with the primary tumour .



PMID: 28453697
(None)  
Terms: retrospective, clinical trial, observational studies
Sent# Symbols Sentence Mnemonics
0 Prediction of overall survival in stage II and III colon cancer beyond TNM system : a retrospective , pooled biomarker study .
1 Background : TNM staging alone does not accurately predict outcome in colon cancer ( CC ) patients who may be eligible for adjuvant chemotherapy .
2 It is unknown to what extent the molecular markers microsatellite instability ( MSI ) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation .
3 Patients and methods : After imputation of missing at random data , a subset of patients accrued in phase 3 trials with adjuvant chemotherapy ( n = 3016 ) -N0147 ( NCT00079274 ) and PETACC3 (NCT00026273) -was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples ( n = 1499 ) , and also externally in different population cohorts of chemotherapy-treated ( n = 949 ) or -untreated ( n = 1080 ) CC patients , and an additional series without treatment annotation ( n = 782 ) .
4 Results : TNM staging , MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies .
5 Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers , 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates .
6 In validation cohorts with complete annotation , the integrated time -dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features , with or without molecular markers .
7   In patient cohorts that received adjuvant chemotherapy , the relative proportion of variance explained ( R2 ) by TNM , clinicopathological features and molecular markers was on an average 65% , 25% and 10% , respectively .
8   Conclusions : Incorporation of MSI , BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients , but only modestly increases prediction accuracy in multivariable models that include clinicopathological features , particularly in chemotherapy-treated patients .



PMID: 28453690
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Subgroups and prognostication in stage III colon cancer : future perspectives for adjuvant therapy .
1 Since the MOSAIC study , oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer .
2 Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival ( OS ) and reduced the risk of recurrence in patients with resected stage III colon cancer .
3 However , only 20% of patients really benefit from adjuvant chemotherapy , exposing 80% of patients to unnecessary toxicity .
4 Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease .
5 Indeed , clinical and pathological prognostic factors , although important , are not sufficient to decide which stage III patients will benefit from adjuvant therapy , and biomarkers will help select patient that need adjuvant treatment .
6 Μ Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored , and molecular signatures have been identified as promising prognostic factor for OS .
7 Furthermore , recent studies have highlighted the prognostic value of immune infiltration .
8   This review focuses on pathologic , immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach .



PMID: 28449055
(None)  
Terms: NCT00364013, NCT00819780, retrospective
Sent# Symbols Sentence Mnemonics
0 Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer : results from two randomized first - line panitumumab studies .
1 Background : : Previous studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer ( mCRC ) and its influence on cetuximab efficacy .
2 The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first - line mCRC patients with RAS wild-type ( WT ) primary tumors .
3 Material and methods : Data from two randomized first - line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients .
4 PRIME ( phase 3 ; NCT00364013 ) compared panitumumab plus FOLFOX versus FOLFOX alone ; PEAK ( phase 2 ; NCT00819780 ) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX .
5 Primary tumors located in the cecum to transverse colon were coded as right-sided , while tumors located from the splenic flexure to rectum were considered left-sided .
6 Results : Tumor sidedness ascertainment ( RAS WT population ) was 83% ( n = 559/675 ) ; 78% of patients ( n = 435 ) had left-sided and 22% ( n = 124 ) had right-sided tumors .
7 Patients with right-sided tumors did worse for all efficacy parameters compared to patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup .
8   In patients with left-sided tumors , panitumumab provided better outcomes than the comparator treatment , including on median overall survival ( OS ) ( PRIME : 30.3 versus 23.6 months , adjusted hazard ratio ( HR ) =0.73 , P =0.0112 ; PEAK : 43.4 versus 32.0 months , adjusted HR = 0.77 , P =0.3125 ) .
9   Conclusion : The results of these retrospective analyses confirm that in RAS WT patients , right-sided primary tumors are associated with worse prognosis than left-sided tumors , regardless of first - line treatment received .
10   RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab , including an OS advantage ( treatment difference : PRIME 6.7 months ; PEAK 11.4 months ) .
11   No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of patients .
12 Further research in this field is warranted .



PMID: 28447565
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Risk factors for brain metastases in patients with metastatic colorectal cancer .
1 BACKGROUND :
2 Brain metastases ( BM ) from colorectal cancer ( CRC ) are rare , but the incidence is suspected to rise as treatment of metastatic (m) CRC improves .
3 The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict later risk of developing BM .
4 Furthermore , we wished to estimate the incidence of BM in long-term surviving patients .
5 MATERIAL AND METHODS :
6 We conducted a retrospective study on a Danish multicenter cohort of patients with mCRC who received cetuximab and irinotecan ( CetIri ) as third - line treatment .
7 All patients had previously progression on 5-FU , irinotecan and oxaliplatin containing regimens and received CetIri treatment independent of RAS mutations status .
8 We subsequently performed KRAS , NRAS , BRAF , PIK3CA , PTEN , ERBB2 and EGFR sequencing of DNA extracted from primary tumor tissue .
9 RESULTS :
10 Totally , 480 patients were included in our study .
11 BM were diagnosed in 42 [8.8% ; 95% confidence interval ( CI ) 6.4-11.6%] patients .
12 Patients with BM had a significantly longer survival from mCRC diagnosis than non-BM patients ( median = 32 versus 28 months , p = 0001 ) .
13 On univariate cox regression analysis , the risk of developing BM was significantly increased in patients with rectal cancer ( HR = 39 ; 95% CI = 12-133 ) , metachronous metastatic disease ( HR = 23 ; 95% CI = 12-44 ) and lung metastases ( HR = 42 ; 95% CI = 22-79 ) .
14 On multivariate cox regression analysis only lung metastases were significantly associated BM ( HR = 35 ; 95% CI = 18-68 ) .
15 None of the investigated mutations were associated with BM .
16 CONCLUSION :
17   The incidence of BM was 8.8% in patients with mCRC who received third - line therapy .
18 The most important risk factor for developing BM was lung metastases .
19 Furthermore , rectal cancer , metachronous metastatic disease and long survival were linked to BM development .



PMID: 28446505
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Features and Outcomes of Patients with Colorectal Cancers Harboring NRAS Mutations .
1 Purpose : NRAS mutations are now routinely included in RAS testing prior to EGFR inhibitor therapy for metastatic colorectal cancer ( mCRC ) .
2 The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy , however , are not known .
3 We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS-mutant mCRC .
4 Experimental Design : We reviewed clinical characteristics , concurrent mutations , and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008 to 2015 .
5 Comparison groups consisted of RAS wild-type and KRAS-mutant mCRC consecutive cases genotyped from 2008 to 2012 .
6 Results : Three percent ( 87/2764 ) of mCRC patients had NRAS-mutant tumors ( 45% exon 2 and 55% exon 3 ) , including three cases with concurrent NRAS and KRAS mutations .
7 Left-sided primary site and African American self-reported race were associated with NRAS mutation ( P <001 ) .
8 Resection rate at 12 months was lower for NRAS-mutant mCRC than for RAS wild-type or KRAS-mutant mCRC .
9 Median survival from time of first known metastasis was 33 months for NRAS-mutant , 47 months for KRAS-mutant , and 78 months for RAS wild-type cases ( P <0001 ) .
10 Multivariate analysis assigned an HR for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation ( P <001 ) .
11 Conclusions : NRAS defines a molecular subset with distinct clinical characteristics from KRAS-mutant and wild-type mCRC .
12 NRAS mutations are enriched in left-sided primary tumors and among African Americans .
13 ✓ Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS-mutant or wild-type mCRC . GM-ASS-RO
14 Clin Cancer Res ; 1-8 .
15 (c) 2017 AACR .



PMID: 28445136
(None)  
Terms: in vivo, In vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 Selective eradication of cancer cells by delivery of adenovirus-based toxins .
1 BACKGROUND AND OBJECTIVE :
2 KRAS mutation is an early event in colorectal cancer carcinogenesis .
3 We previously reported that a recombinant adenovirus , carrying a pro-apoptotic gene ( PUMA ) under the regulation of Ets/AP1 (RAS-responsive elements) suppressed the growth of cancer cells harboring hyperactive KRAS .
4 We propose to exploit the hyperactive RAS pathway , rather than to inhibit it as was previously tried and failed repeatedly .
5 We aim to improve efficacy by substituting PUMA with a more potent toxin , the bacterial MazF-MazE toxin-antitoxin system , under a very tight regulation .
6 RESULTS :
7 A massive cell death , in a dose -dependent manner , reaching 73% at MOI 10 was seen in KRAS cells as compared to 22% in WT cells .
8 Increase expression of MazE ( the anti-toxin ) protected normal cells from any possible internal or external leakage of the system and confirmed the selectivity , specificity and safety of the targeting system .
9 Considerable tumor shrinkage ( 61% ) was demonstrated in vivo following MazEF -encoding adenovirus treatment without any side effects .
10 DESIGN :
11 Efficient vectors for cancer-directed gene delivery were constructed ; LONGTOKEN -MazE-IRES-EGFP" , "pAdEasy-DeltaPy4-SV40mP-mCherry-MazF-IRES-TetR-CMVmp-MazE-IRES - EGFP "and "pAdEasy-mCherry" .
12 Virus particles were produced and their potency was tested .
13 Cell death was measured qualitatively by using the fluorescent microscopy and colony formation assay , and was quantified by MTT .
14 FACS analysis using annexin V and RedDot2 dyes was performed for measuring apoptotic and dead cells , respectively .
15 In vivo tumor formation was measured in a xenograft model .
16 CONCLUSIONS :
17 A proof of concept for a novel cancer safe and effective gene therapy exploiting an aberrant hyperactive pathway is achievable .



PMID: 28435452
(None)  
Terms: , animal models
Sent# Symbols Sentence Mnemonics
0 The YAP1/SIX2 axis is required for DDX3 -mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer .
1 The mechanism underlying tumor aggressiveness and cetuximab ( CTX ) resistance in KRAS-wild-type ( KRAS -WT ) colorectal cancer remains obscure .
2 We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells , as already confirmed in KRAS-mutated cells .
3 Mechanistically , increased KRAS expression induced ROS production , which elevated HIF-1alpha and YAP1 expression .
4 Increased HIF-1alpha persistently promoted DDX3 expression via a KRAS/ROS/HIF-1alpha feedback loop.DDX3 -mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models .
5 ✓ Kaplan-Meier and Cox regression analysis indicated that DDX3 , KRAS , and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors , but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients . GE-ASS-RO
6 The observation from patients seemed to support the mechanistic action of cell and animal models .
7 We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3 -mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer .



PMID: 28433252
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 NRASQ61R immunohistochemistry detects both NRASQ61R and KRASQ61R mutations in colorectal cancer .
1 Μ The NRASQ61R monoclonal antibody ( clone sp174 ) is a mutation-specific antibody that is increasingly being used to detect the NRASQ61R mutation in melanomas .
2 This antibody has been reported to be highly correlated with the NRASQ61R mutation status in melanomas and follicular neoplasms of the thyroid gland .
3 However , its utility in colorectal carcinoma ( CRC ) has remained largely unknown .
4 In this study , we assessed the sensitivity , specificity , and diagnostic utility of NRASQ61R immunohistochemistry in a cohort consisting of tissue sections of 113 CRCs , which were molecularly profiled for the KRAS , NRAS , and BRAF mutations .
5 Five CRCs tested positive for NRASQ61R immunohistochemistry .
6 Four of these CRCs exhibited the NRASQ61R mutation and one exhibited the KRASQ61R mutation .
7 All of the other 108 colorectal carcinomas lacking the NRASQ61R or KRASQ61R mutation tested negative for NRASQ61R immunohistochemistry .
8 In the positively stained cases , we observed a diffuse staining pattern in >90% of the tumour cells with a moderate-to-strong intensity .
9 By contrast , the staining was essentially entirely negative in cases negative for the NRASQ61R or KRASQ61R mutations .
10 We concluded that although it cross-reacts with the mutant KRASQ61R protein , the NRASQ61R antibody is a useful diagnostic tool that assists in the molecular testing of CRCs and facilitates patient management .



PMID: 28432610
(Patient)  
Terms: Clinical Trial, phase I trial, clinical trial
Sent# Symbols Sentence Mnemonics
0 Left Versus Right : Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials ?
1 PURPOSE :
2 Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first - line to metastatic colorectal cancer ( mCRC ) patients .
3 However , little is known regarding the effect of location on prognosis and prediction in refractory mCRC .
4 We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies .
5 METHODS :
6 A historical cohort analysis of mCRC patients , including 44 phase I trials our institution , from March 2004 to September 2012 .
7 Median Progression free survival ( mPFS ) and overall survival ( mOS ) were estimated from Kaplan-Meier curves and groups were statistically compared with the log-rank test .
8 RESULTS :
9 One hundred thirty-nine patients with a median age 59 ( 33-81 ) .
10   73.9% received 3+ lines of therapy .
11 All KRAS wild-type patients had received prior EGFR-I .
12 LOCATION :
13 right 20.9% , left 61.9% , and transverse 4.3% .
14 For survival analysis , transverse CRC were included with right .
15 Of the 112 patients , mOS was left ( N = 80 ) 6.6 months versus right ( N = 32 ) 5.9 months , P = 0.18 .
16 mPFS was left ( n = 86 ) 2.0 months versus right ( N = 35 ) 2.0 months , P = 0.76 .
17 In subgroup analysis , survival was significant for KRAS wild-type patients with left-sided mCRC had mOS of 6.2 months with other agents versus 9.4 months with EGFR-I ( P = 003 ) .
18 CONCLUSIONS :
19   In phase 1 clinical trials , although location alone was not prognostic in heavily pretreated patients , left-sided mCRC had improved survival with EGFR-I .
20   Despite progression on EGFR-I , left-sided KRAS wild mCRC patients should be considered for phase 1 studies of agents targeting growth factor pathways .



PMID: 28429715
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mapping clinicopathological entities within colorectal mucinous adenocarcinomas : a hierarchical clustering approach .
1 The aim of this study was to interrogate the heterogeneity of colorectal mucinous adenocarcinomas .
2 This study is based on hierarchical clustering approach combining clinicopathological and molecular patterns known to be relevant to oncogenesis and therapeutic management of patients with colorectal carcinoma , ie , microsatellite instability , O6-methylguanine-DNA methyltransferase ( MGMT ) status , KRAS , and BRAF mutations and wnt signaling pathway activation .
3 Comparison of the study group of 60 mucinous adenocarcinomas defined according to World Health Organization classification with control group of 136 colorectal adenocarcinomas successively removed shows higher frequency of BRAF and KRAS mutations and microsatellite instability-high status and lower frequency of wnt signaling pathway activation in mucinous adenocarcinomas .
4 Μ Hierarchical clustering isolated three relevant clusters : (i) cluster of microsatellite stable mucinous adenocarcinomas ( 54% ) with KRAS mutation , and frequent MGMT changes , more frequently located in the left colon , often associated with contiguous precursor adenoma ; ( ii ) cluster of BRAF-mutated mucinous adenocarcinomas ( 28% ) with either microsatellite instability-high or microsatellite stable status , occurring in elderly female patients , nearly all located in the right colon , having the signature of serrated pathway of carcinomas ; and ( iii ) a heterogeneous cluster of microsatellite instability-high mucinous carcinomas ( 18% ) , including inherited colorectal carcinomas , displaying a high-grade histological pattern .
5 ✓ Age , TNM stage , and BRAF mutation had prognostic value . GM-ASS-RO
6 Hierarchical clustering analysis led to the identification of several clinicopathological entities of colorectal mucinous adenocarcinomas with epidemiologic , prognostic , and therapy relevance .
7 Both KRAS and BRAF mutations appear as drivers in the alternate oncogenetic pathways governing the development of sporadic colorectal mucinous adenocarcinomas .
8 Modern Pathology advance online publication , 21 April 2017 ; doi : 10.1038/modpathol.2017.18 .



PMID: 28424871
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients .
1 PURPOSE :
2 To report planned final overall ( OS ) and progression-free survival ( PFS ) analyses from the phase II PEAK trial ( NCT00819780 ) .
3 METHODS :
4 Patients with previously untreated , KRAS exon 2 wild-type ( WT ) metastatic colorectal cancer ( mCRC ) were randomised to mFOLFOX6 plus panitumumab or bevacizumab .
5 The primary endpoint was PFS ; secondary endpoints included OS , objective response rate , duration of response ( DoR ) , time to response , resection and safety .
6 Treatment effect by tumour RAS status was a prespecified objective .
7 Exploratory analyses included early tumour shrinkage ( ETS ) and depth of response ( DpR ) .
8 RESULTS :
9 One hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC .
10 Median PFS was longer for panitumumab versus bevacizumab in the RAS WT ( 12.8 versus 10.1 months ; hazard ratio ( HR ) = 0.68 [95% confidence intervals ( CI ) = 0.48-0.96] ; p = 0.029 ) and RAS WT/BRAF WT ( 13.1 versus 10.1 months ; HR = 0.61 [95% CI = 042-088] ; p = 0.0075 ) populations .
11 ✓ Median OS ( 68% OS events ) for panitumumab versus bevacizumab was 36.9 versus 28.9 months ( HR = 0.76 [95% CI = 053-111] ; p = 0.15 ) and 41.3 versus 28.9 months ( HR = 0.70 [95% CI = 048-104] ; p = 0.08 ) , in the RAS WT and RAS WT/BRAF WT populations , respectively . GE-ASS-RO
12 Median DoR ( 11.4 versus 9.0 months ; HR = 0.59 [95% CI = 039-088] ; p = 0.011 ) and DpR ( 650 versus 463% ; p = 00018 ) were improved in the panitumumab group .
13 More panitumumab patients experienced >/ = 30% ETS at week 8 ( 64 versus 45% ; p = 0052 ) ; ETS was associated with improved PFS/OS .
14 No new safety signals occurred .
15 CONCLUSIONS :
16   First - line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC .



PMID: 28424412
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 FBXW7 missense mutation : a novel negative prognostic factor in metastatic colorectal adenocarcinoma .
1 BACKGROUND :
2 FBXW7 functions as a ubiquitin ligase tagging multiple dominant oncogenic proteins and commonly mutates in colorectal cancer .
3 Data suggest missense mutations lead to greater loss of FBXW7 function than other gene aberrations do .
4 However , the clinicopathologic factors and outcomes associated with FBXW7 missense mutations in metastatic colorectal cancer ( mCRC ) have not been described .
5 METHODS :
6 Data were obtained from mCRC patients whose tumors were evaluated by next-generation sequencing for hotspot mutations at The University of Texas MD Anderson Cancer Center .
7 Μ Alterations in FBXW7 were identified , and their associations with clinicopathologic features and overall survival ( OS ) were evaluated .
8 RESULTS :
9 Of 855 mCRC patients , 571 had data on FBXW7 status ; 43 ( 75% ) had FBXW7 mutations , including 37 with missense mutations .
10 R465C mutations in exon 9 were the most common missense mutations ( 186% ) .
11 PIK3CA mutations were associated with FBXW7 missense mutations ( p = 0012 ) .
12 ✓ On univariate analysis , patients with FBXW7 missense mutations had significantly worse OS ( median 287 mo ) than those with wild-type FBXW7 ( median 466 mo ; p = 0003 ) . GM-ASS-RO, RO-ASS-GM
13 ✓ On multivariate analysis including other known prognostic factors such as BRAF mutations , FBXW7 missense mutations were the strongest negative prognostic factor for OS ( hazard ratio 20 ; p = 0003 ) . GM-MRK-RO
14 CONCLUSIONS :
15 ✓ Μ In the largest clinical dataset of mCRC to date , FBXW7 missense mutations showed a strong negative prognostic association . GM-ASS-RO



PMID: 28424201
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer .
1 Purpose : Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor ( EGFR ) blockade in patients with metastatic colorectal cancer ( mCRC ) .
2 However , the potential role of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated .
3 Μ Experimental Design : Using circulating tumor DNA ( ctDNA ) from patients with mCRC and with acquired cetuximab resistance , we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway .
4 Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis .
5 Μ The functional consequences of the identified mutations were validated in cultured cells .
6 Results : We analyzed 32 patients with acquired cetuximab resistance in a development cohort .
7 Of them , seven ( 22% ) carried five novel PIK3CA mutations , whereas eight ( 25% ) carried previously reported KRAS mutations .
8 Μ Functional studies showed that novel PIK3CA mutations ( all in exon 19 ; pK944N , pF930S , pV955G , pV955I , and pK966E ) promote cell viability in the presence of cetuximab .
9 Only one novel PIK3CA mutation (pK944N) was verified in one of the 27 patients with acquired resistance in a validation cohort , simultaneous KRAS and PIK3CA hotspot mutations were detected in two patients .
10 ✓ Μ Among the above 59 acquired resistance patients , those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation . GM-ASS-RO, RO-ASS-GM
11 ✓ Conclusions : The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC .
12 Clin Cancer Res ; 1-15 .
13 (c) 2017 AACR .



PMID: 28422723
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival .
1 Colorectal mucinous adenocarcinoma ( MAC ) and serrated adenocarcinoma ( SAC ) share many characteristics , including right-side colon location , frequent mucin production , and various molecular features .
2 This study examined the frequency of SAC morphology in MACs .
3 We assessed the correlation of SAC morphology with clinicopathological parameters , molecular characteristics , and patient prognosis .
4 Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria .
5 We sequenced KRAS and BRAF , assessed CpG island methylator phenotype ( CIMP ) frequency , and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples .
6 SAC morphology was observed in 38% of MACs , and was associated with proximal location ( P = 0001 ) , BRAF mutation ( P = 0042 ) , CIMP-positive status ( P = 0023 ) , and contiguous traditional serrated adenoma ( P = 0019 ) .
7 Μ Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one ( P = 0035 ) .
8 Our results show that two MAC groups with distinct features can be identified using Makinen's criteria , and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC .



PMID: 28422714
(Patient)  
Terms: In vivo, xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer .
1 New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer ( mCRC ) .
2 This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene ( 40-45% of all patients ) .
3 This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients .
4 Reovirus , a double stranded ( ds ) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors .
5 Toll Like Receptor ( TLR ) 3 , a member of the toll like receptor family of the host innate immune system is the pattern recognition motif for dsRNA pathogens .
6 Using TLR3 expressing commercial HEK-BlueTM-hTLR3 cells we confirm that TLR3 is the host pattern recognition motif responsible for the detection of reovirus .
7 Μ Further , our investigation with KRAS mutated HCT116 cell line showed that effective expression of host TLR3 dampens the infection potential of reovirus by mounting a robust innate immune response .
8 Down regulation of TLR3 expression with siRNA improves the anticancer activity of reovirus .
9 In vivo experiments using human CRC cells derived xenografts in athymic mice further demonstrate the beneficial effects of TLR3 knock down by improving tumor response rates to reovirus .
10 Strategies to mitigate the TLR3 response pathway can be utilized as a tool towards improved reovirus efficacy to specifically target the dissemination of KRAS mutated CRC .



PMID: 28418176
(None)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 Panitumumab-Conjugated Pt - Drug Nanomedicine for Enhanced Efficacy of Combination Targeted Chemotherapy against Colorectal Cancer .
1 Targeted combination chemotherapy ( TCT ) has recently been used to increase the induction of tumor cell death .
2 In particular , the combination of Panitumumab and the platinum ( Pt )- derived chemotherapeutic drug Oxaliplatin is clinically effective against KRAS and BRAF wild-type colorectal cancer ( CRC ) cells that overexpress epidermal growth factor receptors , and significantly greater efficacy is observed than with either drug alone .
3 However , low accumulation of Pt drug in tumor sites prevents achievement of ideal efficacy .
4 To develop an alternative drug therapy that achieves the ideal efficacy of TCT , the novel nanomedicine NANOPt-Pan using self-assembled dichloro ( 1,2-diaminocyclohexane ) Pt (II)- modified Panitumumab is generated .
5 Treatments with NANOPt-Pan lead to significant accumulation of Pt drug and Panitumumab in tumors , reflecting enhanced permeability and retention effect , active targeting , and sustained circulation of the Pt drug in the blood .
6 In addition , NANOPt-Pan has excellent in vivo anti-CRC efficacy .
7 These data indicate that NANOPt-Pan has high potential as a candidate nanomedicine for CRC .



PMID: 28416767
(Patient)  
Terms: prospective, observational study
Sent# Symbols Sentence Mnemonics
0 The molecular heterogeneity of sporadic colorectal cancer with different tumor sites in Chinese patients .
1 PURPOSE :
2 To assess the biological variability of clinical meaningful molecular markers and their clinical correlations in Chinese patients with colorectal cancer ( CRC ) .
3 MATERIALS AND METHODS :
4 In this prospective observational study , frequencies and clinico-pathological features of RAS and BRAFV600E mutations , deficiency of DNA mismatch repair ( dMMR ) were evaluated in patients with colorectal cancer staged I-IV .
5 The molecular heterogeneity between right-sided and left-sided colorectal cancers was studied in our series by classifying patients with different mutations and dMMR status .
6 RESULTS :
7 Μ Among 400 evaluable patients , mutations in KRAS exon 2 , exon 3 or 4 , NRAS and BRAFV600E were detected in 36% , 7.5% , 3.5% and 2.5% , respectively .
8 RAS mutations were significantly higher in metastatic CRCs ( 564% vs. 431% , p = 0015 ) and right-sided CRCs ( 625% versus 417% , p = 0003 ) .
9 In 212 RAS wild-type patients , V600E mutation was higher in older patients ( 95% vs. 22% , p = 0017 ) , women ( 92% vs. 22% , p = 0021 ) and right-sided CRCs ( 105% vs. 34% , p = 006 ) .
10 dMMR was detected in 7.75% of all stages of CRCs , with the highest dMMR rate of 40% in stage II right-sided colon cancer .
11 CONCLUSIONS :
12 By assessing the mutations and clinical correlations of RAS and BRAF genes , and dMMR status , similar RAS mutation , dMMR frequency and lower BRAF mutation was observed in Chinese patients compared to western patients .
13 A distinct molecular heterogeneity was found between patients with right-sided and left-sided CRCs .



PMID: 28415818
(Cell)  
Terms: in vivo, xenograft, tumor xenografts
Sent# Symbols Sentence Mnemonics
0 Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity .
1 BACKGROUND :
2 The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells .
3 We synthesized a copper complex of VLX50 , denoted VLX60 , and characterized its antitumor and mechanistic properties .
4 MATERIALS AND METHODS :
5 The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines , in tumor cells from patients , in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50 .
6 RESULTS :
7 VLX60 showed >/= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and , in contrast to VLX50 , retained its activity in the presence of additional iron .
8 VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model .
9 Μ In contrast to VLX50 , gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen .
10 VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells .
11 CONCLUSIONS :
12 The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug , notably against BRAF mutated colorectal cancer .



PMID: 28414610
(Patient)  
Terms: phase III trial, clinical trial
Sent# Symbols Sentence Mnemonics
0 Targeted inhibition in tumors with ALK dependency .
1 Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood .
2 Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD ( Aide et Recherche en Cancerologie Digestive ) database were pooled .
3 Multivariable logistic regression models for 30 - , 60 - , and 90-day mortality were constructed , including clinically and statistically significant patient and disease factors and interaction terms .
4 A calculator ( nomogram ) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial .
5 The impact of early progression on the likelihood of survival to 90 days was examined with time -dependent Cox proportional hazards models .
6 Results Mortality rates were 1.4% at 30 days , 3.4% at 60 days , and 5.5% at 90 days .
7 Among baseline factors , advanced age , lower body mass index , poorer performance status , increased number of metastatic sites , BRAF mutant status , and several laboratory parameters were associated with increased likelihood of early mortality .
8 A multivariable model for 90-day mortality showed strong internal discrimination ( C-index , 077 ) and good calibration across risk groups as well as accurate predictions in the external validation set , both overall and within patient subgroups .
9   Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer .
10   This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment .



PMID: 28411881
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients .
1 BACKGROUND :
2 The outcome of colon cancer patients without lymph node metastasis is heterogeneous .
3 Searching for new prognostic markers is warranted .
4 METHODS :
5 One hundred twenty stage I-II colon cancer patients who received complete surgical excision during 1995-2004 were selected for this biomarker study .
6 Immunohistochemical method was used to assess p53 , epidermal growth factor receptor , MLH1 , and MSH2 status .
7 KRAS mutation was examined by direct sequencing .
8 RESULTS :
9 Thirty three patients ( 275% ) developed metachronous metastasis during follow up .
10 By multivariate analysis , only female gender ( p = 003 ) , high serum carcinoembryonic antigen ( CEA ) level ( >= = 5 ng/ml ) ( p = 004 ) , and MLH1 overexpression ( p = 0003 ) were associated with the metastasis group .
11 The 5-year-survival rate were also significantly lower for female gender ( 717% versus 889% , p = 0025 ) , high CEA level ( 649% versus 924% , p <0001 ) , and MLH1 overexpression ( 775% versus 944% , p = 0039 ) .
12 In contrast , MSH2 overexpression was associated with better survival , 95.1% versus 75.5% ( p = 0024 ) .
13 CONCLUSIONS :
14 The reversed prognostic implications in the overexpression of MLH1 and MSH2 for stage I-II colon cancer patients is a novel finding and worthy of further confirmation .



PMID: 28407239
(Patient)  
Terms: Clinical trial, prospective
Sent# Symbols Sentence Mnemonics
0 The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer .
1 Colorectal cancer is among the most lethal malignancies globally .
2 BRAF is a member of the RAS/RAF/MEK/ERK signaling pathway .
3 Its constitutive activation can result in increased cellular growth , development , invasion , and resistance to therapy .
4 A mutation of the BRAF gene is present in 5-10% of metastatic colorectal cancers .
5 Μ BRAF mutations have been found to predict a lack of benefit to anti-EGFR therapy in metastatic CRC .
6 ✓ Furthermore , CRC containing the BRAF V600E mutation display an innate resistance to BRAF inhibitors .
7 The mechanisms of cell resistance can be explained atleast in part by ERK dependent and ERK in -dependent pathway .
8 Clinical trials evaluating the combinations of BRAF , PI3K , EGFR , and/or MEK inhibitors have revealed promising activity in BRAF mutant containing CRCs .
9   There may be some benefit from future studies that focus on improving the efficacy of combined therapy in CRC with respect to the sustained effects .
10 The aim of current review is to give an overview about the current status and prospective regarding the therapeutic potential of targeting BRAF mutant colorectal cancer .



PMID: 28407110
(None)  
Terms: phase II trial, retrospective
Sent# Symbols Sentence Mnemonics
0 Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomised trials .
1 Background : There is increasing evidence that metastatic colorectal cancer ( mCRC ) is a genetically heterogeneous disease and that tumours arising from different sides of the colon ( left versus right ) have different clinical outcomes .
2 Furthermore , previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type ( wt ) or RAS wt mCRC suggest that primary tumour location ( side ) , might be both prognostic and predictive for clinical outcome .
3 Methods : This retrospective analysis investigated the prognostic and predictive influence of the localisation of the primary tumour in patients with unresectable RAS wt mCRC included in six randomised trials ( CRYSTAL , FIRE-3 , CALGB 80405 , PRIME , PEAK and 20050181 ) , comparing chemotherapy plus EGFR antibody therapy ( experimental arm ) with chemotherapy or chemotherapy and bevacizumab ( control arms ) .
4 Hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) for overall survival ( OS ) and progression-free survival ( PFS ) for patients with left-sided versus right-sided tumours , and odds ratios ( ORs ) for objective response rate ( ORR ) were estimated by pooling individual study HRs/ORs .
5 The predictive value was evaluated by pooling study interaction between treatment effect and tumour side .
6 Results : Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients ( 375% ) randomised across the six trials , 515 right-sided and 1644 left-sided .
7 A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS ( HRs = 2.03 [95%CI : 1.69-2.42] and 1.38 [117-163] , respectively ) , PFS ( HRs = 1.59 [134-188] and 1.25 [106-147] ) , and ORR ( ORs = 0.38 [028-050] and 0.56 [043-073] ) .
8   In terms of a predictive effect , a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours ( HRs = 0.75 [067-084] and 0.78 [070-087] for OS and PFS respectively ) compared with no significant benefit for those with right-sided tumours ( HRs = 1.12 [087-145] and 1.12 [087-144] for OS and PFS respectively ; P value for interaction <0.001 and 0.002 , respectively ) .
9   For ORR , there was a trend ( P value for interaction = 007 ) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours ( OR = 2.12 [177-255] ) compared with those with right-sided tumours ( OR = 1.47 [094-229] ) .
10 Exclusion of the unique phase II trial or the unique second - line trial had no impact on the results .
11 The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm .
12   Conclusion : This pooled analysis showed a worse prognosis for OS , PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side , with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab , the effect being greatest in patients with left-sided tumours .
13 These predictive results should be interpreted with caution due to the retrospective nature of the analysis , which was performed on subpopulations of patients included in these trials , and because none of these studies contemplated a full treatment sequence strategy .



PMID: 28405764
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer .
1 In this study , we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer ( CRC ) .
2 To this end , 186 microsatellite instability-high ( MSI-H ) and 153 microsatellite stable ( MSS ) CRCs were subjected to immunohistochemistry ( IHC ) analysis for the expression of CD274 and mismatch repair proteins .
3 CD274 expression was evaluated in tumor cells at the center ( TC ) and periphery ( TP ) , and immune cells at the center ( IC ) and periphery ( IP ) of CRC .
4 IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density .
5 Μ Additionally , samples were screened for the B-Raf ( BRAF ) -V600E mutation using a Cobas 4800 System and IHC .
6 In total , CD274TC , CD274TP , CD274IC , and CD274IP were observed in 43 ( 231% ) , 47 ( 253% ) , 107 ( 575% ) , and 102 ( 548% ) of the MSI-H CRCs examined , and in three ( 20% ) , four ( 26% ) , 47 ( 307% ) , and 56 ( 366% ) of the 153 MSS CRCs tested .
7 Μ Meanwhile , intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 ( 129% ) and 47 ( 253% ) MSI-H CRCs , respectively .
8 Notably , in both MSI-H and MSS CRC , CD274IC and CD274IP were independently associated with improved prognosis ( P <005 ) , while BRAF mutation was associated with CD274TP , poor differentiation , sporadic type , and hMLH1(-)/hMSH2(+)/hMSH6(+)/PMS2(-) in MSI-H CRC ( P <0006 ) .
9 In conclusion , CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients .
10 A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies .



PMID: 28405513
(None)  
Terms: , mouse model, mouse, mouse and patient-derived PDAC models
Sent# Symbols Sentence Mnemonics
0 Tumor SQSTM1 ( p62 ) expression and T cells in colorectal cancer .
1 Malignant neoplasms evolve in response to changes in oncogenic signalling .
2 Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance .
3 Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma ( PDAC ) , a malignancy that displays considerable phenotypic diversity and morphological heterogeneity .
4 In this model , stochastic extinction of oncogenic Kras signalling and emergence of Kras -independent escaper populations ( cells that acquire oncogenic properties ) are associated with de-differentiation and aggressive biological behaviour .
5 Transcriptomic and functional analyses of Kras -independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling .
6 A somatic mosaic model of PDAC , which allows time-restricted perturbation of cell fate , shows that depletion of Smarcb1 activates the Myc network , driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways .
7 Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-alpha-MKK4 arm of the endoplasmic-reticulum-stress-response pathway .
8 Specifically , combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models .
9 These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC .



PMID: 28403349
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Analysis of gene expression EGFR and KRAS , microRNA-21 and microRNA-203 in patients with colon and rectal cancer and correlation with clinical outcome and prognostic factors .
1 Purpose : : To evaluate the expression of EGFR , KRAS genes , microRNAs-21 and 203 in colon and rectal cancer samples , correlated with their age at diagnosis , histological subtype , value of pretreatment CEA , TNM staging and clinical outcome .
2 Methods : : Expression of genes and microRNAs by real time PCR in tumor and non-tumor samples obtained from surgical treatment of 50 patients .
3 Results : : An increased expression of microRNAs-21 and 203 in tumor samples in relation to non-tumor samples was found .
4 There was no statistically significant difference between the expression of these genes and microRNAs when compared to age at diagnosis and histological subtype .
5 Μ The EGFR gene showed higher expression in relation to the value of CEA diagnosis .
6 The expression of microRNA-203 was progressively lower in relation to the TNM staging and was higher in the patient group in clinical remission .
7   Conclusions : : The therapy of colon and rectum tumors based on microRNAs remains under investigation reserving huge potential for future applications and clinical interventions in conjunction with existing therapies .
8   We expect , based on the exposed data , to stimulate the development of new therapeutic possibilities , making the treatment of these tumors more effective .



PMID: 28400427
(Patient)  
Terms: phase I
Sent# Symbols Sentence Mnemonics
0 Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer .
1 Μ Purpose : Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment .

Experimental design : We evaluated under blinded conditions the ability of cell free DNA ( cfDNA ) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib , with or without cetuximab .

2   Μ Results : Prior to treatment , sequencing of archival tissue detected mutations in 25/42 patients ( 60% ) , while the cfDNA assay detected mutations in 37/42 patients ( 88% ) .
3 Μ Our cfDNA assay detected mutations with allele frequencies as low as 0.01% .
4   Μ After exposure to treatment , 41/42 patients ( 98% ) had a cfDNA detected RAS/BRAF mutation .
5   Μ Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline , 11 ( 52% ) showed additional point mutation following treatment and 3 ( 14% ) no longer had detectable levels of another mutant allele .
6 Μ Of RAS/BRAF wild type tumors at baseline , 4/5 ( 80% ) showed additional point mutations .
7 cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results , highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.

Conclusions : Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway , demonstrating a convergent evolutionary pattern .




PMID: 28399112
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cetuximab in treatment of metastatic colorectal cancer : final survival analyses and extended RAS data from the NORDIC-VII study .
1 BACKGROUND :
2 The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil , folinic acid , and oxaliplatin (Nordic FLOX) versus FLOX alone in first - line treatment of metastatic colorectal cancer .
3 Μ The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status , 5 years after the primary analysis .
4 METHODS :
5 A total of 566 patients were included in the intention-to-treat ( ITT ) population of the NORDIC-VII study .
6 Updated survival status was obtained from 176 patients who were alive in the primary survival analyses .
7 Μ Samples from 223 tumours previously found to be KRAS ( exon 2 ) and BRAF (V600E) wild-type , were re-analysed for KRAS ( exons 3 and 4 ) and NRAS ( exons 2-4 ) mutations .
8 RESULTS :
9 Including the extended RAS analyses , RAS and BRAF mutational status was available from 457 patients ( 81% of the ITT population ) .
10 RAS was mutated in 46% and BRAF in 12% of the tumours .
11 RAS and BRAF , if mutated , were negative prognostic factors .
12 The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours , neither on progression-free nor overall survival .
13   However , the outcomes in a subset of patients , which , after the first eight treatment cycles , received cetuximab alone , suggested a beneficial effect of cetuximab monotherapy .
14 CONCLUSIONS :
15   Adding cetuximab to Nordic FLOX did not provide any clinical benefit , but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort .
16 The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone .



PMID: 28398227
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Miniaturized Real-Time PCR on a Q3 System for Rapid KRAS Genotyping .
1 Colorectal cancer ( CRC ) is an aggressive human malignancy with a complex genomic landscape harboring KRAS mutations .
2 In 40%-60% of patients with CRC , constantly active KRAS proteins affect the prognosis , surgical strategy , and clinical benefit from therapy with anti-epidermal growth factor receptor ( EGFR ) agents .
3 For this reason , there is a greater demand for minimally-invasive diagnostic devices to characterize the genetic pattern and prevent the acquired mechanism to drug resistance .
4 The rapid developments in cutting-edge diagnostic techniques are expected to play a growing role in medicine and represent an attractive promise to identify potential responders to personalized medicine .
5 Μ Here we propose a new method to simultaneously detect the main KRAS mutations on the portable real-time PCR Q3 platform .
6 This platform is based on hybrid silicon-plastic technology implemented in a miniaturized chip able to achieve a sample-in answer-out rapid analysis , allowing a new approach to genetic counseling and testing .



PMID: 28395759
(Patient)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification .
1 We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics ( PK ) monitoring .
2 Patients were stratified by their pharmacogenetic/phenotypic status : the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter , while the 5-fluorouracil ( 5-FU ) dose was initially adjusted according to dihydropyrimidine dehydrogenase ( DPD ) activity at initial screening ( 5-FUODPM Tox ) followed by PK-guided dose optimization ( 5-FUODPM Protocol ) .
3 An advanced cetuximab PK/pharmacodynamics ( PD ) study was performed but dosage remained unchanged .
4 Eighty-five patients receiving second - line chemotherapy were enrolled .
5 Mean irinotecan doses at 3 months were 247 +/- 50 , 210 +/- 53 and 140 +/- 21 mg/m2 for those with 6/6 ( 33 ) , 6/7 ( 26 ) , and 7/7 (7) TATA repeats in the UGT1A1 promoter region , respectively .
6 The 5-FU dose was initially reduced in four patients with DPD deficiency , but mean 5-FU dose at 3 months was 2,412 +/- 364 mg/m2 ( 1,615-3,170 mg/m2 ) .
7 Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8% , 5.9% , and 0% of patients with 6/6 , 6/7 , and 7/7 UGT1A1 genotypes .
8 The objective response rate was 25.8% among the 85 patients , 57.3% in patients with tumors wild type ( WT ) for KRAS , and 25% in those whose tumor harbored a mutant -KRAS .
9 Secondary resection of hepatic metastases was performed in 31.7% of patients .
10 Median progression-free survival ( PFS ) for all 85 patients was 181 days and 200 , 132 , and 121 days for patients with 6/6 , 6/7 , and 7/7 UGT1A1 genotypes , respectively ; these differences were not statistically different .
11 In parallel , a strong relationship was shown between cetuximab AUC and regimen efficacy .
12 We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification .



PMID: 28392022
(Patient)  
Terms: Retrospective, retrospective
Sent# Symbols Sentence Mnemonics
0 REOX : Evaluation of the Efficacy of Retreatment With an Oxaliplatin-containing Regimen in Metastatic Colorectal Cancer : A Retrospective Single-center Study .
1 BACKGROUND :
2 Treatment of metastatic colorectal adenocarcinoma ( mCRC ) has evolved , and survival is over 30 months in contemporary trials .
3 Nevertheless , there is a paucity of effective regimes after the first or second - line treatment .
4 Thus , reexposure to previously used drugs has become a treatment strategy for some patients .
5 We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features .
6 PATIENTS AND METHODS :
7 We retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin ( REOX ) .
8 REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure .
9 Primary endpoint was time to treatment failure ( TTF ) .
10 RESULTS :
11 The median age was 53.5 years , and the female/male ratio was 51.8%/48.2% .
12 The site of the primary tumor was colon ( 675% ) and rectal ( 325% ) .
13 KRAS was mutated in 39.8% .
14 Liver-limited metastasis was found in 19.3% of patients .
15 The main regimen was 5-fluorouracil , levoleucovorin , and oxaliplatin (mFOLFOX6) ( 843% ) .
16 Bevacizumab and cetuximab were used in 42.2% and 6% of patients , respectively .
17 REOX was used in the third and fourth lines in 48.2% and 25.3% of patients , respectively .
18 The median TTF after REOX was 6.04 months .
19 Overall survival ( OS ) was 10.04 months .
20 Disease control ( complete response + partial response + stable disease ) was observed in 56.6% , whereas 42.2% had progressive disease .
21 Partial response + complete response to previous oxaliplatin was predictive of prolonged OS .
22 Patients who attained disease control had better median OS compared with those with progressive disease ( 145 vs. 624 months ; P <0001 ) .
23 CONCLUSION :
24   In the setting of heavily pretreated patients with mCRC , REOX was an effective treatment , with mTTF of 6.04 months in our cohort .
25   Selection of patients with the longest time since previous oxaliplatin can translate in better outcome .
26 Further studies should be conducted to confirm our data .



PMID: 28386169
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Establishment of apoptotic regulatory network for genetic markers of colorectal cancer .
1 Our purpose is to screen out genetic markers applicable to early diagnosis for colorectal cancer and to establish apoptotic regulatory network model for colorectal cancer , thereby providing theoretical evidence and targeted therapy for early diagnosis of colorectal cancer .
2 Taking databases including CNKI , VIP , Wanfang data , Pub Med , and MEDLINE as main sources of literature retrieval , literatures associated with genetic markers applied to early diagnosis of colorectal cancer were searched to perform comprehensive and quantitative analysis by Meta analysis , hence screening genetic markers used in early diagnosis of colorectal cancer .
3 Gene Ontology ( GO ) analysis and Kyoto Encyclopedia of Genes and Genomes ( KEGG ) analysis were employed to establish apoptotic regulatory network model based on screened genetic markers , and then verification experiment was conducted .
4 Through Meta analysis , seven genetic markers were screened out , including WWOX , K-ras , COX-2 , p53 , APC , DCC and PTEN , among which DCC shows highest diagnostic efficiency .
5 GO analysis of genetic markers found that six genetic markers played role in biological process , molecular function and cellular component .
6 It was indicated in apoptotic regulatory network built by KEGG analysis and verification experiment that WWOX could promote tumor cell apoptotic in colorectal cancer and elevate expression level of p53 .
7 The apoptotic regulatory model of colorectal cancer established in this study provides clinically theoretical evidence and targeted therapy for early diagnosis of colorectal cancer .



PMID: 28382467
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Plasticity of Resistance and Sensitivity to Anti-Epidermal Growth Factor Receptor Inhibitors in Metastatic Colorectal Cancer .
1 Colorectal cancer ( CRC ) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide .
2 Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor ( VEGF ) and epidermal growth factor receptor ( EGFR ) .
3 Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis .
4 The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies .
5 Μ From these genome -scale analyses , we know that a handful of genes are commonly affected by somatic mutations , whereas recurrent copy-number alterations and chromosomal translocations are rarer in this disease .
6 Even though some of these molecular abnormalities make genes acting as drivers of cancer progression , translation of this recognition for therapeutic purposes is still limited , encompassing only as standard of care the exclusion of RAS-mutated cancers for better selecting patients to candidate to EGFR-targeted therapy with monoclonal antibodies .
7 However , the effort of ameliorating molecular selection should not be considered exhausted by demonstration of RAS and BRAF -induced resistance , as the genomic landscape of response to EGFR blockade has been demonstrated to be wider and dynamically multifaceted .
8 In this chapter we will review main molecular biomarkers of de novo ( primary ) and acquired ( secondary ) resistance to EGFR-targeted monoclonal antibodies in metastatic CRC and discuss therapeutic implications .



PMID: 28382227
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Performance of a Web-based Method for Generating Synoptic Reports .
1 CONTEXT :
2 The College of American Pathologists ( CAP ) requires synoptic reporting of all tumor excisions .
3 OBJECTIVE :
4 To compare the performance of different methods of generating synoptic reports .
5 METHODS :
6 Completeness , amendment rates , rate of timely ordering of ancillary studies ( KRAS in T4/N1 colon carcinoma ) , and structured data file extraction were compared for four different synoptic report generating methods .
7 RESULTS :
8 Use of the printed tumor protocols directly from the CAP website had the lowest completeness ( 84% ) and highest amendment ( 18% ) rates .
9 Reformatting these protocols was associated with higher completeness ( 94% , P <0001 ) and reduced amendment ( 1% , P = 020 ) rates .
10 Extraction into a structured data file was successful 93% of the time .
11 Word-based macros improved completeness ( 98% vs. 94% , P <0001 ) but not amendment rates ( 15% ) .
12 KRAS was ordered before sign out 89% of the time .
13 In contrast , a web-based product with a reminder flag when items were missing , an embedded flag for data extraction , and a reminder to order KRAS when appropriate resulted in improved completeness ( 100% , P = 0005 ) , amendment rates ( 03% , P = 003 ) , KRAS ordering before sign out ( 100% , P = 023 ) , and structured data extraction ( 100% , P <0001 ) without reducing the speed ( P = 034 ) or accuracy ( P = 100 ) of data extraction by the reader .
14 CONCLUSION :
15 Completeness , amendment rates , ancillary test ordering rates , and data extraction rates vary significantly with the method used to construct the synoptic report .
16 A web-based method compares favorably with all other methods examined and does not reduce reader usability .



PMID: 28378527
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 The prognostic value of simultaneous tumor and serum RAS/RAF mutations in localized colon cancer .
1 The impact of RAS/RAF mutations in localized colon cancer needs clarification .
2 Based on analysis of tumor-specific DNA , this study aimed at elucidating the prognostic influence of mutational status in tumor and serum using an extended panel of mutations .
3 The study retrospectively included 294 patients with curatively resected stage I-III adenocarcinoma of the colon .
4 Mutations in tumor and serum were determined at time of surgery .
5 Analyses were performed with droplet digital PCR technology .
6 Μ Hazard ratio ( HR ) for the association between mutational status and survival was estimated in multivariate analysis taking known prognostic factors into account .
7 Mutational status in tumor did not on its own have significant prognostic impact ( P = 022 ) .
8 ✓ Patients with a RAS mutation simultaneously in tumor and serum had a significantly worse prognosis , overall survival ( OS ) ( HR = 230 , 95% CI = 127-415 , P = 00057 ) , and disease-free survival ( DFS ) ( HR = 218 , 95%CI = 126-377 , P = 00053 ) . GM-ASS-RO
9 BRAF mutation in the serum and proficient mismatch repair ( pMMR ) protein in tumor also indicated significantly worse prognosis , OS ( HR = 345 , 95% CI = 152-785 , P = 00032 ) and DFS ( HR = 361 , 95% CI = 170-767 , P = 00008 ) .
10 In conclusion , RAS mutations in serum , and BRAF mutation in serum combined with pMMR in tumor were strong independent prognostic factors in patients with RAS/RAF mutated tumors .



PMID: 28378457
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 DNA methylation epigenotype and clinical features of NRAS-mutation(+) colorectal cancer .
1 Sporadic colorectal cancer ( CRC ) is classified into several molecular subtypes .
2 We previously established two groups of DNA methylation markers through genome -wide DNA methylation analysis to classify CRC into distinct subgroups : high - , intermediate - , and low-methylation epigenotypes ( HME , IME , and LME , respectively ) .
3 HME CRC , also called CpG island methylator phenotype ( CIMP )- high CRC , shows methylation of both Group 1 markers ( CIMP markers ) and Group 2 markers , while IME/CIMP-low CRC shows methylation of Group 2 , but not of Group 1 markers , and LME CRC shows no methylation of either Group 1 or Group 2 markers .
4 While BRAF - and KRAS-mutation(+) CRC strongly correlated with HME and IME , respectively , clinicopathological features of NRAS-mutation(+) CRC , including association with DNA methylation , remain unclear .
5 Μ To characterize NRAS-mutation(+) CRC , the methylation levels of 19 methylation marker genes ( 6 Group 1 and 13 Group 2 ) were analyzed in 61 NRAS-mutation(+) and 144 NRAS-mutation(-) CRC cases by pyrosequencing , and their correlation with clinicopathological features was investigated .
6 Different from KRAS-mutation(+) CRC , NRAS-mutation(+) CRC significantly correlated with LME .
7 Μ NRAS-mutation(+) CRC showed significantly better prognosis than KRAS-mutation(+) CRC ( P = 3 x 10-4 ) .
8 Μ NRAS-mutation(+) CRC preferentially occurred in elder patients ( P = 002 ) and at the distal colon ( P = 0006 ) , showed significantly less lymph vessel invasion ( P = 0002 ) , and correlated with LME ( P = 8 x 10-5 ) .
9 DNA methylation significantly accumulated at the proximal colon .
10 NRAS-mutation(+) CRC may constitute a different subgroup from KRAS-mutation(+) CRC , showing significant correlation with LME , older age , distal colon , and relatively better prognosis .



PMID: 28368414
(Cell)  
Terms: , mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 TGFbeta engages MEK/ERK to differentially regulate benign and malignant pancreas cell function .
1 While TGFbeta signals are anti-proliferative in benign and well-differentiated pancreatic cells , TGFbeta appears to promote the progression of advanced cancers .
2 To better understand dysregulation of the TGFbeta pathway , we first generated mouse models of neoplastic disease with TGFbeta receptor deficiencies .
3 These models displayed reduced levels of pERK irrespective of KRAS mutation .
4 Furthermore , exogenous TGFbeta led to rapid and sustained TGFBR1 -dependent ERK phosphorylation in benign pancreatic duct cells .
5 Similar to results that our group has published in colon cancer cells , inhibition of ERK phosphorylation in duct cells mitigated TGFbeta -induced upregulation of growth suppressive pSMAD2 and p21 , prevented downregulation of the pro-growth signal CDK2 and ablated TGFbeta -induced EMT .
6 These observations suggest that ERK is a key factor in growth suppressive TGFbeta signals , yet may also contribute to detrimental TGFbeta signaling such as EMT .
7 In neoplastic PanIN cells , pERK was not necessary for either TGFbeta -induced pSMAD2 phosphorylation or CDK2 repression , but was required for upregulation of p21 and EMT indicating a partial divergence between TGFbeta and MEK/ERK in early carcinogenesis .
8 In cancer cells , pERK had no effect on TGFbeta -induced upregulation of pSMAD2 and p21 , suggesting the two pathways have completely diverged with respect to the cell cycle .
9 Furthermore , inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFbeta , consistent with most observations identifying pERK as a tumor promoter .
10 Combined , these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFbeta -mediated cell cycle arrest , yet remains critical for the pathological , EMT -inducing arm of TGFbeta signaling .
11 Oncogene advance online publication , 3 April 2017 ; doi : 10.1038/onc.2016.500 .



PMID: 28368388
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Methylation of WNT target genes AXIN2 and DKK1 as robust biomarkers for recurrence prediction in stage II colon cancer .
1 Stage II colon cancer ( CC ) still remains a clinical challenge with patient stratification for adjuvant therapy ( AT ) largely relying on clinical parameters .
2 Prognostic biomarkers are urgently needed for better stratification .
3 Previously , we have shown that WNT target genes AXIN2 , DKK1 , APCDD1 , ASCL2 and LGR5 are silenced by DNA methylation and could serve as prognostic markers in stage II CC patients using methylation-specific PCR .
4 Here , we have extended our discovery cohort AMC90-AJCC-II ( N = 65 ) and methylation was analyzed by quantitative pyrosequencing .
5 Subsequently , we validated the results in an independent EPICOLON1 CC cohort ( N = 79 ) .
6 Methylation of WNT target genes is negatively correlated to mRNA expression .
7 A combination of AXIN2 and DKK1 methylation significantly predicted recurrences in univariate ( area under the curve ( AUC ) =0.83 , confidence interval ( CI ) : 0.72-0.94 , P<0.0001 ) analysis in stage II microsatellite stable ( MSS ) CC patients .
8 This two marker combination showed an AUC of 0.80 ( CI : 0.68-0.91 , P<0.0001 ) in the EPICOLON1 validation cohort .
9 Multivariate analysis in the Academic Medical Center ( AMC ) cohort revealed that both WNT target gene methylation and consensus molecular subtype 4 ( CMS4 ) are significantly associated with poor recurrence-free survival ( hazard ratio ( HR ) methylation : 3.84 , 95% CI : 1.14-12.43 ; HRCMS4 : 3.73 , 95% CI : 1.22-11.48 ) .
10 CMS4 subtype tumors with WNT target methylation showed worse prognosis .
11 Combining WNT target gene methylation and CMS4 subtype lead to an AUC of 0.89 ( 0791-0982 , P<00001 ) for recurrence prediction .
12 Μ Notably , we observed that methylation of DKK1 is high in BRAF mutant and CIMP ( CpG island methylator phenotype )- positive cancers , whereas AXIN2 methylation appears to be associated with CMS4 .
13 Methylation of AXIN2 and DKK1 were found to be robust markers for recurrence prediction in stage II MSS CC patients .
14 Further validation of these findings in a randomized and prospective manner could pave a way to identify poor prognosis patients of stage II CC for AT .



PMID: 28368335
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer .
1 Outcomes for metastatic colorectal cancer ( mCRC ) patients have been improved by treatment with anti-epidermal growth factor receptor ( anti-EGFR ) antibodies , particularly when combined with predictive biomarkers to select patients lacking RAS mutations .
2   New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain .
3 Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy .
4   In the current review , we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC .



PMID: 28368067
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Naringin induces autophagy-mediated growth inhibition by downregulating the PI3K/Akt/mTOR cascade via activation of MAPK pathways in AGS cancer cells .
1 Selective BRafV600E inhibitors with DFG-in conformation have been proven effective against a subset of melanoma .
2 However , representative inhibitor vemurafenib rapidly acquires resistance in the BRafWT cells through a CRaf or BRafWT dependent manner .
3 Simultaneous targeting of all subtypes of Raf proteins offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance .
4 Herein , we describe the design and characterization of a series of compounds I-01-I-22 , based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors .
5 Among them , I-15 binds to all Raf protomers with IC50 values of 12.6 nM ( BRafV600E ) , 30.1 nM ( ARaf ) , 19.7 nM ( BRafWT ) and 17.5 nM ( CRaf ) and demonstrates cellular activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colorectal cancer cells .
6 The western blot results for the P-Erk inhibition in human melanoma SK-Mel-2 cell line showed that I-15 inhibited the proliferation of the SK-Mel-2 cell line at concentrations as low as 400 nM , without paradoxical activation of Erk as vemurafenib , which supported that I-15 may become a good candidate compound to overcome the resistance of melanoma induced by vemurafenib .
7 I-15 also has a favorable pharmacokinetic profile in rats .
8 Rational design , synthesis , SAR , lead selection and evaluation of the key compounds studied are described .



PMID: 28366103
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Methods of selecting combination therapy for colorectal cancer patients : a patent evaluation of US20160025730A1 .
1 INTRODUCTION :
2 Colorectal cancer ( CRC ) is the fourth most common cancer worldwide .
3 Targeted therapy drugs ( TTDs ) are a valid treatment , epithelial growth factor receptor ( EGFR ) inhibitors being one of the most commonly used for CRC patients .
4 However , this treatment is only useful for patients with wild-type KRAS ( wtKRAS ) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network .
5 Areas covered : The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting , predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors .
6 The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy ; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation .
7 Expert opinion : To assess the clinical applicability of this invention , further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line ( Lim1215 ) .
8   Furthermore , other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed .



PMID: 28365952
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cell -free DNA as biomarker and source for mutation detection in primary colorectal cancer .
1 PURPOSE :
2 To analyze if cell -free ( cf ) DNA levels and the presence of KRAS and BRAF mutations in serum could be used as diagnostic biomarkers in patients with primary colorectal cancer ( CRC ) .
3 METHODS :
4 This study included 92 individuals who were operated due to primary CRC ( N = 52 ; study group ) and to hemorrhoids ( N = 40 ; control group ) .
5 Serum cfDNA levels were measured with real-time PCR ( RT-PCR ) using PicoGreen dsDNA quantitation reagent .
6 Colorectal tissue and related blood and serum samples taken at the time of surgery were subjected to DNA extraction and analysis of KRAS and BRAF mutations based on multiplex SNaPshot assay and DNA sequencing .
7 RESULTS :
8 The average cfDNA concentration was lower in patients of the study group ( 20+/-7 ng/muL ) in comparison to controls ( 34+/-9 ng/muL ) and this difference was statistically significant ( p<0001 ) .
9 Μ The SNaPshot analysis detected KRAS c35 mutations in colorectal tumor tissue in 14 cases , but the presence of the mutation was not confirmed in cfDNA extracted from blood samples of these patients .
10 CONCLUSIONS :
11 The level of serum cfDNA in CRC is decreased in comparison to patients with hemorrhoids , which questions the usefulness of cfDNA as cancer biomarker .
12 Also , cfDNA does not appear to be suitable as a source for mutation detection in this disease .



PMID: 28365424
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Drug nanocarriers for cancer chemotherapy based on microemulsions : The case of Vemurafenib analog PLX4720 .
1 Oil-in-water ( O/W ) microemulsions based on Tween 80 as the emulsifier and triacetin as the dispersed oil phase were formulated to be used as delivery vehicles of Vemurafenib analog PLX4720 .
2 PLX4720 is a lipophilic antitumor drug against various cancer types correlated with the BRAFV600E mutation .
3 The limits of the single-phase region corresponding to O/W microemulsions as described by ternary phase diagrams were examined .
4 Droplet size measurements determined by dynamic light scattering ( DLS ) showed mean droplet diameters equal to 10+/-0.1nm both in the presence and in absence of the drug .
5 Cryogenic-transmission electron microscopy ( Cryo-TEM ) images of the microemulsions showed the existence of small structures with uniform size distribution having also average diameters of approximately 10nm .
6 Electron paramagnetic resonance ( EPR ) spectroscopy applying the spin probing technique confirmed PLX4720 location in the oil cores excluding its participation in the surfactants monolayer .
7 Furthermore , cell viability assays on colon cancer cell lines Colo-205 and HT29 showed that microemulsions did not exhibit any cytotoxicity when added in ratios between 0.005% v/v and 0.2% v/v .
8 When the cells were treated with encapsulated PLX4720 at two different concentrations ( 0063 and 012muMu ) the same response as when dissolved in classic DMSO was observed .



PMID: 28364795
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The significance of DNA methylation profile in metastasis-related genes for the progression of colorectal cancer .
1 DNA methylation , an epigenetic modification plays a role in the pathogenesis of colorectal cancer ( CRC ) .
2 CRC cases , both sporadic and familial , are often characterized by abnormal pattern of the cytosine methylation in CpG dinucleotides in regulatory regions of genes important for cancer transformation .
3 Also genes mutated in CRC can have their epigenetic pattern altered and we suggest that changes in DNA methylation array can be important for CRC metastatic potential the main reason of CRC-associated mortality .
4 These genes are : KRAS , genes of the Rho family of GTPases , MACC1 , Met , MTA1 and RASSF1A .
5 In addition , genes encoding miRNA important for epithelial mesenchymal transition and other metastasis-related effects , such as mir-9 , miR-34 and miR-210 can be good candidates for associating their DNA methylation profiles with CRC metastasis .
6 Analysis of DNA methylation profile in various stages of CRC along with other genetic/epigenetic changes specific for all main stages of CRC transformation could help in anti-metastatic therapy immediately after CRC diagnosis .
7 However , targeting DNA methylation pattern in CRC therapy is a conception , which requires further work to precisely change DNA methylation array , without affecting genes , whose expression should not be changed .



PMID: 28363909
(Patient)  
Terms: Phase I, phase II
Sent# Symbols Sentence Mnemonics
0 A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer .
1 Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models .
2 Patients with refractory BRAFV600-mutant metastatic CRC ( mCRC ) were treated with a selective RAF kinase inhibitor ( encorafenib ) plus a monoclonal antibody targeting EGFR ( cetuximab ) , with ( n = 28 ) or without ( n = 26 ) a PI3Kalpha inhibitor ( alpelisib ) .
3 The primary objective was to determine the maximum tolerated dose ( MTD ) or a recommended phase II dose .
4 Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment .
5 The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib ( both groups ) and 300 mg alpelisib .
6   Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC ; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual - and triple-therapy groups , respectively .
7   Significance : Herein , we demonstrate that dual - ( encorafenib plus cetuximab ) and triple - ( encorafenib plus cetuximab and alpelisib ) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC .
8 Cancer Discov ; 7(6) ; 610-9 .
9 (c) 2017 AACR .
10 See related commentary by Sundar et al. , p. 558This article is highlighted in the In This Issue feature , p. 539 .



PMID: 28359236
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Challenges in molecular testing in non-small - cell lung cancer patients with advanced disease .
1 Mutant allele specific imbalance in oncogenes with copy number alterations : Occurrence , mechanisms , and potential clinical implications .



PMID: 28358339
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Novel Palladium (II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells .
1 New Pd ( II ) complexes of 1,7-bis ( 2-methoxyphenyl ) hepta-1,6-diene-3,5-dione were synthesized and structurally characterized .
2 The complexes were tested in vitro on human colon and hepatic carcinoma cell lines , normal hepatic cells and hematopoietic progenitor cells .
3 Biological tests proved that Pd ( II ) complexes 1 and 2 ( containing a curcumin derivative ) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma .
4 Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth ; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes .
5 Μ By flow cytometric measurements , an important decrease of prominin-1 ( CD133 ) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2 .
6 Quantitative immune enzymatic assay proved restrictions in stem cell factor ( SCF ) release by treated tumor cells .
7 Although less cytotoxic , the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells , and in HT-29 colon carcinoma .
8 The new synthesized Pd ( II ) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations , which leads to the tumor growth arrest and prevention of metastasis .



PMID: 28356954
(Patient)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 Multicenter phase II study of infusional 5-fluorouracil ( 5-FU ) , leucovorin , and oxaliplatin , plus biweekly cetuximab as first - line treatment in patients with metastatic colorectal cancer ( CELINE trial ) .
1 The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil ( 5-FU ) , leucovorin , and oxaliplatin (FOLFOX-6)] in the first - line treatment of KRAS wild-type metastatic colorectal cancer ( mCRC ) .
2 Sixty patients with a median age of 64 years ( range , 38-82 syears ) received a biweekly intravenous infusion of cetuximab ( 500 mg/m2 on day 1 ) followed by FOLFOX-6 ( 2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2 , and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1-3 ) .
3 Patient response rate was 70% , with 95% disease control rates .
4 The median progression-free survival was 13.8 months .
5 Thirteen patients ( 217% ) were able to undergo resection of previously unresectable metastases , with the aim of curing them .
6 The median follow-up was 22.7 months , and median overall survival was 31.0 months .
7 Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated .
8   The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first - line treatment of KRAS wild-type metastatic colorectal cancer .
9 Efficacy was comparable to other treatment regimens .
10   The results support the administration of biweekly cetuximab in combination with FOLFOX-6 , which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers .



PMID: 28353383
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 SP174 , NRAS Q61R Mutant -Specific Antibody , Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma .
1 CONTEXT :
2 - NRAS is a member of the RAS family oncoproteins implicated in cancer .
3 Gain-of-function NRAS mutations were reported in a subset of colorectal cancers .
4 Μ These mutations occur at codons 12 , 13 , and 61 and are detected by molecular genetic testing .
5 Recently , an antibody (clone SP174) became available to immunohistochemically pinpoint NRAS Q61R mutant protein .
6 In malignant melanoma , NRAS Q61R mutant -specific immunohistochemistry was shown to be a valuable supplement to traditional genetic testing .
7 OBJECTIVE :
8 - To evaluate the significance of NRAS Q61R mutant -specific immunohistochemistry in a cohort of colorectal carcinomas .
9 DESIGN :
10 - A total of 1185 colorectal carcinomas were immunohistochemically evaluated with SP174 antibody .
11 NRAS Q61R mutant -specific immunohistochemistry was validated by molecular genetic testing including Sanger sequencing , quantitative polymerase chain reaction ( qPCR ) , and next-generation sequencing .
12 RESULTS :
13 - Twelve tumors showed strong SP174 immunoreactivity .
14 Μ Sanger sequencing detected an identical c.182A>G substitution , causing NRAS Q61R mutation at the protein level , only in 8 SP174-positive cases .
15 These results were confirmed by qPCR study .
16 Μ Subsequently , NRAS wild-type tumors with strong SP174 staining were evaluated by next-generation sequencing and revealed KRAS c.182A>G substitutions predicted to cause KRAS Q61R mutation .
17 Review of colorectal carcinomas with known KRAS and NRAS genotype revealed that none of 62 wild-type tumors or 47 mutants other than Q61R were SP174 positive .
18 CONCLUSION :
19 - SP174 immunohistochemistry allows sensitive detection of NRAS and KRAS Q61R mutants .
20 However , molecular genetic testing is necessary to determine specifically which RAS gene is mutated .



PMID: 28353122
(None)  
Terms: Phase II study
Sent# Symbols Sentence Mnemonics
0 Phase II study of the Multikinase inhibitor of angiogenesis , Linifanib , in patients with metastatic and refractory colorectal cancer expressing mutated KRAS .
1 Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients .



PMID: 28345467
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mitochondrial DNA alteration in primary and metastatic colorectal cancer : Different frequency and association with selected clinicopathological and molecular markers .
1 This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability .
2 Therefore , we investigated the concordance of microsatellite instability in D310 , D514 , and D16184 ( mitochondrial DNA displacement loop ) , and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients .
3 Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases ( 531% ) compared to primary tumors ( 375% ) and distant metastases ( 214% ) ( p = 00183 and p = 00005 ) .
4 The discordant rate was significantly higher in lymph node metastases/primary tumor pairs ( 746% ) than in distant metastases/primary tumor pairs ( 524% ) or lymph node metastases/distant metastases pairs ( 516% ) ( p = 00113 and p = 00261 ) with more gain ( 867% ) than loss ( 611% ) of microsatellite instability in the discordant lymph node metastases ( p = 00024 ) .
5 Μ Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years ( p = 00122 and p = 00129 ) , was found with a significant high rate in a small cohort of TP53-mutated distant metastases ( p = 00418 ) , and was associated with TP53 wild-type status of primary tumors ( p = 00009 ) , but did not correlate with KRAS , NRAS , BRAF , or PIK3CA mutations .
6 In conclusion , mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer , which could have importance for surveillance and therapeutic strategies .



PMID: 28344745
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis ?
1 In resectable colorectal liver metastasis ( CRLM ) the role and use of molecular biomarkers is still controversial .
2 Several biomarkers have been linked to clinical outcomes in CRLM , but none have so far become routine for clinical decision making .
3 For several reasons , the clinical risk score appears to no longer hold the same predictive value .
4 Some of the reasons include the ever expanding indications for liver resection , which now increasingly tend to involve extrahepatic disease , such as lung metastases ( both resectable and non-resectable ) and the shift in indication from "what is taken out" ( e.g. , how much liver has to be resected ) to "what is left behind" ( that is , how much functional liver tissue the patient has after resection ) .
5 The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection .
6 Added to this complexity is the increasing number of molecular markers , which appear to hold important prognostic and predictive information , for which some will be discussed here .
7 Beyond characteristics of tissue -based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell -free circulating tumor DNA in the blood .
8 These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease .
9 Circulating biomarkers may represent more readily available methods to monitor , characterize and predict cancer biology with future implications for cancer care .



PMID: 28339087
(Cell)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor -like growth factor .
1 In colorectal cancer , gain-of-function mutations in KRas play a critical role in malignant transformation .
2 Tumor growth in colorectal cancer is known to be promoted by the intestinal myofibroblasts ( IMFs ) that localize adjacent to the cancer cells , but the mechanisms of interaction between KRas-mutated cancer cells and the myofibroblasts remain unclear .
3 Here , we investigated the effects of KRas-mutated cells on the behavior of myofibroblasts by using mouse primary IMFs and cells of an IMF cell line ( LmcMF ) and a mouse colon epithelial cell line (aMoC1) .
4 Conditioned medium ( CM ) was collected from aMoC1 cells overexpressing a control vector or KRasV12 vector ( KRasV12-CM ) , and the effects of KRasV12-CM on IMFs were analyzed by performing proliferation assays , wound-healing assays , Boyden chamber assays , and western blotting .
5 Whereas KRasV12-CM exerted little effect on the differentiation and proliferation of primary IMFs , the CM promoted migration of both primary IMFs and LmcMF cells .
6 In KRasV12-overexpressing aMoC1 cells , mRNA expression of heparin-binding epidermal growth factor-like growth factor ( HB-EGF ) was higher than in mock-transfected aMoC1 cells , and HB-EGF promoted the migration of primary IMFs and LmcMF cells .
7 Moreover , KRasV12-CM -induced IMF migration was suppressed by dacomitinib , an inhibitor of HB-EGF receptors .
8 Notably , in LmcMF cells , both KRasV12-CM and HB-EGF activated extracellular signal-regulated kinase ( ERK ) and c-jun N-terminal kinase ( JNK ) , whereas KRasV12-CM -induced migration of IMFs was suppressed following treatment with either an ERK inhibitor (FR180204) or a JNK inhibitor (SP600125) .
9 These results suggest that HB-EGF secreted from KRas-mutated colorectal cancer cells promotes IMF migration through ERK and JNK activation , which , in turn , could support cancer progression .



PMID: 28331530
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS detection on archival cytological smears by the novel fully automated polymerase chain reaction-based Idylla mutation test .
1 BACKGROUND :
2 Molecular techniques are relevant to modern cytopathology , but their implementation is difficult without molecular expertise and infrastructure .
3 The assessment of KRAS mutational status on cytological preparations may be useful either to refine uncertain diagnoses on pancreatic aspirates or to yield predictive information to plan targeted treatment of metastatic colorectal cancer ( mCRC ) .
4 The novel test Idylla enables fully automated KRAS genotyping in approximately 2 h , even in less experienced hands .
5 MATERIALS AND METHODS :
6 Μ This study aims to validate this methodology to detect KRAS mutations on archival cytological preparations of pancreatic cancer ( n = 9 ) and mCRC ( n = 9 ) by comparing the Idylla performance to that of standard real-time polymerase chain reaction .
7 RESULTS :
8 The same 11 mutations ( n = 4 : p.G12D ; n = 2 : p.G12V ; n = 2 : p.A59E/G/T ; n = 1 : p.G12R ; n = 1 : p.G13D ; n = 1 : p.Q61H ) were detected by both techniques .
9 CONCLUSION :
10 Even in less experienced laboratories , a cytopathologist may easily integrate morphological diagnostic report with accurate KRAS mutation detection , which is relevant for diagnostic and treatment decisions .



PMID: 28328959
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 KRAS and VEGF gene 3'-UTR single nucleotide polymorphisms predicted susceptibility in colorectal cancer .
1 Single nucleotide polymorphisms ( SNPs ) in tumor-related genes have been reported to play important roles in cancer development .
2 Recent studies have shown that 3'-untranslated regions ( UTR ) polymorphisms are associated with the occurrence and prognosis of cancers .
3 Μ The aim of this study is to analyze the association between KRAS and VEGF gene 3'-UTR SNPs and genetic susceptibility to colorectal cancer ( CRC ) .
4 Μ In this case-control study of 371 CRC cases and 246 healthy controls , we analyzed the association between one SNP ( rs1137188G >A ) in the KRAS gene and four SNPs ( rs3025039C >T , rs3025040C >T , rs3025053G >A and rs10434A >G ) in the VEGF gene and CRC susceptibility by the improved multiplex ligase detection reaction ( iMLDR ) method .
5 We checked the selected SNPs' minor allele frequency and its distribution in the frequency of Chinese people by Hap-map database and Hardy-Weinberg equilibrium , and used multivariate logistic regression models to estimate adjusted odds ratios ( AORs ) and 95% confidence intervals ( 95% CIs ) .
6 Μ We found that the rs3025039C variant genotype in the VEGF gene was associated with a significant protection for CRC ( AOR = 0693 , 95% CI = 0485-0989 ; P = 0043 for CC and CT+TT ) .
7 Nevertheless , the difference was no longer significant after Bonferroni correction ( Bonferroni-adjusted P = 0172 ) .
8 Μ In genetic polymorphisms analysis , we found that the KRAS rs1137188 variant AA genotype had higher portion of tumor size ( >/= 5 cm ) ( P = 001 ; Bonferroni-adjusted P = 004 ) , which suggested that the rs1137188 variant AA genotype may significantly be associated with increased progression of CRC .
9 In conclusion , our study suggested that these five SNPs in the KRAS gene and the VEGF gene were not associated with CRC susceptibility in Han Chinese in Sichuan province .



PMID: 28328955
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell -free DNA .
1 Treatment of metastatic colorectal cancer ( CRC ) has continuously improved over the last decade .
2 However , disease monitoring remains underdeveloped and mostly dependent on imaging e.g . RECIST 1.1 criteria .
3 The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies .
4 Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic predictions .
5 Carcinoembryonic antigen ( CEA ) , a routinely used tumor marker for CRC , does not meet these goals and thus prevents its use as a reliable monitoring tool .
6 A tumor-derived fraction of circulating cell -free DNA ( cfDNA ) , isolated from blood samples , may bypass the limitations of currently available biomarkers and could be a tool for noninvasive disease monitoring .
7 Here , total cfDNA levels differentiated a cohort of metastatic CRC patients from healthy controls .
8 Furthermore , we correlated cfDNA during chemotherapy of 27 stage IV patients with clinical parameters to establish its prognostic and predictive value .
9   Indeed , cfDNA levels in chemotherapy naive patients correlate with the tumor burden and CEA values at diagnosis and increase upon disease progression during 1st and 2nd line treatment .
10 Moreover , we confirm the possibility of cfDNA-based genotyping of KRAS to early detect the emergence of resistance during chemotherapy .
11 Μ These data indicate that repetitive quantitative and mutational analysis of cfDNA might complement current treatment standards but may have also limited value in some patients .



PMID: 28328812
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Overall survival of patients with KRAS wild-type tumor treated with FOLFOX/FORFIRI+/-cetuximab as the first - line treatment for metastatic colorectal cancer : A meta-analysis .
1 The addition of cetuximab to FOLFIRI or FOLFOX as the first - line treatment for metastatic colorectal cancer ( mCRC ) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease .
2 An updated systematic meta-analysis was undertaken to determine the efficacy of cetuximab plus FOLFIRI or FOLFOX .
3 Major databases were searched to identify RCTs investigating wild-type KRAS mCRC after the first - line treatment , and treatment with FOLFOX/FORFIRI +/- cetuximab was compared .
4 Data on clinical efficacy and safety were pooled and compared by ORs , HRs , and 95% CIs .
5 Five eligible trials with 1464 patients were included in the meta-analysis .
6 Compared to FOLFOX/FORFIRI , cetuximab as the first - line therapy has improved overall survival ( OS ) ( hazard ratio [HR] = 0.82 , 95% confidence interval [CI] : 0.72-0.93 , P = 0.003 ) , progression-free survival ( PFS ) ( HR = 0.66 , 95% CI : 0.56 -0.77 , P <0.00001 ) , and overall response rate ( ORR ) ( odds ratio [OR] = 2.12 , 95% CI : 1.70-2.65 , P <0.00001 ) .
7 However , Grade 3/4 AE was increased with the OR of 2.76 ( 95%CI : 2.01-3.78 , P <0.00001 ) .
8 The most common grade 3/4 toxicity in the wild-type KRAS population was neutropenia and diarrhea .
9 For cetuximab plus FOLFIRI , there was a higher incidence of grade 3 or 4 diarrhea ( OR = 1.76 , 95% CI : 1.15-2.70 , P = 0.01 ) , but there was no significant difference for neutropenia ( OR = 1.35 , 95% CI : 1.00-1.83 , P = 0.05 ) .
10   The addition of cetuximab in mCRC as the first - line treatment is a potential effective approach in the improved outcomes but associated with increased toxicity .



PMID: 28327908
(Patient)  
Terms: prospective, Clinical trial, NCT00003835
Sent# Symbols Sentence Mnemonics
0 Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 ( Alliance ) .
1 Background : Observational studies suggest that higher levels of 25-hydroxyvitamin D3 ( 25 ( OH ) D ) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients .
2 However , the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown .
3 Patients and methods : We prospectively examined the influence of post-diagnosis predicted plasma 25 ( OH ) D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial ( CALGB 89803 ) .
4 Predicted 25 ( OH ) D scores were computed using validated regression models .
5 We examined the influence of predicted 25 ( OH ) D scores on cancer recurrence and mortality ( disease-free survival ; DFS ) using Cox proportional hazards .
6 Results : Patients in the highest quintile of predicted 25 ( OH ) D score had an adjusted hazard ratio ( HR ) for colon cancer recurrence or mortality ( DFS ) of 0.62 ( 95% confidence interval [CI] , 0.44-0.86 ) , compared with those in the lowest quintile ( Ptrend = 0005 ) .
7 Higher predicted 25 ( OH ) D score was also associated with a significant improvement in recurrence-free survival and overall survival ( Ptrend = 001 and 00004 , respectively ) .
8 The benefit associated with higher predicted 25 ( OH ) D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics , including microsatellite instability and KRAS , BRAF , PIK3CA , and TP53 mutation status .
9 Conclusion : Higher predicted 25 ( OH ) D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival .
10 Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted .
11 ClinicalTrials .
12 gov Identifier : NCT00003835 .



PMID: 28325827
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sessile Serrated Polyps and Colon Cancer Prevention .
1   Quantification and dynamic monitoring of EGFR T790M in plasma cell -free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC .



PMID: 28325280
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 miR-134 : A Human Cancer Suppressor ?
1 MicroRNAs ( miRNAs ) are small noncoding RNAs approximately 20-25 nt in length , which play crucial roles through directly binding to corresponding 3' UTR of targeted mRNAs .
2 It has been reported that miRNAs are involved in numerous of diseases , including cancers .
3 Recently , miR-134 has been identified to dysregulate in handles of human cancers , such as lung cancer , glioma , breast cancer , colorectal cancer , and so on .
4   Increasing evidence indicates that miR-134 is essential for human carcinoma and participates in tumor cell proliferation , apoptosis , invasion and metastasis , drug resistance , as well as cancer diagnosis , treatment , and prognosis .
5 Nevertheless , its roles in human cancer are still ambiguous , and its mechanisms are sophisticated as well , referring to a variety of targets and signal pathways , such as STAT5B , KRAS , MAPK/ERK signal pathway , Notch pathway , etc .
6   Herein , we review the crucial roles of miR-134 in scores of human cancers via analyzing latest investigations , which might provide evidence for cancer diagnose , treatment , prognosis , or further investigations .



PMID: 28314739
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Intratumorous heterogeneity for RAS mutations in a treatment-naive colorectal tumour .
1 Activating mutations in KRAS and NRAS genes in patients with colorectal cancer ( CRC ) are associated with a lack of response to treatment with anti-epidermal growth factor receptor ( EGFR ) therapies .
2 Mutations in these genes are thought to be mutually exclusive , however reports have described CRCs with two activating rat sarcoma ( RAS ) mutations .
3 This has fuelled discussion about whether these mutations are the result of intratumorous heterogeneity , or if they are co-occurring in the same cancer cell clone .
4 Μ We present a case of a colorectal tumour with three RAS mutations detected during routine diagnostic testing .
5 Further detailed analysis with laser capture microdissection and next generation sequencing excluded the possibility of all three mutations being present in the same clone , presenting the highest resolution evidence of intratumorous heterogeneity of RAS mutations to date .



PMID: 28314302
(Patient)  
Terms: prospective, retrospective
Sent# Symbols Sentence Mnemonics
0 KRAS Mutant Status May Be Associated with Distant Recurrence in Early-stage Rectal Cancer .
1 BACKGROUND/AIM :
2 Total mesorectal excision combined with neo-adjuvant chemoradiotherary ( CRT ) and adjuvant chemotherapy , has been the standard treatment of locally advanced rectal cancer ( LARC ) .
3 Although TNM ( Tumor , Node , Metastasis ) classification for malignant Tumors is still the cornerstone in rectal cancer staging , there has been an effort to identify molecular biomarkers with additional prognostic or predictive value .
4 MATERIALS AND METHODS :
5 We retrospectively analyzed molecular biomarkers on prospectively collected histological specimens and clinical data from a cohort of 135 consecutive rectal cancer cases who underwent radical excision in a tertiary center between 2011-2014 ( males = 87 , females = 48 , age range = 22-89 years , mean = 64,67 years , SD = 1340 ) .
6 Radiological , histopathological , molecular staging , treatment stratification by the multidisciplinary team ( MDT ) , as well as prognostic outcome data were compared with various biomarkers including KRAS , BRAF , p16 , b-catenin , MSI , MMR and MGMT .
7 RESULTS :
8 The mean follow-up was 39.21 months ( range = 5-83 months , SD = 2134 ) .
9 Twenty-eight cases were Stage I ( 209% ) , n = 30 Stage II ( 224% ) , n = 45 Stage III ( 336% ) and n = 31 Stage IV ( 231% ) .
10 Forty specimens were KRAS-mutant ( mt ) ( 374% ) while n = 67 ( 626% ) wild type ( wt ) .
11 KRAS mt status was associated with female sex ( n = 20 , p = 0021 ) and older age ( 6962 vs. 6227 , p = 0005 ) .
12 Stage I Early Cancer Subgroup analysis showed that KRAS mt status is associated with distant recurrence of disease ( n = 4 , p = 0045 ) .
13 CONCLUSION :
14 ✓ KRAS mt status may affect the prognosis of early rectal cancer , as this is linked with distant recurrence . GE-INV-RO



PMID: 28314271
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification of Methylation Profiles of Cancer-related Genes in Circulating Tumor Cells Population .
1 BACKGROUND :
2 We performed an epigenetic analysis of the first exon of the hVIM gene and the SFRP2 in circulating tumor cells ( CTCs ) and correlation with the corresponding primary colorectal cancer ( CRC ) tissue .
3 PATIENTS AND METHODS :
4 CTCs detection in 52 colorectal cancer patients was managed by a multi-marker immunomagnetic method with the use of quantum dots ( QDs ) .
5 To determine methylation levels we used high-resolution melting ( HRM ) technology .
6 RESULTS :
7 In the case of VIM we found 76.9% methylated samples , compared to 53.8% in tissue samples .
8 Regarding SFRP2 promoter methylation levels in tissue and CTCs samples , 67.3% and 73.1% , were found methylated respectively .
9 Correlation analysis of methylation levels with KRAS and BRAF mutations ( performed in our previous study ) demonstrates that high-methylation epigenotype strongly correlates to BRAF mutation .
10 CONCLUSION :
11 CTCs is a promising diagnostic tool .
12 The combination of genetic mutations and epigenetic aberrations specifically in CTCs , will ameliorate CRC diagnosis in the future .



PMID: 28301591
(Patient)  
Terms: ex vivo, In vivo, xenograft, in vivo
Sent# Symbols Sentence Mnemonics
0 In vivo and ex vivo cetuximab sensitivity assay using three-dimensional primary culture system to stratify KRAS mutant colorectal cancer .
1 In clinic , cetuximab , an anti-EGFR antibody , improves treatment outcomes in colorectal cancer ( CRC ) .
2 KRAS-mutant CRC is generally resistant to cetuximab , although difference of the sensitivity among KRAS-mutants has not been studied in detail .
3 We previously developed the cancer tissue -originated spheroid ( CTOS ) method , a primary culture method for cancer cells .
4 We applied CTOS method to investigate whether ex vivo cetuximab sensitivity assays reflect the difference in sensitivity in the xenografts .
5 Firstly , in vivo cetuximab treatment was performed with xenografts derived from 10 CTOS lines ( 3 KRAS-wildtype and 7 KRAS mutants ) .
6 All two CTOS lines which exhibited tumor regression were KRAS-wildtype , meanwhile all KRAS-mutant CTOS lines grew more than the initial size : were resistant to cetuximab according to the clinical evaluation criteria , although the sensitivity was quite diverse .
7 We divided KRAS-mutants into two groups ; partially responsive group in which cetuximab had a substantial growth inhibitory effect , and resistant group which exhibited no effect .
8 The ex vivo signaling assay with EGF stimulation revealed that the partially responsive group , but not the resistant group , exhibited suppressed ERK phosphorylation ex vivo .
9 Furthermore , two lines from the partially responsive group , but none of the lines in the resistant group , exhibited a combinatory effect of cetuximab and trametinib , a MEK inhibitor , ex vivo and in vivo .
10 Taken together , the results indicate that ex vivo signaling assay reflects the difference in sensitivity in vivo and stratifies KRAS mutant CTOS lines by sensitivity .
11 Therefore , coupling the in vivo and ex vivo assays with CTOS can be a useful platform for understanding the mechanism of diversity in drug sensitivity .



PMID: 28300842
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage .
1 CD95 is best known for its ability to induce apoptosis via a well-characterized pathway involving caspase-mediated proteolytic events .
2 However , in apoptosis-resistant cell lines of diverse cancer types stimulation of CD95 primarily has pro-tumorigenic effects that affect many of the hallmarks of cancer .
3 For instance , in colon cancer cells with a mutant KRAS gene CD95 primarily promotes invasion and metastasis .
4 In the current study , we further investigated the context dependency of the consequences of CD95 activation in colon cancer .
5 We used a series of patient-derived three-dimensional colon cancer cultures and studied their response to stimulation with CD95 ligand ( CD95L ) .
6 CD95L had a strong inhibitory effect on the clone -forming capacity of five out of nine cultures .
7 Μ In line with previous work , these cultures all had a wild-type KRAS gene and expressed high levels of CD95 .
8 Furthermore , the most sensitive cultures were characterized by microsatellite instability ( MSI ) and deficient mismatch repair .
9 The reduced clonogenic growth of MSI-type colonospheres resulting from chronic CD95 stimulation was only partly due to apoptosis as many tumor cells survived treatment , yet were unable to regenerate clones .
10 CD95 stimulation caused an irreversible cell cycle arrest , which was associated with cytokine secretion , similar to the senescence-associated secretory phenotype ( SASP ) , and expression of senescence-associated beta-galactosidase .
11 Μ In human colon cancer cohorts , CD95 expression was strongly correlated with the recently identified consensus molecular subtype 1 ( CMS1 ) , which mainly consists of MSI-high tumors , and with two independent SASP signatures .
12 Mechanistically , CD95 -induced senescence was caused by chronic DNA damage via caspase-activated DNAse resulting in p53 activation and p21 expression , with a minor contribution of the SASP .
13 We conclude that induction of senescence is a hitherto unrecognized consequence of high CD95 expression , which appears to be most relevant for CMS1 .



PMID: 28299879
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 How accurate are medical oncologists' impressions of management of metastatic colorectal cancer in Australia ?
1 AIM :
2 Current efforts to understand patient management in clinical practice are largely based on clinician surveys with uncertain reliability .
3 The TRACC ( Treatment of Recurrent and Advanced Colorectal Cancer ) database is a multisite registry collecting comprehensive treatment and outcome data on consecutive metastatic colorectal cancer ( mCRC ) patients at multiple sites across Australia .
4 This study aims to determine the accuracy of oncologists' impressions of real-word practice by comparing clinicians' estimates to data captured by TRACC .
5 METHODS :
6 Nineteen medical oncologists from nine hospitals contributing data to TRACC completed a 34-question survey regarding their impression of the management and outcomes of mCRC at their own practice and other hospitals contributing to the database .
7 Responses were then compared with TRACC data to determine how closely their impressions reflected actual practice .
8 RESULTS :
9 Data on 1300 patients with mCRC were available .
10 Median clinician estimated frequency of KRAS testing within 6 months of diagnosis was 80% ( range : 20-100% ) ; the TRACC documented rate was 43% .
11   Clinicians generally overestimated the rates of first - line treatment , particularly in patients over 75 years .
12 Estimate for bevacizumab in first line was 60% ( 35-80% ) versus 49% in TRACC .
13 Estimated rate for liver resection varied substantially ( 5-35% ) , and the estimated median ( 27% ) was inconsistent with the TRACC rate ( 12% ) .
14 Oncologists generally felt their practice was similar to other hospitals .
15 CONCLUSIONS :
16 Oncologists' estimates of current clinical practice varied and were discordant with the TRACC database , often with a tendency to overestimate interventions .
17 Clinician surveys alone do not reliably capture contemporary clinical practices in mCRC .



PMID: 28292978
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Validating a fully automated real-time PCR-based system for use in the molecular diagnostic analysis of colorectal carcinoma : a comparison with NGS and IHC .
1 BACKGROUND :
2 Molecular testing is increasingly needed in colorectal carcinoma ( CRC ) and the current clinically relevant mutations are in BRAF , KRAS and NRAS .
3 This study aimed to further validate a new alternative polymerase chain reaction ( PCR ) platform ( Idylla , Biocartis ) against existing next-generation sequencing ( NGS ) and immunohistochemistry ( IHC ) assays .
4 METHODS :
5 56 Idylla tests were performed on 43 CRC cases , in a total of 74 comparisons against an NGS panel ( Ion Torrent ) and the VE1 ( anti-BRAF ) antibody IHC .
6 Discrepant cases were also compared with either conventional ( Cobas ) or droplet digital PCR ( Bio-Rad ) .
7 RESULTS :
8 Idylla showed an overall concordance of 100% ( 95% CI 93% to 100% ) with comparator molecular testing and indications were that Idylla is likely to be more sensitive than routine NGS .
9 BRAF IHC showed 90% concordance with NGS ( 95% CI 70% to 97% ) .
10 CONCLUSIONS :
11 This study validates Idylla in formalin-fixed , paraffin-embedded CRC tissue .
12 BRAF IHC , however , is an unreliable substitute for molecular testing in CRC .



PMID: 28289141
(None)  
Terms: , mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 Oncogenic Kras drives invasion and maintains metastases in colorectal cancer .
1 Μ Human colorectal cancer ( CRC ) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene .
2 To understand the role of oncogenic KRAS in CRC , we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele ( Krasmut ) and conditional null alleles of Apc and Trp53 (iKAP) .
3 The iKAP model recapitulates tumor progression from adenoma through metastases .
4 Μ Whole-exome sequencing revealed that the Krasmut allele was heterogenous in primary tumors yet homogenous in metastases , a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis .
5 System-level and functional analyses revealed the TGF-beta pathway as a key mediator of Krasmut -driven invasiveness .
6 Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors , leading to apoptotic elimination of advanced invasive and metastatic disease .
7 This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases .



PMID: 28283541
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to , and toxicity from , cetuximab .
1 BACKGROUND :
2 Somatic mutations in the epidermal growth factor receptor ( EGFR ) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer ( aCRC ) .
3 We hypothesised that common germline variants within these pathways may also play similar roles .
4 METHODS :
5 Μ We analysed 54 potentially functional , common , inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab .
6 Primary endpoints were response and skin rash ( SR ) .
7 Μ We had >85% power to detect ORs = 1.6 for variants with minor allele frequencies >20% .
8 RESULTS :
9 We identified five potential biomarkers for response and four for SR , although none remained significant after correction for multiple testing .
10 ✓ Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab-in patients with KRAS wild-type CRCs , 36.4% with one allele encoding proline responded , as compared with 71.2% homozygous for allele encoding serine ( OR 023 , 95% CI 009 to 056 , p = 00014 ) , and this association was predictive for cetuximab ( pinteraction = 0017 ) ; however , independent replication failed to validate this association . GM-REG-RO
11 No previously proposed predictive biomarkers were validated .
12 CONCLUSIONS :
13 Our study highlights the need to validate potential pharmacogenetic biomarkers .
14 We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity .



PMID: 28282860
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations .
1 The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy .
2 This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene .
3 Since the initial identification of the BRAF mutation in 2002 , a series of small molecular inhibitors that target the BRAFV600E have been developed , but intrinsic and acquired resistance to these drugs has presented an ongoing challenge .
4 More recently , improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs , such as inhibitors of the downstream effector LONGTOKEN .
5 Despite improved success in response rates and in delaying resistance using combination therapy , ultimately , the acquisition of resistance remains a concern .
6 Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies .
7 This review will explore some of the resistance mechanisms , compare what is known in melanoma cancer to colorectal cancer , and discuss strategies under development to manage the development of resistance .



PMID: 28281325
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF mutations are associated with increased iron regulatory protein -2 expression in colorectal tumorigenesis .
1 A role for iron in carcinogenesis is supported by evidence that iron metabolism proteins are modulated in cancer progression .
2 To date , however , the expression of iron regulatory protein -2 ( IRP2 ) , which is known to regulate several iron metabolism proteins , has not been assessed in colorectal cancer .
3 Expression of IRP2 was assessed by quantitative RT-PCR and immunohistochemistry in human colorectal cancer tissue .
4 By interrogating The Cancer Genome Atlas ( TCGA ) database , expression of IRP2 and transferrin receptor -1 ( TfR1 ) was assessed relative to common mutations that are known to occur in cancer .
5 The impact of suppressing IRP2 on cellular iron metabolism was also determined by using siRNA and by using the MEK inhibitor trametinib .
6 IRP2 was overexpressed in colorectal cancer compared to normal colonic mucosa and its expression was positively correlated with TfR1 expression .
7 In addition , IRP2 expression was associated with mutations in BRAF .
8 The MEK inhibitor trametinib suppressed IRP2 and this was associated with a suppression in TfR1 and the labile iron pool ( LIP ) .
9 Moreover , epidermal growth factor stimulation resulted in decreased ferritin expression and an increase in the LIP which were independent of IRP2 .
10 Results presented here suggest that ablating IRP2 provides a therapeutic platform for intervening in colorectal tumorigenesis .



PMID: 28280626
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Current companion diagnostics in advanced colorectal cancer ; getting a bigger and better piece of the pie .
1 While the treatment of colorectal cancer continues to rely heavily on conventional cytotoxic therapy , an increasing number of targeted agents are under development .
2 Many of these treatments require companion diagnostic tests in order to define an appropriate population that will derive benefit .
3 In addition , a growing number of biomarkers provide prognostic information about a patient's malignancy .
4 As we learn more about these biomarkers and their assays , selecting the appropriate companion diagnostic becomes increasingly important .
5 In the case of many biomarkers , there are numerous assays which could provide the same information to a treating physician , however each assay has strengths and weaknesses .
6 Institutions must balance cost , assay sensitivity , turn-around time , and labor resources when selecting which assay to offer .
7 In this review we will discuss the current state of companion diagnostics available in metastatic colorectal cancer and explore emerging biomarkers and their assays .
8 We will focus on KRAS , BRAF , HER2 , and PIK3CA testing , as well as microsatellite stability assessment and multigene panels .



PMID: 28280620
(Patient)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 Potential actionable targets in appendiceal cancer detected by immunohistochemistry , fluorescent in situ hybridization , and mutational analysis .
1 BACKGROUND :
2 Appendiceal cancers are rare and consist of carcinoid , mucocele , pseudomyxoma peritonei ( PMP ) , goblet cell carcinoma , lymphoma , and adenocarcinoma histologies .
3 Current treatment involves surgical resection or debulking , but no standard exists for adjuvant chemotherapy or treatment for metastatic disease .
4 METHODS :
5 Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory .
6 A total of 588 samples with appendix primary tumor sites were identified ( male/female ratio of 2 : 3 ; mean age =55 ) .
7 Sixty-two percent of samples were adenocarcinomas ( used for analysis ) ; the rest consisted of 9% goblet cell , 15% mucinous ; 6% pseudomyxoma , and less than 5% carcinoids and 2% neuroendocrine .
8 Tests included sequencing [Sanger , next generation sequencing ( NGS ) ] , protein expression/immunohistochemistry ( IHC ) , and gene amplification [fluorescent in situ hybridization ( FISH ) or CISH] .
9 RESULTS :
10 Profiling across all appendiceal cancer histological subtypes for IHC revealed : 97% BRCP , 81% MRP1 , 81% COX-2 , 71% MGMT , 56% TOPO1 , 5% PTEN , 52% EGFR , 40% ERCC1 , 38% SPARC , 35% PDGFR , 35% TOPO2A , 25% RRM1 , 21% TS , 16% cKIT , and 12% for TLE3 .
11 Μ NGS revealed mutations in the following genes : 50.4% KRAS , 21.9% P53 , 17.6% GNAS , 16.5% SMAD4 , 10% APC , 7.5% ATM , 5.5% PIK3CA , 5.0% FBXW7 , and 1.8% BRAF .
12 CONCLUSIONS :
13 Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins ( BCRP and MRP1 ) , which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment .
14 The incidence of low TS ( 79% ) could be used as a backbone of therapy ( using inhibitors such as 5FU/capecitabine or newer agents ) .
15 Therapeutic options includeTOPO1 inhibitors ( irinotecan/topotecan ) , EGFR inhibitors ( erlotinib , cetuximab ) , PDGFR antagonists ( regorafenib , axitinib ) , MGMT ( temozolomide ) .
16 Clinical trials targeting pathways involving KRAS , p53 , GNAS , SMAD4 , APC , ATM , PIK3CA , FBXW7 , and BRAF may be also considered .
17 Overall , appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers ( can we say this , any statistical analysis done? ) and have differential expression from colorectal cancers .
18   These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration , in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers ( supported by a grant from Caris Life Sciences ) .



PMID: 28280609
(Patient)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 [ Research Progress of EGFR-TKI Therapy for Patients with Central Nervous System Metastases from Non-small Cell Lung Cancer ] .
1 Vemurafenib is a potent and selective BRAF inhibitor , which is effective on patients with BRAF V600E mutated late-stage melanoma .
2 Common and less common adverse skin reactions include photosensitivity , maculo-papular exanthema , hand-foot skin reactions , hyperkeratotic follicular rash , pruritus , benign verrucous papillomas , plantar hyperkeratosis , keratoacanthomas , squamous cell carcinomas , infections , and melanoma .
3 To our knowledge , vitiligo has been reported in 2 cases only .
4 This paper reports the case of a 63-year-old man with metastatic melanoma , who developed sudden facial depigmentation after 4 weeks of treatment with vemurafenib 960 mg twice daily .
5 Features consistent with vitiligo were evident at clinical and ultraviolet light examination , as well as at in vivo reflectance confocal microscopy .
6 The latter examination showed lack of normal brightly refractile papillary rings at the dermo-epidermal junction in lesional skin , as well as decreased brightness and half-rings with "scalloped border-like" features in adjacent non-lesional skin .
7 Vitiligo is an adverse reaction to be expected in patients treated with vemurafenib and whether its occurrence may be associated with a positive outcome , as suggested by previous investigations , is still a matter of debate .

J Drugs Dermatol . 2016 ; 15(6) : 766-768 .



PMID: 28280605
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer .
1 BACKGROUND :
2 In the management of metastatic colorectal cancer ( mCRC ) , KRAS , NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients ( pts ) with an aggressive clinical course .
3 We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy , predict for a response and highlight key signaling pathways important for clinical decision making .
4 METHODS :
5 Relapsed and refractory mCRC pts ( N = 32 ) were molecularly profiled utilizing commercially available next generation sequencing ( NGS ) platforms .
6 Web-based bioinformatics tools ( Reactome/Enrichr ) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy .
7 RESULTS :
8 Pts had progressed on fluoropyrimidines , oxaliplatin , irinotecan , bevacizumab , cetuximab and/or panitumumab .
9 Most common histology was adenocarcinoma ( colon N = 29 ; rectal N = 3 ) .
10 Of the mutations TP53 was the most common , followed by APC , KRAS , PIK3CA , BRAF , SMAD4 , SPTA1 , FAT1 , PDGFRA , ATM , ROS1 , ALK , CDKN2A , FBXW7 , TGFBR2 , NOTCH1 and HER3 .
11 Pts had on average had >/ = 5 unique mutations .
12 The most frequent activated signaling pathways were : HER2 , fibroblast growth factor receptor ( FGFR ) , p38 through BRAF-MEK cascade via RIT and RIN , ARMS -mediated activation of MAPK cascade , and VEGFR2 .
13 CONCLUSIONS :
14 Dominant driver oncogene mutations do not always equate to oncogenic dependence , hence understanding pathogenic 'interactomes ' in individual pts is key to both clinically relevant targets and in choosing the next best therapy .
15   Mutational signatures derived from corresponding 'pathway-networks' represent a meaningful tool to (I) evaluate functional investigation in the laboratory ; ( II ) predict response to drug therapy ; and ( III ) guide rational drug combinations in relapsed and refractory mCRC pts .



PMID: 28280603
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma : Review of the Literature .
1 BACKGROUND :
2 Family history of colon cancer often portends increased risk of disease development ; however , the prognostic significance of family history related to disease and survival outcomes is unclear .
3 METHODS :
4 To investigate the relationship between family history of colorectal cancer and survival outcomes in stage III colon cancer patients , a prospective cohort of 1,935 patients with resected stage III colon cancer enrolled in a randomized controlled trial ( N0147 ) , comparing the standard of care FOLFOX to FOLFOX with cetuximab , was studied .
5 Patients completed a baseline questionnaire on family history and were followed every 6 months until death or 5 years after randomization .
6 RESULTS :
7 We examined the endpoints of disease-free survival ( DFS ) , time to recurrence ( TTR ) and overall survival ( OS ) , comparing patients with a positive versus negative family history of colorectal cancer .
8 The adjusted hazard ratios ( HRs ) for patients with a positive family history were 0.95 [95% confidence interval ( CI ) , 0.78-1.16] for DFS , 0.94 ( 95% CI , 076-116 ) for TTR , and 0.92 ( 95% CI , 074-115 ) for OS ( all adjusted P>047 ) .
9 A non-significant trend toward improved DFS ( P = 017 ; adjusted P = 034 ) was observed when 2 or more relatives were affected as compared to 0 relatives ( multivariate HR : 0.72 ; 95% CI , 0.45-1.15 ) , whereas subjects with histories of 0 or 1 affected relatives had similar DFS ( multivariate HR for 1 vs. 0 : 1.00 ; 95% CI , 0.81-1.24 ) .
10 Interactions of the molecular factors KRAS , BRAF , and MMR with family history were also explored .
11 The only significant interaction was for deficient MMR ( dMMR ) and first-degree relatives with a family history of colorectal cancer ( 0 vs. 1 vs. 2+ relatives ) for a benefit on OS ( univariate P = 0001 ) , which remained significant after adjusting for other factors ( P = 0029 ) .
12 CONCLUSIONS :
13 Among patients with stage III resected colon cancer treated with adjuvant FOLFOX , a family history of colorectal cancer did not significantly impact DFS , TTR , or OS outcomes , with the exception of patients with dMMR-expressing tumors .



PMID: 28280091
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer .
1 Μ Genomic Characterization of Low - and High-Grade Pancreatic Mucinous Cystic Neoplasms Reveals Recurrent KRAS Alterations in "High-Risk" Lesions .



PMID: 28278514
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is a heterogeneous disease in terms of molecular carcinogenic pathways .
3 Based on recent findings regarding the multiple serrated neoplasia pathway , we revised an eight-marker panel for a new CIMP classification system .
4 METHODS :
5 1370 patients who received surgical resection for CRCs were classified into three CIMP subtypes ( CIMP-N : 0-4 methylated markers , CIMP-P1 : 5-6 methylated markers and CIMP-P2 : 7-8 methylated markers ) .
6 Our findings were validated in a separate set of high-risk stage II or stage III CRCs receiving adjuvant fluoropyrimidine plus oxaliplatin ( n = 950 ) .
7 RESULTS :
8 A total of 1287/62/21 CRCs cases were classified as CIMP-N/CIMP-P1/CIMP-P2 , respectively .
9 CIMP-N showed male predominance , distal location , lower T , N category and devoid of BRAF mutation , microsatellite instability ( MSI ) and MLH1 methylation .
10 CIMP-P1 showed female predominance , proximal location , advanced TNM stage , mild decrease of CK20 and CDX2 expression , mild increase of CK7 expression , BRAF mutation , MSI and MLH1 methylation .
11 CIMP-P2 showed older age , female predominance , proximal location , advanced T category , markedly reduced CK20 and CDX2 expression , rare KRAS mutation , high frequency of CK7 expression , BRAF mutation , MSI and MLH1 methylation .
12 CIMP-N showed better 5-year cancer-specific survival ( CSS ; HR = 0.47 ; 95% CI : 0.28-0.78 ) in discovery set and better 5-year relapse-free survival ( RFS ; HR = 0.50 ; 95% CI : 0.29-0.88 ) in validation set compared with CIMP-P1 .
13 CIMP-P2 showed marginally better 5-year CSS ( HR = 0.28 , 95% CI : 0.07-1.22 ) in discovery set and marginally better 5-year RFS ( HR = 0.21 , 95% CI : 0.05-0.92 ) in validation set compared with CIMP-P1 .
14 CONCLUSIONS :
15 Μ CIMP subtypes classified using our revised system showed different clinical outcomes , demonstrating the heterogeneity of multiple serrated precursors of CIMP-positive CRCs .



PMID: 28277374
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Predictors for KRAS Codon 13 Mutations in Patients With Colorectal Cancer .
1 GOALS :
2 This study sought to clarify sex differences in KRAS mutations and clinical predictors of KRAS 13 codon mutations .
3 BACKGROUND :
4 Sex differences in KRAS mutations and predictors for KRAS codon 13 mutations in colorectal cancer ( CRC ) are unclear .
5 STUDY :
6 Μ Between October 2007 and May 2016 , 328 patients underwent surgery for CRCs that were analyzed for KRAS mutations at a referral university hospital .
7 Μ Sex differences in the rates and distributions of KRAS mutations , and factors predictive of overall KRAS and KRAS codon 13 mutations were analyzed .
8 RESULTS :
9 KRAS mutations were significantly more common in women than men patients ( 460% vs. 344% , P<0033 ) .
10 Μ However , no sex differences were detected for KRAS mutations by codon subtypes ( P = 0592 ) .
11 Μ The Gly13Asp ( GGC>GAC ) point mutation was identified only within codon 13 in both sexes .
12 Μ For right-sided CRC , KRAS mutations were twice as frequent in men as in women ( univariate analysis ; P = 0016 , multivariate analysis ; P = 0019 ) .
13 High-plasma cholesterol level was an independent predictive factor of KRAS codon 13 mutations by univariate ( odds ratio , 1013 ; 95% confidence interval , 1003-1023 ) and multivariate analysis ( odds ratio , 1011 ; 95% confidence interval , 1001-1021 ) .
14 CONCLUSIONS :
15 Μ Sex differences may affect the presentation of KRAS mutations , as they were more frequently detected in women and in right-sided CRC in men .
16 KRAS codon 13 mutations were significantly associated with high-plasma cholesterol .
17 Further studies are needed on the clinical implications of this finding .



PMID: 28275039
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Right Versus Left Colon Cancer Biology : Integrating the Consensus Molecular Subtypes .
1 Although clinical management of colon cancer generally has not accounted for the primary tumor site , left-sided and right-sided colon cancers harbor different clinical and biologic characteristics .
2 Right-sided colon cancers are more likely to have genome -wide hypermethylation via the CpG island methylator phenotype ( CIMP ) , hypermutated state via microsatellite instability , and BRAF mutation .
3 There are also differential exposures to potential carcinogenic toxins and microbiota in the right and left colon .
4 Gene expression analyses further shed light on distinct biologic subtypes of colorectal cancers ( CRCs ) , with 4 consensus molecular subtypes ( CMSs ) identified .
5 Importantly , these subtypes are differentially distributed between right - and left-sided CRCs , with greater proportions of the "microsatellite unstable/immune" CMS1 and the "metabolic" CMS3 subtypes found in right-sided colon cancers .
6   This review summarizes important biologic distinctions between right - and left-sided CRCs that likely impact prognosis and may predict for differential responses to biologic therapy .
7   Given the inferior prognosis of stage III-IV right-sided CRCs and emerging data suggesting that anti-epidermal growth factor receptor antibody therapy is associated with worse survival in right-sided stage IV CRCs compared with left-sided cancers , these biologic differences between right - and left-sided CRCs provide critical context and may provide opportunities to personalize therapy .



PMID: 28275037
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colon Cancer , Version 1.2017 , NCCN Clinical Practice Guidelines in Oncology .
1 This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease .
2   Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history , extent of disease , goals of treatment , the efficacy and toxicity profiles of the regimens , KRAS/NRAS mutational status , and patient comorbidities and preferences .
3 Location of the primary tumor , the BRAF mutation status , and tumor microsatellite stability should also be considered in treatment decisions .



PMID: 28268248
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers .
1 Decoding Tumor Phenotypes for ALK , ROS1 , and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach .



PMID: 28267766
(Patient)  
Terms: retrospective studies
Sent# Symbols Sentence Mnemonics
0 ✓ Association of SMAD4 mutation with patient demographics , tumor characteristics , and clinical outcomes in colorectal cancer . GM-ASS-RO
1 SMAD4 is an essential mediator in the transforming growth factor -beta pathway .
2 Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers ( CRCs ) but data are limited .
3 In this study , we aimed to evaluate clinicopathologic characteristics , prognosis , and clinical outcome associated with this mutation in CRC cases .
4 Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed .
5 Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations , and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system .
6 Using The Cancer Genome Atlas data on CRC , the characteristics of SMAD4 and transforming growth factor -beta pathway mutations were evaluated according to different consensus molecular subtypes of CRC .
7 Among 734 patients with CRC , 90 ( 12% ) had SMAD4 mutations according to hotspot testing .
8 SMAD4 mutation was associated with colon cancer more so than with rectal cancer ( odds ratio 285 ; p<0001 ) , female sex ( odds ratio 171 ; p = 002 ) , and shorter overall survival than in wild-type SMAD4 cases ( median , 29 months versus 56 months ; hazard ratio 2.08 ; p<0.001 [log-rank test] ) .
9 SMAD4 mutation was not associated with age , stage at presentation , colonic location , distant metastasis , or tumor grade .
10 ✓ A subset of patients with metastatic CRC ( n = 44 ) wild-type for KRAS , NRAS , and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 ( n = 13 ) had shorter progression-free survival duration than did patients wild-type for SMAD4 ( n = 31 ) ( median , 111 days versus 180 days ; p = 0.003 [log-rank test] ) . GE-ASS-RO
11 Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations .
12 Μ In The Cancer Genome Atlas data , SMAD4 mutation frequently occurred with KRAS , NRAS , and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes .
13   This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy .
14 Further studies are required to validate these findings and the role of SMAD4 mutation in CRC .



PMID: 28265402
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel KRAS gene mutation report in sporadic colorectal cancer , from Northwest of Iran .
1   While the role of KRAS gene mutations has been widely accepted for predicting responses to anti-EGFR therapy in patients with colorectal cancer , although this study was based on observation of a single case it gives hope that some KRAS gene mutation may have favorable prognosis .
2 More studies are required on patients with similar mutation to validate this finding .



PMID: 28262927
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting RAS signaling pathway as a potential therapeutic target in the treatment of colorectal cancer .
1 Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma .



PMID: 28260928
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Long-term survival after a favorable response to anti-EGFR antibody plus chemotherapy to treat bone marrow metastasis : a case report of KRAS-wildtype rectal cancer .
1   Bone marrow metastasis is a rare consequence of colorectal cancer that results in a poor prognosis ; few reports describe a favorable response to doublet chemotherapy combined with targeted therapy , which is currently the standard treatment .
2 We experienced a case where anti-epidermal growth factor receptor ( EGFR ) antibody produced a marked anti-tumor response to bone marrow metastasis that led to long-term survival .
3 A 51-year-old man was diagnosed with a primary KRAS-wildtype rectal cancer with multiple metastases , including the bone marrow .
4 Disease control was achieved for 10.8 months following chemotherapy with a modified FOLFOX6 regimen combined with an anti-EGFR antibody .
5 He died of cancer 22.7 and 16.6 months after disease onset and first - line chemotherapy , respectively .
6 This case shows that early tumor shrinkage and deepness of response to the anti-EGFR antibody were observed even in a patient with bone marrow metastasis .
7   Anti-EGFR antibody therapy should therefore be considered even when a patient's medical condition appears to be poor owing to bone marrow metastasis .
8   Moreover , tumors that are likely to be sensitive to chemotherapy , such as RAS-wildtype colorectal cancers , can be considered for anti-EGFR antibody therapy even if the patient is considered unfit for chemotherapy .



PMID: 28259999
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical and molecular assessment of regorafenib monotherapy .
1 Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies .
2 Some patients , however , exhibit severe adverse events ( AEs ) resulting in treatment discontinuation .
3 Therefore , the selection of patients likely to benefit from regorafenib is crucial .
4 Twenty patients were treated with regorafenib for metastatic colorectal cancer ; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA ( ctDNA ) in the blood .
5 The treatment response , AEs , overall survival ( OS ) , progression-free survival ( PFS ) and tumor morphologic changes on CT images were evaluated .
6 KRAS mutant ctDNA was determined using digital PCR .
7 Median PFS and OS were 2.5 and 5.9 months , respectively .
8 Treatment was discontinued because of disease progression ( PD ) in 10 patients , and AEs in another 10 patients .
9 AEs included hyperbilirubinemia , severe fatigue and skin rash .
10 Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases , and severe fatigue in another 2 patients with poor performance status ( PS ) .
11 These severe AEs resulted in treatment discontinuation .
12 Ten patients had a median PFS of 2.1 months with AE related discontinuation ; PD occurred at 3.5 months ( p = 000334 ) .
13 Four patients exhibited a morphologic response , achieving better PFS times of 3.5 , 5.3 , 5.6 and 14.2 months .
14   Μ Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors ; it was detectable in the blood prior to radiographic detection of PD .
15   Moreover , the KRAS mutation declined in two patients during regorafenib monotherapy .
16 These patients were re-challenged with anti-EGFR antibody .
17   Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib .
18   Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs .
19 KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy .



PMID: 28259994
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overexpression of wild-type p21Ras plays a prominent role in colorectal cancer .
1 Colorectal cancer ( CRC ) is the most common gastrointestinal type of cancer .
2 The overexpression of Ras proteins , particularly p21Ras , are involved in the development of CRC .
3 However , the subtypes of the p21Ras proteins that are overexpressed and the mutation status remain unknown restricting the development of therapeutic antibodies targeting p21Ras proteins .
4 The present study aimed to investigate the mutation status of ras genes associated with Ras proteins that are overexpressed in CRC and explore whether or not wild-type p21Ras could be a target for CRC therapy .
5 p21Ras expression was examined immunohistochemically in normal colorectal epithelium , benign lesions and malignant colorectal tumor tissues by monoclonal antibody ( Mab ) KGH-R1 which is able to react with three types of p21Ras proteins : H-p21Ras , N-p21Ras and K-p21Ras .
6 Then , the expression levels of p21Ras subtypes were determined in CRC by a specific Mab for each p21Ras subtype .
7 Μ Mutation status of ras genes in p21Ras-overexpressing CRC was detected by DNA sequencing .
8 There was rare p21Ras expression in normal colorectal epithelium but a high level of p21Ras expression in CRC , with a significant increase from normal colorectal epithelium to inflammatory polyps , low-grade intraepithelial neoplasia , high-grade intraepithelial neoplasia and invasive colorectal adenocarcinoma , respectively .
9 Μ Overexpression of K-p21Ras was found in all CRC tissues tested , overexpression of N-p21Ras was found in 85.7% of the CRC tissues , while H-p21Ras expression was not found in any CRC tissue .
10 Μ DNA sequencing showed that there were no K-ras mutations in 60% of the K-p21Ras-overexpressing CRC , while 40% of the CRC tissues harbored K-ras mutations .
11 Μ N-ras mutations were not found in any N-p21Ras-overexpressing CRC .
12 Our findings indicate that overexpression of wild-type p21Ras may play a prominent role in the development of CRC in addition to ras mutations and could be a promising target for CRC therapy .



PMID: 28259135
(Cell)  
Terms: , mouse, mice
Sent# Symbols Sentence Mnemonics
0 miR-155 is positively regulated by CBX7 in mouse embryonic fibroblasts and colon carcinomas , and targets the KRAS oncogene .
1 BACKGROUND :
2 Loss of CBX7 expression has been described in several malignant neoplasias , including human colon and thyroid carcinomas proposing CBX7 as a tumor suppressor gene with a key role in cancer progression .
3 This role is supported from the development of benign and malignant neoplasias in Cbx7 null mice .
4 The aim of our work has been to investigate the mechanisms underlying the CBX7 oncosuppressor activity by analyzing the microRNAs ( miRNAs ) regulated by CBX7 .
5 METHODS :
6 The miRNA expression profiles of the mouse embryonic fibroblasts ( MEFs ) null for Cbx7 and the wild-type counterpart were analyzed by the miRNACHIP microarray and then validated by qRT-PCR .
7 To asses KRAS as target of miR-155 we evaluated the protein levels after transfection of the synthetic miR-155 .
8 Human colon carcinoma samples have been investigated for the expression of CBX7 and miR-155 .
9 RESULTS :
10 Twenty miRNAs were found upregulated and nine , including miR-155 , downregulated in cbx7-null MEFS in comparison with the wild-type ones .
11 Then , we focused on miR-155 since several studies have shown its deregulated expression in several human malignancies and , moreover , was the most downregulated miRNA .
12 Subsequently , we searched for miR-155 target genes demonstrating that KRAS protein levels are directly modulated by miR-155 .
13 Μ A direct significant correlation ( r = 06779 ) between CBX7 and miR-155 expression levels was found in a set of human colon carcinoma tissue samples .
14 CONCLUSION :
15 miR-155 is positively regulated by CBX7 in MEFs and colon carcinomas , and has KRAS as one of the target genes likely accounting for the anti-apoptotic activity ascribed to miR-155 in some tissue contexts .



PMID: 28258479
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prevalence and clinicopathologic/molecular characteristics of mismatch repair-deficient colorectal cancer in the under-50-year-old Japanese population .
1 PURPOSE :
2 To clarify the prevalence and clinicopathologic/molecular characteristics of mismatch repair ( MMR )- deficient colorectal cancer in the young Japanese population .
3 METHODS :
4 Immunohistochemical analyses for MMR proteins ( MLH1 , MSH2 , MSH6 , and PMS2 ) were performed in formalin-fixed paraffin-embedded sections prepared from the resected CRC specimens of 119 consecutive patients aged <50 years old , who underwent resection of the primary tumor at our institution between 1996 and 2015 .
5 Μ Analyses for somatic BRAF V600E mutation , somatic hypermethylation of the MLH1 promoter , and germline MMR gene mutations were undertaken where indicated .
6 RESULTS :
7 MMR protein loss was found in 10 patients ( 84% ) , 7 ( 59% ) of whom were subsequently identified to have Lynch syndrome ( LS ) .
8 The remaining 3 patients were categorized as having sporadic MMR-deficient CRC ( n = 2 ) or "possible LS ( n = 1 ) " .
9 In multivariate logistic regression analysis , the presence of tumor-infiltrating lymphocytes ( P <001 ) , right-sided location of the tumor ( P = 001 ) , and a history of LS-associated tumors in the first-degree relatives ( P <001 ) were identified as independent factors predictive of MMR-deficient CRC .
10 CONCLUSION :
11 These results are of value in the clinical management of patients with the early onset CRC under circumstances where universal tumor screening approaches for LS are still not available , like in Japan .



PMID: 28252533
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Derived neutrophil to lymphocyte ratio as a prognostic factor in patients with advanced colorectal cancer according to RAS and BRAF status : a post-hoc analysis of the MRC COIN study .
1 The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes , such as cell proliferation , differentiation , metabolism , cytoskeleton reorganization and cell death and survival .
2 Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation , on either genetic or epigenetic grounds , of these pathways has been implicated in the initiation , progression and metastastic spread of lung cances .
3 Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer , although the use of single pathway inhibitors has met with limited clinical success so far .
4 Indeed , the presence of intra - and inter-pathway compensatory loops that re-activate the very same cascade , either upstream or downstream the point of pharmacological blockade , or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated , potentially driving preclinical ( and possibly clinical ) resistance .
5 Therefore , the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect , and thus potentially overcome and/or delay clinical resistance , as compared with single agent .
6 The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting .



PMID: 28249812
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dietary Patterns and Risk of Colorectal Cancer : Analysis by Tumor Location and Molecular Subtypes .
1 BACKGROUND & ; AIMS : Western and prudent dietary patterns have been associated with higher and lower risks of colorectal cancer ( CRC ) , respectively .
2 However , little is known about the associations between dietary patterns and specific anatomic subsites or molecular subtypes of CRC .
3 METHODS :
4 We used multivariable Cox proportional hazards models to examine the associations between Western and prudent dietary patterns and CRC risk in the Health Professionals Follow-up Study and Nurses' Health Study .
5 RESULTS :
6 After up to 32 years of follow-up of 137,217 men and women , we documented 3260 cases of CRC .
7 Among individuals from whom subsite data were available , we observed 1264 proximal colon , 866 distal colon , and 670 rectal tumors .
8 Western diet was associated with an increased incidence of CRC ( Ptrend <0001 ) , with a relative risk ( RR ) of 1.31 ( 95% CI , 115-148 , comparing the highest to lowest quartile ) .
9 The association of Western diet with CRC was evident for tumors of the distal colon ( RR , 155 ; 95% CI , 122-196 ; Ptrend = 0004 ) and rectum ( RR , 135 ; 95% CI , 103-177 ; Ptrend = 01 ) but not proximal colon ( RR , 111 ; 95% CI , 091-135 ; Ptrend = 51 ) when we comparing extreme quartiles .
10 In contrast , for the prudent pattern , we observed a RR of 0.86 for overall CRC ( 95% CI , 077-095 ; Ptrend = 01 ) , with similar trends at anatomic subsites .
11 However , the trend appeared stronger among men than women .
12 Among 1285 cases ( 39% ) with tissue available for molecular profiling , Western diet appeared to be more strongly associated with some CRC molecular subtypes ( no mutations in KRAS [KRAS wildtype] or BRAF [BRAF wildtype] , no or a low CpG island methylator phenotype , and microsatellite stability ) , although formal tests for heterogeneity did not produce statistically significant results .
13 CONCLUSIONS :
14 Western dietary patterns are associated with an increased risk of CRC , particularly distal colon and rectal tumors .
15 Western dietary patterns also appear more strongly associated with tumors that are KRAS wildtype , BRAF wildtype , have no or a low CpG island methylator phenotype , and microsatellite stability .
16 In contrast , prudent dietary patterns are associated with a lower risk of CRC that does not vary according to anatomic subsite or molecular subtype .



PMID: 28246485
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Coexisting tubular adenoma with a neuroendocrine carcinoma of colon allowing early surgical intervention and implicating a shared stem cell origin .
1 High-grade colonic neuroendocrine carcinomas ( NECs ) are uncommon but extremely aggressive .
2 Their co-existence with tubular adenoma ( TA ) has rarely been reported .
3 We present a 68-year-old man who was found on routine colonoscopy to have multiple colorectal TAs and an ulcerated lesion in the ascending colon .
4 Microscopically , a poorly-differentiated invasive carcinoma juxtaposed with a TA was identified .
5 Differential diagnosis included a poorly-differentiated adenocarcinoma , medullary carcinoma , high-grade NEC and lymphoma .
6 Μ The immunohistochemical profile showed positive staining for keratins , synaptophysin and chromogranin but negative for LCA , CDX2 , CK7 , CK20 , TTF-1 and PSA , supporting the NEC diagnosis .
7 Upon subsequent laparoscopic right hemicolectomy , the tumor was identified as a 3.0 cm umbilicated and ulcerated mass with an adjacent TA .
8 Μ Both TA and NEC showed positive staining for beta-catenin indicating a shared colonic origin .
9 The mitotic counts ( 77/10 high power fields ) and a high proliferation rate ( 75% by Ki-67 ) corroborated a high-grade stratification .
10 Μ Mutational analysis indicated a wild-type BRAF and KRAS with mismatch repair proficiency .
11 The AJCC ( 7th edition ) pathologic stage is pT3 , pN0 , pMx .
12   The patient received adjuvant chemotherapy with cisplatin/etoposides for three cycles and will be followed up for a year to detect recurrence .
13 In conclusion , the co-existence of TA with high grade-NEC in our case allowed early identification and intervention of the otherwise asymptomatic but aggressive tumor .
14 In addition , the finding of a high-grade NEC within a large TA in this case suggests a link between the two lesions and could represent a shared stem cell origin .



PMID: 28246207
(Patient)  
Terms: Phase II, rat
Sent# Symbols Sentence Mnemonics
0 A Phase II , Randomized , Double-Blind , Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second - Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma .
1 LESSONS LEARNED :
2 The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group .
3 The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma .
4 BACKGROUND :
5 Simtuzumab , a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 ( LOXL2 ) , blocks desmoplastic reaction in colorectal carcinoma ( CRC ) cells in vitro .
6 METHODS :
7 Patients with metastatic rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutant CRC were randomized to receive second - line 5-fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days .
8 Progression-free survival ( PFS ) , overall survival ( OS ) , objective response rate ( ORR ) , and safety were assessed .
9 RESULTS :
10 In total , 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg ( n = 84 ) , FOLFIRI/simtuzumab 200 mg ( n = 85 ) , and FOLFIRI/placebo ( n = 80 ) .
11 ✓ After a median follow-up of 5.1 , 3.8 , and 5.5 months , respectively , median PFS for each of the respective treatment groups was 5.5 months ( adjusted HR [95% CI] , p value versus placebo ; 1.32 [092,189] ; p = .10 ) , 5.4 months ( 1.45 [101,206] ; p = .04 ) , and 5.8 months . GE-ASS-RO
12 ✓ Median OS was 11.4 months ( 1.23 [080,191] ; p = .25 ) , 10.5 months ( 1.50 [098,230] ; p = .06 ) , and 16.3 months , respectively . GE-ASS-RO
13 ORR was 11.9% , 5.9% , and 10% , respectively .
14 Simtuzumab was tolerable in metastatic KRAS mutant CRC patients .
15 CONCLUSION :
16 The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC .
17 The Oncologist 2017 ; 22 : 243-e8 .



PMID: 28245681
(None)  
Terms: clinical trial, meta-analysis
Sent# Symbols Sentence Mnemonics
0 [ Does the sidedness determine the first line treatment of irresectable metastatic colorectal cancer? ] .
1 INTRODUCTION AND AIM :
2 Median life expectancy of non-resectable metastatic colorectal cancer may surpass three years .
3 However , several points of the treatment strategy are subject of ongoing debate .
4 Optimal sequence of targeted agents is not elucidated either .
5 Based on retrospective analyses of six clinical studies and a metaanalysis , the superiority of anti-EGFR agents such as cetuximab and panitumumab over anti-VEGF bevacizumab has been proposed in the treatment of left sided tumours .
6 METHOD :
7 The results of the six major clinical trials were analysed .
8 Insufficiencies of the meta-analysis are pointed : the lack of homogeneity among control groups , the omission of later lines of therapy , the inconsistency between progression free and overall survival benefit and the high proportion of excluded patients .
9 RESULTS :
10 The trials confirm the worse prognosis of right sided versus left sided colorectal cancers .
11 CONCLUSION :
12   To date the data are not strong enough to support the preference of any of the available targeted agents at the first line setting in the treatment of left sided metastatic RAS and BRAF wild type colorectal cancers .
13   Several trials suggest that anti-EGFR treatment has no additional benefit as compared to chemotherapy alone in the treatment of right-sided tumours .
14 Orv .
15 Hetil. , 2017 , 158(9) , 340-344 .



PMID: 28243320
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Construction of a multiplex mutation hot spot PCR panel : the first step towards colorectal cancer genotyping on the GS Junior platform .
1 Background : To support cancer therapy , development of low cost library preparation techniques for targeted next generation sequencing ( NGS ) is needed .
2 In this study we designed and tested a PCR-based library preparation panel with limited target area for sequencing the top 12 somatic mutation hot spots in colorectal cancer on the GS Junior instrument .
3 Materials and Methods : A multiplex PCR panel was designed to amplify regions of mutation hot spots in 12 selected genes ( APC , BRAF , CTNNB1 , EGFR , FBXW7 , KRAS , NRAS , MSH6 , PIK3CA , SMAD2 , SMAD4 , TP53 ) .
4 Amplicons were sequenced on a GS Junior instrument using ligated and barcoded adaptors .
5 Eight samples were sequenced in a single run .
6 Μ Colonic DNA samples ( 8 normal mucosa ; 33 adenomas ; 17 adenocarcinomas ) as well as HT-29 and Caco-2 cell lines with known mutation profiles were analyzed .
7 Μ Variants found by the panel on APC , BRAF , KRAS and NRAS genes were validated by conventional sequencing .
8 Μ Results : In total , 34 kinds of mutations were detected including two novel mutations ( FBXW7 c1740 : C>G and SMAD4 c413C>G ) that have not been recorded in mutation databases , and one potential germline mutation ( APC ) .
9 Μ The most frequently mutated genes were APC , TP53 and KRAS with 30% , 15% and 21% frequencies in adenomas and 29% , 53% and 29% frequencies in carcinomas , respectively .
10 Μ In cell lines , all the expected mutations were detected except for one located in a homopolymer region .
11 According to re-sequencing results sensitivity and specificity was 100% and 92% respectively .
12 Conclusions : Our NGS-based screening panel denotes a promising step towards low cost colorectal cancer genotyping on the GS Junior instrument .
13 Despite the relatively low coverage , we discovered two novel mutations and obtained mutation frequencies comparable to literature data .
14 Additionally , as an advantage , this panel requires less template DNA than sequence capture colon cancer panels currently available for the GS Junior instrument .



PMID: 28243130
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Effectiveness of circulating tumor DNA for detection of KRAS gene mutations in colorectal cancer patients : a meta-analysis .
1 Μ Circulating tumor DNA ( ctDNA ) can be identified in the peripheral blood of patients and harbors the genomic alterations found in tumor tissues , which provides a noninvasive approach for detection of gene mutations .
2 We conducted this meta-analysis to investigate whether ctDNA can be used for monitoring KRAS gene mutations in colorectal cancer ( CRC ) patients .
3 Medline , Embase , Cochrane Library and Web of Science were searched for the included eligible studies in English , and data were extracted for statistical analysis according to the numbers of true-positive ( TP ) , true-negative ( TN ) , false-positive ( FP ) and false-negative ( FN ) cases .
4 Sensitivity , specificity and diagnostic odds ratio ( DOR ) were calculated , and the area under the receiver operating characteristic curve ( AUROC ) was used to evaluate the diagnostic performance .
5 After independent searching and reviewing , 21 studies involving 1,812 cancer patients were analyzed .
6 The overall sensitivity , specificity and DOR were 0.67 ( 95% confidence interval [CI] =0.55-0.78 ) , 0.96 ( 95% CI =093-098 ) and 53.95 ( 95% CI =2624-11092 ) , respectively .
7 The AUROC was 0.95 ( 95% CI =092-096 ) , which indicated the high diagnostic accuracy of ctDNA .
8 After stratified analysis , we found the higher diagnostic accuracy in subgroup of patients detected in blood sample of plasma .
9 The ctDNA may be an ideal source for detection of KRAS gene mutations in CRC patients with high specificity and diagnostic value .



PMID: 28242812
(Cell)  
Terms: Xenograft, in vitro, in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype .
1 Pancreatic ductal adenocarcinoma ( PDA ) is the third leading cause of cancer-related deaths in the United States , whereas colorectal cancer is the third most common cancer .
2 The RNA -binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal ( GI ) cancer cells through enhanced HuR expression .
3 Using a publically available database , HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues , respectively .
4 CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA ( MIA PaCa-2 and Hs 766T ) and colorectal cancer ( HCT116 ) cell lines .
5 HuR deficiency has a mild phenotype , in vitro , as HuR-deficient MIA PaCa-2 ( MIA .
6 HuR-KO(-/-) ) cells had increased apoptosis when compared with isogenic wild-type ( MIA .
7 HuR-WT(+/+) ) cells .
8 Using this isogenic system , mRNAs were identified that specifically bound to HuR and were required for transforming a two-dimensional culture into three dimensional ( i.e. , organoids ) .
9 Importantly , HuR-deficient MIA PaCa-2 and Hs 766T cells were unable to engraft tumors in vivo compared with control HuR-proficient cells , demonstrating a unique xenograft lethal phenotype .
10 Although not as a dramatic phenotype , CRISPR knockout HuR HCT116 colon cancer cells ( HCT .
11 HuR-KO(-/-) ) showed significantly reduced in vivo tumor growth compared with controls ( HCT .
12 HuR-WT(+/+) ) .
13 Finally , HuR deletion affects KRAS activity and controls a subset of pro-oncogenic genes .
14 Implications : The work reported here supports the notion that targeting HuR is a promising therapeutic strategy to treat GI malignancies .
15 Mol Cancer Res ; 15(6) ; 696-707 .
16 (c) 2017 AACR .



PMID: 28241877
(Cell)  
Terms: Xenograft, in vivo, in vitro, mouse models, mouse, syngeneic mouse, mouse model
Sent# Symbols Sentence Mnemonics
0 Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways .
1 BACKGROUND :
2 An increased expression of Yes-associated protein ( YAP1 ) has been shown to promote tumorigenesis in many cancer types including colon .
3 However , the role of YAP1 in promoting colon tumorigenesis remains unclear .
4 Here , we demonstrate that YAP1 expression is associated with M2 tumor-associated macrophage polarization and the generation of colon cancer stem-like cells .
5 YAP1 downregulation by gene silencing or a phytochemical , ovatodiolide , not only suppresses colon cancer tumorigenesis but also prevents M2 TAM polarization .
6 METHODS :
7 Human monocytic cells , THP-1 , and colon cancer cell lines , HCT116 and DLD-1 , were co-cultured to mimic the interactions between tumor and its microenvironment .
8 M2 polarization of the THP-1 cells were examined using both flow cytometry and q-PCR technique .
9 The inhibition of YAP1 signaling was achieved by gene -silencing technique or ovatodiolide .
10 The molecular consequences of YAP1 inhibition was demonstrated via colony formation , migration , and colon-sphere formation assays. 5-FU and ovatodiolide were used in drug combination studies .
11 Xenograft and syngeneic mouse models were used to investigate the role of YAP1 in colon tumorigenesis and TAM generation .
12 RESULTS :
13 ✓ Μ An increased YAP1 expression was found to be associated with a poor prognosis in patients with colon cancer using bioinformatics approach . GE-ASS-RO
14 Μ We showed an increased YAP1 expression in the colon spheres , and colon cancer cells co-cultured with M2 TAMs .
15 YAP1-silencing led to the concomitant decreased expression of major oncogenic pathways including Kras , mTOR , beta-catenin , and M2-promoting IL-4 and tumor-promoting IL-6 cytokines .
16 TAM co-cultured colon spheres showed a significantly higher tumor-initiating ability in vivo .
17 Ovatodiolide treatment alone and in combination with 5-FU significantly suppressed in vivo tumorigenesis and less TAM infiltration in CT26 syngeneic mouse model .
18 CONCLUSIONS :
19 We have identified the dual function of YAP1 where its suppression not only inhibited tumorigenesis but also prevented the generation of cancer stem-like cells and M2 TAM polarization .
20 Ovatodiolide treatment suppressed YAP1 oncogenic pathways to inhibit colon tumorigenesis and M2 TAM generation both in vitro and in vivo .
21 Ovatodiolide should be considered for its potential for adjuvant therapeutic development .



PMID: 28237539
(Patient)  
Terms: Phase III Study, NCT02394795, NCT02394834
Sent# Symbols Sentence Mnemonics
0 Rationale for and Design of the PARADIGM Study : Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS ( KRAS/NRAS ) Wild-type , Metastatic Colorectal Cancer .
1 BACKGROUND :
2 It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first - line treatment in patients with RAS ( KRAS/NRAS ) wild-type metastatic colorectal cancer ( mCRC ) .
3 Here we outline the PARADIGM study (NCT02394795) , designed to evaluate the superiority of panitumumab over bevacizumab , in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naive mCRC .
4 PATIENTS AND METHODS :
5 Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC .
6 A total of 800 patients are to be randomly assigned ( 1 : 1 ratio ) to mFOLFOX6 plus panitumumab ( n = 400 ) or bevacizumab ( n = 400 ) and stratified according to institution , age ( 20-64 vs. 65-79 years ) , and liver metastases ( present vs. absent ) .
7 Each treatment regimen includes oxaliplatin 85 mg/m2 , l-leucovorin 200 mg/m2 , and 5-fluorouracil ( 5-FU ) I .
8 V. 400 mg/m2 on day 1 ; 5-FU continuous I .
9 V. 2400 mg/m2 on days 1 to 3 ; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks .
10 The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power .
11 Secondary efficacy endpoints include progression-free survival , response rate , duration of response , and curative resection rate .
12   A comprehensive biomarker analysis ( NCT02394834 ) using archival tumor tissue and circulating tumor DNA samples collected at different time points ( pretreatment and confirmed progressive disease ) will investigate potential biomarkers related to primary and secondary resistance .
13 The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020 .



PMID: 28235632
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer .
1 HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type , HER2-positive metastatic colorectal cancer ( CRC ) .
2 In general , HER2 status is determined by the use of immunohistochemistry ( IHC ) and fluorescence in situ hybridization ( FISH ) .
3 Comprehensive genomic sequencing ( CGS ) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification ; however , little is known about the utility of CGS for detecting HER2-positive CRC .
4 To assess its utility , we retrospectively investigated 201 patients with stage I-IV CRC .
5 The HER2 status of the primary site was assessed using IHC and FISH , and HER2 amplification of the primary site was also assessed using CGS , and the findings of these approaches were compared in each patient .
6 Μ CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification .
7 Fifty-nine ( 29% ) patients had a KRAS codon 12/13 mutation .
8 Ten ( 5% ) patients were diagnosed as HER2-positive because of HER2 IHC 3+ , and the same 10 ( 5% ) patients had HER2 amplification evaluated using CGS .
9 The results of HER2 status and HER2 amplification were completely identical in all 201 patients ( P <0001 ) .
10   Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy .
11   CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy , and facilitates precision medicine and tailor-made treatment .



PMID: 28232873
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Application of Liquid Biopsy in Targeted Therapy of Metastatic Colorectal Cancer .
1 Background .
2 Colorectal cancers ( CRC ) shed DNA into blood circulation .
3 There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease , to track tumor heterogeneity and to evaluate response to treatment .
4 Case Presentation .
5 Here , we describe two cases of patients with advanced CRC .
6 The first case is about a patient with no available tissue for analysis of RAS mutation status .
7 Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR ( epidermal growth factor receptor ) monoclonal antibody cetuximab could be initiated .
8 In the second case , the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment .
9 Μ An acquired KRAS exon 3 mutation was detected .
10 The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies .
11 Conclusion .
12 Liquid biopsy provides a rapid genotype result , which accurately reproduces the current mutation status of tumor tissue .
13 Furthermore , liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy .



PMID: 28230016
(None)  
Terms: meta-analysis, Meta-analyses
Sent# Symbols Sentence Mnemonics
0 Evaluation and identification of factors related to KRAS and BRAF gene mutations in colorectal cancer : A meta-analysis .
1 OBJECTIVE :
2 The aim of this meta-analysis is to evaluate the distribution pattern of KRAS and BRAF mutations in colorectal cancer .
3 MATERIALS AND METHODS :
4 The database was searched without language restrictions .
5 Meta-analyses were conducted using the STATA software .
6 We calculated the odds ratio ( OR ) and its 95% confidence interval ( 95% CI ) to estimate the distribution of and correlation between KRAS and BRAF mutations , CpG island methylator phenotype ( CIMP ) , and microsatellite instability ( MSI ) in left - and right-sided colorectal cancer .
7 RESULTS :
8 The studies were divided into five groups : THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
9 CONCLUSION :
10 Μ The meta-analysis reveals that KRAS has a slightly higher mutation rate in MSI-L/MSS tumors .
11 Moreover , BRAF mutations have higher detection rates in right-sided colorectal cancer , which suggests that BRAF mutations are likely in CIMP-H tumors .
12 Therefore , based on these findings , the molecular diagnostic tests to be conducted in colorectal cancer patients can be determined according to the location/clinical features of the tumor .



PMID: 28229371
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overall Survival and Metastasis Resections in Patients with Metastatic Colorectal Cancer Using Electronic Medical Records .
1 PURPOSE :
2 Treatment for patients with metastatic colorectal cancer is chemotherapy commonly combined with monoclonal antibodies against vascular endothelial growth factor ( bevacizumab ) or epidermal growth factor receptor ( cetuximab or panitumumab ) , the efficacy of which has been proven in randomized controlled trials .
3 The objective of the current retrospective study was to analyze the impact of targeted therapy , adverse events , and dose reduction on overall survival ( OS ) and metastasis resection rates .
4 METHODS :
5 A hospital-based electronic informatics center was used to gather clinical data and outcome information in a "real-life" setting in a single academic hospital .
6 A total of 178 patients were included in 2010-2013 .
7 RESULTS :
8   In patients whose tumors expressed the KRAS wild type , the longest median OS was observed with irinotecan-based chemotherapy combined with bevacizumab ( 38 months ) , or with cetuximab ( 41 months ) .
9 Μ In the KRAS-mutated group , the longest median OS was observed with oxaliplatin with or without bevacizumab ( 34 months ) .
10 Beneficial liver metastasis resections were observed in 12 out of 20 patients .
11 Patients with KRAS wild-type tumors who received cetuximab were the most likely to undergo surgery .
12 Age was a negative predictor of OS .
13   Patients whose chemotherapy dose was reduced to below 80% had lower OS compared to those remaining above 80% .
14   Treatment delays in chemotherapy did not affect OS .
15 Pulmonary embolism and infections were common but did not have an impact on OS .
16 CONCLUSIONS :
17 A hospital-based electronic informatics center provides comparable OS results , even though adverse events were frequently observed in the present study .



PMID: 28228152
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cardiac metastasis from colon cancer effectively treated with 5-fluorouracil , leucovorin , and oxaliplatin ( modified FOLFOX6 ) plus panitumumab : a case report .
1 BACKGROUND :
2 Cardiac metastasis from colorectal cancer is rare .
3 There is little evidence supporting the effectiveness of chemotherapy , and standard therapy for metastatic cardiac tumors has not been established .
4 CASE PRESENTATION :
5 A 76-year-old woman presented with a right ventricle tumor that was detected incidentally on screening cardiac ultrasonography .
6 The initial computed tomography ( CT ) scan showed the cardiac tumor , which was approximately 40 mm in size , and multiple pulmonary nodules .
7 Serum levels of tumor markers CEA and CA19-9 were elevated aberrantly .
8 The suspected primary tumor , a well-differentiated adenocarcinoma of the transverse colon with wild-type KRAS was found by colonoscopy , and treatment with 5-fluorouracil , leucovorin , and oxaliplatin ( modified FOLFOX6 ) plus panitumumab was initiated .
9 After 4 courses of the therapy , a CT scan showed that the cardiac tumor size had markedly decreased and the pulmonary nodules had diminished .
10 The serum levels of CEA and CA19-9 were also markedly decreased .
11   After 12 courses of chemotherapy during 10 months of treatment , the patient continued to show a partial response , and she remained asymptomatic with continuation of the treatment through 15 courses .
12 CONCLUSION :
13 To the best of our knowledge , this is the first report of the efficacy of combination therapy using cytotoxic and molecular targeted agents against cardiac metastasis from colon cancer .



PMID: 28223103
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF .
1 BACKGROUND :
2 Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer ( mCRC ) harboring wild-type RAS .
3 Human epidermal growth factor receptor 2 ( HER2 ) amplification may be a mechanism of cetuximab resistance .
4 We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF .
5 PATIENTS AND METHODS :
6 Between December 2003 and June 2013 , we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2 , 3 , and 4 in KRAS and NRAS , and wild-type exon 15 in BRAF using high throughput sequencing ( OncoMap version 40 ) .
7 All patients received cetuximab after oxaliplatin , irinotecan , and fluoropyrimidine failure .
8 HER2 status was determined using immunohistochemistry and silver in situ hybridization ( SISH ) and correlated with cetuximab efficacy .
9 RESULTS :
10 Μ Of 142 RAS and BRAF wild-type tumors , we observed 7 cases ( 49% ) of HER2 amplification by SISH .
11 ✓ After a median follow-up of 13.2 months ( range , 14-781 months ) , median progression-free survival ( PFS ) was significantly different according to HER2 status : 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 ( hazard ratio , 273 ; 95% confidence interval , 118-631 ; P = 019 ) . GM-ASS-RO
12 Overall survival ( OS ) was not significantly different between groups , although there was a tendency towards shorter OS in patients with HER2-amplified tumors ( hazard ratio , 131 ; 95% confidence interval , 061-282 ; 101 vs. 135 months ; P = 488 ) .
13 CONCLUSIONS :
14 ✓ HER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF . GM-MRK-RO
15 Further study is warranted for this patient population .



PMID: 28222664
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prevalence and coexistence of KRAS , BRAF , PIK3CA , NRAS , TP53 , and APC mutations in Indian colorectal cancer patients : Next-generation sequencing-based cohort study .
1 Colorectal cancer incidences are on a rise in India .
2 Μ In this study , we have analyzed the mutation frequencies of six potential biomarkers , their coexistence , association with clinicopathological characteristics , and tumor location in Indian colorectal cancer patients .
3 Μ Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients .
4 Μ The mutation frequency observed in KRAS , BRAF , PIK3CA , NRAS , TP53 , and APC was 35.7% , 7.1% , 16.1% , 6.3% , 39.3% , and 29.5% , respectively .
5 The significant associations of mutations were KRAS with age less than 60 years ( p = 0041 ) , PIK3CA with males ( p = 0032 ) , tumor stage I-II ( p = 0013 ) , lack of metastasis in lymph nodes ( p = 0040 ) , NRAS with rectum ( p = 0002 ) , and APC with T2 stage of tumor growth ( p = 0013 ) .
6 Μ No single patient harbored mutations in these six genes or any five genes simultaneously .
7 Significance was noted in coexistence of KRAS with APC ( p = 0024 ) and mutual exclusion of KRAS with BRAF ( p = 0029 ) .
8 Μ PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 ( p = 0072 ) .
9 NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations .
10 As per our knowledge , this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients .
11 Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease .
12 In addition , infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis .



PMID: 28220124
(Cell)  
Terms: In Vivo, in vivo, phase I, clinical trial, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 In Vivo Efficacy of Umbilical Cord Blood Stem Cell -Derived NK Cells in the Treatment of Metastatic Colorectal Cancer .
1 Therapeutic monoclonal antibodies against the epidermal growth factor receptor ( EGFR ) act by inhibiting EGFR downstream signaling and by eliciting a natural killer ( NK ) cell -mediated antitumor response .
2 The IgG1 mAb cetuximab has been used for treatment of RASwt metastatic colorectal cancer ( mCRC ) patients , showing limited efficacy .
3 In the present study , we address the potential of adoptive NK cell therapy to overcome these limitations investigating two allogeneic NK cell products , i.e. , allogeneic activated peripheral blood NK cells ( A-PBNK ) and umbilical cord blood stem cell-derived NK cells ( UCB-NK ) .
4 While cetuximab monotherapy was not effective against EGFR - RASwt , EGFR+ RASmut , and EGFR+ BRAFmut cells , A-PBNK were able to initiate lysis of EGFR+ colon cancer cells irrespective of RAS or BRAF status .
5 Cytotoxic effects of A-PBNK ( but not UCB-NK ) were further potentiated significantly by coating EGFR+ colon cancer cells with cetuximab .
6 Of note , a significantly higher cytotoxicity was induced by UCB-NK in EGFR-RASwt ( 42 +/- 8 versus 67 +/- 7% ) , EGFR+ RASmut ( 20 +/- 2 versus 37 +/- 6% ) , and EGFR+ BRAFmut ( 23 +/- 3 versus 43 +/- 7% ) colon cancer cells compared to A-PBNK and equaled the cytotoxic efficacy of the combination of A-PBNK and cetuximab .
7 The antitumor efficacy of UCB-NK cells against cetuximab-resistant human EGFR+ RASmut colon cancer cells was further confirmed in an in vivo preclinical mouse model where UCB-NK showed enhanced antitumor cytotoxicity against colon cancer independent of EGFR and RAS status .
8 As UCB-NK have been proven safe in a recently conducted phase I clinical trial in acute myeloid leukemia , a fast translation into clinical proof of concept for mCRC could be considered .



PMID: 28219002
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular Testing for Gastrointestinal Cancer .
1 With recent advances in molecular diagnostic methods and targeted cancer therapies , several molecular tests have been recommended for gastric cancer ( GC ) and colorectal cancer ( CRC ) .
2 Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome , predict favorable prognosis , and screen patients for immunotherapy .
3 The epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS ( KRAS and NRAS exon 2-4 ) .
4 A BRAF mutation is required for predicting poor prognosis .
5 Additionally , amplification of human epidermal growth factor receptor 2 ( HER2 ) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients .
6 Μ The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs , and thus is helpful for ruling out Lynch syndrome .
7 In addition , the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients .
8 Additionally , HER2 testing should be performed in all recurrent or metastatic GCs .
9 If the results of HER2 immunohistochemistry are equivocal , HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status .
10 Epstein-Barr virus-positive GCs have distinct characteristics , including heavy lymphoid stroma , hypermethylation phenotype , and high expression of immune modulators .
11 Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test .
12 Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians .



PMID: 28218784
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Mutations in codons 12 and 13 of K-ras exon 2 in colorectal tumors of Saudi Arabian patients : frequency , clincopathological associations , and clinical outcomes .
1 Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer ( CRC ) .
2 Here , we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC .
3 The genetic status of K-ras was determined in 300 patients diagnosed with CRC .
4 Clinical information was collected retrospectively .
5 K-ras was wild-type in 58% and mutated in 42% of the tumors .
6 ✓ Most mutations were at codon 12 ( 89% ) and were associated with metastasis [odds ratio ( OR ) = 1.38 ( 95%CI = 114-167] and occurrence of >40 microg/L carcinoembryonic antigen ( CEA ) [OR = 1.33 ( 11-174 ) ] during diagnosis . GM-ASS-RO
7 Patients in stages I-III of the disease with wild-type K-ras tumors had a median relapse free survival ( RFS ) of 29 months in contrast to 22 months for those with the mutated K-ras tumor ( P = 00357 ) .
8 In multivariate analysis , only the stage of the disease significantly predicted RFS ( P = 0001 ) .
9 Patients in stage IV of CRC with the wild-type K-ras tumor did not reach the median overall survival ( OS ) , whereas patients with the mutated K-ras tumor survived for 23.5 months ( P = 0044 ) .
10 ✓ CEA level >40 microg/L ( P = 0004 ) and status of K-ras ( P = 0044 ) were independent predictors of OS . GE-MRK-RO
11 This is the largest study investigating K-ras mutations in patients with CRC in the Middle East .
12 ✓ Mutations were associated with advanced stage of CRC , higher serum CEA , shorter RFS and OS . GM-ASS-RO



PMID: 28218473
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer .
1 Diacylglycerol kinases ( DGKs ) are important regulators of cell signaling and have been implicated in human malignancies .
2 Whether epigenetic alterations are involved in the dysregulation of DGKs in cancer is unknown , however .
3 We therefore analyzed methylation of the promoter CpG islands of DGK genes in colorectal cancer ( CRC ) cell lines .
4 We found that DGKG , which encodes DGKgamma , was hypermethylated in all CRC cell lines tested ( n = 9 ) , but was not methylated in normal colonic tissue .
5 Correspondingly , DGKG expression was suppressed in CRC cell lines but not in normal colonic tissue , and was restored in CRC cells by treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine ( 5-aza-dC ) .
6 DGKG methylation was frequently observed in primary CRCs ( 73/141 , 518% ) and was positively associated with KRAS and BRAF mutations and with the CpG island methylator phenotype ( CIMP ) .
7 DGKG methylation was also frequently detected in colorectal adenomas ( 89 of 177 , 503% ) , which suggests it is an early event during colorectal tumorigenesis .
8 Ectopic expression of wild-type DGKgamma did not suppress CRC cell proliferation , but did suppress cell migration and invasion .
9 Notably , both constitutively active and kinase -dead DGKgamma mutants exerted inhibitory effects on CRC cell proliferation , migration and invasion , and the wild-type and mutant forms of DGKgamma all suppressed Rac1 activity in CRC cells .
10 These data suggest DGKG may play a tumor suppressor role in CRC .



PMID: 28216246
(Patient)  
Terms: Meta-Analysis, meta-analysis, prospective, rat
Sent# Symbols Sentence Mnemonics
0 ✓ Effect of KRAS and BRAF Mutations on Survival of Metastatic Colorectal Cancer After Liver Resection : A Systematic Review and Meta-Analysis . GE-INV-RO, GM-INV-RO
1 BACKGROUND :
2 The purpose of the study was to evaluate whether the mutational status of rat Kirsten sarcoma viral oncogene homolog ( KRAS ) or b-viral oncogene homolog B1 (BRAF) could be an independent prognostic factor in the subset of patients with colorectal cancer liver metastases ( CRLM ) who undergo complete liver resection .
3 MATERIALS AND METHODS :
4 A systematic literature review was performed to identify articles reporting relapse-free survival ( RFS ) and/or overall survival ( OS ) of patients who underwent complete liver resection for CRLM , stratified according to KRAS and BRAF mutational status .
5 Hazard ratios ( HRs ) from multivariate analyses were pooled in the meta-analysis .
6 RESULTS :
7 Eleven studies , including 1833 patients , were eligible for the meta-analysis .
8 Nine of them reported OS stratified according to KRAS mutation .
9 ✓ Μ The pooled analysis revealed that KRAS mutation was negatively associated with OS ( HR , 1.674 ; 95% confidence interval [CI] , 1.341-2.089 ; P <.001 ) . GM-ASS-RO
10 Μ Nine among 11 studies reported RFS stratified according to KRAS mutation and HRs in multivariate analysis were available in 7 .
11 ✓ In a pooled analysis , KRAS mutation was negatively associated with RFS ( HR , 1529 ; 95% CI , 1287-1817 ; P <001 ) . GM-ASS-RO
12 In 3 studies HRs of the multivariate analysis regarding the OS according to BRAF mutational status were also available , showing a negative association with OS ( HR , 3055 ; 95% CI , 1794-5204 ; P <001 ) .
13 CONCLUSION :
14 ✓ KRAS mutations are negatively associated with OS and RFS in patients who undergo complete liver resection for CRLM . GM-ASS-RO
15 Μ A similar negative effect on OS was observed also for BRAF mutation , although fewer studies were included .
16 These data support integration of KRAS and BRAF mutational status into a combined predictive score for prospective assessment of outcome after resection of CRLM in clinical studies .



PMID: 28215705
(Cell)  
Terms: prospective, mice
Sent# Symbols Sentence Mnemonics
0 KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer .
1 Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity .
2 We performed preclinical trials investigating primary murine acute myeloid leukemias ( AMLs ) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 ( PD901 ) .
3 One outlier AML responded and exhibited intrinsic drug resistance at relapse .
4 Loss of wild-type ( WT ) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition .
5 ✓ Similarly , human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition , and CRISPR-Cas9 -mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment .
6 In a prospectively characterized cohort of patients with advanced cancer , 642 of 1,168 ( 55% ) with KRAS mutations exhibited allelic imbalance .
7 These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency .



PMID: 28214977
(None)  
Terms: meta-analysis, clinical trial
Sent# Symbols Sentence Mnemonics
0 BRAF-Mutated Colorectal Cancer : What Is the Optimal Strategy for Treatment ?
1 OPINION STATEMENT :
2 Μ The BRAF activating mutation , harbored by approximately 10% of colorectal cancers ( CRC ) , confers dramatic prognosis to advanced diseases .
3 In early-stage setting , the identification of the BRAF mutation does not impact the therapeutic decision .
4 Yet , the BRAF mutation could be considered as a stratification factor in adjuvant trials , because of its prognostic impact after relapse .
5 Moreover , both BRAF mutation and mismatch repair ( MMR ) statuses should be determined in all CRC to help identify sporadic tumors versus Lynch syndrome-related tumors .
6 Indeed , in patients with MMR-deficient ( dMMR ) tumors and MLH1 loss of expression , the BRAFV600E mutation indicates a sporadic origin .
7 In advanced BRAF-mutated CRC , the standard of care remains fluoropyrimidine-based cytotoxic regimen in combination with bevacizumab .
8 Although a recent meta-analysis showed that there was insufficient data to justify the exclusion of anti-EGFR monoclonal antibodies , antiangiogenic agents should be preferred in the first - line setting .
9 Despite the lack of a randomized phase 3 study dedicated to BRAF-mutated CRC , chemotherapy intensification combining a quadruple association of 5-fluorouracil , oxaliplatin , irinotecan ( FOLFOXIRI ) , and bevacizumab seems like a valid option .
10   Although first results with BRAF inhibitors as single agents in BRAF-mutated CRC were disappointing , their association with therapies targeting the MAPK pathway seems to overcome the primary resistance to BRAF inhibition .
11 ✓ In the field of sporadic CRC , the BRAF mutation is strongly associated with MMR deficiency . GM-ASS-RO
12 Considering breakthrough results of immune checkpoint inhibitors in dMMR repair tumors , determination of the MMR status appears to be mandatory .
13 ✓ Μ Given the dramatic prognosis conferred by the BRAF mutation , patients with BRAF-mutated advanced CRC need to be systematically identified and proposed for clinical trial enrolment in order to benefit from innovative therapies . RO-REG-GM



PMID: 28214514
(Patient)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Detecting circulating tumor DNA in renal cancer : An open challenge .
1 BACKGROUND :
2 Detection of circulating tumor DNA ( ctDNA ) in blood of cancer patients is regarded as an important step towards personalized medicine and treatment monitoring .
3 In the present study , we investigated the clinical applicability of ctDNA as liquid biopsy in renal cancer .
4 METHODS :
5 ctDNA in serum and plasma samples derived from ccRCC and colon cancer patients as well as ctDNA isolated from RCC xenografts with known VHL mutation status was investigated using next generation sequencing ( NGS ) .
6 Additionally , a Taqman mutation specific assay was used for specific VHL mutation detection in blood .
7 RESULTS :
8 Μ In our study , we successfully identified KRAS mutation in colon cancer patients .
9 We also confirmed the presence of specific VHL mutations in ctDNA derived from RCC xenografts indicating the capability of renal tumors to release DNA into the blood circulation .
10 Μ However , we could not detect any VHL mutation in plasma or serum samples derived from nine ccRCC patients .
11 To increase the sensitivity , a VHL mutation specific Taqman assay was tested .
12 Μ With this approach , the pVHL mutation p.Val130Leu in exon 2 in one patient was successfully detected .
13 CONCLUSION :
14 These data suggest a reduced tumor DNA shedding and an increased clearance of the tumor DNA from the circulation in renal cancer patients independently of tumor size , metastases , and necrosis .
15 This implies that highly sensitive detection methods for mutation calling and prior knowledge of the mutation are required for liquid biopsies in ccRCC .



PMID: 28208157
(Patient)  
Terms: Retrospective
Sent# Symbols Sentence Mnemonics
0 ✓ Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer . GM-ASS-RO
1 BACKGROUND :
2 Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers .
3 However , the prognostic impact of specific point mutations remains less clear .
4 This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer .
5 METHODS :
6 Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network .
7 RESULTS :
8 We evaluated the impact of KRAS genotype in 392 patients .
9 Μ Mutated KRAS was detected in 42.9% of tumours .
10 KRAS mutations were more common in moderate versus well-differentiated tumours .
11 On multivariate analysis , primary tumour T stage ( HR 2.77 ( 154-498 ) , P = 0.001 ) , N stage ( HR 1.51 ( 101-226 ) , P = 0.04 ) , curative intent surgery ( HR 0.51 ( 034-076 ) , P = 0.001 ) , tumour grade ( HR 0.44 ( 030-065 ) , P = 0.001 ) and KRAS mutation ( 1.54 ( 123-212 ) , P = 0.005 ) were all predictive of overall survival .
12 ✓ Patients with KRAS codon 12 mutations had worse overall survival ( HR 1.76 ( 95% CI 127-243 ) , P = 0.001 ) . GM-ASS-RO
13 ✓ Among the five most common codon 12 mutations , only p.G12C ( HR 2.21 ( 115-425 ) , P = 0.01 ) and p.G12V ( HR 1.69 ( 108-262 ) , P = 0.02 ) were predictive of overall survival . GM-MRK-RO
14 CONCLUSIONS :
15 For patients with colorectal cancer , p.G12C and p .
16 ✓ G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis . GM-ASS-RO



PMID: 28202525
(Cell)  
Terms: xenograft, in vivo
Sent# Symbols Sentence Mnemonics
0 Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations .
1 About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling , which promotes tumor invasion and progression .
2 Here , we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status .
3 Μ Using primary colorectal cancer tissues , xenograft models , and MAPK reporter constructs , we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge , ceased to proliferate , underwent epithelial-mesenchymal transition ( EMT ) , and expressed markers related to colon cancer stem cells .
4 In KRAS-mutant colon cancer , regulation of MAPK signaling was preserved through remaining wild-type RAS isoforms .
5 Moreover , using a lineage tracing strategy , we provide evidence that high MAPK activity marked a progenitor cell compartment of growth-fueling colon cancer cells in vivo Our results imply that differential MAPK signaling balances EMT , cancer stem cell potential , and tumor growth in colorectal cancer .
6 Cancer Res ; 77(7) ; 1763-74 .
7 (c) 2017 AACR .



PMID: 28201998
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical performance evaluation of a sensitive , rapid low-throughput test for KRAS mutation analysis using formalin-fixed , paraffin-embedded tissue samples .
1 BACKGROUND :
2 Testing for KRAS mutations in metastatic colorectal cancer ( mCRC ) on formalin-fixed , paraffin embedded ( FFPE ) tumor tissue has become standard of care .
3 Different molecular methods exist to determine hotspot KRAS mutations in exon 2 , 3 and 4 , but testing is often limited by the sensitivity and the speed of analysis .
4 The aim of this retrospective study was to establish the clinical performance of the Idylla KRAS Mutation Test on FFPE tumor samples of patients with mCRC .
5 METHODS :
6 Μ KRAS mutation analysis was performed using the therascreen KRAS on the RotorGene Q platform ( CE-IVD ; Qiagen ) and results were subsequently compared to the Idylla KRAS Mutation Test .
7 Discordant result testing was performed with massive parallel sequencing or alternative routine approaches .
8 RESULTS :
9 Data from 182 samples were used to show that the overall agreement between the two methods for mutation characterization was 96.7% [95%CI : 93.0%-98.5%] .
10 Six out of 182 samples ( 33% ) showed true discordant results .
11 CONCLUSION :
12   Μ The Idylla KRAS Mutation Test allows for a fast and reliable analysis of FFPE samples with a turnaround-time of two hours without the need of molecular infrastructure or expertise in order to guide the personalized treatment of colorectal cancer patients .



PMID: 28197787
(Patient)  
Terms: phase I
Sent# Symbols Sentence Mnemonics
0 Dermatux : phase IV trial of Cetuximab plus FOLFIRI in first - line metastatic colorectal cancer receiving a pre-defined skin care .
1 PURPOSE :
2 Cetuximab-induced skin rash Gd3+ occurs in >/ = 16% patients ( pts ) ( Heinemann et al. , Lancet Oncol 15 ( 10 ) : 1065-1075 , 2014 ; Van Cutsem et al .
3 J Clin Oncol 27 ( 19 ) : 3117-25 ; 2009b ) .
4 Survival , response , and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline .
5 METHODS :
6 This is a national , multicenter , phase 4 , first - line mCRC ( K-RAS wt ) trial .
7 Pts received irinotecan 180 mg/m(2) ( d1 ) , FA 400 mg/m(2) ( d1 ) , 5-FU 400 mg/m(2) ( d1 ) , 5-FU 2400 mg/m(2) ( d1-2 ) , and cetuximab [400 mg/m(2) ( d1 ) , and then 250 mg/m(2) qw] , prophylactic 0.1% vitamin K1 ointment qd , and oral doxycycline 100 mg bid .
8 PRIMARY OBJECTIVE :
9 1-year PFS rate ; secondary objectives : skin side-effects ( grade , onset ) , objective response rate ( ORR ) , disease control rate ( DCR ) , progression-free survival ( PFS ) time , and overall survival ( OS ) time and safety .
10 RESULTS :
11 Twenty centers recruited 55 patients .
12 Recruitment started Q1 2011 and ended Q3 2013 due to slow accrual .
13 Characteristics were in line with CRYSTAL trial except for age and colonic location. 1-year PFS rate was 25.9% , mOS 21.8 months (m) , and mPFS 8.5 m .
14 ORR was 63.0% , DCR 77.8% .
15 Rash Gd2+ occurred in 42.6% [median onset was 4.0 weeks (w) ] ; paronychia Gd2+ occurred in 22.2% ( median onset 154w ) ; skin fissures Gd2+ occurred in 31.5% ( median onset 199 weeks ) 7% pts abandoned cetuximab treatment due to toxicity .
16 CONCLUSION :
17 Our data reveal encouraging improvements in skin reactions and their time to occurrence due to a pre-defined skin care .



PMID: 28196490
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Rechallenge and maintenance therapy using cetuximab and chemotherapy administered to a patient with metastatic colorectal cancer .
1 BACKGROUND :
2 Cetuximab combined with chemotherapy is one of the first - line treatments of metastatic colorectal cancer .
3 Although disease progression inevitably occurs , rechallenge and maintenance therapies using cetuximab-based regimens may be beneficial , particularly for patients with wild-type ( WT ) KRAS .
4 CASE PRESENTATION :
5 A 47-year-old female patient who underwent right hemicolectomy presented with an ulcerative adenocarcinoma ( grade 2 ) revealed by histopathological analysis .
6 The patient received three cycles of adjuvant chemotherapy , but disease recurred 15 months later .
7 Cetuximab and a FOLFOX-4 regimen were administered , followed by surgery and adjuvant chemotherapy that was administered for approximately one year .
8 Three years after completing adjuvant therapy , her serum carcinoembryonic antigen levels rapidly increased , and enhanced computed tomography showed widespread metastases .
9 Rechallenge with cetuximab and the FOLFIRI regimen was then initiated , and after 12 cycles , lesions in the lung and liver shrank significantly , and serum CEA levels dramatically declined .
10 Maintenance therapy with cetuximab and capecitabine was then administered for 10 months until the metastatic lesions in the lung and liver enlarged .
11 CONCLUSION :
12   Rechallenge and maintenance therapy with cetuximab-based chemotherapy were relatively effective for managing a female patient with WT KRAS .
13 Optimization of this strategy requires further in-depth investigations of more patients .



PMID: 28192450
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel RNA sequencing data analysis method for cell line authentication .
1 We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories .
2 Μ The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell -specific mutational profiles .
3 Cell lines constitute key model systems widely used within cancer research , but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis .
4 Using both public and novel data , we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205 , DLD1 , HCT15 , HCT116 , HKE3 , HT29 and RKO colorectal cancer cell lines .
5 We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous .
6 Μ We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant , rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS .
7 This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories , analyse new experiments where whole genome sequencing is not available , as well as facilitate comparisons of data from different experiments , platforms and laboratories .



PMID: 28188750
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS and PIK3CA mutations in colorectal adenocarcinomas correlate with aggressive histological features and behavior .
1 Tumor budding ( TB ) in colorectal carcinoma ( CRC ) is related to epithelial-mesenchymal transition ( EMT ) and has been recently characterized as an indicator of poor prognosis along with lymphovascular tumor emboli ( LVE ) , perineural invasion ( PNI ) , and an infiltrative growth pattern .
2 Mutations in the genes of the Ras-MAPK and PI3K pathways are associated with EMT and an aggressive CRC phenotype and have been used in patient stratification for anti-EGF receptor therapies ; however , the impact of these mutations on CRC morphology and behavior remains unclear .
3 Μ In this study , using a multi - gene panel , we detected KRAS , NRAS , BRAF , PIK3CA , TP53 , and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters , including TB .
4 Μ Our results showed that 21 of 34 tumors with high-grade TB had KRAS mutations ( P = 001 ) and KRAS G12D and PIK3CA exon 9 variants were significantly associated with high-grade TB ( P = 002 and 006 , respectively ) ; furthermore , tumors with KRAS mutations in exons 3 and 4 tended to have LVE and PNI ( P = 044 and 049 , respectively ) .
5 PIK3CA exon 9 mutations indicated a tendency for shorter disease-free survival ( P = 030 ) , whereas BRAF mutations were associated with extracellular mucin deposition ( P = 016 ) .
6 Μ Our study revealed a correlation of KRAS mutations with high-grade TB , an association of certain KRAS and PIK3CA variants with aggressive clinicopathological features , as well as a possible relationship between BRAF mutations and mucin production in CRC .



PMID: 28188432
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Correlations of IGF-1R and COX-2 Expressions with Ras and BRAF Genetic Mutations , Clinicopathological Features and Prognosis of Colorectal Cancer Patients .
1 This case-control study aims to investigate the correlations of insulin-like growth factor receptor 1 ( IGF-1R ) and cyclooxygenase 2 ( COX-2 ) expressions with Ras and BRAF genetic mutations , clinicopathological features and prognosis of colorectal cancer ( CRC ) patients .
2 A total of 213 CRC patients ( case group ) and 200 healthy individuals ( control group ) were selected from our hospital .
3 Μ Ras ( K-Ras/N-Ras ) and BRAF genetic mutations were detected by direct sequencing .
4 The positive expression rates of IGF-IR and COX-2 in CRC and normal tissues were detected using immunohistochemistry .
5 Μ RT-qPCR and Western blotting were applied to detect the mRNA and protein expressions of IGF-IR and COX-2 in CRC tissues and normal tissues .
6 Total mutation rate of N-Ras , BRAF and K-Ras in case group were 5.2% , 12.2% and 47.4% , respectively .
7 The expressions of IGF-IR and COX-2 were higher in CRC tissues with Ras and BRAF mutations than in those without .
8 Μ CRC tissues with Ras mutation showed higher COX-2 expression than those with BRAF mutation .
9 ✓ IGF-IR and COX-2 expressions were correlated to infiltration degree , lymphatic metastasis ( in CRC tissues with and without Ras and BRAF mutations ) , and Dukes stages ( only in CRC tissues with Ras and BRAF mutations ) . GE-ASS-RO
10 CRC patients with negative expressions of IGF-IR and COX-2 had significantly higher accumulative survival rate and longer mean survival duration than those with positive expressions of IGF-IR and COX-2 .
11 ✓ These findings indicate that IGF-1R and COX-2 expressions may be associated with Ras and BRAF genetic mutations , clinicopathological feature and prognosis of CRC patients . GE-ASS-RO, GE-ASS-DS



PMID: 28188228
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Time-resolved Phosphoproteome Analysis of Paradoxical RAF Activation Reveals Novel Targets of ERK .
1 Small molecules targeting aberrant RAF activity , like vemurafenib ( PLX4032 ) , are highly effective against cancers harboring the V600E BRAF mutation and are now approved for clinical use against metastatic melanoma .
2 However , in tissues showing elevated RAS activity and in RAS mutant tumors , these inhibitors stimulate RAF dimerization , resulting in inhibitor resistance and downstream "paradoxical" ERK activation .
3 To understand the global signaling response of cancer cells to RAF inhibitors , we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines ( Colo205 and HCT116 ) that respond differently to vemurafenib .
4 Comprehensive data mining and filtering identified a total of 37,910 phosphorylation sites , 660 of which were dynamically modulated upon treatment with vemurafenib .
5 We established that 83% of these dynamic phosphorylation sites were modulated in accordance with the phospho-ERK profile of the two cell lines .
6 Accordingly , kinase substrate prediction algorithms linked most of these dynamic sites to direct ERK1/2 -mediated phosphorylation , supporting a low off-target rate for vemurafenib .
7 Functional classification of target proteins indicated the enrichment of known ( nuclear pore , transcription factors , and RAS-RTK signaling ) and novel ( Rho GTPases signaling and actin cytoskeleton ) ERK -controlled functions .
8 Our phosphoproteomic data combined with experimental validation established novel dynamic connections between ERK signaling and the transcriptional regulators TEAD3 ( Hippo pathway ) , MKL1 , and MKL2 ( Rho serum-response elements pathway ) .
9 We also confirm that an ERK-docking site found in MKL1 is directly antagonized by overlapping actin binding , defining a novel mechanism of actin-modulated phosphorylation .
10 Altogether , time-resolved phosphoproteomics further documented vemurafenib selectivity and identified novel ERK downstream substrates .



PMID: 28186961
(Patient)  
Terms: phase II
Sent# Symbols Sentence Mnemonics
0 Combination epigenetic therapy in metastatic colorectal cancer ( mCRC ) with subcutaneous 5-azacitidine and entinostat : a phase 2 consortium/stand up 2 cancer study .
1 PURPOSE :
2 Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal ( CRC ) cell lines and in vivo studies .
3 EXPERIMENTAL DESIGN :
4 We conducted a phase II , multi-institutional study of the combination in metastatic CRC patients .
5 Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10 .
6 An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease .
7 A 2nd cohort with added eligibility restrictions was accrued : prior therapies were limited to no more than 2 or 3 ( KRAS-mutated and KRAS-wildtype cancers , respectively ) and <30% of liver involvement .
8 The primary endpoint was RECIST response .
9 Serial biopsies were performed at baseline and after 2 cycles of therapy .
10 RESULTS :
11 Forty-seven patients were enrolled ( 24 : Cohort 1 , 23 : Cohort 2 ) .
12   Patients were heavily pre-treated ( median prior therapies 4 : Cohort 1 and 2.5 : cohort 2 ) .
13 No responses were observed .
14 Median progression-free survival was 1.9 months ; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2 , respectively .
15 Toxicity was tolerable and as expected .
16 Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median .
17 CONCLUSION :
18   In this first trial of CRC patients with combination epigenetic therapy , we show tolerable therapy without significant clinical activity as determined by RECIST responses .
19 Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS .



PMID: 28186237
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Perioperative bevacizumab improves survival following lung metastasectomy for colorectal cancer in patients harbouring v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue exon 2 codon 12 mutationsdagger .
1 OBJECTIVES :
2 The role of perioperative chemotherapy ( POC ) and targeted therapies in lung metastasectomy for colorectal cancer ( CRC ) is still subject to debate .
3 We aimed to evaluate whether POC and targeted therapies were associated with different outcomes according to the mutational status .
4 METHODS :
5 We reviewed data from 223 patients who underwent pulmonary metastasectomy for CRC from 1998 to 2015 and for whom the V-Ki-ras2 Kirsten sarcoma viral oncogene homologue ( KRAS ) and V-raf Murine sarcoma viral oncogene homologue B1 (BRAF) mutational statuses were known .
6 RESULTS :
7   A total of 167 patients ( 74% ) underwent POC : 62 ( 37% ) received neoadjuvant therapy , 59 ( 35% ) were in the adjuvant setting and 46 ( 28% ) were in both the neoadjuvant and adjuvant settings .
8 POC did not significantly influence either the loco-regional recurrence free survival ( LRRFS ) ( P = 021 ) or the overall survival ( OS ) ( P = 029 ) .
9   Furthermore , in cases of adjuvant chemotherapy , outcomes were not significantly different in cases of neoadjuvant chemotherapy or both neoadjuvant and adjuvant treatment ( P = 026 for OS , P = 014 for LRRFS ) .
10 For patients with KRAS mutation , perioperative bevacizumab was associated with a significant improvement in both LRRFS [70 months ( 4158-9842 ) versus 24 months ( 115-4686 ) , P = 0.001] and OS [101 versus 55 months ( 4977-6023 ) , P = 0.004] .
11 However , this benefit was only significant in cases of KRAS exon 2 codon 12 mutations [median OS : 101 months ( 8397-11802 ) versus 60 months ( 53-6699 ) , P <0.001 ; median LRRFS : 76 months ( 6462-8738 ) versus 44 months ( 3527-5273 ) , P <0.001] .
12 CONCLUSION :
13   Perioperative bevacizumab appears to be beneficial in patients with exon 2 codon 12 KRAS mutations who have undergone lung metastasectomy for CRC .



PMID: 28184012
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable , Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival .
1 Here , comprehensive analysis was performed on the molecular and clinical features of colorectal carcinoma harboring chromosome 20q amplification .
2 Tumor and normal DNA from patients with advanced colorectal carcinoma underwent next-generation sequencing via MSK-IMPACT , and a subset of case samples was subjected to high-resolution microarray ( Oncoscan ) .
3 Relationships between genomic copy number and transcript expression were assessed with The Cancer Genome Atlas ( TCGA ) colorectal carcinoma data .
4 Of the colorectal carcinoma patients sequenced ( n = 401 ) with MSK-IMPACT , 148 ( 37% ) had 20q gain , and 30 ( 7% ) had 20q amplification .
5 Μ In both the MSK-IMPACT and TCGA datasets , BCL2L1 was the most frequently amplified 20q oncogene .
6 However , SRC was the only recognized 20q oncogene with a significant inverse relationship between mRNA upregulation and RAS/RAF mutation ( OR , -04 +/- 02 , P = 002 ) .
7 In comparison with 20q diploid colorectal carcinoma , 20q gain/amplification was associated with wild-type KRAS ( P <0001 ) and BRAF ( P = 001 ) , microsatellite stability ( P <0001 ) , distal primary tumors ( P <0001 ) , and mutant TP53 ( P <0001 ) , but not stage .
8 Μ On multivariate analysis , longer overall survival from the date of metastasis was observed with chromosome 20q gain ( P = 002 ) or amplification ( P = 004 ) compared with diploid 20q .
9 Implications : 20q amplification defines a subset of colorectal cancer patients with better overall survival from the date of metastasis , and further studies are warranted to assess whether the inhibition of 20q oncogenes , such as SRC , may benefit this subset of patients .
10 Mol Cancer Res ; 15(6) ; 708-13 .
11 (c) 2017 AACR .



PMID: 28183047
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Are TKIs favourable for the elderly with non-small - cell lung cancer .
1 CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T - cell Immunity in Pancreatic Ductal Adenocarcinoma .



PMID: 28179313
(Patient)  
Terms: retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 Sequential Combination of Chemotherapy With Egfr-Tki As The First - Line Treatment for Unselected Patients With Advanced Non-Small Cell Lung Cancer : Systematic Review of Randomized Controlled Trials .
1 Although third-generation epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR-TKI ) can overcome T790M -mediated resistance in non-small-cell lung cancer ( NSCLC ) , rebiopsy to confirm T790M status is occasionally difficult .
2 We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice .
3 This study included 139 consecutive NSCLC patients with EGFR mutations , who had experienced progressive disease ( PD ) after EGFR-TKI treatment .
4 We retrospectively reviewed patient characteristics , tumor progression sites and rebiopsy procedures .
5 Of 120 patients ( out of the original 139 ) who were eligible for clinical trials , 75 ( 63% ) underwent rebiopsy for 30 pleural effusions , 32 thoracic lesions , four bone , two liver , and seven at other sites .
6 Rebiopsy procedures included 30 thoracocentesis , 24 transbronchial biopsies , 13 computed tomography ( CT )- guided needle biopsies and 8 other procedures .
7 Of the 75 rebiopsied patients , 71 ( 95% ) were pathologically diagnosed with malignancy ; and 34 ( 45% ) had available tissue samples for EGFR analyses .
8 Μ Of the 75 biopsied patients , 61 ( 81% ) were analyzed for EGFR mutation , using tissue or cytology samples ; T790M mutations were identified in 20 ( 33% ) of the 61 patients .
9 Of the 120 patients , 45 ( 38% ) did not undergo rebiopsy , because of inaccessible tumor sites ( n = 19 ) , patient refusal ( n = 6 ) or decision of physician ( n = 10 ) .
10   In conclusion , among patients with EGFR mutations who had PD after EGFR-TKI treatment , 63% underwent rebiopsy .
11 Most rebiopsy samples were diagnosed with malignancy .
12 Μ However , tissue samples were less available and T790M mutations were identified less frequently than in previous studies .
13 Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important .



PMID: 28178681
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Molecular profiling of metastatic colorectal tumors using next-generation sequencing : a single-institution experience .
1 BACKGROUND :
2 Μ Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 We conducted a single-institution , retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing ( NGS ) via FoundationOne .
5 RESULTS :
6 Overall , RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients .
7 Μ We found a novel KRASR68S1 mutation associated with an aggressive phenotype .
8 RAS amplifications ( 14% KRAS and 07% NRAS ) , MET amplifications ( 22% ) , BRAFL597Ralterations ( 07% ) , ARAFS214F alterations ( 07% ) , and concurrent RAS+RAF ( 14% ) , BRAF+RAF1 ( 07% ) , and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis .
9 Μ ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon .
10 Three cases ( 22% ) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden ( TMB ) : 2 cases with MSI-H and 1 case with a POLE mutation .
11 CONCLUSIONS :
12 ✓ Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance .
13 ERBB2 amplified tumors commonly originate from the rectosigmoid colon , are predominantly RAS/BRAF wild-type , and may predict benefit to HER2 -directed therapy .
14   Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy .



PMID: 28173629
(Cell)  
Terms: in vitro, in vivo
Sent# Symbols Sentence Mnemonics
0 Enhanced dependency of KRAS-mutant colorectal cancer cells on RAD51 -dependent homologous recombination repair identified from genetic interactions in Saccharomyces cerevisiae .
1 Activating KRAS mutations drive colorectal cancer tumorigenesis and influence response to anti-EGFR-targeted therapy .
2 Despite recent advances in understanding Ras signaling biology and the revolution in therapies for melanoma using BRAF inhibitors , no targeted agents have been effective in KRAS-mutant cancers , mainly due to activation of compensatory pathways .
3 Μ Here , by leveraging the largest synthetic lethal genetic interactome in yeast , we identify that KRAS-mutated colorectal cancer cells have augmented homologous recombination repair ( HRR ) signaling .
4 Μ We found that KRAS mutation resulted in slowing and stalling of the replication fork and accumulation of DNA damage .
5 Moreover , we found that KRAS-mutant HCT116 cells have an increase in MYC -mediated RAD51 expression with a corresponding increase in RAD51 recruitment to irradiation-induced DNA double-strand breaks ( DSBs ) compared to genetically complemented isogenic cells .
6 MYC depletion using RNA interference significantly reduced IR -induced RAD51 foci formation and HRR .
7 On the contrary , overexpression of either HA-tagged wild-type ( WT ) MYC or phospho-mutant S62A increased RAD51 protein levels and hence IR -induced RAD51 foci .
8 Likewise , depletion of RAD51 selectively induced apoptosis in HCT116-mutant cells by increasing DSBs .
9 Pharmacological inhibition targeting HRR signaling combined with PARP inhibition selectivity killed KRAS-mutant cells .
10 Interestingly , these differences were not seen in a second isogenic pair of KRAS WT and mutant cells (DLD-1) , likely due to their nondependency on the KRAS mutation for survival .
11 Our data thus highlight a possible mechanism by which KRAS-mutant -dependent cells drive HRR in vitro by upregulating MYC-RAD51 expression .
12 These data may offer a promising therapeutic vulnerability in colorectal cancer cells harboring otherwise nondruggable KRAS mutations , which warrants further investigation in vivo .



PMID: 28169239
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Modified mismatch polymerase chain reaction-restriction fragment length polymorphism detected mutations in codon 12 and 13 of exon 2 of K-ras gene in colorectal cancer patients and its association with liver metastases : Data from a South Asian country .
1 AIM :
2 Mutations in K-ras codon 12 and 13 of exon 2 are known to affect prognosis and impart resistance to anti-epidermal growth factor monoclonal antibody therapy in colorectal carcinoma ( CRC ) .
3 Μ Our aim was to investigate the utility value of modified mismatch polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP ) assay to detect mutation in K-ras codons of CRC patients and to relate the mutational status to liver metastasis .
4 METHODOLOGY :
5 Μ Mismatch PCR-RFLP was developed to detect K-ras mutations in DNA isolated from paraffinized tumor tissue of thirty CRC patients .
6 All patients had 5 year follow-up data to detect liver metastasis .
7 Cross-tabulations were generated between K-ras mutations and the metastatic status .
8 The Chi-square test was used to indicate statistical significance of the association .
9 RESULTS :
10 Μ Of the 30 CRC patients investigated , K-ras mutations of codons 12 and/or 13 of exon 2 were detected in 14 ( 466% ) .
11 Meanwhile , 13 patients ( 433% ) were observed to have developed liver metastases .
12 There was a significant association between the presence of the K-ras mutation in codon 12 and the occurrence of liver metastasis ( chi2 = 4693 , P = 0030 ) on the contrary to the mutation in codon 13 to which such occurrence of liver metastases was not seen ( chi2 = 1884 , P = 0169 ) .
13 CONCLUSION :
14 ✓ Codon 12 of exon 2 of K--ras gene detected by modified mismatch PCR-RFLP assay is significantly associated with liver metastasis in CRC patients during the first 5 years after surgery . GM-ASS-RO
15 Μ Thus , modified mismatch PCR-RFLP protocol is a suitable method in this setting to detect K-ras gene mutations predicting liver metastasis in CRC patients .



PMID: 28167959
(Patient)  
Terms: Meta-Analysis, meta-analysis
Sent# Symbols Sentence Mnemonics
0 Chemotherapy Plus Cetuximab versus Chemotherapy Alone for Patients with KRAS Wild Type Unresectable Liver-Confined Metastases Colorectal Cancer : An Updated Meta-Analysis of RCTs .
1 Purpose .
2 Our study analyses clinical trials and evaluates the efficacy of adding cetuximab in systematic chemotherapy for unresectable colorectal cancer liver-confined metastases patients .
3 Materials and Methods .
4 Search EMBASE , PubMed , and the Cochrane Central Register of Controlled Trials for RCTs comparing chemotherapy plus cetuximab with chemotherapy alone for KRAS wild type patients with colorectal cancer liver metastases ( CRLMs ) .
5 We calculated the relative risks ( RRs ) with 95% confidence interval and performed meta-analysis of hazard ratios ( HRs ) for the R0 resection rate , the overall response rate ( ORR ) , the progression-free survival ( PFS ) and overall survival ( OS ) .
6 Results. 1173 articles were retrieved and 4 RCTs were available for our study .
7 The four studies involved 504 KRAS wild type patients with CRLMs .
8 The addition of cetuximab significantly improved all the 4 outcomes : the R0 resection rate ( RR 203 , p = 0004 ) , the ORR ( RR 176 , p <000001 ) , PFS ( HR 063 , p <00001 ) , and also OS ( HR 074 , p = 004 ) ; the last outcome is quite different from the conclusion published before .
9 Conclusions .
10 Although the number of patients analysed was limited , we found that the addition of cetuximab significantly improves the outcomes in KRAS wild type patients with unresectable colorectal cancer liver-confined metastases .
11   Cetuximab combined with systematic chemotherapy perhaps suggests a promising choice for KRAS wild type patients with unresectable liver metastases .



PMID: 28161825
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Correlation between KRAS mutation and 18F-FDG uptake in stage IV colorectal cancer .
1 PURPOSE :
2 The purpose of this study is to evaluate the correlation between KRAS mutation , 18F-FDG uptake , and metastatic pattern in advanced stage colorectal cancer ( CRC ) patients .
3 METHODS :
4 Μ Medical records of stage IV CRC patients who underwent 18F-FDG PET/CT for staging and KRAS mutation analysis were selected .
5 On PET scans , a volume of interest ( VOI ) was drawn on the primary lesion. 18F-FDG indices ( SUVmax , SUVmean , MTV , TLG ) of the primary lesions were obtained and correlated with KRAS mutation of the primary lesion .
6 Also , metastatic sites were recorded .
7 Association between metastatic pattern and KRAS expression and FDG indices were analyzed .
8 RESULTS :
9 KRAS mutation was positive in 40 ( 43% ) patients .
10 Evaluation of FDG indices showed that higher SUVmax ( 140 vs. 112 , p = 0004 ) , higher SUVmean ( 53 vs. 47 , p = 0005 ) , and higher TLG ( 3014 vs. 2055 , p = 0023 ) were predictive of KRAS mutation compared to wild-type ( WT ) KRAS .
11 ✓ Μ Lung metastasis was more frequently involved in patients with KRAS mutation ( 500% vs. 226% , p = 0006 ) , and liver metastasis was more frequently involved in patients with WT KRAS ( 811% vs. 550% , p = 0007 ) . RO-INV-GM
12 ✓ Μ Multivariate analysis showed that primary tumor location ( OR 392 , p = 007 ) and KRAS mutation ( OR 245 , p = 009 ) were significant factors in lung metastasis model . GM-MRK-RO
13 CONCLUSION :
14 ✓ KRAS mutation patients had more frequent lung metastasis and had higher 18F-FDG uptake compared to WT KRAS in stage IV CRC . GM-ASS-RO, RO-ASS-GM



PMID: 28154202
(Cell)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 ✓ Aspirin-Induced Chemoprevention and Response Kinetics Are Enhanced by PIK3CA Mutations in Colorectal Cancer Cells . GM-REG-RO
1 This study was designed to determine how aspirin influences the growth kinetics and characteristics of cultured colorectal cancer cells that harbor a variety of different mutational backgrounds , including PIK3CA - and KRAS -activating mutations , and the presence or absence of microsatellite instability .
2 Colorectal cancer cell lines ( HCT116 , HCT116 + Chr3/5 , RKO , SW480 , HCT15 , CACO2 , HT29 , and SW48 ) were treated with pharmacologically relevant doses of aspirin ( 05-10 mmol/L ) and evaluated for proliferation and cell -cycle distribution .
3 These parameters were fitted to a mathematical model to quantify the effects and understand the mechanisms by which aspirin modifies growth in colorectal cancer cells .
4 We also evaluated the effects of aspirin on key G0-G1 cell -cycle genes that are regulated by the PI3K-Akt pathway .
5 Aspirin decelerated growth rates and disrupted cell -cycle dynamics more profoundly in faster growing colorectal cancer cell lines , which tended to be PIK3CA mutants .
6 Additionally , microarray analysis of 151 colorectal cancer cell lines identified important cell -cycle regulatory genes that are downstream targets of PIK3 and were also dysregulated by aspirin treatment ( PCNA and RB1 ) .
7 Our study demonstrated what clinical trials have only speculated , that PIK3CA-mutant colorectal cancers are more sensitive to aspirin .
8 Aspirin inhibited cell growth in all colorectal cancer cell lines regardless of mutational background , but the effects were exacerbated in cells with PIK3CA mutations .
9 Μ Mathematical modeling combined with bench science revealed that cells with PIK3CA-mutations experience significant G0-G1 arrest and explains why patients with PIK3CA mutant colorectal cancers may benefit from aspirin use after diagnosis .
10 Cancer Prev Res ; 10(3) ; 208-18 .
11 (c) 2017 AACR .



PMID: 28154181
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 USP39 Deubiquitinase Is Essential for KRAS Oncogene -driven Cancer .
1 Μ KRAS is the most frequently mutated oncogene in human cancer , but its therapeutic targeting remains challenging .
2 Here , we report a synthetic lethal screen with a library of deubiquitinases and identify USP39 , which encodes an essential splicing factor , as a critical gene for the viability of KRAS -dependent cells .
3 We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells .
4 Moreover , depletion of DHX38 , encoding an USP39 -interacting splicing factor , also reduces the viability of these cells .
5 In agreement with these results , USP39 depletion caused a significant reduction in pre-mRNA splicing efficiency , as demonstrated through RNA-seq experiments .
6 Furthermore , we show that USP39 is up-regulated in lung and colon carcinomas and its expression correlates with KRAS levels and poor clinical outcome .
7   Accordingly , our work provides critical information for the development of splicing-directed antitumor treatments and supports the potential of USP39-targeting strategies as the basis of new anticancer therapies .



PMID: 28153952
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 QMC-PCRx : a novel method for rapid mutation detection .
1 AIMS :
2 Μ We previously described the quick multiplex consensus PCR ( QMC-PCR ) as a method for rapid mutation screening in low-quality template .
3 QMC-PCR has two-stages : a prediagnostic multiplex ( PDM ) reaction followed by a single specific diagnostic reaction with high-resolution melting ( HRM ) analysis .
4 We aimed to develop QMC-PCRx in which second stage was multiplexed to allow testing of multiple targets .
5 METHODS :
6 The PDM reaction was retained without change .
7 For the second stage , in silico design was used to identify targets amenable to a multiplex specific diagnostic reaction and multiplex HRM ( mHRM ) analysis .
8 Following optimisation , 17 colorectal cancers were tested for mutation in five hotspots .
9 For QMC-PCR , each target was tested individually .
10 For QMC-PCRx , the targets were tested in the following combinations (i) KRAS exon 3/PIK3CA exon 20/PTEN exon 3 in triplex and ( ii ) PTEN exon 7/NRAS exon 2 in duplex .
11 The degree of agreement between the novel QMC-PCRx and the standard QMC-PCR was tested by the percentage concordance .
12 RESULTS :
13 Optimisation of mHRM showed that peaks needed to be separated ( without overlap ) and the optimal number was three targets per test .
14 Our experimental design produced distinct and widely separated peaks for the individual targets although one of the primers needed a GC-tail .
15 A total of 85 individual targets were tested ; this required 85 second-stage PCR/HRM tests by QMC-PCR versus 34 second-stage tests by QMC-PCRx .
16 The percentage concordance between the singleplex and multiplex methodologies was 100% .
17 CONCLUSIONS :
18 A multiplexed analysis using HRM is possible without loss of diagnostic accuracy .
19 Μ The novel QMC-PCRx protocol can significantly reduce workload and costs of mutation screening .



PMID: 28153858
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Drug Combo Beats Vemurafenib Alone for Colorectal Cancer .
1 Vemurafenib doesn't shrink BRAF-mutated colorectal tumors , but a regimen that also includes irinotecan and cetuximab improves vemurafenib's effectiveness , more than doubling progression-free survival in patients with metastatic tumors .
2 The drug trio also increases disease-control rates .



PMID: 28147317
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM .
1 Oncogenic BRaf V600E mutation is involved in the development , invasion and metastasis of colon cancer .
2 Selective inhibition of BRafV600E mutant has been recognized as a therapeutic strategy for the cancer .
3 Here , we carried out atomistic molecular dynamics ( MD ) simulations to characterize the structural basis , energetic property , and dynamics behavior of conformational change in BRaf activation loop upon the mutation .
4 Μ It is found that V600E mutation destabilizes inactive DFG-out conformation of activation loop and promotes its conversion to the active DFG-in conformation , thus conferring constitutive activity for BRaf kinase .
5 A further analysis revealed that the conformational change is induced by electrostatic effect of the negatively charged mutant residue Glu600 , which can form a potent salt bridge with the positively charged residue Lys570 ; this is naturally consistent with phosphorylation of activation loop to activate the kinase .
6 Both of them introduce a negative charge to activation loop and , consequently , the DFG-out is destabilized and conversed to DFG-in .
7 Energetic analysis unraveled that small-molecule kinase inhibitor PLX4720 has a similar selectivity profile for mutant over wild-type kinases and for phosphorylated and dephosphorylated kinases .
8 This can be substantiated in part by in vitro kinase assay that the inhibitor exhibits 12.6 and 10.4-fold higher potencies against mutant than wild type and against phosphorylated than dephosphorylated , respectively .
9 It is suggested that the activation loop conformation , but neither V600E mutation nor phosphorylation , directly determines inhibitor affinity ; the mutation and phosphorylation can only indirectly influence inhibitor binding via regulation of activation loop conformation .
10 Graphical Abstract Chemotherapeutic drug selectivity between wild-type and mutant BRaf kinases in colon cancer .



PMID: 28145097
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer .
1 Intratumor heterogeneity ( ITH ) contributes to cancer progression and chemoresistance .
2 We sought to comprehensively describe ITH of somatic mutations , copy number , and transcriptomic alterations involving clinically and biologically relevant gene pathways in colorectal cancer ( CRC ) .
3 We performed multiregion , high-depth ( 384x on average ) sequencing of 799 cancer-associated genes in 24 spatially separated primary tumor and nonmalignant tissues from four treatment-naive CRC patients .
4 Μ We then used ultra-deep sequencing ( 17 075x on average ) to accurately verify the presence or absence of identified somatic mutations in each sector .
5 We also digitally measured gene expression and copy number alterations using NanoString assays .
6 Μ We identified the subclonal point mutations and determined the mutational timing and phylogenetic relationships among spatially separated sectors of each tumor .
7 Truncal mutations , those shared by all sectors in the tumor , affected the well-described driver genes such as APC , TP53 , and KRAS .
8 Μ With sequencing at 17 075x , we found that mutations first detected at a sequencing depth of 384x were in fact more widely shared among sectors than originally assessed .
9 Μ Interestingly , ultra-deep sequencing also revealed some mutations that were present in all spatially dispersed sectors , but at subclonal levels .
10 Ultra-high-depth validation sequencing , copy number analysis , and gene expression profiling provided a comprehensive and accurate genomic landscape of spatial heterogeneity in CRC .
11 Ultra-deep sequencing allowed more sensitive detection of somatic mutations and a more accurate assessment of ITH .
12 By detecting the subclonal mutations with ultra-deep sequencing , we traced the genomic histories of each tumor and the relative timing of mutational events .
13 Μ We found evidence of early mixing , in which the subclonal ancestral mutations intermixed across the sectors before the acquisition of subsequent nontruncal mutations .
14 Our findings also indicate that different CRC patients display markedly variable ITH , suggesting that each patient's tumor possesses a unique genomic history and spatial organization .



PMID: 28141798
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis .
1 BACKGROUND :
2 A compromised base excision repair ( BER ) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis , a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine .
3 Remarkably , DNA global demethylation has been shown to be mediated by BER , suggesting a relevant interplay with early colorectal tumourigenesis .
4 To check this hypothesis , we investigated a cohort of 49 adenomas and 10 carcinomas , derived from 17 MUTYH-associated polyposis patients ; as adenoma controls , we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps .
5 METHODS :
6 Samples were analysed for their mutational and epigenetic status , measured as global LINE-1 ( long interspersed nuclear element ) and gene -specific LINE-1 MET methylation by mass spectrometry and pyrosequencing .
7 RESULTS :
8 MUTYH-associated polyposis adenomas were strikingly more hypomethylated than familial adenomatous and sporadic polyps for both DNA demethylation markers ( P = 0032 and P = 0007 for LINE-1 ; P = 0004 and P<00001 for LINE-1 MET , respectively ) with levels comparable to those of the carcinomas derived from the same patients .
9 They also had mutations due mainly to KRAS/NRAS p.G12C , which was absent in the controls ( P<00001 for both sets ) .
10 CONCLUSIONS :
11 Our results show that DNA demethylation , together with specific KRAS/NRAS mutations , drives the early steps of oxidative damage colorectal tumourigenesis .



PMID: 28133304
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Metastatic Colorectal Cancer with HER2 Overexpression/Amplification ] .
1 Μ We report a case of panitumumab-resistant rectal cancer with HER2 gene amplification detected by CancerPlex(R) .
2 A 51 - year-old man was diagnosed with an obstructive rectal cancer having lung and adrenal metastases .
3 Μ He underwent the Hartmann 's operation , and KRAS mutations were not detected .
4 After the surgery , 3 courses of CapeOx plus bevacizumab were administered as first - line chemotherapy ; however , the lung and adrenal metastases progressed .
5 Subsequently , 24 courses of IRIS/panitumumab was administered as second - line chemotherapy , and the metastases slowly progressed .
6 Six courses of regorafenib were administered as third - line chemotherapy followed by a course of TAS-102 as fourth - line chemotherapy .
7 Subsequently , a left femoral head metastasis and cerebellar metastases were detected .
8 The patient received best supportive care including palliative femoral head replacement and stereotactic irradiation for the cerebellar metastases , and he died of cancer 3 years 5 months after the primary surgery .
9 Μ The comprehensive genomic analysis focusing on 413 cancer-related genes with CancerPlex(R) revealed that EGFR , BRAF , KRAS , NRAS , and HRAS had no mutations ; however , ERBB2 amplification was detected .
10 Furthermore , immunohistochemical staining revealed overexpression of HER2 protein in both the primary and bone metastatictumor .
11 HER2 and EGFR independently promote the RAS-RAF-MAPK pathway .
12   In the present case , the efficacy of anti-EGFR therapy may be attenuated because of ERBB2 amplification in the metastatic tumor .



PMID: 28133295
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Systematic Analysis of Oncogene and Tumor Suppressor Genes for Panitumumab-Resistant Rectal Cancer with Wild RAS Gene - A Case Report ] .
1 A 58-year-old man was admitted with the complaint of bloody stools .
2 Colonoscopy and computed tomography revealed a rectal cancer with a liver metastasis and multiple lung metastases .
3 After administering a regimen comprising 3 courses of XELOX plus bevacizumab chemotherapy , the sizes of the primary and metastatic lesions decreased remarkably .
4 Abdominoperineal resection was performed for local control of the cancer ; the specimen from the initial tumor was found to be KRAS wild type .
5 After 14 courses of XELOX chemotherapy , brain metastases were detected .
6 Although 3 courses of IRIS plus panitumumab were administered , the liver , lung , and brain metastases spread rapidly .
7 Μ A comprehensive genomic analysis focused on cancer-related genes with CancerPlex(R) found a mutation of the BRAF gene (I326V) .
8 BRAF is a downstream molecule of KRAS in the RAS-RAF-MAPK pathway .
9 Therefore , this mutation of the BRAF gene has the possibility of causing resistance against panitumumab that was found in this case .
10   Furthermore , we expect that the systematic analysis of oncogene and suppressor oncogenes will enable us to choose the optimal regimen of chemotherapy or molecular targeting therapy for each patient with colorectal cancer .



PMID: 28133294
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Rectal Cancer with Unresectable Liver Metastasis Responding to Rechallenge with FOLFIRI ] .
1 A 63-year-old man underwent low anterior resection for rectal cancer .
2 A synchronous liver metastasis located in segment 8 was 12 cm in diameter and unresectable due to its proximity to the inferior vena cava ( IVC ) .
3 The postoperative pathological findings revealed a T3 (SS) , N0 , M1 ( liver ) Stage IV tumor , and wild type K-RAS was expressed .
4 We chose FOLFIRI plus cetuximab ( Cmab ) for first - line chemotherapy .
5 After 6 courses , we changed the molecular target drug from Cmab to bevacizumab ( Bmab ) because the liver metastasis remained unresectable .
6 The patient had long-term stable disease ( SD ) for approximately 30 months with the FOLFIRI-based regimen .
7 We then changed the regimen to mFOLFOX6 plus Bmab for second - line , Cmab for third - line , and trifluridine/tipiracil hydrochloride for fourth - line chemotherapy to treat progressive disease ( PD ) .
8 After treatment with these chemotherapies , the patient wished to continue treatment .
9 We restarted FOLFIRI plus Bmab for fifth - line chemotherapy as his general condition was still good .
10 Consequently , his tumor markers levels decreased with stabilization of the disease on CT scans , and he continued therapy for 6 months while maintaining a good quality of life .
11   This case suggested that rechallenge with anti-cancer agents could be effective and improve the prognosis of colorectal cancer patients after using all key drugs .



PMID: 28133136
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Metastatic Colon Cancer Dramatically Affected by Anti-EGFR Antibody Therapy ] .
1 RAS mutation is an established predictive biomarker of resistance to anti-epidermal growth factor receptor ( EGFR ) therapy in metastatic colorectal cancer .
2 Μ In addition , previous studies identified mutations in ERBB2 , FGFR1 , PDGFRA , BRAF , MAP2K1 , PTEN , and PIK3CA as potential mechanisms of resistance to anti-EGFR therapy .
3 Testing for these mutations might be necessary to determine eligibility for anti-EGFR therapy in patients with metastatic colorectal cancer .
4 CancerPlex(R) is a nextgeneration sequencer for 413 cancer genes .
5 An analysis panel includes genes that may be associated with resistance to anti - EGFR therapy .
6 A 65-year-old man with unresectable rectal cancer , multiple lung metastases , and a bulky liver metastasis was evaluated for expression of genes associated with resistance to anti-EGFR .
7 The analysis found that all genes indicating resistance were wild-type genes .
8 Cetuximab monotherapy was administered after rectal resection , with dramatic shrinkage of the metastatic tumors .
9   A more accurate selection of patients according to tumor genetic status using CancerPlex(R) might improve the risk-benefit profile of anti-EGFR therapy .



PMID: 28133101
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Evaluation of BRAF V600E Mutations in High-Level Microsatellite Instability ( MSI-H ) Colon Cancer - Comparison Between Genetic Testing and Immunohistochemical Staining ] .
1 BRAF V600E mutation plays an important role in the serrated neoplasia pathway of colorectal tumorigenesis and is a negative predictive factor for chemotherapy response as well as a prognostic factor in patients with colorectal cancer .
2 To evaluate BRAF V600E mutations , a conventional polymerase chain reaction ( PCR ) is performed but recently immunohistochemistry ( IHC ) with a BRAF antibody has been used .
3 Μ Although similarities between the PCR and IHC methods have been reported , some investigators have doubts about the usefulness of IHC for BRAF mutation analysis .
4 The subjects were 38 colorectal cancer patients with tumors demonstrating loss of both MLH1 and PMS2 , and high-level microsatellite instability .
5 Μ Of the original 39 patients , 1 was excluded due to Lynch syndrome , which was identified using germline mutation testing .
6 The mutation rate of BRAF V600E was 57.9% using both methods , but the concordance rate was 68.4% , with a kappa-value of 0.33 .
7 We should consider the usefulness of the IHC method in the evaluation of BRAF mutations in colorectal cancer patients .



PMID: 28125730
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Influence of BRAF and KRAS Mutation Status on the Association between Aspirin Use and Survival after Colon Cancer Diagnosis .
1 BACKGROUND :
2 Use of aspirin after diagnosis of colon cancer has been associated with improved survival .
3 Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens .
4 The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis .
5 METHODS :
6 Μ A random selection of 599 patients with colon cancer were analyzed , selected from the Eindhoven Cancer Registry , and BRAF and KRAS mutation status was determined .
7 Data on aspirin use ( 80 mg ) were obtained from the PHARMO Database Network .
8 Parametric survival models with exponential ( Poisson ) distribution were used .
9 RESULTS :
10 Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors , adjusted rate ratio ( RR ) of 0.60 ( 95% CI 044-083 ) .
11 In contrast , aspirin use in BRAF mutated tumors was not associated with an improved survival ( RR 111 , 95% CI 057-216 ) .
12 P-value for interaction was non-significant .
13 KRAS mutational status did not differentiate in the association between aspirin use and survival .
14 CONCLUSION :
15 Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only .
16 However , the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit .
17   These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin , if aspirin becomes regular adjuvant treatment for colon cancer patients in the future .



PMID: 28123896
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 CXCR4-CXCL12-CXCR7 , TLR2-TLR4 , and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients .
1 A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases ( CRLM ) .
2 At a median follow up of 28 months , 20/33 patients were dead of disease , 8 were alive with disease and 5 were alive with no evidence of disease .
3 To shed further insight into biological features accounting for different outcomes , the expression of CXCR4-CXCL12-CXCR7 , TLR2-TLR4 , and the programmed death receptor-1 ( PD-1 ) /programmed death-1 ligand ( PD-L1 ) was evaluated in excised liver metastases .
4 Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients .
5 CXCR4 and CXCR7 , TLR2/TLR4 , and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues .
6 CXCR4 protein was negative/low in 10/31 , and high in 21/31 , CXCR7 was negative/low in 16/31 and high in 15/31 , CXCL12 was negative/low in 14/31 and high in 17/31 CRLM .
7 PD-1 was negative in 19/30 and positive in 11/30 , PD-L1 was negative/low in 24/30 and high in 6/30 CRLM .
8 Stromal PD-L1 expression , affected the progression-free survival ( PFS ) in the CRLM population .
9 Μ Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival ( CSS ) ( p = 0001 and p = 00008 ) ; in these patients , KRAS mutation identified a subgroup with a significantly worse CSS ( p <001 ) .
10 Thus , CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients .
11 Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group .
12   Thus , CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs .



PMID: 28122448
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sensitive High-Resolution Melting Analysis for Screening of KRAS and BRAF Mutations in Iranian Human Metastatic Colorectal Cancers .
1 Μ Background : Investigations of methods for detection of mutations have uncovered major weaknesses of direct sequencing and pyrosequencing , with their high costs and low sensitivity in screening for both known and unknown mutations .
2 High resolution melting ( HRM ) analysis is an alternative tool for the rapid detection of mutations .
3 Μ Here we describe the accuracy of HRM in screening for KRAS and BRAF mutations in metastatic colorectal cancer ( mCRCs ) samples .
4 Materials and Methods : A total of 1000 mCRC patients in Mehr Hospital , Tehran , Iran , from Feb 2008 to May 2012 were examined for KRAS mutations and 242 of them were selected for further assessment of BRAF mutations by HRM analysis .
5 In order to calculate the sensitivity and specificity , HRM results were checked by pyrosequencing as the golden standard and Dxs Therascreen as a further method .
6 Results : In the total of 1,000 participants , there were 664 ( 664% ) with wild type and 336 ( 336% ) with mutant codons 12 and/or 13 of the KRAS gene .
7 Among 242 samples randomly checked for the BRAF gene , all were wild type by HRM .
8 Pyrosequencing and Dxs Therascreen results were in line with those of the HRM .
9 In this regard , the sensitivity and specificity of HRM were evaluated as 100% .
10 Conclusion : The findings suggest that the HRM , in comparison with DNA sequencing , is a more appropriate method for precise scanning of KRAS and BRAF mutations .
11 It is also possible to state that HRM may be an attractive technique for the detection of known or unknown somatic mutations in other genes .



PMID: 28117362
(Patient)  
Terms: Prospective Study
Sent# Symbols Sentence Mnemonics
0 A Prospective Study of Smoking and Risk of Synchronous Colorectal Cancers .
1 OBJECTIVES :
2 Cigarette smoking has been linked to somatic genetic and epigenetic aberrations , including CpG island methylator phenotype ( CIMP )- high , microsatellite instability ( MSI )- high and BRAF mutation .
3 These molecular features have been associated with synchronous primary colorectal cancers ( CRCs ) .
4 Thus , we examined the hypothesis that smoking might be associated with the risk of synchronous CRCs .
5 METHODS :
6 Within the Health Professionals Follow-up Study and Nurses' Health Study , we examined the relationship of smoking and incidence of CRC according to tumor synchronicity , using duplication-method Cox proportional hazards regression analysis .
7 RESULTS :
8 We confirmed 1,981 solitary CRC and 45 synchronous CRC cases during follow-up of 134,305 individuals .
9 CRC risk associated with smoking differed significantly by tumor synchronicity status ( Pheterogeneity<0001 ) .
10 When comparing current smokers with never smokers , multivariable hazard ratios ( HR ) were 5.27 ( 95% confidence interval ( CI ) , 2.08-13.40 ) for synchronous CRCs and 0.97 ( 95% CI , 083-114 ) for solitary CRC .
11 Similarly , differential associations were observed when examining cumulative pack-years smoked ( Pheterogeneity = 0006 ) .
12 Smoking cessation for >/ = 10 years relative to current smoking might reduce the risk of synchronous CRCs ( multivariable HR = 042 ; 95% CI , 019-095 ) , but not solitary CRC ( multivariable HR = 110 ; 95% CI , 094-129 ; Pheterogeneity = 0001 ) .
13 Comparing current and former smokers with never smokers , multivariable HRs for synchronous CRCs were significantly higher than those of solitary CRC positive for either CIMP-high , MSI-high , or BRAF mutation ( Pheterogeneity = 0002 ) .
14 CONCLUSIONS :
15 Smoking is associated with an elevated risk of synchronous CRCs .
16 Our data support a model where smoking contributes to an etiologic field effect that favors these somatic molecular alterations and the development of multiple primary tumors .



PMID: 28105615
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Improvement of prognostic and predictive network of colorectal cancer based upon the 8th edition of AJCC colorectal cancer staging system ] .
1 The 8th edition of AJCC cancer staging system will be launched all over the world in January 1 , 2018 .
2 The major advances in the 8th edition are the introduction of non-anatomic prognostic and predictive factors supported by I ( -II ( grade evidence based on histopathology and molecular biology , and the improvement of prognostic assessment system based on these factors , including CEA level , cancer retraction score , circumference margin , lymphatic invasion , peripheral nerve invasion , microsatellite instability , KRAS/NRAS gene mutation and BRAF gene mutation .
3 In the background of evidence-based medicine and precise medicine , combination of anatomic staging and non-anatomic classification system is very important for establishing and improving the prognostic and predictive assessment system of colorectal cancer .
4   This will help to assess colorectal cancer staging and grouping much better , evaluate the prognosis , predict individualized efficacy , and promote clinical practice of colorectal cancer from traditional population-based diagnosis and treatment to the precise individualized care .



PMID: 28105192
(None)  
Terms: , mice, transgenic ( Tg ) mice, mouse
Sent# Symbols Sentence Mnemonics
0 Akt -dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity .
1 A total of two major isoforms , cyclin D1a and cyclin D1b , are generated from the human cyclin D1 gene by alternative splicing .
2 Μ Cyclin D1b is scarcely expressed in normal tissues ; however , it is expressed at a high frequency in certain types of cancerous tissue .
3 The present authors previously constructed cyclin D1b transgenic ( Tg ) mice and identified rectal tumors , including adenocarcinoma and sessile serrated adenoma , in 62.5% of female Tg mice .
4 In addition , the present authors indicated that cyclin D1b expression enhances phosphorylation of extracellular signal-regulated kinase ( Erk ) in these rectal tumors , and in mouse embryonic fibroblast ( MEF ) cells and human 293T cells .
5 In the present study , it was initially demonstrated that cyclin D1b has the ability to enhance cell invasiveness by itself ; it additionally increases cell invasiveness , anchorage -independent growth and tumorigenicity in cooperation with an activated K-ras oncogene in MEF cells .
6 Phosphorylation of Akt was increased in cyclin D1b-expressing MEF cells and in the rectal tumor tissues of cyclin D1b Tg mice .
7 Phosphorylation of Akt was also enhanced by transfection of cyclin D1b , but not cyclin D1a , in human 293T cells .
8 Treatment with an Akt inhibitor suppressed phosphorylation of Erk in 293T cells expressing cyclin D1b and D1bTgRT cells established from rectal cancer of the cyclin D1b Tg mouse .
9 Furthermore , the Akt inhibitor suppressed the invasiveness of D1bTgRT cells and the tumor growth of these cells in nude mice when the Akt inhibitor was injected into the tumors .
10 These results indicate that cyclin D1b activates Erk through Akt , and that activation of Akt contributes to the tumorigenicity of the cyclin D1b Tg mice .
11   Inhibitors targeting the phosphoinositide 3-kinase/Akt signaling pathway are thus expected to have therapeutic potential in a variety of human cancer types expressing cyclin D1b .



PMID: 28105166
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 miR-217 regulates tumor growth and apoptosis by targeting the MAPK signaling pathway in colorectal cancer .
1 MicroRNA ( miR ) -217 has been reported to participate in carcinogenesis and tumor progression in several cancers ; however , its expression and biological functions in colorectal cancer ( CRC ) are still unclear .
2 Μ The present study demonstrated that miR-217 expression was significantly higher in matched adjacent noncancerous tissues than in CRC tissues ( P<0001 ) .
3 Μ In addition , it was observed that low-grade CRC exhibited greater expression of miR-217 compared with high-grade CRC ( P<005 ) .
4 Μ Kaplan-Meier survival and Cox regression analyses revealed that overall survival rates were significantly poorer in the low-expression group relative to the high-expression group ( P<0005 ) .
5 Next , a potential miR-217 target , mitogen -activated protein kinase ( MAPK ) 1 , was identified .
6 Upregulation of miR-217 could significantly downregulate MAPK1 expression .
7 CRC cells overexpressing miR-217 exhibited cell growth inhibition by significant enhancement of apoptosis in vitro .
8 Μ The present study further investigated the MAPK signaling pathway to verify the mechanisms , and revealed that KRAS and Raf-1 expression was downregulated in miR-217-overexpressing RKO cells .
9 Taken together , our results revealed that miR-217 inhibits tumor growth and enhances apoptosis in CRC , and that this is associated with the downregulation of MAPK signaling .
10   These results indicate that miR-217 is a promising therapeutic target for the treatment of CRC .



PMID: 28104492
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression .
1 High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer .
2 RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways .
3 We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D ( 1,25 ( OH ) 2D )- mediated gene expression in cultured colon and intestinal cell lines .
4 Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12 V) significantly reduced 1,25 ( OH ) 2D -induced activity of both a human 25-hydroxyvitamin D , 24 hydroxyase (CYP24A1) promoter -luciferase and an artificial 3X vitamin D response element ( VDRE ) promoter -luciferase reporter gene .
5 Mouse Young Adult Colon ( YAMC ) and Rat Intestinal Epithelial ( RIE ) cell lines with stable expression of mutant H-RAS had suppressed 1,25 ( OH ) 2D -mediated induction of CYP24A1 mRNA .
6 The RAS effects were associated with lower Vitamin D receptor ( VDR ) mRNA and protein levels in YAMC and RIE cells and they could be partially reversed by VDR overexpression .
7 RAS -mediated suppression of VDR levels was not due to either reduced VDR mRNA stability or increased VDR gene methylation .
8 However , chromatin accessibility to the VDR gene at the proximal promoter ( -300bp ) , an enhancer region at -6kb , and an enhancer region located in exon 3 was significantly reduced in RAS transformed YAMC cells ( YAMC-RAS ) .
9 These data show that constitutively active RAS signaling suppresses 1,25 ( OH ) 2D -mediated gene transcription in colon epithelial cells by reducing VDR gene transcription but the mechanism for this suppression is not yet known .
10 These data suggest that cancers with RAS -activating mutations may be less responsive to vitamin D mediated treatment or chemoprevention .



PMID: 28099523
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Role of Liquid Based Cytology and Ancillary Techniques in the Peritoneal Washing Analysis : Our Institutional Experience .
1 BACKGROUND :
2 The cytological analysis of peritoneal effusions serves as a diagnostic and prognostic aid for either primary or metastatic diseases .
3 Among the different cytological preparations , liquid based cytology ( LBC ) represents a feasible and reliable method ensuring also the application of ancillary techniques ( ie immunocytochemistry-ICC and molecular testing ) .
4 METHODS :
5 We recorded 10348 LBC peritoneal effusions between January 2000 and December 2014 .
6 They were classified as non-diagnostic ( ND ) , negative for malignancy-NM , atypical-suspicious for malignancy-SM and positive for malignancy-PM .
7 RESULTS :
8 The cytological diagnosis included 218 ND , 9.035 NM , 213 SM and 882 PM .
9 A total of 8048 ( 7228 NM , 115SM , 705 PM ) cases with histological follow-up were included .
10 Our NM included 21 malignant and 7207 benign histological diagnoses .
11 Our 820 SMs+PMs were diagnosed as 107 unknown malignancies ( 30SM and 77PM ) , 691 metastatic lesions ( 81SM and 610PM ) , 9 lymphomas ( 2SM and 7PM ) , 9 mesotheliomas ( 1SM and 8SM ) , 4 sarcomas ( 1SM and 3PM ) .
12 Primary gynecological cancers contributed with 64% of the cases .
13 We documented 97.4% sensitivity , 99.9% specificity , 98% diagnostic accuracy , 99.7% negative predictive value ( NPV ) and 99.7% positive predictive value ( PPV ) .
14 Furthermore , the morphological diagnoses were supported by either 173 conclusive ICC results or 50 molecular analyses .
15 Μ Specifically the molecular testing was performed for the EGFR and KRAS mutational analysis based on the previous or contemporary diagnoses of Non Small Cell Lung Cancer ( NSCLC ) and colon carcinomas .
16 Μ We identified 10 EGFR in NSCCL and 7 KRAS mutations on LBC stored material .
17 CONCLUSIONS :
18 Peritoneal cytology is an adjunctive tool in the surgical management of tumors mostly gynecological cancers .
19 LBC maximizes the application of ancillary techniques such as ICC and molecular analysis with feasible diagnostic and predictive yields also in controversial cases .



PMID: 28097409
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer .
1 INTRODUCTION :
2 Colorectal cancer ( CRC ) is a highly heterogeneous disease , with pathologically similar cancers having completely different responses to treatment and patient survival .
3 Intra-tumour heterogeneity ( defined as distinct morphological and phenotypic differences ) has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine response to anticancer therapy .
4 METHOD :
5 Μ Patients with resected CRC had DNA extracted from eight defined tumour areas which were analysed for two genetic mutations ( BRAF and KRAS ) and one epigenetic trait ( CpG island methylator phenotype/CIMP ) .
6 Normal adjacent tissue was studied as control .
7 RESULTS :
8 Twelve patients with CRC were included .
9 Intra-tumoural heterogeneity for KRAS mutation was seen in 2 patients ( 17% ) .
10 There was no statistical evidence of CIMP status heterogeneity ( p = 085 ) , but 6 of the 12 patients ( 50% ) demonstrated atleast one heterogeneous area within the tumour .
11 DISCUSSION :
12 Intra-tumoural heterogeneity for both genetic and epigenetic factors in CRC is more prevalent than previously thought in Stage II and Stage III CRC .
13 This study provides new insight into epigenetic heterogeneity of CRC and supports the development of a more targeted biopsy strategy to support expansion of personalised treatment .



PMID: 28095174
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Medical Oncologists' Experiences in Using Genomic Testing for Lung and Colorectal Cancer Care .
1 PURPOSE :
2 Genomic testing improves outcomes for many at-risk individuals and patients with cancer ; however , little is known about how genomic testing for non-small-cell lung cancer ( NSCLC ) and colorectal cancer ( CRC ) is used in clinical practice .
3 PATIENTS AND METHODS :
4 In 2012 to 2013 , we surveyed medical oncologists who care for patients in diverse practice and health care settings across the United States about their use of guideline - and non-guideline -endorsed genetic tests .
5 Multivariable regression models identified factors that are associated with greater test use .
6 RESULTS :
7 Of oncologists , 337 completed the survey ( participation rate , 53% ) .
8 Oncologists reported higher use of guideline -endorsed tests ( eg , KRAS for CRC ; EGFR for NSCLC ) than non-guideline -endorsed tests ( eg , Onco typeDX Colon ; ERCC1 for NSCLC ) .
9 Many oncologists reported having no patients with CRC who had mismatch repair and/or microsatellite instability ( 24% ) or germline Lynch syndrome ( 32% ) testing , and no patients with NSCLC who had ALK testing ( 11% ) .
10 Of oncologists , 32% reported that five or fewer patients had KRAS and EGFR testing for CRC and NSCLC , respectively .
11 Oncologists , rather than pathologists or surgeons , ordered the vast majority of tests .
12 In multivariable analyses , fewer patients in nonprofit integrated health care delivery systems underwent testing than did patients in hospital or office-based single-specialty group settings ( all P <05 ) .
13 High patient volume and patient requests ( CRC only ) were also associated with higher test use ( all P <05 ) .
14 CONCLUSION :
15 Genomic test use for CRC and NSCLC varies by test and practice characteristics .
16 Μ Research in specific clinical contexts is needed to determine whether the observed variation reflects appropriate or inappropriate care .
17 One potential way to reduce unwanted variation would be to offer widespread reflexive testing by pathology for guideline -endorsed predictive somatic tests .



PMID: 28091917
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prostate-specific G-protein -coupled receptor collaborates with loss of PTEN to promote prostate cancer progression .
1 Molecular genetic analysis of KRAS , NRAS , and BRAF genes was carried out in order to develop an optimal algorithm for detection of minor mutations .
2 We analyzed 35 melanoma and 33 colorectal cancer specimens .
3 Μ Frequent G12D/V/A/C/S mutations were detected in KRAS .
4 The most frequent BRAF mutation in melanoma was V600E , the percentage of rare mutations is significant for DNA diagnosis ( 24% ) .
5 Identification of rare BRAF mutations 1790C-->G ( L597R ) , 1798 1799delinsAA (V600K) , 1798 1799delinsAG (V600R) , and 1799 1800delinsAA (V600E) and NRAS mutation 38G-->T ( G13V ) was possible only by Sanger sequencing .
6 The combination of real-time PCR and sequencing can improve analysis sensitivity and ensure concordance of the tested loci with the international recommendations .



PMID: 28082821
(Patient)  
Terms: , mice, mice breast cancer models
Sent# Symbols Sentence Mnemonics
0 Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein .
1 Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics .
2 It is developing quickly in the field of cancer therapy .
3 For example , KRAS , NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer ( CRC ) .
4 Besides for these well-known mutations , the purpose of performing larger genetic testing in this pathology is unknown .
5 Recent reports have shown that using the poly ADP ribose polymerase ( PARP ) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast , ovarian and prostate cancers .
6 We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses .
7 Μ The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients ( Check2 for the first patient and RAD51C for the second one ) .
8 Both patients were treated with off-label usage of olaparib .
9 Μ While the first patient showed clinical benefit , reduction of carcinoembryonic antigen tumor marker and radiologic response , the second patient quickly presented a progression of the tumor .
10 Μ Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed .
11 ✓ Interestingly , deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models .
12 Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency .



PMID: 28081962
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Quality of Life Analysis in Patients With RAS Wild-Type Metastatic Colorectal Cancer Treated With First - Line Cetuximab Plus Chemotherapy .
1 BACKGROUND :
2 Adding cetuximab to FOLFIRI ( 5-fluorouracil , leucovorin , irinotecan ) significantly improved progression-free survival ( PFS ) , overall survival ( OS ) , and objective response rate ( ORR ) in patients with KRAS or RAS ( KRAS/NRAS , exons 2-4 ) wild-type ( wt ) metastatic colorectal cancer ( mCRC ) in the first - line CRYSTAL study .
3 The present exploratory and descriptive retrospective analysis assessed the quality of life ( QoL ) of CRYSTAL study patients with RAS wt mCRC-the labeled indication for cetuximab in many countries .
4 PATIENTS AND METHODS :
5 Patient QoL was investigated using the European Organisation for Research and Treatment of Cancer QoL questionnaire core-30 ( EORTC QLQ-C30 ) .
6 QoL assessments were performed at baseline , after every 8 weeks of treatment , and at the final tumor assessment .
7 RAS wt patients were considered evaluable for QoL if they had provided >/= 1 evaluable EORTC QLQ-C30 .
8 RESULTS :
9 Of the 367 patients with RAS wt tumors , 351 were evaluable for QoL .
10 Global health status ( GHS ) /QoL and the time to worsening of Eastern Cooperative Oncology Group performance status were similar between the treatment groups .
11 However , the analysis was complicated by a large decrease in the number of evaluable patients in the FOLFIRI arm between weeks 32 and 40 .
12 The individual dimensions of interest in mCRC ( eg , social functioning , fatigue , nausea/vomiting , pain , appetite loss , constipation , diarrhea , and functional difficulties ) were also similar between the treatment arms .
13 Changes in GHS/QoL and social functioning from baseline to week 8 were similar , irrespective of whether patients experienced early skin reactions .
14 CONCLUSION :
15   The findings of the present descriptive retrospective analysis suggest that adding cetuximab to first - line FOLFIRI improves PFS , OS , and ORR without negatively affecting the QoL of CRYSTAL study patients with RAS wt mCRC .



PMID: 28078112
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Molecular spectrum of KRAS , NRAS , BRAF , PIK3CA , TP53 , and APC somatic gene mutations in Arab patients with colorectal cancer : determination of frequency and distribution pattern .
1 BACKGROUND :
2 The frequency rates of mutations such as KRAS , NRAS , BRAF , and PIK3CA in colorectal cancer ( CRC ) differ among populations .
3 The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features .
4 METHODS :
5 Arab patients from the Arab Gulf region and a population of age - and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing ( NGS ) were identified and retrospectively reviewed .
6 The mutation rates of KRAS , NRAS , BRAF , PIK3CA , TP53 , and APC were recorded , along with clinicopathological features .
7 Μ Other somatic mutation and their rates were also identified .
8 Fisher's exact test was used to determine the association between mutation status and clinical features .
9 RESULTS :
10 A total of 198 cases were identified ; 99 Arab patients and 99 Western patients .
11 Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation , 74.2% had left-sided tumors .
12 Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma .
13 The prevalence rates of KRAS , NRAS , BRAF , PIK3CA , TP53 , APC , SMAD , FBXW7 mutations in Arab population were 44.4% , 4% , 4% , 13.1% , 52.5% , 27.3% , 2% and 3% respectively .
14 Compared to 48.4% , 4% , 4% , 12.1% , 47.5% , 24.2% , 11.1% and 0% respectively in matched Western population .
15 Associations between these mutations and patient clinicopathological features were not statistically significant .
16 CONCLUSIONS :
17 This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC .
18 The frequency of KRAS , NRAS , BRAF , TP53 , APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation .



PMID: 28077799
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer : a meta-analysis .
1 Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer ( IBD-CRC ) and sporadic colorectal cancer ( S-CRC ) , molecular events leading to carcinogenesis may be different .
2 Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent .
3 We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC , S-CRC , and IBD without dysplasia .
4 A total of 19 publications ( 482 patients with IBD-CRC , 4,222 with S-CRC , 281 with IBD without dysplasia ) met the study inclusion criteria .
5 KRAS mutation was less frequent ( RR = 071 , 95%CI 056-090 ; P = 0004 ) while TP53 mutation was more common ( RR = 124 , 95%CI 110-139 ; P<0001 ) in patients with IBD-CRC compared to S-CRC .
6 Both KRAS ( RR = 309 , 95%CI 147-651 ; P = 0003 ) and TP53 ( RR = 215 , 95%CI 107-431 P = 003 ) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia .
7 In conclusion , IBD-CRC and S-CRC appear to have biologically different molecular pathways .
8 TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC .
9   Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC .



PMID: 28074351
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS , NRAS and BRAF mutations in colorectal cancer and melanoma .
1   Realizing the potential of plasma genotyping in an age of genotype-directed therapies .



PMID: 28072391
(None)  
Terms: , mouse, mouse tumor model
Sent# Symbols Sentence Mnemonics
0 BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis .
1 While 20-30% of colorectal cancers ( CRCs ) may arise from precursors with serrated glands , only 8-10% of CRCs manifest serrated morphology at diagnosis .
2 Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking .
3 Μ We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together ( p = 004 ) .
4 CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors ( including carcinomas ) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression .
5 Μ Like human serrated lesions , CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers .
6 Μ Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features , and partially recapitulated the gene expression pattern in mouse colon tissues .
7 We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E .
8 The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis .



PMID: 28068936
(Patient)  
Terms: Retrospective study
Sent# Symbols Sentence Mnemonics
0 ✓ Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first - line chemotherapy with bevacizumab in metastatic colorectal cancer patients . GM-MRK-RO
1 BACKGROUND :
2 After analysis of minor RAS mutations ( KRAS exon 3 , 4/NRAS ) in the FIRE-3 and PRIME studies , an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment .
3 BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies .
4 However , it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer .
5 We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first - line treatment for metastatic colorectal cancer .
6 METHODS :
7 Of the 1001 consecutive colorectal cancer patients examined for RAS , PIK3CA , and BRAF tumor mutations using a multiplex kit ( Luminex(R) ) , we studied 90 patients who received combination chemotherapy with bevacizumab as first - line treatment for metastatic colorectal cancer .
8 The objective response rate ( ORR ) and progression-free survival ( PFS ) were evaluated according to mutational status .
9 RESULTS :
10 ✓ The ORR was higher among patients with wild-type tumors ( 643% ) compared to those with tumors that were only wild type with respect to KRAS exon 2 ( 548% ) , and the differences in ORR between patients with wild-type and mutant -type tumors were greater when considering only KRAS exon 2 mutations ( 68% ) rather than RAS/PIK3CA/BRAF mutations ( 184% ) . RO-ASS-GM
11 Μ There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations .
12 ✓ Μ Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first - line treatment with bevacizumab . GM-MRK-RO
13 CONCLUSIONS :
14   Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment .
15   We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors .



PMID: 28067073
(None)  
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0 Translating genomic profiling to gastrointestinal cancer treatment .
1 Next-generation sequencing enables faster , cheaper and more accurate whole - genome sequencing , allowing genome profiling and discovery of molecular features .
2 As molecular targeted drugs are developed , treatment can be tailored according to molecular subtype .
3 Gastric and colorectal cancers have each been divided into four subtypes according to molecular features .
4 Profiling of the esophageal cancer genome is underway and its classification is anticipated .
5 To date , identification of HER2 expression in gastric adenocarcinoma and KRAS , NRAS and BRAF mutations in colon cancer have proved essential for treatment decisions .
6   However , to overcome therapy resistance and improve prognosis , further individualized therapy is required .
7 Here , we summarize the treatment options for gastrointestinal cancer according to genomic profiling and discuss future directions .



PMID: 28059100
(Patient)  
Terms:
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0 A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome .
1 To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome ( LS ) , a universal screening program for LS was established in two medical centers .
2 Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation .
3 Tumors positive for both were considered sporadic , and genetic testing was recommended for all others .
4 A total 1011 colorectal cancer cases were screened for Lynch syndrome , and 148 ( 146% ) exhibited absent MLH1 immunostaining .
5 Both BRAF and MLH1 methylation testing were completed in 126 cases .
6 Concordant results ( both positive or both negative ) were obtained in 86 ( 683% ) and 16 ( 127% ) cases , respectively , with 81% concordance overall .
7 The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41% , respectively , and the negative predictive value fell to 15% in patients >/ = 70 years old .
8 Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone ( 31% versus 135% , respectively , P<001 ) .
9 However , a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7% .
10 A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation .
11 A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs .



PMID: 28059096
(Patient)  
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0 Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas .
1 Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity .
2 Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce , hampering optimized patient treatment and care .
3 Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms ( neuroendocrine carcinomas ) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma , and poorly differentiated neuroendocrine neoplasm tumorigenesis .
4 Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status .
5 In three mixed adenoneuroendocrine carcinomas , exocrine and endocrine components were analyzed separately .
6 Μ Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes .
7 Μ Sixteen ( 84% ) tumors harbored atleast one somatic mutation , two tumors ( 11% ) displayed high microsatellite instability .
8 Compared with colorectal adenocarcinomas , mixed adenoneuroendocrine carcinomas were more frequently BRAF ( 37% ; P = 0006 ) , and less frequently KRAS ( 21% ; P = 0043 ) and APC ( 16% ; P = 0001 ) mutated .
9 Μ Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected , but one tumor harbored a heterozygous RB1 deletion .
10 Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis .
11 Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas , but compared with mixed adenoneuroendocrine carcinomas , had a higher rate of APC mutations ( P = 0027 ) .
12 Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas , suggesting that the cells giving rise to these tumors primarily have an intestinal coinage .
13 Μ The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas .



PMID: 28058585
(Patient)  
Terms: prospective study
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0 Detection of KRAS Mutations in Plasma DNA Using a fully Automated Rapid Detection System in Colorectal Cancer Patients .
1 KRAS mutations have been recognized as predictive markers of primary resistance to anti-EGFR - antibodies in colorectal cancer patients .
2 Μ In addition , newly detected KRAS mutations have been reported to be related with acquired resistance to chemotherapy containing anti-EGFR antibody .
3 Considering this evidence , monitoring of KRAS mutations is indispensable for making treatment decisions , and the method should be non-invasive allowing repeated examinations .
4 Recently , we established a novel automated sensitive detection system for KRAS mutations , named mutation-biased PCR quenching probe system ( MBP-QP ) .
5 The goal of our study was to investigate the potential for monitoring KRAS mutations during treatment with anti-EGFR antibodies .
6 The detection limit of MBP-QP using a control plasmid containing KRAS mutations was 1-9 copies , and 0.05-0.3% mutant plasmid was detectable in a mixture of wild type and mutants .
7 One-hundred twenty colorectal cancer patients were genotyped for KRAS mutations with MBP-QP as well as LONGTOKEN , which has already been applied to cancer tissue samples in the clinical setting .
8 Concordance rates between plasma DNA and cancer tissues were 68% with MBP-QP and 66% with PCR-rSSO , indicating that these systems are equivalent in terms of detecting KRAS mutations with plasma DNA .
9   Μ KRAS mutations in plasma DNA were frequently observed in systemic metastatic cancer patients , and in three patients KRAS mutations appeared after chemotherapy containing anti-EGFR antibody .
10 ✓ Μ A prospective study is needed for clarifying whether KRAS mutations detected in plasma DNA are predictive markers of treatment efficacy with anti-EGFR antibody . GM-MRK-RO



PMID: 28053287
(Patient)  
Terms:
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0 Clinical parameters to guide decision-making in elderly metastatic colorectal CANCER patients treated with intensive cytotoxic and anti-angiogenic therapy .
1 INTRODUCTION :
2 Bevacizumab addiction to triplet chemotherapy , according to FIr-B/FOx schedule , as first - line treatment in young-elderly metastatic colorectal CANCER ( MCRC ) patients may be more effective .
3 Tailored treatments show worse clinical outcome in unfit patients .
4 METHODS :
5 Elderly patients were clinically evaluated according to age and comorbidity ( Cumulative Illness Rating Scale ) to select FIr-B/FOx regimen in fit or tailored treatments in unfit elderly .
6 Limiting toxicity syndromes ( LTS ) were evaluated .
7 RESULTS :
8 At 17 months follow-up , in 28 young-elderly patients treated with first line FIr-B/FOx : objective response rate ( ORR ) 79% , progression-free survival ( PFS ) 11 months , overall survival ( OS ) 21 months .
9 Clinical outcome was not significantly different according to KRAS genotype .
10 G3-4 toxicities were diarrhea 21% , mucositis 11% , neutropenia 11% .
11 LTS were 46% , significantly more multiple than single site .
12 At 8 months follow-up , in 37 unfit patients : ORR 37% , PFS 7 months , OS 13 months .
13 PFS was significantly different in KRAS wild-type compared to mutant patients , while not OS .
14 PFS and OS were significantly worse in KRAS c.35 G >A compared to wild-type and/or other mutant .
15 CONCLUSIONS :
16   Careful decision-making process including evaluation of patient's fitness , and individual safety should be included to select FIr-B/FOx intensive first line regimen in young-elderly MCRC patients .
17 ✓ KRAS , and specifically c.35 G >A mutant genotype , may significantly affect clinical outcome in patients unfit for FIr-B/FOx . GM-INV-RO



PMID: 28050146
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study .
1 BACKGROUND :
2 Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting .
3 Whole - genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways .
4 METHODS :
5 We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency .
6 Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary , to explore treatment response to bevacizumab in a colorectal cancer , and to characterize an appendiceal adenocarcinoma .
7 RESULTS :
8   Μ In the first case , genomic profiling revealed an IDH1 somatic mutation , supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin , and further guided therapy by identifying epidermal growth factor receptor amplification .
9   In the second case , a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma .
10 The third case was an appendiceal adenocarcinoma defined by a p53 inactivation ; Ras/raf/mek , Akt/mtor , Wnt , and notch pathway activation ; and overexpression of ret , erbb2 ( her2 ) , erbb3 , met , and cell cycle regulators .
11 SUMMARY :
12 We show that whole - genome and transcriptome sequencing can be achieved within clinically effective timelines , yielding clinically useful and actionable information .



PMID: 28045335
(Patient)  
Terms: Phase II trial
Sent# Symbols Sentence Mnemonics
0 Phase II trial of capecitabine plus erlotinib versus capecitabine alone in patients with advanced colorectal cancer .
1 Aim & ; methods : Capecitabine monotherapy as palliation for advanced colorectal cancer ( CRC ) is generally well tolerated .
2 Adding erlotinib , an EGFR-tyrosine kinase inhibitor , might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone ( Arm 1 ) or capecitabine with erlotinib ( Arm 2 ) .
3 RESULTS :
4 Median time-to-progression ( TTP ) in Arm 1 was 7.9 months versus 9.2 in Arm 2 .
5 In KRAS-wild type ( WT ) patients TTP was 8.4 and 11.7 months in Arms 1 and 2 , respectively .
6 In KRAS-mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2 , respectively ( p = 0023 ) .
7 Arm 2 KRAS-WT patients , left-sided primaries , had an overall survival of 16.0 versus 12.1 months in right-sided primaries .
8 CONCLUSION :
9 Adding erlotinib to capecitabine increased TTP by 3.2 months in KRAS-WT patients .
10 This study suggests that erlotinib harms patients with KRAS-mutated advanced CRC while it may provide benefit to those with KRAS-WT CRC .
11 Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided KRAS-WT CRC is warranted .



PMID: 28044264
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Clinicopathological Associations of K-RAS and N-RAS Mutations in Indonesian Colorectal Cancer Cohort .
1 BACKGROUND :
2 K-RAS and recently N-RAS gene mutation testing are mandatory requirements prior to anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody treatment of metastatic CRC .
3 Mutation prevalence and distribution in Indonesian colorectal cancer ( CRC ) are not known .
4 METHODS :
5 Combined methods of PCR high-resolution melt ( HRM ) , restriction fragment length polymorphism ( RFLP ) , and direct DNA sequencing were used to genotype exons 2 , 3 , and 4 of both K-RAS and N-RAS genes for routine clinical testing of CRC patients .
6 Μ Descriptive analytical review of 595 consecutive CRC patients ( years 2013 to 2016 ) was performed to find associations between gene mutations and clinicopathologic features .
7 RESULTS :
8 Μ This retrospective study revealed overall K-RAS gene mutation in exon 2 ( codon 12 and 13 ) rates being 34.9% .
9 Women ( 425% ) , stages I and II ( 434% ) , and well and moderate differentiations ( 377% ) had higher frequency of K-RAS exon 2 mutations than men ( 29% , p = 0006 ) , stages ( III and IV 319% , p = 005 ) , and poor differentiation ( 118% , p = 0002 ) , respectively .
10 At later period ( 2015-2016 ) , 121 of 595 patients were genotyped for the remaining exons 3 and 4 of K-RAS as well as exons 2 , 3 , and 4 of N-RAS mutations resulting in overall RAS mutation prevalence of 41% .
11 Mucinous histology had highest frequency of N-RAS mutation .
12 CONCLUSIONS :
13 Μ Combination of PCR HRM with either RFLP or direct DNA sequencing was useful to detect K-RAS exon 2 and extended RAS mutations , respectively .
14 ✓ Frequency of all RAS mutations in stage IV Indonesian ( 41% ) was similar among Asians ( 41-49% ) , which tend to be lower than western ( 55% ) CRC . GM-ASS-DS



PMID: 28044229
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic Biomarker Prevalence Is Similar in Fecal Immunochemical Test Positive and Negative Colorectal Cancer Tissue .
1 BACKGROUND :
2 Fecal immunochemical test ( FIT ) screening detects most asymptomatic colorectal cancers .
3 Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer , but whether DNA biomarkers ( biomarkers ) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population .
4 AIMS :
5 To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening .
6 METHODS :
7 FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age , sex , and cancer stage .
8 Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients .
9 Quantitative allele -specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers ( NDRG4 , BMP3 , SFMBT2 895 , SFMBT2 896 , SFMBT2 897 , CHST2 7890 , PDGFD , VAV3 , DTX1 , CHST2 7889 ) .
10 RESULTS :
11 One or more biomarkers were found in 414 of 421 CRCs ( 983% ) .
12 Biomarker expression was not associated with FIT status , with the exception of higher SFMBT2 897 expression in FIT-negative ( 194 of 210 ; 924% ) than in FIT-positive cancers ( 180 of 211 ; 853% ; p = 002 ) .
13 There were no consistent differences in biomarker expression by FIT status within age , sex , stage , and cancer location subgroups .
14 CONCLUSIONS :
15 The biomarkers of a currently in-use multi-target stool DNA test ( K-ras , NDRG4 , and BMP3 ) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens , independent of FIT result .
16 Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity , specificity , and clinical utility .



PMID: 28040715
(Patient)  
Terms: Clinical trial
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0 Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified , Rapidly Progressive Metastatic Colorectal Cancer .
1 HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers ( mCRCs ) .
2 HER2-targeted therapy is not standard of care , although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2 -activating mutations may benefit from HER2 -directed therapy .
3 HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor -based therapy .
4 This report describes a patient with KRAS , NRAS , and BRAF wild-type mCRC who experienced disease progression on first - line treatment with FOLFIRI and cetuximab after only 5 months , and subsequently experienced progression on second - line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline .
5 Μ Next-generation sequencing of the primary tumor identified HER2 amplification , and we were able to obtain trastuzumab-DM1 for off-label use .
6   The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months .
7   On progression , therapy was changed to trastuzumab and pertuzumab , but the patient's disease progressed 3 months later .
8   Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment , with a dramatic improvement in the patient's functional status .
9 This case represents the first report , to our knowledge , of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1 .
10 Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway .
11   Molecular insights from investigating HER2 activation and the impact of HER2 -directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care .



PMID: 28040692
(Patient)  
Terms: clinical trial
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0 Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer .
1 Background : The prognostic value of BRAF and KRAS mutations within microsatellite-unstable ( MSI ) and microsatellite-stable ( MSS ) subgroups of resected colon carcinoma patients remains controversial .
2 We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials .
3 Methods : Three groups were defined : BRAF Mutant , KRAS Mutant , and double wild-type .
4 The analytic strategy involved estimation of study-specific effects , assessment of homogeneity of results , and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials .
5 Μ Associations of mutations with patient outcome were analyzed , and multivariable models were adjusted for treatment and relevant factors .
6 Results : Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status ; 3934 were MSS and 477 were MSI .
7 ✓ In MSS patients , all BRAF V600E mutations ( hazard ratio [HR] = 1.54 , 95% confidence interval [CI] = 1.23 to 1.92 , P <.001 ) , KRAS codon 12 alterations , and p.G13D mutations ( HR = 160 , 95% CI = 140 to 183 , P <001 ) were associated with shorter time to recurrence ( TTR ) and shorter survival after relapse ( SAR ; HR = 302 , 95% CI = 232 to 393 , P <001 , and HR = 120 , 95% CI = 101 to 144 , P = 04 , respectively ) . GM-ASS-RO
8 Overall survival ( OS ) in MSS patients was poorer for BRAF-mutant patients ( HR = 201 , 95% CI = 156 to 257 , P <001 ) and KRAS-mutant patients ( HR = 162 , 95% CI = 138 to 191 , P <001 ) versus wild-type .
9 No prognostic role of KRAS or BRAF mutations was seen in MSI patients .
10   Μ Furthermore , no interaction was found between treatment arm ( with or without cetuximab ) and KRAS and BRAF mutations for TTR or OS in MSS patients .
11 Conclusions : In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX , BRAF or KRAS mutations are independently associated with shorter TTR , SAR , and OS in patients with MSS , but not MSI , tumors .
12 Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors .



PMID: 28035251
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Role of circulating free DNA in colorectal cancer .
1 The gradual elucidation of the underlying biology of colorectal cancer has provided new insights and therapeutic options for patients with metastatic disease which are selected according to predictive biomarkers .
2 This precision medicine paradigm , however , is incomplete since not all eligible patients respond to these agents and prognostic stratification is largely based on clinicopathologic variants .
3 Importantly , no robust data exist to help properly select patients with localized disease at high risk for recurrence and most likely to benefit from adjuvant chemotherapy .
4 There is a rapidly expanding body of literature regarding the role of the qualitative and quantitative analysis of circulating free DNA in various neoplasms , which consistently outperforms traditional tumor markers both as a predictive and as a prognostic marker .
5   Several lines of evidence suggest that circulating free DNA may exhibit a complementary role to existing modalities for the early diagnosis of colorectal cancer , the selection of patients for adjuvant chemotherapy , for the follow-up of treated patients , for the selection of treatment for advanced disease and the assessment of response and for determining the prognosis of patients .
6 These data , which are reviewed here , illustrate the important role that circulating biomarkers may soon have at the daily clinical practice .



PMID: 28032641
(None)  
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0 Relation of early tumor shrinkage ( ETS ) observed in first - line treatment to efficacy parameters of subsequent treatment in FIRE-3 (AIOKRK0306) .
1 We explored the association of early tumor shrinkage ( ETS ) and non-ETS with efficacy of first - line and consecutive second - line treatment in patients with KRAS wild-type metastatic colorectal cancer treated in FIRE-3 .
2 Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions , evaluated after 6 weeks of treatment .
3 Shrinkage was classified as ETS ( shrinkage by >/= 20% ) , mETS ( shrinkage by 0 to <20% ) , mPD ( minor progression >0 to <20% ) and PD ( progression >/ = 20% ) .
4 Overall survival ( OS ) was 33.2 ( 95% CI 280-384 ) months in ETS patients , while non-ETS was associated with less favorable outcome ( mETS 24.0 ( 95% CI 212-269 ) months , mPD 19.0 ( 95% CI 130-250 ) months , PD 12.8 ( 95% CI 111-145 ) months ) .
5 Differences in PFS of first - line therapy were less pronounced .
6 ETS subgroups defined in first - line therapy also correlated with efficacy of second - line therapy .
7 Progression-free survival in second-line ( PFS2nd ) was 6.5 months ( 58-72 ) for ETS , and was 5.6 ( 95% CI 47-65 ) months for mETS , 4.9 ( 95% CI 37-61 ) months for mPD and 3.3 ( 95% CI 23-43 ) months for PD .
8 PFS of first - line and PFS2nd showed a linear correlation ( Bravais-Pearson coefficient : 0.16 , p = 0.006 ) .
9 While ETS is associated with the most favorable outcome , non-ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment .
10   This is the first analysis to demonstrate that early tumor response observed during first - line FOLFIRI-based therapy may also relate to efficacy of second - line treatment .
11 Early response parameters may serve as stratification factors in trials recruiting pretreated patients .



PMID: 28032593
(Patient)  
Terms: prospective studies
Sent# Symbols Sentence Mnemonics
0 The impact of co-expression of wild-type EGFR and its ligands determined by immunohistochemistry for response to treatment with cetuximab in patients with metastatic colorectal cancer .
1 Anti-EGFR mAbs cetuximab and panitumumab are routinely used for the treatment of patients with KRAS-wild type metastatic colorectal cancer ( mCRC ) .
2 However , in some patients their efficacy remains modest and with no clear association between the EGFR protein expression determined by PharmDx kit , and response to anti-EGFR therapies .
3 Therefore , we investigated the relative expression and predictive value of wild-type EGFR ( wtEGFR ) , mutated EGFRvIII and EGFR ligand proteins in mCRC patients treated with cetuximab .
4 The expression levels of wtEGFR , EGFRvIII , and EGFR ligand were determined by immunohistochemistry ( IHC ) in 60 tumour specimens using specific antibodies .
5 Sections were scored according to the percentage of positive tumour cells , intensity and cellular location of staining , and these were associated with response , overall survival ( OS ) and progression-free survival ( PFS ) .
6 At cut-off value >5% , wtEGFR , and EGFRvIII were present in 44% , and 41% , betacellulin ( BTC ) in 72% , followed by epigen ( 67% ) , TGFalpha ( 58% ) , amphiregulin ( 34% ) , EGF ( 31% ) of the cases , respectively and 96% of the wtEGFR positive cases had co-expression of atleast one ligand .
7 Μ We found a significant association between the expression of wtEGFR and poor response to cetuximab .
8 In addition , the co-expression of wtEGFR with one ligand at a cut-off value of >5% and >10% was associated with worse response to cetuximab ( P = 0021 , and P = 0005 respectively ) .
9 We found a 3-fold and 5-fold increased risk of shorter OS with expression of BTC and epigen .
10 Interestingly , the expression of wtEGFR and its co-expression with one or two ligands was associated with shorter PFS but not with OS .
11   The relative expression of wtEGFR and its competing ligands , which is the target for therapeutic interventions with anti-EGFR antibodies , could serve as a more reliable predictive biomarker of response to therapy with anti-EGFR mAbs in mCRC patients and warrants further investigation in large prospective studies .



PMID: 28032528
(Patient)  
Terms: retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 Chemotherapy rechallenge after regorafenib treatment in metastatic colorectal cancer : still hope after the last hope ?
1 INTRODUCTION :
2 The introduction of biological agents in cancer therapy is changing the progression of metastatic colorectal cancer .
3 Currently , resistance to biological agents is an emerging problem ; the progression of the disease is caused by the development of resistant clones .
4 According to some authors , these clones can be re-sensitized to traditional and previously utilized chemotherapy agents .
5 The results of the CORRECT study demonstrated the efficacy of regorafenib monotherapy in both KRAS wild type and mutant pretreated patients ( pts ) .
6 Two recent reports showed the potential of reintroduction of chemotherapy , even after treatment with regorafenib .
7 PATIENTS AND METHODS :
8 We performed a retrospective review of clinical data from patients treated with regorafenib at our institution between March 2012 and March 2013 .
9 We analysed patient characteristics , KRAS/NRAS status , response to treatment ( evaluated by RECIST v11 criteria ) and survival .
10 RESULTS :
11   Regorafenib was administered to 128 patients , and 11 ( 86% ) received post-regorafenib therapy ( to our knowledge ) .
12 Seven ( 636% ) patients were wild type for KRAS/NRAS .
13   Post-regorafenib therapy represented for all the patients atleast the fourth line : all the pts received both oxaliplatin - and irinotecan-based chemotherapy , all of them were treated with bevacizumab , and 7 patients also received cetuximab .
14   Eight patients ( 727% ) were treated with standard chemotherapy after regorafenib ( irinotecan monotherapy , capecitabine plus oxaliplatin or irinotecan , dacarbazine or raltitrexed ) , while 3 patients received an experimental therapy ( clinical trial ) .
15 Nine of the 11 ( 818% ) patients had PD and 2 patients had SD .
16 The median progression-free survival was 1.6+ months ( range 05-35 ) , the median OS post-regorafenib was 2.1+ months ( range 05-102 ) and the 6-month OS was 27.3% .
17 CONCLUSION :
18 Our retrospective analysis showed that after regorafenib therapy , re-introduction of chemotherapy is possible .
19   Unfortunately , we reported a high percentage of disease progression beyond regorafenib , which is likely due to the high percentage of heavily pretreated patients ( some received four or five types of therapy before regorafenib ) .
20   We think that regorafenib could represent a chemotherapy resensitizing agent ; however , additional studies are needed in patients who have received less pretreatment .



PMID: 28031175
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients .
1 Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia .



PMID: 28029553
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA , primary tumor and metastases from patients undergoing resection of colorectal liver metastases .
1 Assessing circulating tumor DNA ( ctDNA ) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way .
2 In a group of twelve metastatic colorectal cancer ( mCRC ) patients undergoing liver metastasectomy , from each patient DNA from cell -free DNA ( cfDNA ) , the primary tumor , metastatic liver tissue , normal tumor-adjacent colon or liver tissue , and whole blood were obtained .
3 Μ Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA .
4 This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay , and for selected mutations with digital PCR ( dPCR ) .
5 All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21 - gene panel , which was analyzed using a standard and a modified calling pipeline .
6 Μ In addition , cfDNA , whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue .
7 Μ NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC , ATM , CREBBP , FBXW7 , KRAS , KMT2D , PIK3CA and TP53 .
8 Using this approach , variant allele frequencies in plasma ranged predominantly from 1 to 10% , resulting in limited concordance between ctDNA and the primary tumor ( 39% ) and the metastases ( 55% ) .
9 Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS , PIK3CA and TP53 mutations by the OnTarget assay ( 80% ) and digital PCR ( 93% ) .
10 Μ Additionally , using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients , which were not observed in whole blood .
11 Μ In conclusion , in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible , but had limited sensitivity to detect all somatic mutations present in tissue .
12 Μ Digital PCR and mutant allele enrichment before NGS appeared to be more sensitive to detect somatic mutations .



PMID: 28025786
(Patient)  
Terms: Phase II trial
Sent# Symbols Sentence Mnemonics
0 EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer .
1 Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer .
2 Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown .
3 We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab .
4 Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified .
5 Tumor tissue was available for 33 patients .
6 Μ Genomic DNA was extracted and used for mutational analysis of KRAS , BRAF , and p53 genes .
7 Fluorescence in situ hybridization was performed to assess EGFR copy number .
8 The status of single genes and various combinations were tested for association with response .
9 Seven of 33 patients responded to treatment .
10   Μ KRAS mutations were found in 14/33 cases , and 0 responded to treatment ( p = 001 ) .
11 EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment ( p <0001 ) .
12 Μ TP53 and BRAF mutations were found in 18/33 and 0/33 tumors , respectively , and there were no associations with response to either gene .
13   EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer .
14   One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty .
15 The role for molecular markers in combination biologic therapy seems promising .



PMID: 28025078
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Analysis of KRAS , NRAS , PIK3CA , and BRAF mutational profile in poorly differentiated clusters of KRAS-mutated colon cancer .
1 Recently , a grading system based on the counting of poorly differentiated clusters ( PDCs ) of neoplastic cells was shown to be a strong predictor of nodal metastases and negative prognosis in colon cancer ( CC ) .
2 In this study , we assessed and compared the mutational status of KRAS , NRAS , and PIK3CA in PDCs and corresponding main tumor tissue of 25 CCs with KRAS mutations .
3 For each tumor , PDC and main tumor tissue were distinctly analyzed by using laser microdissection and mass spectrometry .
4 Μ In 3 CCs , the main tumor tissue had also PIK3CA mutations ( C420R : 1 ; E545K : 1 ; H1047R : 1 ) , and in 1 , it showed NRAS mutation ( codon 12 ) .
5 In 20 cases , PDCs had the same biomolecular profile as the main tumor , but in 5 , they had different biomolecular profiles .
6 In detail , PDCs had KRAS wild type in 2 cases and additional PIK3CA mutations ( E542K : 1 ; H1047Y : 1 ; E545Q : 1 ) in 3 .
7 ✓ All 3 cases with additional PIK3CA mutations in PDCs had nodal metastases , high pathological TNM stage , and lymphatic invasion . GM-ASS-RO
8 Μ In 1 of 3 cases , additional PIK3CA mutation detected in PDC , but not in the main tumor , was also found in the corresponding nodal metastases .
9 Our findings show for the first time that heterogeneous biomolecular profile previously observed in CC may depend on different histologic aspects of the lesion .
10   Because PDCs may represent the tumor cells with the highest potential to metastatize , their molecular status may be relevant for the prediction of response to targeted therapies .



PMID: 28013534
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS Mutation Test in Korean Patients with Colorectal Carcinomas : A Methodological Comparison between Sanger Sequencing and a Real-Time PCR-Based Assay .
1 BACKGROUND :
2 Μ Mutations in the KRAS gene have been identified in approximately 50% of colorectal cancers ( CRCs ) .
3 KRAS mutations are well established biomarkers in anti-epidermal growth factor receptor therapy .
4 Therefore , assessment of KRAS mutations is needed in CRC patients to ensure appropriate treatment .
5 METHODS :
6 We compared the analytical performance of the cobas test to Sanger sequencing in 264 CRC cases .
7 In addition , discordant specimens were evaluated by 454 pyrosequencing .
8 RESULTS :
9 Μ KRAS mutations for codons 12/13 were detected in 43.2% of cases ( 114/264 ) by Sanger sequencing .
10 Μ Of 257 evaluable specimens for comparison , KRAS mutations were detected in 112 cases ( 436% ) by Sanger sequencing and 118 cases ( 459% ) by the cobas test .
11 Concordance between the cobas test and Sanger sequencing for each lot was 93.8% positive percent agreement ( PPA ) and 91.0% negative percent agreement ( NPA ) for codons 12/13 .
12 Results from the cobas test and Sanger sequencing were discordant for 20 cases ( 78% ) .
13 Twenty discrepant cases were subsequently subjected to 454 pyrosequencing .
14 After comprehensive analysis of the results from combined Sanger sequencing-454 pyrosequencing and the cobas test , PPA was 97.5% and NPA was 100% .
15 CONCLUSIONS :
16 The cobas test is an accurate and sensitive test for detecting KRAS -activating mutations and has analytical power equivalent to Sanger sequencing .
17 Prescreening using the cobas test with subsequent application of Sanger sequencing is the best strategy for routine detection of KRAS mutations in CRC .



PMID: 28012848
(Patient)  
Terms: ex vivo, NCT02156557
Sent# Symbols Sentence Mnemonics
0 Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy .
1 BACKGROUND & ; AIMS : Many cancers in the proximal colon develop via from sessile serrated adenomas ( SSAs ) , which have flat , subtle features that are difficult to detect with conventional white-light colonoscopy .
2 Many SSA cells have the V600E mutation in BRAF .
3 We investigated whether this feature could be used with imaging methods to detect SSAs in patients .
4 METHODS :
5 We used phage display to identify a peptide that binds specifically to SSAs , using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738 .
6 St/Int cells as a control .
7 Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy .
8 Rats received intra-colonic 0.0086 mg/kg , 0.026 mg/kg , or 0.86 mg/kg peptide or vehicle and morbidity , mortality , and injury were monitored twice daily to assess toxicity .
9 In the clinical safety study , fluorescently labeled peptide was topically administered , using a spray catheter , to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies ( 3 subjects were given 225 mumol/L and 22 patients were given 764 mumol/L ) .
10 We performed blood cell count , chemistry , liver function , and urine analyses approximately 24 hours after peptide administration .
11 In the clinical imaging study , 38 subjects undergoing routine outpatient colonoscopies , at high risk for colorectal cancer , or with a suspected unresected proximal colonic polyp , were first evaluated by white-light endoscopy to identify suspicious regions .
12 The fluorescently labeled peptide ( 764 mumol/L ) was administered topically to proximal colon , unbound peptide was washed away , and white-light , reflectance , and fluorescence videos were recorded digitally .
13 Fluorescence intensities of SSAs were compared with those of normal colonic mucosa .
14 Endoscopists resected identified lesions , which were analyzed histologically by gastrointestinal pathologists ( reference standard ) .
15 We also analyzed the ability of the peptide to identify SSAs versus adenomas , hyperplastic polyps , and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan .
16 RESULTS :
17 We identified the peptide sequence KCCFPAQ and measured an apparent dissociation constant of Kd = 72 nM and an apparent association time constant of K = 0.174 min-1 ( 576 minutes ) .
18 During fluorescence imaging of patients during endoscopy , regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa .
19 Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity .
20 The peptide had no observed toxic effects in animals or patients .
21 In the analysis of ex vivo specimens , peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps .
22 CONCLUSIONS :
23 We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon .
24 It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity .
25 This targeted imaging method might be used in early detection of premalignant serrated lesions during routine colonoscopies .
26 ClinicalTrials .
27 gov ID : NCT02156557 .



PMID: 28011498
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Metastatic Pattern of Stage IV Colorectal Cancer with High-Frequency Microsatellite Instability as a Prognostic Factor .
1 BACKGROUND :
2 A recent clinical trial on the immune check-point inhibitor pembrolizumab demonstrated that microsatellite instability ( MSI ) is a good biomarker for response to this inhibitor .
3 However , clinicopathological features of advanced colorectal cancer ( CRC ) with high-frequency MSI ( MSI-H ) are unclear .
4 PATIENTS AND METHODS :
5 A total of 2,439 surgically resected CRC tissues were analyzed for MSI status , and mutational status of rat V-Ki-Ras2 Kirsten sarcoma 2 viral oncogene homolog ( KRAS ) , neuroblastoma RAS viral oncogene homolog ( NRAS ) and v-Raf murine sarcoma viral oncogene homolog B ( BRAF ) .
6 Stage IV cases were selected , and clinical and molecular features were evaluated .
7 RESULTS :
8 There was no significant survival difference observed between MSI-H CRC and microsatellite-stable ( MSS ) CRC in patients with stage IV disease ( 392 vs. 250 years ; p = 0766 ) .
9 However , hematogenous and lymphogenous metastasis-dominant CRC with MSI-H demonstrated poor prognosis , whereas peritoneal metastasis-dominant CRC with MSI-H demonstrated good prognosis , ( 133 vs. 52 years ; p = 0006 ) .
10 CONCLUSION :
11 Prognosis of stage IV CRC with MSI-H depended on the metastatic pattern .
12   These findings provide useful information for the adaptation of CRC immunotherapy .



PMID: 28010901
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical relevance of colorectal cancer molecular subtypes .
1 Colorectal cancer ( CRC ) is characterized by alteration of critical pathways such TP53 inactivation , BRAF , PI3CA mutations , APC inactivation , KRAS , TGF-beta , CTNNB mutations , disregulation of Epithelial to mesnechymal transition ( EMT ) genes , WNT signaling activation , MYC amplification , and others .
2 Differences in these molecular events results in differences in phenotypic characteristics of CRC , that have been studied and classified by different models of molecular subtypes .
3   It could have potential applications to prognosis , but also to therapeutical approaches of the CRC patients .
4 We review and summarized the different molecular classifications and try to clarify their clinical and therapeutical relevance .



PMID: 28008623
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Combined targeting of TGF-beta , EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model .
1 BACKGROUND :
2 While the significance of carcinoembryonic antigen ( CEA ) , lactate dehydrogenase ( LDH ) , and Kirsten rat sarcoma ( KRAS ) status as individual prognostic factors for patients with metastatic colorectal cancer has been addressed , the relationship and interdependence between these prognostic factors on survival is limited .
3 METHODS :
4 Patients with unresectable colorectal liver metastases with known KRAS status , and with baseline CEA and LDH levels who were treated with hepatic arterial infusion and systemic chemotherapy were identified .
5 Patients were divided into two groups : hepatic-only disease and extra-hepatic disease .
6 RESULTS :
7 A total of 193 patients were included : 121 with hepatic-only and 72 with extra-hepatic disease .
8 In the hepatic-only group , median overall survival ( OS ) was 55 months .
9 On multivariate analysis , KRAS mutated tumors ( HR 17 , P <005 ) , LDH >200 U/L ( HR 20 , P <005 ) , and prior chemotherapy ( HR 21 , P <005 ) had lower OS .
10 In patients with extra-hepatic disease , median OS was 32 months .
11 On multivariate analysis , baseline CEA >200 ng/mL ( HR 21 , P = 0051 ) , LDH >200 U/L ( HR 38 , P <005 ) , and right-sided tumors ( HR 28 , P <005 ) had lower OS .
12 CONCLUSIONS :
13 This analysis verifies two distinct patterns in terms of biomarkers in patients with unresectable colorectal liver metastases .
14 ✓ In patients with hepatic-only disease , KRAS mutation and elevated LDH negatively influenced survival . GM-REG-RO
15 In patients with extra-hepatic disease , elevated LDH negatively impacted survival .



PMID: 28008271
(Patient)  
Terms: prospective study
Sent# Symbols Sentence Mnemonics
0 Early detection of poor outcome in patients with metastatic colorectal cancer : tumor kinetics evaluated by circulating tumor cells .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is the third most prevalent cancer worldwide .
3 New prognostic markers are needed to identify patients with poorer prognosis , and circulating tumor cells ( CTCs ) seem to be promising to accomplish this .
4 PATIENTS AND METHODS :
5 A prospective study was conducted by blood collection from patients with metastatic CRC ( mCRC ) , three times , every 2 months in conjunction with image examinations for evaluation of therapeutic response .
6 CTC isolation and counting were performed by Isolation by Size of Epithelial Tumor Cells ( ISET ) .
7 RESULTS :
8 A total of 54 patients with mCRC with a mean age of 57.3 years ( 31-82 years ) were included .
9   Among all patients , 60% ( n = 32 ) were carriers of wild-type KRAS ( WT KRAS ) tumors and 90% of them ( n = 29 ) were exposed to monoclonal antibodies along with systemic treatment .
10 Μ Evaluating CTC kinetics , when we compared the baseline ( pretreatment ) CTC level ( CTC1 ) with the level at first follow-up ( CTC2 ) , we observed that CTC1-positive patients ( CTCs above the median ) , who became negative ( CTCs below the median ) had a favorable evolution ( n = 14 ) , with a median progression-free survival ( PFS ) of 14.7 months .
11 This was higher than that for patients with an unfavorable evolution ( CTC1 - that became CTC2+ ; n = 13 , 69 months ; P = 006 ) .
12 Patients with WT KRAS with favorable kinetics had higher PFS ( 147 months ) in comparison to those with WT KRAS with unfavorable kinetics ( 94 months ; P = 002 ) .
13 Moreover , patients whose imaging studies showed radiological progression had an increased quantification of CTCs at CTC2 compared to those without progression ( P = 004 ) .
14 CONCLUSION :
15 This study made possible the presentation of ISET as a feasible tool for evaluating CTC kinetics in patients with mCRC , which can be promising in their clinical evaluation .



PMID: 28007036
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic landscape of colorectal cancer in Japan : clinical implications of comprehensive genomic sequencing for precision medicine .
1 BACKGROUND :
2 Comprehensive genomic sequencing ( CGS ) has the potential to revolutionize precision medicine for cancer patients across the globe .
3 However , to date large-scale genomic sequencing of cancer patients has been limited to Western populations .
4 In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations , we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer ( CRC ) .
5 METHODS :
6 Using next-generation sequencing methods , we examined all exons of 415 known cancer genes in Japanese CRC patients ( n = 201 ) and evaluated for concordance among independent data obtained from US patients with CRC ( n = 108 ) and from The Cancer Genome Atlas-CRC whole exome sequencing ( WES ) database ( n = 224 ) .
7 Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns .
8 Two different sets of genes from the 415 - gene panel were used for clustering : 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC .
9 RESULTS :
10 Μ The 415 - gene panel is able to identify all of the critical mutations in tumor samples as well as WES , including identifying hypermutated tumors .
11 Μ Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population , we found significant differences in the frequencies of mutations in ERBB2 and BRAF .
12 Μ We show that the 415 - gene panel identifies a number of clinically actionable mutations in KRAS , NRAS , and BRAF that are not detected by hot-spot testing .
13 We also discovered that 26% of cases have mutations in genes involved in DNA double - strand break repair pathway .
14   Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories , each of which can optimally be treated with a particular combination therapy .
15 CONCLUSIONS :
16   Μ Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities .



PMID: 28006055
(Patient)  
Terms: Clinical Trial, NCT00079274, NCT00096278
Sent# Symbols Sentence Mnemonics
0 ✓ Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon Cancers : A Secondary Analysis of 2 Randomized Clinical Trials . GM-ASS-RO
1 Importance : The association of biomarkers with patient survival after recurrence ( SAR ) of cancer is poorly understood but may guide management and treatment .
2 Objective : To determine the association of DNA mismatch repair ( MMR ) status and somatic mutation in the B-Raf proto-oncogene ( c.1799T>A [V600E] ; BRAFV600E ) or exon 2 of the KRAS proto-oncogene ( KRAS ) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy .
3 Design , Setting , and Participants : Patients with resected stage III colon cancers were randomized to adjuvant FOLFOX ( folinic acid [leucovorin calcium] , fluorouracil , and oxaliplatin ) chemotherapy with or without cetuximab ( North Central Cancer Treatment Group N0147 trial ) or adjuvant FOLFOX chemotherapy with or without bevacizumab ( National Surgical Adjuvant Breast and Bowel Project C-08 trial ) .
4 Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features and time to recurrence ( data collected February 10 , 2004 , to August 7 , 2015 ) .
5 Main Outcomes and Measures : The primary study outcome was survival after recurrence of cancer .
6 A secondary outcome measure was the effect of the site of the primary tumor on the association of biomarkers with SAR .
7 Results : Among 871 patients with cancer recurrence in the N0147 trial ( 472 men [542%] and 399 women [458%] ; mean [SD] age , 57.8 [112] years ) and 524 in the C-08 trial ( 269 men [513%] and 255 women [487%] ; mean [SD] age , 57.0 [117] years ) , multivariable analysis revealed that patients whose tumors had deficient versus proficient MMR had significantly better SAR ( adjusted hazard ratio [AHR] , 0.70 ; 95% CI , 0.52-0.96 ; P = .03 ) .
8 Patients whose tumors harbored mutant BRAFV600E ( AHR , 245 ; 95% CI , 185-325 ; P <001 ) or mutant KRAS ( AHR , 121 ; 95% CI , 100-147 ; P = 052 ) had worse SAR compared with those whose tumors had wild-type copies of both genes , although only results for BRAFV600E achieved statistical significance .
9 Significant interactions were found for MMR ( P = 03 ) and KRAS ( P = 02 ) by primary tumor site for SAR .
10 Improved SAR was observed for patients with deficient MMR tumors of the proximal versus distal colon ( AHR , 057 ; 95% CI , 040-083 ; P = 003 ) , and worse SAR was observed for tumors of the distal colon with mutant KRAS in codon 12 ( AHR , 176 ; 95% CI , 130-238 ; P <001 ) and codon 13 ( AHR , 176 ; 95% CI , 108-286 ; P = 02 ) .
11 Conclusions and Relevance : In patients with recurrence of stage III colon cancer , deficient MMR was significantly associated with better SAR , and this benefit was limited to primary tumors of the proximal colon .
12 Mutations in BRAFV600E were significantly associated with worse SAR , and worse SAR for BRAFV600E or KRAS mutant tumors was more strongly associated with distal cancers .
13 These biomarkers have implications for patient management at recurrence .
14 Trial Registration : clinicaltrials .
15 gov Identifiers : NCT00079274 and NCT00096278 .



PMID: 28004119
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Yttrium-90 radioembolization for colorectal cancer liver metastases in KRAS wild-type and mutant patients : Clinical and ccfDNA studies .
1 Patients with unresectable , chemo-refractory colorectal cancer liver metastases ( CRCLM ) have limited local treatment options .
2 We report our institutional experience on the efficacy of resin-based yttrium-90 ( 90Y ) radioembolization for the treatment of CRCLM and our findings on associated circulating cell -free DNA ( ccfDNA ) studies .
3 ✓ A total of 58 patients treated with 90Y for CRCLM at the Medstar Georgetown University Hospital had a median survival of 6 months [95% confidence interval ( CI ) , 4.557.45 months] after treatment , with a 12-month survival rate of 33% . GM-ASS-RO
4 ✓ The median survival from treatment stratified by mutational status was longer in the wild-type ( WT ) as compared to the KRAS mutant patients at 7 vs. 5 months , but did not achieve statistical significance ( p = 0059 ) . RO-ASS-GM
5   Median tumor local control duration after 90Y treatment was 2 months ( 95% CI , 034366 months ) for the entire cohort and was longer in the WT vs.the mutant patients ( 2 vs. 1 month , respectively , p = 0088 ) .
6   Plasma was prospectively collected from a subset of 9 patients both before and after single lobe treatment , and ccfDNA concentration and fragmentation index ( FI ) were measured using quantitative PCR and atomic-force microscopy ( AFM ) .
7   In the WT and KRAS mutant patients , DNA FI was reduced from a median of 0.73-0.65 after treatment .
8 A reduction in DNA FI after single lobe treatment was associated with an improved overall survival ( p = 0046 ) .
9   Μ Analysis by AFM of paired pre - and post-treatment samples from KRAS mutant and WT patients revealed a larger average decrease in fragment size in the WT patients ( p = 0013 ) .
10 ✓ 90Y radioembolization extends local control for CRCLM , however , KRAS mutant tumors may be more radio-resistant to treatment .
11   Changes in the FI of patients following treatment were noted and may be evaluated in a larger study for relevance as a biomarker of response .



PMID: 28003766
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A pilot study employing hepatic intra-arterial irinotecan injection of drug -eluting beads as salvage therapy in liver metastatic colorectal cancer patients without extrahepatic involvement : the first southern Italy experience .
1 Circulating tumor cells ( CTCs ) have been implicated in tumor progression and prognosis .
2 Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma ( NSCLC ) may help to identify individuals likely to benefit from early systemic treatment .
3 However , the detection of CTCs with a single marker is challenging , owing to low specificity and sensitivity and due to the heterogeneity and rareness of CTCs .
4 Herein , the probability of cell -free RNA content in the peripheral blood as a potential biomarker for detecting CTCs in cancer patients was investigated .
5 An immunomagnetic enrichment of real-time reverse-transcription PCR ( RT-PCR ) technology for analysis of CTCs in NSCLC patients was also developed .
6 The mRNA levels of four candidate genes , cytokeratin 7 ( CK7 ) , E74-like factor 3 ( ELF3 ) , epidermal growth factor receptor ( EGFR ) , and erythropoietin-producing hepatocellular carcinoma receptor B4 ( EphB4 ) that were significantly elevated in tumor tissues and peripheral blood mononuclear cells ( PBMCs ) were determined .
7 The expression of CK7 and ELF3 in tumor tissues and EGFR in PBMCs was associated with lymph node metastasis ( all p <005 ) .
8 The expression of CK7 in PBMCs was correlated with age and EphB4 in PBMCs correlated with histopathological type , respectively ( all p <005 ) .
9 The expression of all four genes in tumor tissues and PBMCs was significantly correlated with the clinical stage ( all p <001 ) .
10 Μ Survival analysis showed that the patients with enhanced expression of CK7 , ELF3 , EGFR , and EphB4 mRNA in PBMCs had poorer disease-free survival ( DFS ) and overall survival ( OS ) than those without ( all p <00001 ) .
11   Μ The present study showed that this alteration of cell -free RNA content in peripheral blood might have clinical ramifications in the diagnosis and treatment of NSCLC patients .



PMID: 28002807
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells .
1 Μ Receptor tyrosine kinase ( RTK ) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF .
2 ✓ About 40% colorectal cancers ( CRCs ) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs , AKT , MEK , or BRAF .
3 Therefore , an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases .
4 Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments .
5 The reactivations of AKT and ERK after the AKT or MEK inhibitor treatment were caused by a relief of an AKT or ERK -mediated feedback inhibition of the RTKs and/or their downstream pathways .
6 A combination of RTK inhibitors , based on the RTK activation/phosphorylation profile , synergized with the AKT inhibitor , but not the MEK inhibitor , to completely inhibit the AKT phosphorylation and to block the growth of KRAS/BRAF mutant CRC cells .
7   These results underscored the importance of AKT and the AKT feedback signaling to cancer cell growth and offered a novel therapeutic approach for the treatment of KRAS/BRAF mutant CRC cells .



PMID: 28002797
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer .
1 PURPOSE :
2 Next Generation Sequencing ( NGS ) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer ( CRC ) , which is on the rise in many parts of the developing World including , Iran .
3 Little is known about its genetic hallmarks in these populations .
4 AIM :
5 Μ To identify variants in 15 CRC-associated genes in patients of Iranian descent .
6 RESULTS :
7 There were 51 validated variants distributed on 12 genes : 22% MSH3 ( n = 11/51 ) , 10% MSH6 ( n = 5/51 ) , 8% AMER1 ( n = 4/51 ) , 20% APC ( n = 10/51 ) , 2% BRAF ( n = 1/51 ) , 2% KRAS ( n = 1/51 ) , 12% PIK3CA ( n = 6/51 ) , 8% TGFbetaR2A ( n = 4/51 ) , 2% SMAD4 ( n = 1/51 ) , 4% SOX9 ( n = 2/51 ) , 6% TCF7L2 ( n = 3/51 ) , and 6% TP53 ( n = 3/51 ) .
8 Most known and distinct variants were in mismatch repair genes ( MMR , 32% ) and APC ( 20% ) .
9 Among oncogenes , PIK3CA was the top target ( 12% ) .
10 MATERIALS AND METHODS : CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing .
11 To rule-out technical artifacts , the variants were validated in 13 of these samples using an Illumina NGS platform .
12 Validated variants were annotated and compared to variants from publically available databases .
13 An in-silico functional analysis was performed .
14 MSI status of the analyzed samples was established .
15 CONCLUSION :
16 These results illustrate for the first time CRC mutational profile in Iranian patients .
17 MSH3 , MSH6 , APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population .
18 These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies .



PMID: 28002313
(Patient)  
Terms: prospective studies
Sent# Symbols Sentence Mnemonics
0 Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first - line treatment for patients with metastatic colorectal cancer : Results of a registry-based cohort analysis .
1 The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first - line treatment in Chinese patients with metastatic colorectal cancer ( mCRC ) .
2 Clinical data were collected from a single-center registry study where mCRC patients received first - line fluoropyrimidine-based chemotherapy combined with either bevacizumab ( 188 patients with KRAS wild-type or mutated tumors ) or cetuximab ( 101 patients with KRAS wild-type tumors ) between January 2009 and December 2013 .
3 The Kaplan-Meier method was used for survival analysis .
4 Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics .
5 No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival ( PFS ) ( 106 versus 87 months , P = 0317 ) , median overall survival ( OS ) ( 277 versus 283 months , P = 0525 ) , or overall response rate ( 431% versus 535% , P = 0108 ) .
6 For the subset of patients with peritoneal dissemination , bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS ( 96 versus 61 months ) and OS ( 263 versus 127 months ) , but not for patients without peritoneal dissemination ( PFS , 106 versus 91 months ; OS , 279 versus 307 months ) ( all unadjusted and adjusted interaction P <005 ) .
7   Our study suggests that bevacizumab - or cetuximab-based regimens have similar effectiveness as first - line treatment of mCRC in Chinese population .
8   Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment .
9 Future prospective studies are required to further confirm these results .



PMID: 28000889
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases .
1 Genetic testing is needed for the treatment of colorectal cancer ( CRC ) , especially molecular-targeted therapy .
2 The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations .
3 However , whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear .
4 In the present study , we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability ( MSI ) in primary CRC and corresponding metastases .
5 Μ This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC ( 499 synchronous metastases and 57 metachronous metastases ) and seven local recurrences , and KRAS/BRAF mutation and MSI status were analysed for these tumours .
6 The concordance rates of KRAS mutation , BRAF mutation , wild-type , MSI-H and MSS between primary CRC and corresponding metastases were 93.9% ( 214/228 ) , 100% ( 30/30 ) , 99.3% ( 304/306 ) , 87.5% ( 21/24 ) and 100% ( 137/137 ) , respectively .
7 These high concordance rates were not different between synchronous and metachronous metastases .
8 Μ In conclusion , a high concordance of KRAS/BRAF mutation status and MSI status was observed between primary CRC and corresponding metastases in this study .
9 Either primary CRC or metastatic tissues can be used for testing KRAS/BRAF mutation status and MSI status .



PMID: 28000854
(Cell)  
Terms: In vitro
Sent# Symbols Sentence Mnemonics
0 Identification of microRNA-487b as a negative regulator of liver metastasis by regulation of KRAS in colorectal cancer .
1 Recent studies have shown that microRNAs ( miRNAs ) are involved in the progression of colorectal cancer ( CRC ) .
2 The aim of this study is to identify a novel miRNA that especially relates to liver metastasis and to explore the underlying mechanism .
3 Differentially expressed miRNAs were analyzed using microarray , in primary CRC tumors without metastasis ( n = 16 ) , those with liver metastasis ( n = 12 ) , and liver metastatic lesions ( n = 8 ) .
4 We found that miR-487b level decreased in liver metastatic lesions , and qRT-PCR confirmed the results in the validating cohort ( n = 134 ) .
5 Survival analysis indicated that high expression of miR-487b was associated with better prognosis .
6 In vitro studies were also performed to investigate the functional significance of miR-487b in human CRC cell lines .
7 miR-487b showed an inhibitory effect on cell proliferation and invasion of CRC cells .
8 miR-487b downregulated KRAS and inhibited its downstream signal pathways , and the luciferase reporter assay revealed that miR-487b directly targeted LRP6 , a receptor for WNT/beta-catenin signaling .
9 These findings showed that decrease in miR-487b was related with liver metastasis .
10 Our data suggest a possibility that miR-487b may suppress metastasis of CRC progression through inhibition of KRAS .



PMID: 27999270
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers .
1 Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority .
2 For colorectal cancer ( CRC ) patients , international guidelines made RAS ( KRAS and NRAS ) status a prerequisite for the use of anti-epidermal growth factor receptor agents ( anti-EGFR ) .
3 Daily , new data emerge on the theranostic and prognostic role of molecular biomarkers , which is a strong incentive for a validated , sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials .
4 Next generation sequencing ( NGS ) has begun to supplant other technologies for genomic profiling .
5 Targeted NGS is a method that allows parallel sequencing of thousands of short DNA sequences in a single test offering a cost-effective approach for detecting multiple genetic alterations with a minimum amount of DNA .
6 In the present review , we collected data concerning the clinical application of NGS technology in the setting of colorectal cancer .



PMID: 27999210
(Cell)  
Terms: in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 LY3009120 , a panRAF inhibitor , has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer .
1 Activating mutations in the KRAS and BRAF genes , leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade , are common in patients with colorectal cancer ( CRC ) .
2 While selective BRAF inhibitors are efficacious in BRAFmut melanoma , they have limited efficacy in BRAFmut CRC patients .
3 In a RASmut background , selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity .
4 A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms .
5 Here , we further examined the effects of LY3009120 , a panRAF and RAF dimer inhibitor , in human models of CRC with various mutational backgrounds .
6 We demonstrate that LY3009120 induced anti-proliferative effects in BRAFmut and KRASmut CRC cell lines through G1-cell cycle arrest .
7 The anti-proliferative effects of LY3009120 in KRASmut CRC cell lines phenocopied molecular inhibition of RAF isoforms by simultaneous siRNA -mediated knockdown of ARAF , BRAF and CRAF .
8 Additionally , LY3009120 displayed significant activity in in vivo BRAFmut and KRASmut CRC xenograft models .
9 Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRASmut CRC cell line HCT 116 .
10 These findings describe the preclinical activity of a panRAF inhibitor in a BRAFmut and KRASmut CRC setting .



PMID: 27994469
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Association between proto - oncogene mutations and clinicopathologic characteristics and overall survival in colorectal cancer in East Azerbaijan , Iran . GM-ASS-RO
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is the third-most common cancer in Iran .
3 The increasing incidence of CRC in the past three decades has made it a major public health burden in the country .
4 This study aimed to determine any relationship of specific mutations in CRCs with clinicopathologic aspects and outcome of patients .
5 MATERIALS AND METHODS :
6 This study was conducted on 100 CRC patients by the case-only method .
7 Polymerase chain -reaction products were analyzed by Sanger sequencing , and sequence results were compared with the significant KRAS and BRAF gene mutations in the My Cancer Genome database .
8 Μ Logistic regression models were used to detect associations of clinicopathologic characteristics with each of the mutations .
9 Kaplan-Meier and Cox regression models were constructed to estimate overall survival in patients .
10 RESULTS :
11 Μ A total of 26 subjects ( 26% ) had heterozygote-mutant KRAS , and mutations were not detected in the amplified exon of BRAF in both tumor and normal tissues of the 100 CRCs .
12 Rectal tumors had 1.53-fold higher likelihood of KRAS mutations than colon tumors , and men had 1.37-fold higher odds than women .
13 The presence of metastasis increased the likelihood of KRAS mutations 2.36-fold over those with nonmetastatic CRCs .
14 ✓ Compared to patients with KRAS wild-type cancers , those with KRAS mutations had significantly higher mortality ( hazard ratio 374 , 95% confidence interval 144-968 ; log-rank P = 0003 ) . GM-ASS-RO, RO-ASS-GM
15 CONCLUSION :
16 Better understanding of the causality of CRC can be established by combining epidemiology and research on molecular mechanisms of the disease .



PMID: 27993800
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer : analysis from 2530 patients in randomised clinical trials .
1 Background : To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer ( aCRC ) patients , we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types .
2 Patients and methods : 2530 aCRC patients were assessed from three randomised trials .
3 End-points were progression-free survival , response rate , disease control rate , post-progression survival ( P-PS ) and overall survival .
4 Treatments included first - line oxaliplatin/fluorouracil ( OxFU ) and second - line irinotecan .
5 Clinicians were unaware of BRAF-status .
6 Results : 231 patients ( 91% ) had BRAF-mutant tumours .
7 ✓ BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic . GM-ASS-RO, GM-REG-RO
8 Compared with wild-type , BRAF-mutant patients treated with first - line OxFU had similar DCR ( 592% versus 72% ; adjusted OR = 076 , P = 024 ) and PFS ( 57 versus 63 months ; adjusted HR = 114 , P = 026 ) .
9   Following progression on first - line chemotherapy , BRAF-mutant patients had a markedly shorter P-PS ( 42 versus 92 months , adjusted HR = 169 , P <0001 ) .
10 ✓ Fewer BRAF-mutant patients received second - line treatment ( 33% versus 51% , P <0001 ) , but BRAF-mutation was not associated with inferior second - line outcomes ( RR adjusted OR = 056 , P = 045 ; PFS adjusted HR = 101 , P = 093 ) . GM-ASS-RO
11 Μ Significant clinical heterogeneity within the BRAF-mutant population was observed : a proportion ( 243% ) had good first - line PFS and P-PS ( both >6 months ; OS = 240 months ) ; however , 36.5% progressed rapidly through first - line chemotherapy and thereafter , with OS = 4.7 months .
12 Conclusions : BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features .
13   Chemotherapy provides meaningful improvements in outcome throughout treatment lines .
14   Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first - line progression .



PMID: 27993628
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Exosomal microRNA concentrations in colorectal cancer : A mathematical model .
1 Colorectal cancer ( CRC ) is the second leading cause of cancer related deaths in the United States .
2 Early detection increases survival very significantly .
3 Indeed , five year survival for people diagnosed at stage I-II is 90% , while for those diagnosed at stage IV it is only 13% .
4 The gold standard for early detection is colonoscopy , but this procedure is limited due to its invasive nature and its high cost .
5 Hence there is a need to identify non-invasive biomarkers for CRC .
6 Exosomal miRs secreted by cancer cells and overexpressed in the blood have been suggested as biomarkers for cancer .
7 In particular , exosomal miRs 21 , 23a , 92a and 1246 are overexpressed in CRC , and thus have the potential to be used as serum biomarkers for early detection of the disease .
8 The present paper develops for the first time a mathematical model for early stage of CRC which includes the effect of these miRs on the growth of the cancer .
9 The model is represented by a system of partial differential equations .
10 Simulations of the model show a relationship between the growth of the tumor diameter and the total mass of these miRs under some of the common mutations which occur in CRC , namely , KRAS , PI3K , APC , p53 and SMAD mutations .
11 The model may serve as a step toward establishing miRs 21 , 23a , 92a and 1246 as reliable blood biomarkers for CRC as more experimental results and clinical data become available .



PMID: 27986363
(Patient)  
Terms: prospective, clinical trial, NCT01163396, NCT00719797, NCT02271464
Sent# Symbols Sentence Mnemonics
0 Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer : A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest .
1 Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer ( mCRC ) patients with unresectable liver-limited disease .
2 Medical treatment has a dual goal : to induce tumour shrinkage and to prevent disease relapse .
3 The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting , and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors .
4 We performed a pooled analysis of patients with unresectable and liver-limited mCRC , treated with first - line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 ( 379% ) patients with liver-limited disease were selected , out of 541 treated patients .
5 Liver metastases were synchronous , >/ = 4 and bilobar in 90% , 61% , and 79% of cases , respectively .
6 The largest diameter was >5 cm in 42% of cases , and >/ = 6 segments were involved in 25% .
7 Seventy-four patients ( 361% ) underwent R0 or R1 resection of metastases .
8 R2 resections were performed in 17 cases ( 83% ) .
9 Having <6 involved segments ( p <0001 ) and achieving RECIST response ( p = 0019 ) were associated with higher chances of resection .
10 R0/R1 resected patients had significantly longer median progression-free survival ( PFS ) ( 18.1 versus 10.7 months , HR : 0.48 [035-066] , p <0.001 ) and overall survival ( OS ) ( 44.3 versus 24.4 months , HR : 0.32 [022-048] , p <0.001 ) compared with other patients , both in the univariate and multivariate analyses ( PFS p = 0025 ; OS p <0001 ) .
11 The 5-year PFS and OS rate in R0 resected patients were 12% and 43% , respectively .
12 ✓ Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes . GM-ASS-RO
13 In conclusion , FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors ( NCT00719797 , NCT01163396 and NCT02271464 ) .



PMID: 27982025
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations : clinical and biological implications .
1 The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles .
2 Tumor morphology , however , has not been fully integrated into the analysis .
3 The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma .
4 Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population .
5 Μ Upon analysis , a tight association between 'microsatellite instability-high histology' and microsatellite instability-high ( P<0001 ) was readily detected and helped validate our image-based histology evaluation .
6 Further , we showed , (1) among all histologies , the not otherwise specified type had the lowest overall mutation count ( P<0001 for entire cohort , P<003 for the microsatellite-instable group ) , and among the microsatellite-instable tumors , this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes ( P<001 ) ; (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns : the former more often mucinous and the latter more often not otherwise specified ; (3) mucinous histology was associated with more frequent alterations in BRAF , PIK3CA , and the transforming growth factor -beta pathway when compared with non-mucinous histologies ( P<0001 , P = 001 , and P<0001 , respectively ) ; and (4) few colorectal cancers ( <9% ) exhibited upregulation of immune-inhibitory genes including major immune checkpoints ; these tumors were primarily microsatellite-instable ( up to 43% , versus <3% in microsatellite-stable group ) and had distinctly non-mucinous histologies with a solid growth .
7 These morphology-molecular associations are interesting and propose important clinical implications .
8   The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer , and provide directions for future studies .



PMID: 27979806
(Patient)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women .
1 Background : Host immune response may predict the course of colorectal cancer .
2 We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers , the number of cytotoxic T lymphocytes ( CTLs ) , and the activated CTLs , as reflected by the number of cells expressing granzyme B ( GZMB ) in the prospective Iowa Women's Health Study .
3 Methods : Using paraffin-embedded tissue samples , we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies .
4 We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker ( sum of the scores across tissue compartments ) .
5 Cox regression estimated the HR and 95% confidence intervals ( CI ) for all-cause and colorectal cancer-specific death associated with each composite score .
6 Results : CTL and GZMB composite scores were positively correlated ( r = 065 ) and each biomarker was inversely correlated with stage at diagnosis .
7 Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high , CIMP-high , or BRAF mutation status .
8 HRs ( 95% CI ) were 0.53 ( 038-075 ; Ptrend = 00004 ) and 0.66 ( 051-086 ; Ptrend = 0002 ) for all-cause death , respectively , and 0.30 ( 018-051 ; Ptrend <00001 ) and 0.41 ( 027-063 ; Ptrend <00001 ) for colorectal cancer-related death , respectively .
9 Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death .
10 Conclusions : Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients .
11 Impact : Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer , irrespective of stage .
12 Cancer Epidemiol Biomarkers Prev ; 26(4) ; 622-31 .
13 (c) 2016 AACR .



PMID: 27979717
(Patient)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 Perioperative Triplet Chemotherapy and Cetuximab in Patients With RAS Wild Type High Recurrence Risk or Borderline Resectable Colorectal Cancer Liver Metastases .
1 BACKGROUND :
2 For borderline resectable colorectal cancer liver metastases ( CLM ) , systemic treatment can help to achieve R0 resection and reduce the risk of relapse .
3 We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM .
4 PATIENTS AND METHODS :
5 This was a monocenter , open-label phase II study .
6 Borderline resectability was defined technically as tumor involvement of >1 hepatic vein , or >4 hepatic segments , need for 2-stage hepatectomy or radiofrequency ablation , and/or biologically ( high risk ) : >/ = 4 metastatic nodules , or synchronous metastases .
7 Patients were treated with 4 pre - and postoperative cycles of biweekly COI-E ( cetuximab 500 mg/m2 and irinotecan 180 mg/m2 on day 1 , oxaliplatin 85 mg/m2 on day 2 , and capecitabine 1000 mg/m2 twice per day on days 2-6 ) .
8 The primary end point was overall response rate .
9 RESULTS :
10 Forty patients were enrolled .
11 Nine patients with KRAS mutation were excluded after amendment in 2010 .
12 Μ In an extended RAS test we did not find additional RAS mutations .
13 The final population was comprised of 31 patients with RAS wild type CLM ( technically borderline resectable 39% ; synchronous 84% ; >/ = 4 metastatic nodules 29% ) .
14 The overall response , R0 resection , and pathological response rates were 87% , 84% , and 33% , respectively .
15 At a median follow-up of 4 years , median progression-free survival and overall survival were 17.8 and 62.5 months , respectively .
16 Treatment toxicity was relevant but did not jeopardize the surgical plan .
17 CONCLUSION :
18 The COI-E regimen was associated with high response and R0 resection rates in patients with RAS wild type CLM with borderline resectability and/or high-risk features .



PMID: 27977612
(Patient)  
Terms: retrospective, rat
Sent# Symbols Sentence Mnemonics
0 ✓ Coexistence of MSI with KRAS mutation is associated with worse prognosis in colorectal cancer . GM-ASS-RO
1 rat Kristen sarcoma viral oncogene homolog ( KRAS ) and microsatellite instability ( MSI ) are prognostic markers of colorectal cancer ( CRC ) .
2 However , the clinical value is still not fully understood , when giving the consideration to both the molecular makers .
3 Five hundred fifty-one patients with CRC were retrospectively assessed by determining their clinicopathological features .
4 Μ KRAS mutations were detected by polymerase chain reaction .
5 MSI , a defect in the mismatch repair ( MMR ) system , was detected by immunohistochemistry .
6 The prognostic value of KRAS in combination with MSI was studied .
7 Μ Among 551 CRC patients , mutations in KRAS codon 12 and KRAS codon 13 were detected in 34.5% and 10.5% of patients , respectively .
8 Μ Four hundred one tumors were randomly selected to detect for MMR proteins expression .
9 In this analysis , 30 ( 75% ) tumors that had atleast 1 MMR protein loss were defined as MMR protein-deficient ( MMR-D ) , and the remaining tumors were classed as MMR protein-intact ( MMR-I ) .
10 According to KRAS mutation and MSI status , CRC was classified into 4 groups : Group 1 , KRAS-mutated and MMR-I ; Group 2 , KRAS-mutated and MMR-D ; Group 3 , KRAS wild and MMR-I ; and Group 4 , KRAS wild and MMR-D .
11 We found that patients in Group4 had the best prognosis .
12 ✓ In conclusion , combination status of KRAS and MSI status may be used as a prognostic biomarker for CRC patient , if validated by larger studies . GE-MRK-DS



PMID: 27977573
(Patient)  
Terms: meta-analysis, clinical trial
Sent# Symbols Sentence Mnemonics
0 The efficacy and safety of panitumumab plus irrinotecan-based chemotherapy in the treatment of metastatic colorectal cancer : A meta-analysis .
1 BACKGROUND :
2 Panitumumab , a fully human monoclonal antibody targeting epidermal growth factor receptor , is used in combination with chemotherapy for patients with metastatic colorectal cancer ( mCRC ) .
3 However , the effects of panitumumab in combination with irrinotecan-based chemotherapy remain uncertain .
4 Therefore , we conducted this meta-analysis to assess the efficacy and safety of combination treatment of panitumumab plus chemotherapy in the treatment of mCRC .
5 METHODS :
6 By searching electronic databases ( PubMed , Embase , and Web of Science ) , all clinical trials which assessed the effects of panitumumab plus irrinotecan-based chemotherapy in mCRC would be included .
7 Main outcome measures included progression-free survival ( PFS ) , overall survival ( OS ) , overall response rate ( ORR ) , and adverse events .
8 Pooled estimates were calculated by a fixed-effects model or random-effects model , according to the heterogeneity among the included studies .
9 RESULTS :
10 Eleven trials with a total number of 1338 patients met the inclusion criteria and were included in this meta-analysis .
11   The combination treatment of panitumumab and irrinotecan-based chemotherapy was associated with a median PFS of 5.83 months , OS of 11.15 months , and ORR of 33% .
12   Subgroup analysis showed that , in the first - line and second - line treatment , the combination therapy for PFS was 9.27 and 5.01 months , for OS was 8.87 and 11.68 months , and for ORR was 61% and 26% , respectively .
13 In the wild-type and mutant KRAS populations , the combination therapy for PFS was 5.76 and 5.27 months , for OS was 11.15 and 10.64 months , and for ORR was 37% and 18% , respectively .
14   Moreover , combination therapy also induced an incidence of 56% treatment-related adverse events .
15 CONCLUSION :
16   Panitumumab plus irrinotecan-based chemotherapy is effective and well-tolerated in the treatment of patients with mCRC , especially in those with wild-type KRAS tumors .



PMID: 27965933
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal Choriocarcinoma in a Patient with Probable Lynch Syndrome .
1 BACKGROUND :
2 Personalized therapy of colorectal cancer is influenced by morphological , molecular , and host-related factors .
3 Here , we report the comprehensive clinicopathological and molecular analysis of an extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome .
4 CASE PRESENTATION :
5 A 61-year-old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis .
6 A right hemicolectomy was performed .
7 Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation , consistent with choriocarcinoma .
8 Disease progression was rapid under oxaliplatin , capecitabine , irinotecan , and bevacizumab .
9 Molecular phenotyping identified loss of mismatch-repair protein immunostaining for PMS2 , microsatellite instability , a lack of MLH1 promoter methylation , and lack of BRAF mutation suggestive of Lynch syndrome .
10 Μ Targeted next-generation sequencing revealed an ataxia telangiectasia mutated ( pP604S ) missense mutation .
11 A bleomycin , etoposide , and cisplatin treatment protocol targeting germ cell neoplasia lead to disease remission and prolonged survival of 34 months .
12 CONCLUSION :
13 Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome .
14 For rare tumors , personalized therapeutic approaches should take both molecular and morphological information into account .



PMID: 27965461
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS mutant colorectal cancer gene signatures identified angiotensin II receptor blockers as potential therapies .
1   Association of EGFR Exon 19 Deletion and EGFR-TKI Treatment Duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients .



PMID: 27965097
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC : Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients .
1 In BRAF-mutated melanoma cells , the BRAF inhibitor , vemurafenib , induces phosphorylation of eukaryotic initiation factor 2alpha ( eIF2alpha ) and subsequent induction of activating transcription factor 4 ( ATF4 ) , the central regulation node of the integrated stress response ( ISR ) .
2 While the ISR supports cellular adaptation to various stresses , the role of vemurafenib-triggered ISR has not been fully characterized .
3 Μ Here , we showed that in response to vemurafenib , BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 ( GCN2 ) , an eIF2alpha kinase sensing amino acid levels .
4 The vemurafenib-triggered ISR , an event independent of downstream MEK inhibition , was specifically prevented by silencing GCN2 , but not other eIF2alpha kinases , including protein kinase -like endoplasmic reticulum kinase , which transmits endoplasmic reticulum ( ER ) stress .
5 Consistently , the ER stress gatekeeper , GRP78 , was not induced by vemurafenib .
6 Interestingly , ATF4 silencing by siRNA rendered BRAF-mutated melanoma cells sensitive to vemurafenib .
7 Thus , the GCN2 -mediated ISR can promote cellular adaptation to vemurafenib-induced stress , providing an insight into the development of drug resistance .



PMID: 27959684
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 T - Cell Transfer Therapy Targeting Mutant KRAS in Cancer .
1 We identified a polyclonal CD8+ T - cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer .
2 We observed objective regression of all seven lung metastases after the infusion of approximately 1.11x1011 HLA-C*08 : 02-restricted tumor-infiltrating lymphocytes that were composed of four different T - cell clonotypes that specifically targeted KRAS G12D .
3 However , one of these lesions had progressed on evaluation 9 months after therapy .
4 The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08 : 02 class I major histocompatibility complex ( MHC ) molecule .
5 The loss of expression of this molecule provided a direct mechanism of tumor immune evasion .
6 Μ Thus , the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08 : 02 .



PMID: 27956538
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Differential Radiographic Appearance of BRAF V600E-Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location .
1 BACKGROUND :
2 BRAF-mutant metastatic colorectal cancers ( mCRCs ) share many clinicopathologic features with right-sided colon tumors , including frequent peritoneal involvement .
3 Because of the poorer outcomes associated with BRAF mutations , early enrollment in clinical trials has been encouraged .
4 However , the use of standard eligibility and assessment criteria , such as measurable disease , has anecdotally impeded patient accrual and restricted appraisal of treatment response .
5 We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location .
6 METHODS :
7 A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor ( right or left colon ; rectum ) , sex , and age .
8 Μ Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests .
9 Survival was summarized with Kaplan-Meier and Cox regression methods .
10 RESULTS :
11 The distribution of primary tumor locations was : 60% right colon , 30% left colon , and 10% rectum .
12 Compared with BRAF wild-type tumors , BRAF-mutant tumors more commonly associated with peritoneal metastases ( 50% versus 31% ; P = 045 ) and ascites ( 50% versus 24% ; P = 0038 ) .
13 In patients with left colon primaries , BRAF mutations were associated with more frequent ascites ( 58% versus 12% ; P = 0038 ) and less frequent liver metastases ( 42% versus 79% ; P = 024 ) .
14 Μ Among patients with right colon primaries , no significant difference in sites of disease by BRAF mutation status was observed .
15 Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors , irrespective of BRAF mutation status .
16 In the BRAF-mutated cohort , ascites correlated unfavorably with survival ( hazard ratio , 235 ; 95% CI , 114 , 483 ; P = 02 ) .
17 CONCLUSIONS :
18 Greater frequency of ascites and peritoneal metastases , which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes , are seen with BRAF-mutant mCRC , even when patients are matched for primary tumor location .



PMID: 27951718
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Molecular Pathogenesis of Colorectal Cancer ] .
1 EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells .



PMID: 27943689
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Role of Biologics in First - Line Treatment of Colorectal Cancer .
1 In the past decade , significant advances have been made in the treatment of advanced colorectal cancer .
2 Multiple cytotoxic agents and targeted therapies have been approved for management of metastatic colorectal cancer , leading to improvement of median overall survival in clinical trials to more than 30 months .
3 Of note , before the introduction of biologics into treatment algorithms for metastatic colorectal cancer , median survival in phase III trials never exceeded 24 months .
4 In 2016 , the most common treatment approach in first line is a combination of chemotherapy with a biologic agent .
5 The choice of therapy is influenced by patient factors ( eg , age , comorbidities ) , tumor characteristics ( eg , overall tumor burden , pattern of metastatic spread , mutation signature ) , potential adverse effects of therapy , and goals of treatment .
6 The choice between irinotecan - or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy .
7 Currently , three biologic agents-bevacizumab , cetuximab , and panitumumab-are approved for first - line treatment of metastatic colorectal cancer .
8 For patients with mutant RAS and likely mutant BRAF V600E tumors , bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy .
9 The choice of anti-epidermal growth factor antibody or anti-vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario .
10 Recently , some clinical and molecular biomarkers have emerged that may help in decision making .
11   In this review , we discuss the role of biologics in the management of first - line treatment of metastatic colorectal cancer .



PMID: 27943267
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS - but not BRAF+ colorectal cancer .
1 Ethanol in alcoholic beverages is a causative agent for colorectal cancer .
2 Colorectal cancer is a biologically heterogeneous disease , and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist .
3 We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer .
4 We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study .
5 Cox regression was performed to derive hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) for the association between lifetime alcohol intake and colorectal cancer risk .
6 Heterogeneity in the HRs across subtypes of colorectal cancer was assessed .
7 A positive dose -dependent association between lifetime alcohol intake and overall colorectal cancer risk ( mean follow-up = 146 years ; n = 596 colon and n = 326 rectal cancer ) was observed ( HR = 1.08 , 95% CI : 1.04-1.12 per 10 g/day increment ) .
8 The risk was greater for rectal than colon cancer ( phomogeneity = 002 ) .
9 Alcohol intake was associated with increased risks of KRAS+ ( HR = 1.07 , 95% CI : 1.00-1.15 ) and BRAF-/KRAS - ( HR = 1.05 , 95% CI : 1.00-1.11 ) but not BRAF+ tumors ( HR = 0.89 , 95% CI : 0.78-1.01 ; phomogeneity = 0.01 ) .
10 Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS - tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway .
11 Therefore , limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway .



PMID: 27940131
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of the quantification of KRAS mutations by digital PCR and E-ice-COLD-PCR in circulating-cell -free DNA from metastatic colorectal cancer patients .
1 Circulating cell -free DNA ( ccfDNA ) bears great promise as biomarker for personalized medicine , but ccfDNA is present only at low levels in the plasma or serum of cancer patients .
2 Μ E-ice-COLD-PCR is a recently developed enrichment method to detect and identify mutations present at low-abundance in clinical samples .
3 However , recent studies have shown the importance to accurately quantify low-abundance mutations as clinically important decisions will depend on certain mutation thresholds .
4 The possibility for an enrichment method to accurately quantify the mutation levels remains a point of concern and might limit its clinical applicability .
5 In the present study , we compared the quantification of KRAS mutations in ccfDNA from metastatic colorectal cancer patients by E-ice-COLD-PCR with two digital PCR approaches .
6 For the quantification of mutations by E-ice-COLD-PCR , cell lines with known mutations diluted into WT genomic DNA were used for calibration .
7 Μ E-ice-COLD-PCR and the two digital PCR approaches showed the same range of the mutation level and were concordant for mutation levels below the clinical relevant threshold .
8 Μ E-ice-COLD-PCR can accurately detect and quantify low-abundant mutations in ccfDNA and has a shorter time to results making it compatible with the requirements of analyses in a clinical setting without the loss of quantitative accuracy .



PMID: 27938333
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pseudomyxoma peritonei of a mature ovarian teratoma caused by mismatch repair deficiency in a patient with Lynch syndrome : a case report .
1 BACKGROUND :
2 Pseudomyxoma peritonei ( PMP ) is a rare disease with an estimated incidence of 1-2 cases per million individuals per year .
3 PMP is characterized by the accumulation of abundant mucinous or gelatinous fluid derived from disseminated tumorous cells .
4 Most of the tumorous cells are originated from rupture of appendiceal neoplasms , but some are from the metastasis of cancer of the colon , ovary , fallopian tube , urachus , colorectum , gallbladder , stomach , pancreas , lung and breast .
5 Although frequent mutations in KRAS and/or GNAS genes have been reported , precise molecular mechanism underlying PMP remains to be elucidated .
6 It is of note that mucinous tumour is one of the frequent histological features of colorectal cancer ( CRC ) in Lynch syndrome ( LS ) , an autosomal dominantly inherited disease caused by a germline mutation of the DNA mismatch repair ( MMR ) genes including human mutL homolog 1 ( MLH1 ) , human mutS homolog 2 ( MSH2 ) , human mutS homolog 6 ( MSH6 ) , and postmeiotic segregation increased 2 ( PMS2 ) .
7 Therefore , typical LS-associated tumours show mismatch repair instability .
8 Although LS patients are most strongly predisposed to CRC , PMPs from mucinous CRC have not been reported in LS patients .
9 CASE PRESENTATION :
10 In this report , we report a case of PMP originating from an ovarian teratoma in a LS patient .
11 The patient had surgical treatment of PMP arising from an ovarian teratoma at the age of 38 years , and later developed a transverse colon cancer at the age of 40 .
12 Μ The patient's family history fulfilled the Amsterdam criteria , and genetic analysis of the peripheral leukocytes identified a germ line mutation in the MLH1 gene (MLH1 c1546dupC pQ516PfsX3) .
13 Μ Interestingly , immunohistochemical staining showed that the expression of MLH1 was lost in the colon cancer as well as the ovarian teratoma .
14 Μ Consistent with the loss of MLH1 expression , both tumours showed high microsatellite instability ( MSI-H ) .
15 CONCLUSION :
16 This case suggested that LS patients may develop various types of tumours including ovarian PMP , and that mismatch repair deficiency may play a role in the development of PMP derived from , atleast , a part of ovarian teratomas .



PMID: 27936934
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 pathTiMEx : Joint Inference of Mutually Exclusive Cancer Pathways and Their Progression Dynamics .
1 High-throughput sequencing technologies have facilitated the generation of an unprecedented amount of genomic cancer data , opening the way to a more profound understanding of tumorigenesis .
2 In this endeavor , two fundamental questions have emerged , namely (1) which alterations drive tumor progression and (2) in which order do they occur? Answering these questions is crucial for therapeutic decisions involving targeted agents .
3 Because of interpatient heterogeneity , progression at the level of pathways is more reproducible than progression at the level of single genes .
4 In this study , we introduce pathTiMEx , a generative probabilistic graphical model that describes tumor progression as a partially ordered set of mutually exclusive driver pathways .
5 pathTiMEx employs a stochastic optimization procedure to jointly optimize the assignment of genes to pathways and the evolutionary order constraints among pathways .
6 On real cancer data , pathTiMEx recapitulates previous knowledge on tumorigenesis , such as the temporal order among pathways which include APC , KRAS , and TP53 in colorectal cancer , while also proposing new biological hypotheses , such as the existence of a single early causal event consisting of the amplification of CDK4 and the deletion of CDKN2A in glioblastoma .
7 pathTiMEx is available as an R package .



PMID: 27928469
(Cell)  
Terms: , mouse models, mouse, transgenic mouse, transgenic mice, mice
Sent# Symbols Sentence Mnemonics
0 Mechanisms underlying 18F-fluorodeoxyglucose accumulation in colorectal cancer .
1 Μ Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A ( AURKA ) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types .
2 Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro , findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated .
3 In the present study , we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine beta-lactoglobulin promoter , activated through multiple pregnancy and lactation cycles , results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition .
4 The tumor incidence was 38.9% ( 7/18 ) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles .
5 Aurora-A overexpression in the tumor tissues accompanied activation of Akt , elevation of Cyclin D1 , Tpx2 and Plk1 along with downregulation of ERalpha and p53 proteins , albeit at varying levels .
6 Microarray comparative genomic hybridization ( CGH ) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5 , Pten and Tcf7l2 loci .
7 Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations .
8 Μ Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers .
9 Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer .



PMID: 27924922
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer .
1 Tumor cells respond to their microenvironment , which can include hypoxia and malnutrition , and adapt their metabolism to survive and grow .
2 Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters .
3 However , the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear .
4 ✓ We found that colorectal cancer cells survived under the condition of glucose depletion , and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone .
5 Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions .
6 Furthermore , we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress .
7 GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer .
8 In conclusion , GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments .



PMID: 27921184
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Chemotherapeutic drug selectivity between wild-type and mutant BRaf kinases in colon cancer .
1 Oncogenic BRaf V600E mutation is involved in the development , invasion and metastasis of colon cancer .
2 Selective inhibition of BRafV600E mutant has been recognized as a therapeutic strategy for the cancer .
3 Here , we carried out atomistic molecular dynamics ( MD ) simulations to characterize the structural basis , energetic property , and dynamics behavior of conformational change in BRaf activation loop upon the mutation .
4 Μ It is found that V600E mutation destabilizes inactive DFG-out conformation of activation loop and promotes its conversion to the active DFG-in conformation , thus conferring constitutive activity for BRaf kinase .
5 A further analysis revealed that the conformational change is induced by electrostatic effect of the negatively charged mutant residue Glu600 , which can form a potent salt bridge with the positively charged residue Lys570 ; this is naturally consistent with phosphorylation of activation loop to activate the kinase .
6 Both of them introduce a negative charge to activation loop and , consequently , the DFG-out is destabilized and conversed to DFG-in .
7 Energetic analysis unraveled that small-molecule kinase inhibitor PLX4720 has a similar selectivity profile for mutant over wild-type kinases and for phosphorylated and dephosphorylated kinases .
8 This can be substantiated in part by in vitro kinase assay that the inhibitor exhibits 12.6 and 10.4-fold higher potencies against mutant than wild type and against phosphorylated than dephosphorylated , respectively .
9 It is suggested that the activation loop conformation , but neither V600E mutation nor phosphorylation , directly determines inhibitor affinity ; the mutation and phosphorylation can only indirectly influence inhibitor binding via regulation of activation loop conformation .
10 Graphical Abstract Chemotherapeutic drug selectivity between wild-type and mutant BRaf kinases in colon cancer .



PMID: 27920101
(Patient)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Improved decision making for prioritizing tumor targeting antibodies in human xenografts : Utility of fluorescence imaging to verify tumor target expression , antibody binding and optimization of dosage and application schedule .
1 INTRODUCTION :
2 Lung cancer is one of the most common causes of cancer deaths worldwide .
3 Adenocarcinoma is taking over squamous cell lung cancer as the predominant histological subtype .
4 Several cytotoxic drugs are available for the treatment of lung cancer , but side effects limit their use .
5 Recently , targeted therapies for cancers have come into clinical practice .
6 AIMS AND OBJECTIVES :
7 Μ To determine the prevalence of epidermal growth factor receptor ( EGFR ) mutation in adenocarcinoma lung in a North Indian population and its relation with different clinical variables .
8 MATERIALS AND METHODS :
9 A total of 57 patients who met inclusion criteria were recruited into the study .
10 Relevant history , clinical examination and investigations were done .
11 EGFR mutation was done in all patients .
12 RESULTS :
13 A total of twenty patients tested positive for EGFR mutation .
14 Μ EGFR was more frequently detected in female patients ( 538% ) , while as only 19.4% of the male patients expressed EGFR mutation , which was statistically very significant ( P = 0007 ) .
15 Μ EGFR mutation was more frequently detected in nonsmokers ( 52% ) as compared to smokers ( 219% ) which also was statistically significant ( P value of 0018 ) .
16 EGFR mutation was more common in Stage III and IV adenocarcinomas ( 48% ) as compared to Stage I and II ( 214% ) which was statistically significant ( P value 0034 ) .
17 CONCLUSION :
18 EGFR mutation should be routinely done in all patients of adenocarcinoma lung particularly non-smoker females with Stage III and IV disease .



PMID: 27917697
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Current and future biomarkers in the treatment of colorectal cancer .
1 Colorectal cancer ( CRC ) is a leading cause of cancer deaths worldwide .
2 CRC develops as a consequence of genomic instability , characterized by various genetic and epigenetic alterations .
3 Its molecular heterogeneity explains the large variability in patient prognosis and treatment response , emphasizing the need for development of accurate prognostic and predictive biomarkers .
4 This article delineates the different pathways of colorectal carcinogenesis and its molecular subtype classification .
5   With this review , we aim to provide a comprehensive overview of the current and future biomarkers guiding clinical decision-making and CRC treatment .



PMID: 27916952
(Patient)  
Terms: phase II, retrospective
Sent# Symbols Sentence Mnemonics
0 Final overall survival in JO22903 , a phase II , open-label study of first - line erlotinib for Japanese patients with EGFR mutation-positive non-small - cell lung cancer .
1 Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies ( anti-EGFR mAbs ) , possibly due to undetected tumoral subclones harboring RAS mutations .
2 Μ The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor , metastatic lymph nodes and distant metastasis .
3 A retrospective cohort of 18 patients with a colorectal cancer ( CRC ) was included in the study .
4 Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis ( pTNM ) staging and KRAS , NRAS and BRAF mutations were tested using pyrosequencing .
5 Μ In primary tumors , intra-tumoral heterogeneity for RAS mutation was found in 33% of cases .
6 Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases .
7 Moreover , 28% of tumors had multiple RAS mutated subclones in the same tumor .
8 A high proportion of CRCs presented intra - and/or inter-tumoral heterogeneity , which has relevant clinical implications for anti-EGFR mAbs prescription .
9 These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques .



PMID: 27916938
(Cell)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells .
1 MicroRNAs ( miRNAs ) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer ( CRC ) .
2 Sorafenib , a multi - kinase inhibitor which has been approved for the treatment of liver , renal and thyroid cancer , is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC .
3 In this study , we explored sorafenib-induced cellular effects in rat Kirsten sarcoma viral oncogene homolog olog ( KRAS ) wild-type and KRAS-mutated CRC cell lines ( Caco-2 and HRT-18 ) , and finally profiled expression changes of specific miRNAs within the miRNome ( >1000 human miRNAs ) after exposure to sorafenib .
4 Overall , sorafenib induced a time - and dose -dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells .
5 In HRT-18 cells , two human miRNAs ( hsa-miR-597 and hsa-miR-720 ) and two small RNAs ( SNORD 13 and hsa-miR-3182 ) were identified as specifically sorafenib-induced .
6 In Caco-2 cells , nine human miRNAs ( hsa-miR-3142 , hsa-miR-20a , hsa-miR-4301 , hsa-miR-1290 , hsa-miR-4286 , hsa-miR-3182 , hsa-miR-3142 , hsa-miR-1246 and hsa-miR-720 ) were identified to be differentially regulated post sorafenib treatment .
7   In conclusion , we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle-arresting effect of this drug .
8 Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response , drug resistance and potential targets for combinatorial miRNA-based drug strategies .



PMID: 27915339
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathological Features and Predictive Factors for Colorectal Cancer Outcome in the Kingdom of Saudi Arabia .
1 BACKGROUND/AIMS :
2 Colorectal cancer ( CRC ) is the most frequent cancer and a leading cause of cancer death in the Kingdom of Saudi Arabia ( KSA ) .
3 To date , no nationwide screening programs have been adopted .
4 This prospective , longitudinal study investigated factors influencing the outcome of CRC in Saudi patients .
5 METHODS :
6 Patients completed a CRC awareness questionnaire .
7 Colonoscopy , CT/MRI , histopathology of tumor biopsies , and KRAS and BRAF testing were performed .
8 Patients were treated according to their stage .
9 All patients were followed until the end of the study and 3 - and 5-year survival was assessed .
10 RESULTS :
11 Sixty percent of study patients with sporadic CRC presented with significantly advanced disease ( stages III and IV ) with or without metastases at entry .
12 Μ Patients showed low levels of awareness of the risk factors and signs of CRC .
13 Patients presented at a median age of 50 years .
14 Family history of CRC and ulcerative colitis were positive in 11 and 6% of patients , respectively .
15 ✓ Stage III/IV tumors with distant metastases at enrollment , right-sided tumors , mucinous tumors , lymphovascular invasion , and KRAS ( 51% ) or BRAF ( 28% ) mutations predicted poor prognosis and survival . GM-REG-RO
16 CONCLUSION :
17 CRC in KSA is usually diagnosed at advanced stages with metastases and KRAS/BRAF , and is associated with poor prognosis and short survival .
18 Nationwide awareness campaigns and screening programs for CRC are critical for prevention , early detection and adequate management of CRC .



PMID: 27914130
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF-Mutated Colorectal Cancer Exhibits Distinct Clinicopathological Features from Wild-Type BRAF-Expressing Cancer Independent of the Microsatellite Instability Status .
1 In patients with colorectal cancer ( CRC ) , the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival .
2 However , the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial .
3 Therefore , we reviewed various clinicopathological features , including BRAF status , in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors , including overall survival .
4 Similar to previous studies conducted in Eastern countries , the incidence of the BRAF V600E mutation in the current study was relatively low ( 57% ) .
5 BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability ( MSI ) status .
6 This mutation was significantly associated with a proximal tumor location ( P = 0002 ) ; mucinous , signet ring cell , and serrated tumor components ( P <0001 , P = 0003 , and P = 0008 , respectively ) ; lymphovascular invasion ( P = 0004 ) ; a peritumoral lymphoid reaction ( P = 0009 ) ; tumor budding ( P = 0046 ) ; and peritoneal seeding ( P = 0012 ) .
7 In conclusion , the incidence of the BRAF V600E mutation was relatively low in this study .
8 Μ BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs , such as a proximal location ; mucinous , signet ring cell , and serrated components ; and marked peritumoral lymphoid reactions .



PMID: 27911859
(None)  
Terms: retrospective, Prospective
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer . GM-ASS-RO
1 INTRODUCTION :
2 The utilization of molecular markers as routinely used biomarkers is steadily increasing .
3 We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer ( CRC ) .
4 RESULTS :
5 Μ KRAS codon 12 mutations were observed in 116 patients ( 77% ) , whereas codon 13 mutations were observed in 34 patients ( 23% ) .
6 KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence ( TTPR ) ( median TTPR : 78 months ( 95% CI : 50.61-82.56 ) versus 56 months ( 95% CI : 68.71-127.51 ) , P = 0.008 ) and improved overall survival ( OS ) ( median OS : 82 months versus 54 months ( 95% CI : 48.93-59.07 ) , P = 0.009 ) .
7 ✓ Multivariate analysis confirmed that codon 13 mutations were associated with better outcomes ( TTPR : HR : 0.40 ( 95% CI : 0.17-0.93 ) , P = 0.033 ) ; OS : HR : 0.39 ( 95% CI : 0.14-1.07 ) , P = 0.07 ) . GM-ASS-RO
8 ✓ Μ Otherwise , no significant difference in OS ( P = 078 ) or TTPR ( P = 072 ) based on the type of amino-acid substitutions was observed among KRAS codon 12 mutations . RO-ASS-GM
9 MATERIALS AND METHODS :
10 We retrospectively reviewed data from 525 patients who underwent a lung metastasectomy for CRC in two departments of thoracic surgery from 1998 to 2015 and focused on 150 patients that had KRAS exon 2 codon 12/13 mutations .
11 CONCLUSIONS :
12 ✓ KRAS exon 2 codon 13 mutations , compared to codon 12 mutations , seem to be associated with better outcomes following lung metastasectomy in CRC . GM-ASS-RO
13 Prospective multicenter studies are necessary to fully understand the prognostic value of KRAS mutations in the lung metastases of CRC .



PMID: 27900088
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Favorable control of advanced colon adenocarcinoma with severe bone marrow metastasis : A case report .
1 Colorectal cancer ( CRC ) has a propensity to metastasize to the liver , lungs and regional abdominal lymph nodes , but rarely to the bone marrow .
2 A 60-year-old man presented to the National Hospital Organization Kyushu Cancer Center with a 4-week history of persistent lower back pain , anorexia and difficulty defecating .
3 Complete blood count revealed severe thrombocytopenia and erythroblastosis , suggesting a hematological malignancy .
4 However , the bone marrow examination demonstrated involvement by a moderately to poorly differentiated adenocarcinoma , but no hematopoietic abnormalities .
5 A computed tomography scan revealed thickening of the wall of the sigmoid colon , with para-aortic , hilar , mediastinal and supraclavicular lymphadenopathy .
6 The patient was thus diagnosed with sigmoid colon adenocarcinoma with lymph node and bone marrow metastasis .
7 Modified FOLFOX6 was promptly initiated , with concurrent therapy for disseminated intravascular coagulation ( DIC ) .
8 An increased number of thrombocytes was observed on day 6 .
9   After 3 cycles of treatment , the patient recovered from DIC and the levels of serum carcinoembryonic antigen and cytokeratin 19 fragment were decreased .
10 Μ Tumor biopsy during colonoscopy following recovery from DIC demonstrated poorly differentiated adenocarcinoma with mucin production , without mutations in the RAS , BRAF or PIK3CA genes , and a cytokeratin ( CK ) 7-negative , CK20-positive phenotype .
11   The patient has been treated with chemotherapy for 150 days without disease progression .
12 However , the efficacy of chemotherapy for rarely encountered bone marrow metastasis from CRC is poor .
13 The present case was favorably maintained on chemotherapy and survived for 10 months .



PMID: 27900004
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Role of specific DNA mutations in the peripheral blood of colorectal cancer patients for the assessment of tumor stage and residual disease following tumor resection .
1 In the present study , the detection of tumor-specific KRAS proto-oncogene , GTPase (KRAS) and B-Raf proto-oncogene , serine/threonine kinase (BRAF) mutations in the peripheral blood of colorectal cancer ( CRC ) patients at all stages and adenomas was used for the estimation of disease stage prior to surgery and for residual disease following surgery .
2 A total of 65 CRC patients were enrolled .
3 The primary tumor tested positive for the specific mutations ( KRAS mutations in codons 12 , 13 , 61 , 117 or 146 and BRAF mutations in codon 600 ) in 35 patients .
4 In all these patients , the specimen of normal bowel resected with the tumor was also tested for the presence of the same mutations in order to exclude the germ - line mutations .
5 Μ Only patients who tested positive for the specific mutation in the primary tumor were included in further analysis for the presence of tumor-specific mutation in the peripheral blood .
6 Μ No statistically significant differences were found between the detection rates of tumor mutations in the blood and different tumor stages ( P = 0491 ) .
7 Μ However , statistically significant differences in the proportions of patients with detected tumor-specific DNA mutations in the peripheral blood were found when comparing the groups of patients with R0 and R2 resections ( P = 0038 ) .
8 Μ Tumor-specific DNA mutations in the peripheral blood were more frequently detected in the patients with an incomplete surgical clearance of the tumor due to macroscopic residual disease ( R2 resections ) .
9 Therefore , the study concludes that the follow-up of somatic KRAS - and BRAF-mutated DNA in the peripheral blood of CRC patients may be useful in assessing the surgical clearance of the disease .



PMID: 27899972
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Efficacy and safety of aflibercept in metastatic colorectal cancer pretreated with bevacizumab : A report of five cases .
1 Aflibercept is a recombinant fusion protein that acts by inhibiting tumoural angiogenesis .
2 Efficacy data obtained in the VELOUR randomised study has contributed to the approval of aflibercept as a second - line metastatic colorectal cancer ( mCRC ) treatment following an oxaliplatin-based regimen .
3 The present study reports a case series of five patients with mCRC , who were treated in two centres since 2011 in the Compassionate Use Program for aflibercept .
4 All patients had a KRAS mutation and previously received palliative fluoropyrimidine-oxaliplatin-based chemotherapy with bevacizumab .
5 A doublet with irinotecan combined with aflibercept was administered until progression of disease .
6 The majority of patients received a greater number of aflibercept cycles than the median reported in the VELOUR study ( 12 vs. 7 cycles ) , with manageable and reversible toxicity .
7 The most frequent adverse events observed were diarrhoea , neutropenia , fatigue , proteinuria and hypertension .
8   Most cases obtained a progression-free survival greater than the median reported in the VELOUR study ( 11 vs. 69 months ) and , in a subgroup of patients previously treated with bevacizumab , and a median survival time of ~47 months was reached from the initial treatment of the disease .
9 The present study contrasts the efficacy and safety results obtained from the pivotal VELOUR trial , and confirms that aflibercept , used in routine clinical practice outside of the clinical trial environment , is active and well-tolerated following bevacizumab treatment .



PMID: 27899776
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ New Classification for Advanced Colorectal Cancer Using CancerPlex(R) Genomic Tests ] .
1 Recently , targeted drugs have been developed for the treatment of colorectal cancer ( CRC ) .
2 Among targets , it is well known that KRAS mutations are associated with resistance to epidermal growth factor receptor ( EGFR ) monoclonal antibodies .
3 However , response rates using anti-EGFR monotherapy for CRC were less than 20-30% in previous clinical studies .
4 Μ Thus , because the RAS/MAP2K/MAPK and PI3K/AKT pathways are associated with CRC resistance to chemotherapy , we analyzed gene mutations in Stage IV CRC patients using a genomic test ( CancerPlex(R) ) .
5 Medical records were reviewed for 112 patients who received treatment for CRC between 2007 and 2015 in Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital .
6 There were 66 male and 46 female patients , and their median age was 62.5 ( range , 30-86 ) years .
7 Cluster analyses were performed in 110 non-hypermutated Japanese CRC patients using Euclidean distance and Ward's clustering method , and 6 typical groups were identified .
8   Among these , patients with all wild-type actionable genes benefited from anti-EGFR therapies .
9   The expense of targeted drugs warrants consideration of cost-effectiveness during treatment decision-making for advanced CRC patients .
10 To this end , based on the genetic information on CRC , it is possible to develop precision medicine using CancerPlex(R) .



PMID: 27897268
(Patient)  
Terms: meta-analysis, meta-analyses, Meta-analysis
Sent# Symbols Sentence Mnemonics
0 ✓ Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies : a systematic review and meta-analysis . GM-MRK-RO
1 ✓ Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results . GM-MRK-RO
2 Μ We performed a systematic review of studies from 1990 to September 2015 , followed by random-effects meta-analyses for polymorphisms examined in atleast three studies .
3 Of 87 studies , 40 passed the criteria for systematic review and 23 for meta-analysis .
4 Μ The polymorphisms suitable for meta-analysis were CCND1 ( rs17852153 ) , COX2 ( rs20417 ) , EGF ( rs4444903 ) , EGFR ( rs712829 , rs11543848 , 3'UTR CA repeat ) , FCGR2A ( rs1801274 ) , FCGR3A ( rs396991 ) , IL8 ( rs4073 ) , KRAS ( rs61764370 ) and VEGFA ( rs3025039 ) .
5 Meta-analysis yielded nominal significance ( at alpha = 005 ) for rs4444903 and rs11543848 , but showed no significant results after multiple testing correction ; this was unchanged by sensitivity analyses to address subgroups , funnel-plot asymmetries , and study quality .
6 This highlights a tendency for lack of replication in the face of initial positive results , and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting .
7 The Pharmacogenomics Journal advance online publication , 29 November 2016 ; doi : 10.1038/tpj.2016.56 .



PMID: 27896617
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas .
1 Colorectal sessile serrated adenomas ( SSA ) are hypothesized to be precursor lesions of an alternative , serrated pathway of colorectal cancer , abundant in genes with aberrant promoter DNA hypermethylation .
2 In our present pilot study , we explored DNA methylation profiles and examined selected gene mutations in SSA .
3 Biopsy samples from patients undergoing screening colonoscopy were obtained during endoscopic examination .
4 After DNA isolation and quality analysis , SSAs ( n = 4 ) and healthy controls ( n = 5 ) were chosen for further analysis .
5 DNA methylation status of 96 candidate genes was screened by q ( RT ) PCR using Methyl-Profiler PCR array system .
6 Amplicons for 12 gene mutations were sequenced by GS Junior Instrument using ligated and barcoded adaptors .
7 Analysis of DNA methylation revealed 9 hypermethylated genes in both normal and SSA samples. 12 genes ( CALCA , DKK2 , GALR2 , OPCML , PCDH10 , SFRP1 , SFRP2 , SLIT3 , SST , TAC1 , VIM , WIF1 ) were hypermethylated in all SSAs and 2 additional genes ( BNC1 and PDLIM4 ) were hypermethylated in 3 out of 4 SSAs , but in none of the normal samples. 2 SSAs exhibited BRAF mutation and synchronous MLH1 hypermethylation and were microsatellite instable by immunohistochemical analysis .
8 Μ Our combined mutation and DNA methylation analysis revealed that there is a common DNA methylation signature present in pre-neoplastic SSAs .
9 This study advocates for the use of DNA methylation as a potential biomarker for the detection of SSA ; however , further investigation is needed to better characterize the molecular background of these newly recognized colorectal lesions .



PMID: 27892494
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes .
1 The discovery of endothelial growth factor receptor ( EGFR ) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma ( NSCLC ) .
2 Μ In phase III trials , the first-generation tyrosine kinase inhibitors ( TKI ) , gefitinib and erlotinib , demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations , achieving progression-free survival of 8-13.5 months .
3 Afatinib , a second-generation irreversible pan-ErbB inhibitor , is the first TKI that has shown a benefit in overall survival ( OS ) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first - line treatment .
4 ✓ Exon 19 deletion ( Del19 ) and the single-point substitution mutation ( L858R ) in exon 21 , called activating mutations due to their ability to confer sensitivity to TKI , represent approximately 90% of the EGFR mutations in NSCLC .
5 ✓ Μ Distinct sensitivity to TKI has been observed depending on the type of mutation , with greater progression-free survival in patients with the Del19 mutation .
6   The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation , but no significant increase in that of patients with the L858R mutation .
7   Direct comparison of afatinib and gefitinib as first - line therapy ( LUX-Lung 7 trial ) showed a statistically-significant increase in progression-free survival ( hazard ratio : 0.73 ; 95% confidence interval , 0.57-0.95 ; p = 0.0165 ) with afatinib .
8 Μ In the analysis by type of mutation , this benefit was observed for both the Del19 and the L858R mutations .



PMID: 27885175
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway .
1 The concept of a CpG island methylator phenotype ( CIMP ) was first introduced by Toyota and Issa to describe a subset of colorectal cancers ( CRCs ) with concurrent hypermethylation of multiple CpG island loci .
2 The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway , in which CIMP participates in the initiation and progression of serrated adenomas .
3 Distinct clinicopathological and molecular features of CIMP-high ( CIMP-H ) CRCs have been characterized , including proximal colon location , older age of onset , female preponderance , and frequent associations of high-level microsatellite instability and BRAF mutations .
4 CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas , including epithelial serration , vesicular nuclei , and abundant cytoplasm .
5   Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications .
6 In this review , we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway .



PMID: 27881709
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy : Results From North Central Cancer Treatment Group N0147 ( Alliance ) .
1 BACKGROUND :
2 Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer ( CC ) .
3 However , the effect of metformin use on patient survival in stage III CC after curative resection is unknown .
4 The survival outcomes were comparable regardless of the duration of metformin use .
5 PATIENTS AND METHODS :
6 Before randomization to FOLFOX ( folinic acid , 5-fluorouracil , oxaliplatin ) with or without cetuximab , 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus ( DM ) and metformin use .
7 Cox models were used to assess the association between metformin use and disease-free survival ( DFS ) , overall survival ( OS ) , and the time to recurrence ( TTR ) , adjusting for clinical and/or pathological factors .
8 RESULTS :
9 Of the 1,958 patients , 1,691 ( 86% ) reported no history of DM , 115 reported DM with metformin use ( 6% ) , and 152 reported DM without metformin use ( 8% ) .
10 The adjuvant treatment arms were pooled , because metformin use showed homogeneous effects on outcomes across the two arms .
11 Among the patients with DM ( n = 267 ) , DFS ( adjusted hazard ratio [aHR] , 0.90 ; 95% confidence interval [CI] , 0.59-1.35 ; p = .60 ) , OS ( aHR , 099 ; 95% CI , 065-149 ; p = 95 ) , and TTR ( aHR , 087 ; 95% CI , 056-135 ; p = 53 ) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors .
12 The survival outcomes were comparable regardless of the duration of metformin use ( <1 , 1-5 , 6-10 , >/ = 11 years ) before randomization ( ptrend = 64 for DFS , ptrend = 84 for OS , and ptrend = 87 for TTR ) .
13 Μ No interaction effects were observed between metformin use and KRAS , BRAF mutation status , tumor site , T/N stage , gender , or age .
14 CONCLUSIONS :
15   Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS , OS , and TTR similar to those for non-DM patients and DM patients without metformin use .
16 IMPLICATIONS FOR PRACTICE :
17   The present study did not find any relationship between metformin use or its duration and disease-free survival , time to recurrence , and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX ( folinic acid , fluorouracil , oxaliplatin ) -based chemotherapy .
18 This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status .
19 Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events .



PMID: 27880995
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Frequency of K-RAS and N-RAS Gene Mutations in Colorectal Cancers in Southeastern Iran .
1 ✓ Background : K-RAS and N-RAS gene mutations cause resistance to treatment in patients with colorectal cancer .
2 Based on this , awareness of mutation of these genes is considered a clinically important step towards better diagnosis and appropriate treatment .
3 Materials and Methods : Fifty paraffin-embedded blocks of colorectal cancer were obtained from Imam Reza Hospital of Birjand , Iran .
4 Μ Following DNA extraction , the samples were analyzed for common mutations of exons 2 , 3 and 4 of KRAS and NRAS genes using real time PCR and pyrosequencing .
5 Μ Results : According to this study , the prevalence of mutations was respectively 28% ( 14 out of 50 ) and 2% ( 1 out of 50 ) in KRAS and NRAS genes .
6 Μ All the mutations were observed in patients >50 years old .
7 Μ Conclusions : Mutations were found in both KRAS and NRAS genes in colorectal cancers in Iranian patients .
8   Determining the frequency of these mutations in each geographical region may be necessary to benefit from targeted cancer therapy .



PMID: 27880935
(None)  
Terms: , mouse, mouse colorectal cancer model, mouse CRC model
Sent# Symbols Sentence Mnemonics
0 Evolutionary biologic changes of gut microbiota in an 'adenoma-carcinoma sequence' mouse colorectal cancer model induced by 1 , 2-Dimethylhydrazine .
1 The molecular biological mechanisms underlying the evolutionary biologic changes leading to carcinogenesis remain unclear .
2 The main objective of our study was to explore the evolution of the microbiota community and molecules related with CRC in the dynamic transition from normal colon epithelium to premalignant adenoma with the aid of an 'adenoma-carcinoma sequence' mouse CRC model induced by DMH .
3 We generated a modified mouse CRC model induced by DMH for DNA sequences , and characterized the molecular networks .
4 Data from 454 pyrosequencing of the V3 - V5 region of the 16S rDNA gene and immunohistochemical detection of APC , P53 , K-RAS and BRAF genes were assessed with Principal coordinates , UniFrac , and Kruskal-Wallis rank sum test .
5 The inflammatory group showed enrichment of Bacteroidetes and Porphyromonadaceae ( P <001 ) .
6 OTUs affiliated with Firmicutes were enriched in the hyperproliferative group ( P <001 ) .
7 Rikenellaceae and Ruminococcaceae showed an increasing trend during the CRC process while the opposite pattern was observed for Prevotellaceaeand Enterobacteriaceae .
8 OTUs related to Alistipes finegoldii were significantly increased during CRC development , P53 , K-RAS and BRAF , were gradually increased ( P <005 ) .
9 Conversely , expression of APC was decreased during the course of development of CRC .
10 Our results demonstrate that the biological evolutionary shift of gut microbiota , characterized by a gradual decrease in 'driver' bacteria and an increase in DNA damage-causing bacteria , is accompanied by tumor development in the CRC model .
11 The synergistic actions of microbiota dysbiosis and effects of bacterial metabolites on related molecular events are proposed to contribute to the progression of CRC tumorigenesis .



PMID: 27879995
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 EGFR gene copy number predicts response to anti-EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer .
1 Quality Measures in Clinical Stage I Non-Small Cell Lung Cancer : Improved Performance Is Associated With Improved Survival .



PMID: 27878357
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 On-treatment markers as predictors to guide anti-EGFR MoAb treatment in metastatic colorectal cancer : a systematic review with meta-analysis .
1 PURPOSE :
2 Skin toxicity ( ST ) and early tumor shrinkage ( ETS ) are early phenomenon during the anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody ( MoAb ) treatment .
3 We conducted a meta-analysis and included relevant studies that reported the impact of ST and ETS on survival - and life quality-based outcome of metastatic colorectal cancer ( mCRC ) patients treated with anti-EGFR MoAb .
4 METHODS :
5 Relevant studies were identified from PubMed and Embase reporting the correlation of ST and ETS with the clinical outcome of mCRC patients treated with anti-EGFR MoAb .
6 We also collected evidences on the impact of ST and ETS on absolute benefit acquired from additional anti-EGFR treatment and quality of life ( ST only ) .
7 Pooled hazard ratio and rate difference were all estimated by using random-effects model .
8 RESULTS :
9 Pooled data revealed that the occurrence of ST and ETS >/ = 20% ( v <20% ) during anti-EGFR MoAb treatment were both associated with better OS , PFS and ORR .
10 This association could not be disturbed by KRAS status .
11 Mean changes in safety follow-up life health state from baseline appeared unaffected by ST .
12   Only mCRC patients with wild-type KRAS tumor who suffered grade 2+ ST could benefit from additional anti-EGFR treatment to chemotherapy or best supportive care ( BSC ) alone .
13   ETS was also a predictor for absolute survival benefit acquired from additional anti-EGFR treatment for patients with wild-type KRAS tumors , and the more early shrinkage the tumor was , the much benefit was observed .
14 CONCLUSION :
15   ST and ETS are predictive of absolute benefit acquired from anti-EGFR treatment in mCRC patients with wild-type KRAS tumors .
16 These two on-treatment markers can be used for clinical decision-making if no adequate biological markers from tissues are provided .



PMID: 27878354
(Patient)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 Randomized phase II study of cetuximab versus irinotecan and cetuximab in patients with chemo-refractory KRAS codon G13D metastatic colorectal cancer ( G13D-study ) .
1 PURPOSE :
2 This study investigated the efficacy and safety of cetuximab-based treatment in patients with chemotherapy-resistant refractory mCRC with KRAS G13D mutation .
3 PATIENTS AND METHODS :
4 An assessment of the efficacy and safety of cetuximab-based treatment was performed in an observation-enriched randomized controlled study comparing the cetuximab alone group ( Cet group ) and the combination of cetuximab and irinotecan group ( CetI group ) for KRAS G13D-mutated mCRC in Japan .
5 In this study , the patients received a biweekly ( 500 mg/m2 on day 1 ) or weekly ( 250 mg/m2 ) intravenous infusion of cetuximab in Cet group , or a biweekly ( 500 mg/m2 on day 1 ) or weekly ( 250 mg/m2 ) intravenous infusion of cetuximab followed by irinotecan ( 150 mg/m2 ) in CetI group .
6 Propensity score adjustment was used to achieve balance in the observational arm .
7 RESULTS :
8 Data from a total of 29 patients ( 10 in Cet group , 19 in CetI group ) were analyzed .
9 Crude median progression-free survival time was 2.9 months in the Cet group and 2.5 months in the CetI group .
10 Crude disease control rates were 55.6% in the Cet group and 47.4% in the CetI group .
11 After a median follow-up of 43 months , the crude median overall survival was 8.0 months in the Cet group and 7.6 months in the CetI group .
12 Cetuximab-based treatment did not markedly increase any characteristic toxicity and was generally well tolerated .
13 Propensity score analyses adjusted for performance status and number of metastases showed comparable results with the crude results .
14 CONCLUSION :
15   Cetuximab-based treatment seemed to benefit patients with chemotherapy-resistant , refractory KRAS G13D-mutated mCRC .
16 Our results might support the administration of cetuximab-based treatment for KRAS-mutant mCRC and would be able to provide treatment flexibility in this setting .



PMID: 27875625
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical and genetic determinants of ovarian metastases from colorectal cancer .
1 BACKGROUND :
2 Ovarian metastases from colorectal cancer ( OM-CRC ) often are unresponsive to chemotherapy and are associated with poor survival .
3 To the authors' knowledge , the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear .
4 METHODS :
5 Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified .
6 Next-generation somatic mutation profiling ( Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] ) was performed on 38 OM-CRC cases , including 21 matched tumor pairs/trios .
7 Regression models were used to analyze variables associated with progression-free survival and overall survival ( OS ) .
8 RESULTS :
9 Rat Kirsten Sarcoma Viral Oncogene Homolog ( KRAS ) , SMAD family member 4 ( SMAD4 ) , and neurotrophic receptor tyrosine kinase 1 ( NTRK1 ) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM .
10 ✓ SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS . GM-ASS-RO
11 Μ Matched multisite tumor sequencing did not identify OM-specific genomic alterations .
12 Of the 195 patients who underwent oophorectomy for OM-CRC ( median age , 49 years with a progression-free survival of 94 months and an OS of 23 months from oophorectomy ) , 76% had extraovarian metastasis ( EOM ) .
13 In multivariable analysis , residual disease after surgery ( R2 resection ) was associated with worse survival .
14 Patients with EOM were less likely to achieve R0/R1 surgical resection status ( complete macroscopic resection without clinical/radiological evidence of disease ) ( 48% versus 94% ) .
15 However , if R0/R1 resection status was achieved , both patients with ( 359 months versus 12 months ) and without ( 432 months versus 145 months ) EOM were found to have better OS .
16 Among 114 patients with R0/R1 resection status , 23 ( 20% ) had no disease recurrence , including 10 patients ( 9% ) with >3 years of follow-up.CONCLUSIONS :
17 Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC .
18 Similar to oligometastatic CRC to the lung or liver , surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected .
19 Cancer 2017 ; 123 : 1134-1143 .
20 (c) 2016 American Cancer Society .



PMID: 27865140
(Patient)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer : Multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR .
1 In metastatic colorectal cancer ( mCRC ) , fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first - line treatment .
2 Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF ( bevacizumab ) , VEGFR2 ( ramucirumab ) or EGFR ( cetuximab or panitumumab ) in first - and second - line therapies .
3   However , all patients treated with chemotherapy and targeted therapies will eventually relapse , and recently the emergence of alterations in EGFR , RAS , BRAF , ERB-B2 , MET and possibly in other genes has been shown to jeopardize response to EGFR blockade .
4   In chemorefractory patients , multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued .
5 This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting .



PMID: 27863403
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Enumeration and targeted analysis of KRAS , BRAF and PIK3CA mutations in CTCs captured by a label-free platform : Comparison to ctDNA and tissue in metastatic colorectal cancer .
1 Treatment of advanced colorectal cancer ( CRC ) requires multimodal therapeutic approaches and need for monitoring tumor plasticity .
2 Liquid biopsy biomarkers , including CTCs and ctDNA , hold promise for evaluating treatment response in real-time and guiding therapeutic modifications .
3 From 15 patients with advanced CRC undergoing liver metastasectomy with curative intent , we collected 41 blood samples at different time points before and after surgery for CTC isolation and quantification using label-free Vortex technology .
4 Μ For mutational profiling , KRAS , BRAF , and PIK3CA hotspot mutations were analyzed in CTCs and ctDNA from 23 samples , nine matched liver metastases and three primary tumor samples .
5 Mutational patterns were compared. 80% of patient blood samples were positive for CTCs , using a healthy baseline value as threshold ( 04 CTCs/mL ) , and 81.4% of captured cells were EpCAM+ CTCs .
6 Μ At least one mutation was detected in 78% of our blood samples .
7 Μ Among 23 matched CTC and ctDNA samples , we found a concordance of 78.2% for KRAS , 73.9% for BRAF and 91.3% for PIK3CA mutations .
8 Μ In several cases , CTCs exhibited a mutation that was not detected in ctDNA , and vice versa .
9 Complementary assessment of both CTCs and ctDNA appears advantageous to assess dynamic tumor profiles .



PMID: 27857191
(Cell)  
Terms: in vivo, in vitro, xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Deregulation of the miR-16-KRAS axis promotes colorectal cancer .
1 KRAS plays a significant role in the etiology and progression of colorectal cancer ( CRC ) , but the mechanism underlying this process has not been fully elucidated .
2 In this study , we found that the KRAS protein levels were higher in CRC tissues than in the normal adjacent tissues , whereas its mRNA levels varied irregularly , suggesting that a post-transcriptional mechanism is involved in the regulation of KRAS .
3 Then , we performed bioinformatic analyses to search for miRNAs that potentially target KRAS .
4 We predicted and experimentally validated that miR-16 directly recognizes the 3'-UTR of the KRAS transcript and regulates KRAS expression .
5 Furthermore , the in vitro results showed that the repression of KRAS by miR-16 suppressed the proliferation and invasion and induced the apoptosis of CRC cells , and the in vivo results revealed that miR-16 exerted a tumor-suppressive effect by negatively regulating KRAS in xenograft mice .
6 Taken together , our findings provide evidence supporting the role of miR-16 as a tumor suppressor in CRC by targeting KRAS .



PMID: 27856123
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Prognostic Impact of Primary Tumor Location on Clinical Outcomes of Metastatic Colorectal Cancer Treated With Cetuximab Plus Oxaliplatin-Based Chemotherapy : A Subgroup Analysis of the JACCRO CC-05/06 Trials .
1 INTRODUCTION :
2 Primary tumor location is a critical prognostic factor in metastatic colorectal cancer ( mCRC ) ; however , it remains unclear whether tumor location is a predictor of the response to cetuximab treatment .
3 It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival .
4 We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first - line cetuximab chemotherapy .
5 PATIENTS AND METHODS :
6 The associations of tumor location with overall survival and progression-free survival were evaluated in mCRC patients with KRAS exon 2 wild-type tumors who were enrolled onto 2 clinical trials : JACCRO CC-05 of cetuximab plus FOLFOX ( n = 57 , UMIN000004197 ) and CC-06 of cetuximab plus SOX ( n = 61 , UMIN000007022 ) .
7 Tumors proximal or from splenic flexure to rectum were defined as right-sided or left-sided , respectively .
8 Μ In addition , exploratory RAS and BRAF mutation analyses were performed .
9 RESULTS :
10 A total of 110 patients were assessable for tumor location ; 90 had left-sided tumors .
11 Left-sided tumors were significantly associated with longer overall survival ( 362 vs. 126 months , hazard ratio = 028 , P <0001 ) and progression-free survival ( 111 vs. 56 months , hazard ratio = 047 , P = 0041 ) than right-sided tumors ; similar results were obtained in multivariate analysis .
12   A subanalysis showed that the association was evident in the FOLFOX group and that tumor location was an independent prognostic factor irrespective of BRAF status in RAS wild-type patients .
13 CONCLUSION :
14   Primary tumor location might be a predictor of survival independent of BRAF status in mCRC patients who receive first - line cetuximab combined with oxaliplatin-based chemotherapy .



PMID: 27852040
(Patient)  
Terms: prospective, retrospective studies, clinical trial
Sent# Symbols Sentence Mnemonics
0 Clinical validation of prospective liquid biopsy monitoring in patients with wild-type RAS metastatic colorectal cancer treated with FOLFIRI-cetuximab .
1 Cancer genomics and translational medicine rely on the molecular profiling of patient's tumor obtained during surgery or biopsy .
2 Alternatively , blood is a less invasive source of tumor DNA shed , amongst other ways , as cell -free DNA ( cfDNA ) .
3 Highly-sensitive assays capable to detect cancer genetic events from patient's blood plasma became popularly known as liquid biopsy ( LqB ) .
4   Μ Importantly , retrospective studies including small number of selected patients with metastatic colorectal cancer ( mCRC ) patients treated with anti-EGFR therapy have shown LqB capable to detect the acquired clonal mutations in RAS genes leading to therapy resistance .
5 However , the usefulness of LqB in the real-life clinical monitoring of these patients still lack additional validation on controlled studies .
6   In this context , we designed a prospective LqB clinical trial to monitor newly diagnosed KRAS wild-type ( wt ) mCRC patients who received a standard FOLFIRI-cetuximab regimen .
7 We used BEAMing technique for evaluate cfDNA mutations in KRAS , NRAS , BRAF , and PIK3CA in twenty-five patients during a 2-y period .
8 Μ A total of 2,178 cfDNA mutation analyses were performed and we observed that : a ) continued wt circulating status was correlated with a prolonged response ; b ) smoldering increases in mutant cfDNA were correlated with acquired resistance ; while c ) mutation upsurge/explosion anticipated a remarkable clinical deterioration .
9 The current study provides evidences , obtained for the first time in an unbiased and prospective manner , that reinforces the utility of LqB for monitoring mCRC patients .



PMID: 27845624
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening .
1 Rapid progression of intracranial melanoma metastases controlled with combined BRAF/MEK inhibition after discontinuation of therapy : a clinical challenge .



PMID: 27840154
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Multimodal tumor suppression by miR-302 cluster in melanoma and colon cancer .
1 The miR-302 family is one of the main groups of microRNAs , which are highly expressed in embryonic stem cells ( ESCs ) .
2 Previous reports have indicated that miR-302 can reduce the proliferation rate of some cancer cells while compromising on their oncogenic potential at the same time without having the same effect on normal somatic cells .
3 In this study we aimed to further investigate the role of the miR-302 cluster in multiple cancer signaling pathways using A-375 melanoma and HT-29 colorectal cancer cells .
4 Our results indicate that the miR-302 cluster has the potential to modulate oncogenic properties of cancer cells through inhibition of proliferation , angiogenesis and invasion , and through reversal of the epithelial-to-mesenchymal transition ( EMT ) in these cells .
5 We showed for the first time that overexpression of miR-302 cluster sensitized A-375 and HT-29 cells to hypoxia and also to the selective BRAF inhibitor vemurafenib .
6 MiR-302 is a pleiotropically acting miRNA family which may have significant implications in controlling cancer progression and invasion .
7 It acts through a reprogramming process , which has a global effect on a multitude of cellular pathways and events .
8 We propose that reprogramming of cancer cells by epigenetic factors , especially miRNAs might provide an efficient tool for controlling cancer and especially for those with more invasive nature .



PMID: 27838401
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The evolving role of microsatellite instability in colorectal cancer : A review .
1 Microsatellite instability ( MSI ) is a molecular marker of a deficient mismatch repair ( MMR ) system and occurs in approximately 15% of colorectal cancers ( CRCs ) , more frequently in early than late-stage of disease .
2 While in sporadic cases ( about two-thirds of MSI-H CRCs ) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene , the remainder are associated with Lynch syndrome , that is linked to a germ - line mutation of one of the MMR genes ( MLH1 , MSH2 , MSH6 , PMS2 ) .
3 MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location , early-stage ( predominantly stage II ) , poor differentiation , mucinous histology and association with BRAF mutations .
4 In early-stage CRC , MSI can select a group of tumors with a better prognosis , while in metastatic disease it seems to confer a negative prognosis .
5 Although with conflicting results , a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors .
6 The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response , counterbalanced by the expression of immune inhibitory signals , such as PD-1 or PD-L1 , that resist tumor elimination .
7   Based on these considerations , MSI-H CRCs seem to be particularly responsive to immunotherapy , such as anti-PD-1 , opening a new era in the treatment landscape for patients with metastatic CRC .



PMID: 27837635
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pharmacogenetics in cancer therapy - 8 years of experience at the Institute for Oncology and Radiology of Serbia .
1 PURPOSE :
2 Pharmacogenetics is a study of possible mechanism by which an individual's response to drugs is genetically determined by variations in their DNA sequence .
3 The aim of pharmacogenetics is to identify the optimal drug and dose for each individual based on their genetic constitution , i.e.to individualize drug treatment .
4 This leads to achieving the maximal therapeutic response for each patient , while reducing adverse side effects of therapy and the cost of treatment .
5 A centralized pharmacogenetics service was formed at the Institute for Oncology and Radiology of Serbia ( IORS ) with the aim to provide a personalized approach to cancer treatment of Serbian patients .
6 METHODS :
7 Μ Analyses of KRAS mutations in metastatic colorectal cancer , EGFR mutations in advanced non-small cell lung cancer , CYP2D6 polymorphism in breast cancer , DPD polymorphism in colorectal cancer and MTHFR polymorphism in osteosarcoma have been performed by real time polymerase chain reaction ( PCR ) and PCR-restriction fragment length polymorphism ( PCR-RFLP ) .
8 RESULTS :
9 Μ Mutation testing analyses were successful for 1694 KRAS samples and 1821 EGFR samples , while polymorphism testing was successful for 9 CYP2D6 samples , 65 DPD samples and 35 MTHFR samples .
10 CONCLUSIONS :
11   Pharmacogenetic methods presented in this paper provide cancer patients in Serbia the best possible choice of treatment at the moment .



PMID: 27836416
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer .
1 BACKGROUND :
2 Microsatellite instability arises due to defect mismatch repair ( MMR ) and occurs in 10-20% of sporadic colorectal cancer .
3 The purpose was to investigate correlations between defect MMR , prognosis and heredity for colorectal cancer in first-degree relatives .
4 MATERIAL AND METHODS :
5 Tumour tissues from 318 patients consecutively operated for colorectal cancer were analysed for immunohistochemical expression of MLH1 , MSH2 and MSH6 on tissue microarrays .
6 Information on KRAS and BRAF mutation status was available for selected cases .
7 RESULTS :
8 Forty-seven ( 15% ) tumours displayed MSI .
9 No correlation was seen between patients exhibiting MSI in the tumour and heredity ( p = 0789 ) .
10 Patients with proximal colon cancer and MSI had an improved cancer-specific survival ( p = 0006 ) and prolonged time to recurrence ( p = 0037 ) .
11 In a multivariate analysis including MSI status , gender , CEA , vascular and neural invasion , patients with MSS and proximal colon cancer had an impaired cancer-specific survival compared with patients with MSI ( HR , 432 ; CI , 146-1278 ) .
12 The same prognostic information was also seen in distal colon cancer ; no recurrences seen in the eight patients with stages II and III distal colon cancer and MSI , but the difference was not statistically significant .
13 CONCLUSION :
14 No correlation between MSI and heredity for colorectal cancer in first-degree relatives was seen .
15 Patients with MSI tumours had improved survival .



PMID: 27835889
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer .
1 BACKGROUND :
2 The immunoscore ( IS ) , an index based on the density of CD3+ and CD8+ tumor-infiltrating lymphocytes ( TILs ) in the tumor center ( CT ) and invasive margin ( IM ) , has gained considerable attention as a prognostic marker .
3 Tumor-associated macrophages ( TAMs ) have also been reported to have prognostic value .
4 However , its clinical significance has not been fully clarified in patients with advanced CRC who present with distant metastases .
5 METHODS :
6 The density of CD3+ , CD4+ , CD8+ , FOXP3+ , CD68+ , and CD163+ immune cells within CRC tissue procured from three sites -the primary CT , IM , and distant metastasis ( DM ) -was determined using immunohistochemistry and digital image analyzer ( n = 196 ) .
7 The IS was obtained by quantifying the densities of CD3+ and CD8+ TILs in the CT and IM .
8 IS-metastatic and IS-macrophage-additional IS models designed in this study-were obtained by adding the score of CD3 and CD8 in DM and the score of CD163 in primary tumors ( CT and IM ) , respectively , to the IS .
9 RESULTS :
10 Higher IS , IS-metastatic , and IS-macrophage values were significantly correlated with better prognosis ( p = 0020 , p
11 Μ Multivariate analysis revealed that only IS-metastatic was an independent prognostic marker ( p = 0012 ) .
12 Μ No significant correlation was observed between KRAS mutation and three IS models .
13 However , in the subgroup analysis , IS-metastatic showed a prognostic association regardless of the KRAS mutational status .
14 CONCLUSIONS :
15 IS is a reproducible method for predicting the survival of patients with advanced CRC .
16 Additionally , an IS including the CD3+ and CD8+ TIL densities at DM could be a strong prognostic marker for advanced CRC .



PMID: 27835580
(None)  
Terms: in vivo, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 KY1022 , a small molecule destabilizing Ras via targeting the Wnt/beta-catenin pathway , inhibits development of metastatic colorectal cancer .
1 Μ APC ( 80-90% ) and K-Ras ( 40-50% ) mutations frequently occur in human colorectal cancer ( CRC ) and these mutations cooperatively accelerate tumorigenesis including metastasis .
2 In addition , both beta-catenin and Ras levels are highly increased in CRC , especially in metastatic CRC ( mCRC ) .
3 Therefore , targeting both the Wnt/beta-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients .
4 In this study , we characterized the roles of KY1022 , a small molecule that destabilizes both beta-catenin and Ras via targeting the Wnt/beta-catenin pathway , in inhibiting the cellular events , including EMT , an initial process of metastasis , and apoptosis .
5 As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice , KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis .
6 A small molecular approach degrading both beta-catenin and Ras via inhibition of the Wnt/beta-catenin signaling would be an ideal strategy for treatment of mCRC .



PMID: 27827395
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Death receptor 5 ( DR5 ) and a 5 - gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer .
1 High expression of Inhibitor of apoptosis proteins ( IAPs ) has been related to colorectal cancer ( CRC ) progression , resistance to treatment and poor prognosis .
2 TRAIL ( TNF-related apoptosis-inducing ligand ) through its receptors DR4 ( TRAIL-R1 ) and DR5 ( TRAIL-R2 ) can selectively induce cancer cell apoptosis .
3 The mRNA expression of DR4 , DR5 , c-IAP1 , c-IAP2 , XIAP and BIRC5/Survivin genes was examined in 100 paired ( cancerous-normal ) colorectal tissue specimens by real-time PCR , 50 of which were KRAS wild-type and 50 KRAS-mutant .
4 DR5 , XIAP and BIRC5/Survivin genes are significantly up-regulated ( p <00001 , p = 0012 and p = 00003 , respectively ) , whereas c-IAP1 and c-IAP2 genes are significantly down-regulated at mRNA and protein levels in CRC ( p <00001 for both ) .
5 Μ ROC analyses showed that DR5 , cIAP1 and cIAP2 expression has discriminatory value between CRC and normal tissue ( AUC = 0700 , p <00001 for DR5 ; AUC = 0628 , p = 0011 for cIAP1 ; AUC = 0673 , p <00001 for cIAP2 ) .
6 Combinatorial ROC analysis revealed the marginally fair discriminatory value of 5 genes as a panel ( AUC = 0685 , p <00001 ) .
7 Kaplan-Meier survival curves revealed significant association of cIAP2 down-regulation in CRC with lower overall survival probability of CRC patients ( p = 00098 ) .
8 DR5 , BIRC5/Survivin , XIAP , c-IAP1 and c-IAP2 mRNA expression are significantly deregulated in CRC and could provide a panel of markers with significant discriminatory value between CRC and normal colorectal tissue .



PMID: 27827301
(Cell)  
Terms: in vitro, xenograft, in vivo
Sent# Symbols Sentence Mnemonics
0 Validation and development of MTH1 inhibitors for treatment of cancer .
1 BACKGROUND :
2 Previously , we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells .
3 Recently , several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells , challenging the utility of MTH1 inhibition as a target for cancer treatment .
4 MATERIAL AND METHODS :
5 Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay .
6 Thermal Proteome profiling , proteomics , cellular thermal shift assays , kinase and CEREP panel were used for target engagement , mode of action and selectivity investigations of MTH1 inhibitors .
7 Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models .
8 RESULTS :
9 Here , we demonstrate that recently described MTH1 inhibitors , which fail to kill cancer cells , also fail to introduce the toxic oxidized nucleotides into DNA .
10 We also describe a new MTH1 inhibitor TH1579 , ( Karonudib ) , an analogue of TH588 , which is a potent , selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo .
11 CONCLUSION :
12 We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA .
13 Furthermore , we describe TH1579 as a best-in-class MTH1 inhibitor , which we expect to be useful in order to further validate the MTH1 inhibitor concept .



PMID: 27825133
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc .
1 Resistance to epidermal growth factor receptor ( EGFR ) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type ( WT ) metastatic colorectal cancer ( mCRC ) .
2 However , the molecular mechanisms and key factors conferring this resistance are largely unknown .
3 Forkhead transcription factors of the O class 3a ( FoxO3a ) , an important regulator of cell survival , has been reported with dual functions in tumor recently .
4 In this study , we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues .
5 We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells ( Caco2-CR ) and intrinsic resistant cells with BRAF mutation (HT29) .
6 We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells .
7 Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability .
8 Further , biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene , thus participated in regulating of c-Myc downstream genes , including ACO2 , LARS2 , MRPL12 and PKM2 in these resistant cells .
9 Moreover , knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently .
10 Altogether , our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy .



PMID: 27821793
(None)  
Terms: prospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 ✓ A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer : Alliance ( Cancer and Leukemia Group B ) 9581 and 89803 . GE-MRK-DS
1 PURPOSE :
2 Tumor levels of thymidylate synthase ( TS ) , a target of 5-fluorouracil ( 5-FU )- based chemotherapy for colorectal cancer , have been studied as a predictive or prognostic biomarker with mixed results .
3 PATIENTS AND METHODS :
4 Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer .
5 TS expression was determined by standard immunohistochemistry and by automated quantitative analysis .
6 Tumor mismatch repair deficiency ( MMR-D ) and BRAF c.1799T >A ( pV600E ) mutation status were also examined .
7 Relationships between tumor TS , MMR-D , and BRAF mutation status , overall survival ( OS ) , and disease-free survival ( DFS ) were investigated in the subset of stage III patients .
8 RESULTS :
9 ✓ Μ Patients whose tumors demonstrated high TS expression experienced better treatment outcomes , with DFS hazard ratio ( HR ) = 0.67 , 95% confidence interval ( CI ) = 0.53 , 0.84 ; and OS HR = 0.68 , 95% CI = 0.53 , 0.88 , for high versus low TS expression , respectively . GE-ASS-RO, RO-ASS-GE
10 Μ No significant interaction between TS expression and stage was observed ( DFS : interaction HR = 0.94 ; OS : interaction HR = 0.94 ) .
11 Tumors with high TS expression were more likely to demonstrate MMR-D ( 222% vs. 128% ; p = 0003 ) .
12 Μ Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77% , compared with 58% for those whose tumors had low TS and were non-MMR-D ( log-rank p = 0006 ) .
13 ✓ Tumor TS expression did not predict benefit of a particular therapeutic regimen . GE-REG-RO
14 CONCLUSION :
15 ✓ Μ This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer , although tumor TS expression did not predict benefit of 5-FU-based chemotherapy . GE-REG-RO
16 The Oncologist 2017 ; 22 : 107-114Implications for Practice : This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer .
17 It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility .



PMID: 27816197
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Peritoneal carcinomatosis of colorectal cancer : novel clinical and molecular outcomes .
1 BACKGROUND :
2 The objective of this study was to identify the prognostic impact of parameters in peritoneal carcinomatosis from colorectal cancer .
3 METHODS :
4 We collected data from patients treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy for peritoneal carcinomatosis secondary to colorectal cancer .
5 RESULTS :
6 Ninety-one procedures were performed .
7 In univariate analysis , an increased peritoneal cancer index was associated with decreased survival ( P <001 ) .
8 The presence of signet ring cells was associated to a decrease in survival from 45.8 to 12.1 months ( P <001 ) .
9 Microsatellite sequences instability status was the only molecular prognostic factor correlated with an increase in median disease-free survival : 12.4 versus 24.9 months ( P = 01 ) .
10 The presence of a mucinous component was associated with a decreased of survival from 51.9 to 35.1 months ( P = 02 ) .
11 CONCLUSIONS :
12 Clinical factors were affecting the survival of patients .
13 The absence of signet ring cells and mucinous component and the presence of microsatellite sequences instability may be favorable prognostic factors .



PMID: 27815357
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF and NRAS Locus -Specific Variants Have Different Outcomes on Survival to Colorectal Cancer .
1 Purpose : Somatic mutation status at KRAS , BRAF , and NRAS is associated with prognosis in patients with advanced colorectal cancer ( aCRC ) ; however , it remains unclear whether there are intralocus , variant -specific differences in survival and other clinicopathologic parameters .
2 Experimental Design : We profiled 2,157 aCRCs for somatic mutations in KRAS , BRAF , and NRAS and determined microsatellite instability status .
3 We sought inter - and intralocus correlations between mutations and variant -specific associations with survival and clinicopathology .
4 Μ Results : KRAS mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio ( HR ) , 1.44 ; 95% confidence interval ( CI ) , 1.28-1.61 ; P = 6.4 x 10-10 and HR , 1.53 ; 95% CI , 1.26-1.86 ; P = 1.5 x 10-05 , respectively] .
5 For BRAF , more c.1781A>G ( pD594G ) CRCs carried RAS mutations [14% ( 3/21 )] compared with c.1799T>A ( pV600E ) CRCs [1% ( 2/178 ) , P = 9.0 x 10-03] .
6 ✓ c.1799T>A ( pV600E ) was associated with poor prognosis ( HR , 260 ; 95% CI , 206-328 ; P = 10 x 10-15 ) , whereas c.1781A>G ( pD594G ) was not ( HR , 130 ; 95% CI , 073-231 ; P = 037 ) ; this intralocus difference was significant ( P = 004 ) . GM-ASS-RO
7 More c.1799T>A ( pV600E ) colorectal cancers were found in the right colon [47% ( 47/100 )] , compared with c.1781A>G ( pD594G ) colorectal cancers [7% ( 1/15 ) , P = 3.7 x 10-03] .
8 For NRAS , 5% ( 3/60 ) of codon 61 mutant colorectal cancers had KRAS mutations compared with 44% ( 10/23 ) of codons 12 and 13 mutant colorectal cancers ( P = 79 x 10-05 ) .
9 ✓ Codon 61 mutations conferred poor prognosis ( HR , 147 ; 95% CI , 109-199 ; P = 001 ) , whereas codons 12 and 13 mutations did not ( HR , 129 ; 95% CI , 064-258 ; P = 048 ) . GM-REG-RO
10   Conclusions : Our data show considerable intralocus variation in the outcomes of mutations in BRAF and NRAS These data need to be considered in patient management and personalized cancer therapy .
11 Clin Cancer Res ; 23 ( 11 ) ; 2742-9 .
12 (c) 2016 AACR .



PMID: 27813511
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic profile , immunophenotype , and genotype of CD274 (PD-L1)- positive colorectal carcinomas .
1 The CD274 (PD-L1) /PDCD1 ( PD-1 ) pathway is crucial for the modulation of immune responses and self-tolerance .
2 Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance .
3 Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy .
4 Μ Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer , clinicopathologic profile of these CD274-positive tumors has not been extensively studied .
5 In this study , 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274 , mismatch repair ( MMR ) proteins , intestinal differentiation marker ( CDX2 ) , and stem cell markers ( ALCAM , ALDH1A1 , and SALL4 ) .
6 CD274-positive colorectal carcinomas ( 54/454 ( 12% ) ) usually ( 83% ) involved the right or transverse colon with poorly differentiated and solid/medullary histology .
7 On the basis of multivariate logistic regression analysis , CD274 positivity was significantly associated with poorly differentiated histotype ( OR : 3.32 ; 95% CI : 1.46-7.51 ; P = 0.004 ) , MMR deficiency ( OR : 10.0 ; 95% CI : 4.66-21.5 ; P<0.001 ) , and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity ( OR : 5.51 ; 95% CI : 1.66-18.3 ; P = 0.005 ) .
8 Μ Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually ( 88% ) carried the BRAF V600E mutation .
9 Thus , colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway .
10 Μ Moreover , colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently ( 71% ) showed CD274 positivity .
11 This might suggest association of CD274 expression with 'stem-like' phenotype .
12 Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion .



PMID: 27811854
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 No association of CpG island methylator phenotype and colorectal cancer survival : population-based study .
1 BACKGROUND :
2 Previous studies have shown adverse effects of CpG island methylator phenotype ( CIMP ) on colorectal cancer ( CRC ) prognosis .
3 However , sample sizes were often limited and only few studies were able to adjust for relevant molecular features associated with CIMP .
4 The aim of this study was to investigate the impact of CIMP on CRC survival in a large population-based study with comprehensive adjustment .
5 METHODS :
6 The CIMP status and other molecular tumour features were analysed in 1385 CRC patients diagnosed between 2003 and 2010 .
7 Detailed information were obtained from standardised personal interviews and medical records .
8 During follow-up ( median : 4.9 years ) , we assessed vital status , cause of death and therapy details .
9 Cox proportional hazard regression models were used to estimate adjusted hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) of survival after CRC .
10 RESULTS :
11 The CIMP-H occurred more frequently in patients with older age , female gender , cancer in the proximal colon , BRAF mutation and microsatellite instability-high ( MSI-H ) .
12 However , CIMP status was not associated with CRC prognosis in CRC patients ( HR = 100 ; 95% CI = 072-140 for overall survival ; HR = 096 ; 95% CI = 065-141 for disease-specific survival ) or in any of the subgroups .
13 Although CIMP status was associated with the presence of MSI-H and BRAF mutation , the prognostic effects of MSI-H ( HR = 049 ; 95% CI = 027-090 ) and BRAF mutation ( HR = 178 ; 95% CI = 110-284 ) were independent of CIMP status .
14 Μ Similar benefit of chemotherapy was found for CRC outcomes in both the CIMP-low/negative group and the CIMP-high group .
15 CONCLUSIONS :
16 CpG island methylator phenotype was not associated with CRC prognosis after adjusting for other important clinical factors and associated mutations .



PMID: 27805251
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 In silico RNA-seq and experimental analyses reveal the differential expression and splicing of EPDR1 and ZNF518B genes in relation to KRAS mutations in colorectal cancer cells .
1 Several drugs used for the treatment of colorectal cancer ( CRC ) are targeted at the epidermal growth factor receptor , but mutations in genes of the RAS family cause resistance to these drugs .
2 Thus , extensive research is being carried out to counterbalance this resistance .
3 The G13D mutation of KRAS is common in humans , and we previously reported that this mutation results in the epigenetic modification of hnRNP proteins , involved in RNA splicing .
4 Μ As aberrant splicing often results in oncogenicity , the present study aimed to identify the genes which show altered splicing patterns in connection with the G13D KRAS mutation .
5 Μ To accomplish this , we first carried out an in silico analysis of RNA-seq databases and found that the distribution of alternative splicing isoforms of genes RPL13 , HSP90B1 , ENO1 , EPDR1 and ZNF518B was altered in human CRC cell lines carrying the G13D KRAS mutation when compared to cell lines carrying wild-type KRAS .
6 The in silico results were experimentally validated by quantitative realtime PCR .
7 Expression of the genes EPDR1 and ZNF518B was negligible in the Caco2 , RKO and SW48 cell lines , which possess wild-type KRAS , while the HCT116 , DLD1 and D-Mut1 cell lines , harbouring the G13D mutation , expressed these genes .
8 Moreover , in both genes , the ratio of isoforms was significantly different between the parental DLD1 (+/G13D) and D-Mut1 cells , in which the wild-type allele had been knocked out .
9 DWT7m cells also expressed both genes .
10 These cells , derived from DLD1 , have spontaneously acquired a G12D mutation in their single KRAS allele in 20% of the population .
11   The present data suggest a relationship between KRAS mutations , particularly G13D , and the expression of the EPDR1 and ZNF518B genes and expression of their isoforms and provide enhanced understanding of the molecular mechanisms involved in the resistance of CRC cells to antiEGF receptor therapies .



PMID: 27803597
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Patterns of practice with third - line anti-EGFR antibody for metastatic colorectal cancer .
1 BACKGROUND :
2 Therapy with anti-epidermal growth factor receptor ( egfr ) monoclonal antibody improves outcomes for patients with metastatic colorectal cancer ( mcrc ) in the first - , second - , and third - line trial settings .
3 In British Columbia , the use of egfr inhibitors ( egfris ) is confined to third - line therapy , which might lower the proportion of patients who receive this therapy .
4 The objective of the present study was to describe egfri treatment patterns when those agents are limited to the third - line setting .
5 The results will inform decisions about optimal use of egfri agents , including earlier in the course of therapy for metastatic disease .
6 METHODS :
7 All patients with newly diagnosed mcrc who were referred to BC Cancer Agency clinics in 2009 were included in the study .
8 Prognostic and treatment information was prospectively collected ; KRAS test results were determined by chart review .
9 RESULTS :
10 The study included 443 patients with a median age of 66 years .
11   For the 321 patients who received systemic therapy , median survival was 22.3 months .
12   Of the 117 patients who were treated with 5-fluorouracil , oxaliplatin , and irinotecan , and who were potentially eligible for egfri therapy , 90% ( 105 patients ) were tested for KRAS status .
13   Of the 60 patients with KRAS wild-type tumours , 82% ( 49 patients ) received egfri therapy .
14 CONCLUSIONS :
15   When egfri therapy is limited to the third - line setting , only a small proportion of patients receive such therapy , with death and poor performance status preventing its use in the rest .
16   Availability of egfri in earlier lines of therapy could increase the proportion of patients treated with all active systemic agents .



PMID: 27737877
(Cell)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 MicroRNA let-7 , T Cells , and Patient Survival in Colorectal Cancer .
1 Experimental evidence suggests that the let-7 family of noncoding RNAs suppresses adaptive immune responses , contributing to immune evasion by the tumor .
2 We hypothesized that the amount of let-7a and let-7b expression in colorectal carcinoma might be associated with limited T-lymphocyte infiltrates in the tumor microenvironment and worse clinical outcome .
3 Utilizing the molecular pathological epidemiology resources of 795 rectal and colon cancers in two U .
4 S.-nationwide prospective cohort studies , we measured tumor-associated let-7a and let-7b expression levels by quantitative reverse-transcription PCR , and CD3+ , CD8+ , CD45RO (PTPRC) + , and FOXP3+ cell densities by tumor tissue microarray immunohistochemistry and computer-assisted image analysis .
5 Logistic regression analysis and Cox proportional hazards regression were used to assess associations of let-7a ( and let-7b ) expression ( quartile predictor variables ) with T - cell densities ( binary outcome variables ) and mortality , respectively , controlling for tumor molecular features , including microsatellite instability , CpG island methylator phenotype , LINE-1 methylation , and KRAS , BRAF , and PIK3CA mutations .
6 Compared with cases in the lowest quartile of let-7a expression , those in the highest quartile were associated with lower densities of CD3+ [multivariate odds ratio ( OR ) , 0.40 ; 95% confidence interval ( CI ) , 0.23-0.67 ; Ptrend = 0.003] and CD45RO+ cells ( multivariate OR , 031 ; 95% CI , 017-058 ; Ptrend = 00004 ) , and higher colorectal cancer-specific mortality ( multivariate hazard ratio , 182 ; 95% CI , 142-313 ; Ptrend = 0001 ) .
7 ✓ In contrast , let-7b expression was not significantly associated with T - cell density or colorectal cancer prognosis . GE-ASS-RO
8   Our data support the role of let-7a in suppressing antitumor immunity in colorectal cancer and suggest let-7a as a potential target of immunotherapy .
9 Cancer Immunol Res ; 4 ( 11 ) ; 927-35 .
10 (c) 2016 AACR .



PMID: 27798894
(Patient)  
Terms: case, control, case control, prospective
Sent# Symbols Sentence Mnemonics
0 Assessment of BRAF V600E ( VE1 ) protein expression and BRAF gene mutation status in codon 600 in benign and malignant salivary gland neoplasms .
1 BACKGROUND/AIM :
2 Transanal endoscopic microsurgery ( TEMS ) is emerging as an alternative treatment for rectal cancer Stage I .
3 There remains a risk of local recurrence .
4 The Aim of the study was to study the effect of biomarkers in local recurrence for Stage I rectal cancer following TEMS plus or minus radiotherapy .
5 MATERIALS AND METHODS :
6 This is a case control study where we compared 10 early rectal cancers that had recurred , against 19 cases with no recurrence , total 29 patients ( age = 2825-8687 , mean age = 6792 years , SD = 1491 , Male , N = 18 , Female , N = 11 ) .
7 All patients underwent TEMS for radiological Stage I rectal cancer ( yT1N0M0 or yT2N0M0 ) established with combination of magnetic resonance imaging ( MRI ) and endorectal ultrasound .
8 We prospectively collected all data on tumour histology , morphological features , as well as follow-up parameters .
9 Molecular analysis was performed to identify their status on BRAF , KRAS , p16 O6-methylguanine-DNA methyltransferase ( MGMT ) and beta-catenin .
10 RESULTS :
11 Out of 29 specimens analyzed , 19 were KRAS wild type ( 659% ) and 10 mutant ( 345% ) .
12 Recurrence of the tumour was noted in 10 cases ( 345% ) from which 60% were pT1 ( N = 6 ) and 40% pT2 ( N = 4 ) .
13 There was a statistically significant association between KRAS mutant status and local recurrence ( N = 6 , p = 0037 ) .
14 P16 expression greater than 5% ( mean = 108% , min = 0 , max = 95 ) is linked with earlier recurrence within 11.70 months ( N = 7 , p = 0004 ) .
15 Membranous beta-catenin expression ( N = 12 , 48% ) was also related with KRAS mutant status ( p = 0006 ) but not with survival ( p>005 ) .
16 BRAF gene was found to be wild type in all cases tested ( N = 23 ) .
17 CONCLUSION :
18 KRAS/p16/beta-catenin could be used as a combined biomarker for prediction of local recurrence and stratification of the risk for further surgery .



PMID: 27798693
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification of Binding Targets of a Pyrrole-Imidazole Polyamide KR12 in the LS180 Colorectal Cancer Genome .
1 Pyrrole-imidazole polyamides are versatile DNA minor groove binders and attractive therapeutic options against oncological targets , especially upon functionalization with an alkylating agent such as seco-CBI .
2 These molecules also provide an alternative for oncogenes deemed "undruggable" at the protein level , where the absence of solvent-accessible pockets or structural crevices prevent the formation of protein -inhibitor ligands ; nevertheless , the genome -wide effect of pyrrole-imidazole polyamide binding remain largely unclear to-date .
3 Here we propose a next-generation sequencing-based workflow combined with whole genome expression arrays to address such issue using a candidate anti-cancer alkylating agent , KR12 , against codon 12 mutant KRAS .
4 Biotinylating KR12 enables the means to identify its genome -wide effects in living cells and possible biological implications via a coupled workflow of enrichment-based sequencing and expression microarrays .
5 The subsequent computational pathway and expression analyses allow the identification of its genomic binding sites , as well as a route to explore a polyamide's possible genome -wide effects .
6 Μ Among the 3,343 KR12 binding sites identified in the human LS180 colorectal cancer genome , the reduction of KR12-bound gene expressions was also observed .
7 Additionally , the coupled microarray-sequencing analysis also revealed some insights about the effect of local chromatin structure on pyrrole-imidazole polyamide , which had not been fully understood to-date .
8 Μ A comparative analysis with KR12 in a different human colorectal cancer genome SW480 also showed agreeable agreements of KR12 binding affecting gene expressions .
9 Combination of these analyses thus suggested the possibility of applying this approach to other pyrrole-imidazole polyamides to reveal further biological details about the effect of polyamide binding in a genome .



PMID: 27780856
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer .
1 Μ Purpose : Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer ( mCRC ) patients frequently respond to anti-EGFR mAbs , acquired resistance almost invariably occurs .
2 Mechanisms of resistance to EGFR blockade include the emergence of KRAS , NRAS , and EGFR extracellular domain mutations as well as HER2/MET alterations .
3 However , these findings derive from retrospective studies that analyzed one single resistance mechanism at a time ; moreover , it is still unclear how molecular heterogeneity affects clonal evolution in patients .
4 In this work , we aimed at extensively characterizing and correlating the molecular characteristics of tissue - and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies .
5 Experimental design : Twenty-two RAS-BRAF wild-type , HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy .
6 Next-generation sequencing and silver in situ hybridization ( SISH ) /IHC analyses were performed both on archival tumors and postprogression samples .
7 Circulating tumor ( ctDNA ) molecular profiles were obtained in matched tissue -plasma samples .
8 Μ Results : RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis .
9 On the other hand , BRAF and EGFR ectodomain mutations were much rarer .
10 ✓ Patients with acquired MET amplification showed worse PFS on anti-EGFRs . GM-ASS-RO
11 We detected both intralesion heterogeneity , as suggested by co-occurrence of different resistance mechanisms in the same sample , and interlesion heterogeneity .
12 The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade .
13   Conclusions : Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC .
14 Clin Cancer Res ; 23 ( 10 ) ; 2414-22 .
15 (c) 2016 AACR .



PMID: 27708166
(None)  
Terms: , mouse, mouse models, mouse model
Sent# Symbols Sentence Mnemonics
0 Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research .
1 Current mouse models for colorectal cancer often differ significantly from human colon cancer , being largely restricted to the small intestine .
2 Here , we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression .
3 Carbonic anhydrase I ( Car1 ) is a gene expressed uniquely in colonic epithelial cells .
4 We generated a colon-specific inducible Car1CreER knock-in ( KI ) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum .
5 Deletion of the tumor suppressor gene Apc using the Car1CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon .
6 Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon , which progressed to macroadenomas with significant morbidity .
7 Μ Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc , Kras , p53 , and Smad4 Importantly , no adenomas were observed in the small intestine .
8 Μ Additionally , we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations , suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations .
9 Our results establish the Car1CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions .



PMID: 27647226
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 How the lab is changing our view of colorectal cancer .
1 In metastatic colorectal cancer , the optimization of upfront treatment and the continuum of care based on patients' exposure to multiple treatment lines have reached a plateau of efficacy .
2 Therefore , a paradigm shift is ongoing towards precision medicine and personalized treatments based on the specific molecular features of the disease .
3 In this perspective , the improved knowledge of disease biology coming from the lab has prompted a rapid translation from bench to bedside of newer targeted strategies .
4 Here , we focus on the most promising biomarkers already included or close to adoption in daily clinical practice .
5 ✓ In particular , evidence about the potential roles of BRAF mutation , HER2 amplification , MGMT methylation , microsatellite instability , and ALK , ROS and NTRK1-3 rearrangements as positive predictors of benefit from biological agents is reviewed and discussed . GM-MRK-RO



PMID: 27784278
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS testing practices and RAS mutation prevalence among patients with metastatic colorectal cancer : results from a Europe-wide survey of pathology centres .
1 BACKGROUND :
2 Treatment options for patients with metastatic colorectal cancer ( mCRC ) include anti-epithelial growth factor therapies , which , in Europe , are indicated in patients with RAS wild-type tumours only and require prior mutation testing of "hot-spot" codons in exons 2 , 3 and 4 of KRAS and NRAS .
3 The aim of this study was to evaluate the implementation of RAS testing methods and estimate the RAS mutation prevalence in mCRC patients .
4 METHODS :
5 Overall , 194 pathology laboratories were invited to complete an online survey .
6 Participating laboratories were asked to provide information on their testing practices and aggregated RAS mutation data from 20 to 30 recently tested patients with mCRC .
7 RESULTS :
8 A total of 96 ( 495 % ) laboratories across 24 European countries completed the survey .
9 All participants tested KRAS exon 2 , codons 12 and 13 .
10 Seventy ( 729 % ) laboratories reported complete testing of all RAS hot-spot codons , and three ( 31 % ) reported only testing KRAS exon 2 .
11 Sixty-nine ( 719 % ) laboratories reported testing >80 patients yearly for RAS mutation status .
12 Testing was typically performed within the reporting institution ( 938 % , n = 90 ) , at the request of a treating oncologist ( 895 % , n = 85 ) ; testing methodology varied by laboratory and by individual codon tested .
13 For laboratory RAS testing , turnaround times were
14 The overall crude RAS mutation prevalence was 48.5 % ( 95 % confidence interval : 46.4-50.6 ) for laboratories testing all RAS hot-spot codons .
15 Prevalence estimates varied significantly by primary tumour location , approximate number of patients tested yearly and indication given for RAS testing .
16 CONCLUSION :
17 Our findings indicate a rapid uptake of RAS testing in the majority of European pathology laboratories .



PMID: 27748041
(Patient)  
Terms: Observational study, prospective study, clinical trial
Sent# Symbols Sentence Mnemonics
0 Observational study on quality of life , safety , and effectiveness of first - line cetuximab plus chemotherapy in KRAS wild-type metastatic colorectal cancer patients : the ObservEr Study .
1 Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer ( mCRC ) .
2 Effective management of skin reactions from cetuximab improves quality of life ( QoL ) , and treatment compliance in clinical trials .
3 No data are available from real-world settings .
4 The ObservEr observational , multicenter , prospective study evaluated QoL , the incidence of skin reactions , and management of chemotherapy plus cetuximab in first - line for mCRC .
5 The primary endpoint was QoL measured with the Dermatology Life Quality Index ( DLQI ) and EORTC QLQ-C30 .
6 Secondary endpoints were the incidence of skin and serious adverse events , median overall and progression-free survival , tumor response , and resection rates .
7 Between May 2011 and November 2012 , 228 patients with KRASwt mCRC were enrolled at 28 Italian centers , 225 evaluable , median age 65 years .
8 QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management .
9 The incidence of cetuximab-specific grade >/ = 3 skin reactions was 14% , with no grade 4/5 events .
10 Skin reactions correlated with survival ( P = 0016 ) , and their incidence was influenced by chemotherapy regimen ( oxaliplatin vs. irinotecan-Incidence rate ratio [IRR] 1.72 , P <0.0001 ) and gender ( male vs. female-IRR 138 , P = 00008 ) .
11 Compliance at first postbaseline evaluation was 97.75% .
12 Median overall survival was 23.6 months , median progression-free survival 8.3 months .
13   Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions .
14 We observed the same correlation between overall survival ( OS ) and skin reactions reported in controlled clinical trials , also in this setting .



PMID: 27781259
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Research progress of serrated polyposis syndrome ] .
1 Serrated polyposis syndrome ( SPS ) is closely associated with the initiation and development of colorectal cancer ( CRC ) , however , there is few research on SPS in China .
2 Serrated polyps can be divided into hyperplastic polyps , sessile serrated polyps and traditional serrated polyps .
3 The diagnosis standard of SPS is as following : (1) There are atleast 5 serrated lesions in proximal colon , and diameter of more than 2 lesions is >10 mm ; (2) The patient has one serrated polyp with family history of SPS ; (3) More than 20 serrated polyps can be found in the entire large bowel .
4 The risk of SPS is relatively high in the development of colorectal cancer and 25%-70% of the SPS patients is diagnosed with synchronous or metachronous colorectal cancer during following-up.The clinical characteristics of SPS include that patients are relatively old ; no significant racial difference exists in the morbidity ; patients have family history of colorectal cancer .
5 The mutation of BRAF or KRAS gene , which induces colorectal cancer through the RAS-RAF-MAPK signaling pathway , is often found in SPS as well as CpG island methylation phenotype ( CIMP ) and microsatellite instability ( MSI ) .
6 The difference between SPS and traditional familial adenomatous polyposis ( FAP ) should be noted because of the different pathology mechanism , clinical characteristics and the risk of malignancy .
7 Nowadays , the common technologies of detecting serrated polyps are auto-fluorescence imaging ( AFI ) and narrow-band imaging ( NBI ) , whose detective rate is around 55% .
8 The SPS patients are advised to undergo the resection of all the serrated polyps with diameter larger than 3-5 mm and receive the colonoscopy examination every 1 or 2 year .
9 Not only the research about SPS is on the initiation step and the molecular mechanism is still unknown , but also the scholars do not come to achieve agreement about the risk of SPS in the malignancy of colorectal cancer , which is essential for further research therefore .



PMID: 27780749
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Efficacy , Tolerability , and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First - Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer : The Phase 2 APEC Study .
1 BACKGROUND :
2 In patients with KRAS wild-type ( wt ) metastatic colorectal cancer ( mCRC ) , outcomes with first - line chemotherapies are improved by adding weekly cetuximab .
3 The APEC study investigated first - line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC ; additional biomarker subgroups were also analyzed .
4 PATIENTS AND METHODS :
5 APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region .
6 Patients ( n = 289 ) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy ( FOLFOX or FOLFIRI ) .
7 The primary end point was best confirmed overall response rate ( BORR ) ; progression-free survival ( PFS ) and overall survival ( OS ) were secondary end points .
8 Early tumor shrinkage ( ETS ) and depth of response ( DpR ) were also evaluated .
9 RESULTS :
10 In the KRAS wt population , BORR was 58.8% , median PFS 11.1 months , and median OS 26.8 months .
11 Μ Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes ( BORR = 647% ; median PFS = 130 months ; median OS = 284 months ) .
12 The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population .
13   Although this study was not designed to formally assess differences in outcome between treatment subgroups , efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI .
14 There were no new safety findings ; in particular , grade 3/4 skin reactions were within clinical expectations .
15 CONCLUSION :
16 The observed activity and safety profile is similar to that reported in prior first - line pivotal studies involving weekly cetuximab , suggesting once-every-2-weeks cetuximab is effective and tolerable as first - line therapy and may represent an alternative to weekly administration .



PMID: 27737491
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases .
1 BACKGROUND :
2 In the past 3 decades , a better understanding of gene mutations and their role in carcinogenesis has led to improvement in our ability to treat patients with metastatic disease .
3 The objective of the current study was to determine whether the location of a driver mutation within an affected gene impacts the biology of metastatic colorectal cancer .
4 METHODS :
5 DNA was collected from 165 randomly selected specimens of patients who underwent margin-negative resection of colorectal liver metastases with curative intent .
6 Sequenom analysis and Sanger sequencing were used to evaluate mutations in K/NRAS , PIK3CA , BRAF , and TP53 .
7 RESULTS :
8 BRAF mutation was associated with early recurrence and death , whereas no impact of TP53 or PIK3CA mutation was identified .
9 ✓ Although K/NRAS mutation was associated with worse survival in this cohort , this difference was no longer evident when those who had received anti-EGFR therapy were excluded . GM-ASS-RO
10 When stratifying patients according to the exon on which K/NRAS was mutated , there were dramatic differences in both survival and pathologic features .
11 Exon 4 mutations were associated with large , solitary metastases occurring at long disease-free intervals compared with exon 3 mutations , which presented with small , numerous lesions .
12 Patients who had exon 4 mutations recurred infrequently and had significantly longer survival compared with those who had wild type or other mutations .
13 CONCLUSIONS :
14 By using this model of curative-intent , margin-negative resection in patients at high risk of recurrence , the authors were able to establish a link between mutation location within the K/NRAS gene and the biology of metastatic colorectal cancer .
15 Cancer 2017 ; 123 : 568-575 .
16 (c) 2016 American Cancer Society .



PMID: 27422777
(None)  
Terms: prospective, rat
Sent# Symbols Sentence Mnemonics
0 Potential biomarkers for anti-EGFR therapy in metastatic colorectal cancer .
1 Anti-epidermal growth factor receptor ( EGFR ) therapy has established efficacy in metastatic colorectal cancer , but a significant number of patients do not respond to such treatment .
2 Recently , various biomarkers were reported to be useful in predicting resistance to anti-EGFR .
3 All the potential biomarkers predicting resistance to anti-EGFR are reviewed herein from five aspects .
4 First , upstream molecules , including epiregulin ( EREG ) and amphiregulin ( AREG ) , might play different roles according to their abnormal levels in tumor tissue and serum .
5 Second , the EGFR amplification and distinct polymorphisms may have roles in identifying patients for initial anti-EGFR mAbs therapy , while rare EGFR mutations have limited predictive values .
6 Third , among the downstream molecularly related factors , rat sarcoma viral oncogene ( Ras ) has been identified as a successful predictor , while B-Raf proto - oncogene (BRAF) is considered as a prognostic factor rather than a predictor .
7   Fourth , among the molecular bypass pathway components , phosphatidylinositol 3-kinase ( PI3K ) and phosphatase and tensin homolog ( PTEN ) may be potential biomarkers in the future , while activation of hepatocyte growth factor ( HGF ) /c-Met signaling confers resistance to anti-EGFR therapy .
8   Fifth , many microRNAs and additional molecular biomarkers are promising in predicting the efficacy of anti-EGFR therapy .
9   Applications of multiple biomarkers are more effective than the use of a single biomarker in selecting patients who might benefit from cetuximab - or panitumumab-based treatments .
10 Comprehensive molecular analyses of the EGFR signaling pathways should be considered in the future .
11 Subsequent prospective trials will be required to further confirm the clinical utility of these biomarkers .



PMID: 27777877
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer .
1 Epidermal growth factor receptor ( EGFR ) has been an attractive target for treatment of epithelial cancers , including colorectal cancer ( CRC ) .
2 Evidence from clinical trials indicates that cetuximab and panitumumab ( anti-EGFR monoclonal antibodies ) have clinical activity in patients with metastatic CRC .
3 The discovery of intrinsic EGFR blockade resistance in Kirsten RAS ( KRAS )- mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency .
4 Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade .
5 Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS , BRAF , PIK3CA and PTEN could be intrinsically resistant to EGFR blockade .
6 Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients .
7 While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC , further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade .



PMID: 27384430
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor Biology Rather Than Surgical Technique Dictates Prognosis in Colorectal Cancer Liver Metastases .
1 INTRODUCTION :
2 The interplay of tumor biology and surgical margin status after resection for colorectal liver metastasis ( CRLM ) remains controversial .
3 Consequently , we sought to determine the impact of surgical margin status on overall survival ( OS ) stratified by KRAS mutational status .
4 MATERIALS AND METHODS :
5 Four hundred eighty-five patients with known KRAS mutational status were identified .
6 Clinicopathologic and long-term survival data were collected and assessed .
7 RESULTS :
8 On pathology , most patients ( n = 380 ; 783 % ) had an R0 margin , while 105 ( 217 % ) had an R1 .
9 Roughly two thirds of tumors were KRAS wild type ( wtKRAS ) ( n = 307 , 633 % ) , while 36.7 % ( n = 178 ) had KRAS mutations (mutKRAS) .
10 Median and 5-year OS of the entire cohort was 65.8 months and 53.8 % , respectively .
11 An R1 resection was associated with worse 5-year OS compared with R0 ( 42.4 % vs. 57.1 % ; hazard ratio ( HR ) 1.82 , 95 % CI 1.28-2.57 ; P = 0.001 ) .
12 After controlling for KRAS status , the survival benefit associated with an R0 resection persisted only among patients with wtKRAS tumors ( HR 216 , 95 % CI 142-330 ; P <0001 ) .
13 In contrast , surgical margin had no impact on OS among patients with mutKRAS tumors ( 5-year OS R0 , 407 % vs . R1 , 467 % ; HR 134 , 95 % CI 073-248 ; P = 0348 ) .
14 CONCLUSION :
15 The impact of margin status differed by KRAS mutation status .
16 An R0 margin only provided a survival benefit to patients with wtKRAS tumors .
17 Tumor biology and not surgical technique determined prognosis .



PMID: 27283768
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutations of KRAS , NRAS , BRAF , EGFR , and PIK3CA genes in urachal carcinoma : Occurence and prognostic significance .
1 PURPOSE :
2 Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma ( UrC ) .
3 The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer .
4 MATERIALS AND METHODS :
5 Mutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing .
6 Mutational patterns were compared to those published for colorectal and urothelial cancers .
7 Furthermore , we sought correlations between mutations and clinicopathological and follow-up data .
8 RESULTS :
9 Μ We found 11 mutations in 10 of 22 ( 45% ) patients .
10 Μ The most frequently mutated gene was KRAS ( 27% ) followed by BRAF ( 18% ) and NRAS ( 5% ) , while no mutations were detected in the EGFR and PIK3CA genes .
11 Μ No correlation was found between the mutation status and clinicopathological parameters ( Sheldon/Mayo stage , tumor grade , metastases ) .
12 ✓ Furthermore , none of the mutations correlated with progression-free or overall survival . GM-ASS-RO
13 CONCLUSIONS :
14 The mutation pattern of UrC is more similar to colorectal than to urothelial cancer .
15 However , the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma .
16 The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC .



PMID: 27167191
(Cell)  
Terms: in vivo, in vitro, xenograft, phase II, clinical trial
Sent# Symbols Sentence Mnemonics
0 Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models .
1 PURPOSE :
2 Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers ( CRC ) , early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity .
3 Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation .
4 Since ERK increases cyclin D expression and increases entry into the cell cycle , we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo .
5 RESULTS :
6 The combination of MEK and CDK4/6 inhibitors synergistically inhibited cancer cell growth in vitro and caused tumor regression in vivo in cell line and patient-derived xenograft models .
7 Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo .
8 EXPERIMENTAL DESIGN :
9 We performed in vitro proliferation , colony formation , apoptosis , and senescence assays , and Western blots , on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162 , the CDK4/6 inhibitor palbociclib , or the combination .
10 We also treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib , the CDK4/6 inhibitor palbociclib , or the combination , and performed immunohistochemical and reverse phase protein array analysis .
11 CONCLUSIONS :
12 Combined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC .
13 Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models .



PMID: 27771609
(Patient)  
Terms: PDX, xenograft, In vivo, in vivo, mice
Sent# Symbols Sentence Mnemonics
0 Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated , Clinically Aggressive Colorectal Cancer .
1 Background : The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins , and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings .
2 However , systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing .
3 Methods : We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer ( CRC ) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry .
4 Associations between pevonedistat sensitivity and CRC molecular features were assessed by Student's t test .
5 A 184 - gene transcriptional predictor was generated in cell lines and applied to 87 metastatic CRC samples for which patient-derived xenografts ( PDXs ) were available .
6 In vivo reponse to pevonedistat was assessed in PDX models ( >/ = 5 mice per group ) .
7 All statistical tests were two-sided .
8 Results : Sixteen ( 131% ) cell lines displayed a marked response to pevonedistat , featuring DNA re-replication , proliferative block , and increased apoptosis .
9 ✓ Pevonedistat sensitivity did not statistically significantly correlate with microsatellite instability or mutations in KRAS or BRAF and was functionally associated with low EGFR pathway activity .
10 While ineffective on predicted resistant PDXs , in vivo administration of pevonedistat statistically significantly impaired growth of five out of six predicted sensitive models ( P <01 ) .
11   In samples from CRC patients , transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery ( hazard ratio [HR] = 2.49 , 95% confidence interval [CI] = 1.34 to 4.62 , P = .003 ) and early progression under cetuximab treatment ( HR = 359 , 95% CI = 160 to 804 , P <001 ) .
12 Histological and immunohistochemical analyses revealed that the pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma .
13   Conclusions : These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated , clinically aggressive CRC .



PMID: 27721019
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-kappaB .
1 Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL ) is well known for its ability to preferentially induce apoptosis in malignant cells without causing damage to most normal cells .
2 However , inherent and acquired resistance of tumor to TRAIL -induced apoptosis limits its therapeutic applicability .
3 ✓ Here we show that the orally available tyrosine kinase inhibitor , BAY61-3606 , enhances the sensitivity of human colon cancer cells , especially those harboring active mutations in Rat Kirsten Sarcoma Viral Oncogene Homolog ( KRAS ) gene , to TRAIL -induced apoptosis in vitro and in vivo .
4 The sensitization was achieved by up-regulating death receptor 4 ( DR4 ) and the tumor suppressor p53 .
5 BAY61-3606 -induced the up-regulation of DR4 is p53 -dependent .
6 Knockout of p53 decreased BAY61-3606 -induced DR4 expression and inhibited the effect of BAY61-3606 on TRAIL -induced apoptosis .
7 In addition , BAY61-3606 suppressed activity of NF-kappaB and regulated its gene products , which might also contribute to TRAIL -induced apoptosis .
8   In conclusion , our results showed that BAY61-3606 sensitizes colon cancer cells to TRAIL -induced apoptosis via up-regulating DR4 expression in p53 -dependent manner and inhibiting NF-kappaB activity , suggesting that the combination of TRAIL and BAY61-3606 may be a promising therapeutic approach in the treatment of colon cancer .



PMID: 27770401
(Patient)  
Terms: In Vivo, clinical trial, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAFV600E In Vivo .
1 PURPOSE :
2 This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells , such as increased glutamine uptake .
3 Given this , quantitative measures of glutamine uptake may reflect critical processes in oncology .
4 Approximately , 10 % of patients with colorectal cancer ( CRC ) express BRAF V600E , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes .
5 Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting .
6 The primary objective of this study was to explore 4-[18F]fluoroglutamine ( 4-[18F]F-GLN ) positron emission tomography ( PET ) to predict response to BRAFV600E-targeted therapy in preclinical models of colon cancer .
7 PROCEDURES :
8 Tumor microarrays from patients with primary human colon cancers ( n = 115 ) and CRC liver metastases ( n = 111 ) were used to evaluate the prevalence of ASCT2 , the primary glutamine transporter in oncology , by immunohistochemistry .
9 Subsequently , 4-[18F]F-GLN PET was evaluated in mouse models of human BRAF V600E -expressing and BRAF wild-type CRC .
10 RESULTS :
11 Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity , suggesting that [18F] 4-F-GLN PET could be applicable to a majority of patients with colon cancer .
12 ASCT2 expression was not associated selectively with the expression of mutant BRAF .
13 Decreased 4-[18F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF V600E -mutant Colo-205 tumors .
14   In contrast , a similar decrease was not observed in BRAF wild-type HCT-116 tumors , a setting where BRAFV600E-targeted therapies are ineffective .
15 CONCLUSIONS :
16 4-[18F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[18F]fluoro-D-glucose PET , which was decreased non-specifically for all treated cohorts , regardless of downstream pathway inhibition .
17   These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation .



PMID: 27770002
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Triple Therapy Improves Colorectal Cancer Response .
1   Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual , as opposed to single-level , MAPK blockade .
2 Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival , however ; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors .



PMID: 27769041
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 MiR-384 inhibits human colorectal cancer metastasis by targeting KRAS and CDC42 .
1 Colorectal cancer ( CRC ) is the third most common cancer worldwide .
2 Metastatic progression is a primary factor contributing to lethality of CRC patients .
3 However , the molecular mechanisms forming early local invasion and distant metastatic colonies are still unclear and the present therapeutic approaches for CRC are unsatisfactory .
4 Therefore , novel therapies targeting metastatic invasion that could prevent tumor spreading and recurrence are urgently needed .
5 Our study showed that the decrease of miR-384 was found in 83.0% ( 83/100 ) CRC patients .
6 And low-leveled expression of miR-384 was closely correlated with the invasive depth , lymph node and distant metastasis of CRC .
7 Overexpression of miR-384 could inhibit the invasive and migrating abilities of CRC cells in vitro and the metastatic potential in vivo .
8 Μ Luciferase assays showed that miR-384 repressed the expression of Kirsten Ras ( KRAS ) and Cell division cycle 42 ( CDC42 ) by directly targeting their 3'-untranslated regions .
9 There is functional and mechanistic relationship between miRNA-384 and KRAS , CDC42 in the invasion and metastasis of CRC .
10 And our findings suggest that miR-384could be a potent therapeutic target for CRC .
11 Restoration of miR-384 expression might provide novel therapeutic approach to the reduction of CRC metastasis .



PMID: 27768923
(Patient)  
Terms: retrospective, NCT00852228
Sent# Symbols Sentence Mnemonics
0 Early tumour response as a survival predictor in previously - treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer .
1 BACKGROUND :
2 Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer ( LM-CRC ) .
3 We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab ( 500 mg/m2 ) and triplet hepatic artery infusion ( HAI ) within European trial OPTILIV .
4 METHODS :
5 Irinotecan ( 180 mg/m2 ) , 5-fluorouracil ( 2800 mg/m2 ) and oxaliplatin ( 85 mg/m2 ) were given as chronomodulated or conventional delivery .
6 Patients were retrospectively categorised as early responders ( complete or partial RECIST response after three courses ) or non-early responders ( late or no response ) .
7 Prognostic factors were determined using multivariate logistic or Cox regression models .
8 RESULTS :
9 Response was assessed in 57 of 64 registered patients ( 89% ) , who had previously received one to three prior systemic chemotherapy protocols .
10 An early response occurred at 6 weeks in 16 patients ( 28% ; 9 men , 7 women ) , aged 33-76 years , with a median of 12 liver metastases ( LMs ) ( 2-50 ) , involving five segments ( 1-8 ) .
11 Ten patients had a late response , and 31 patients had no response .
12 Grade 3-4 fatigue selectively occurred in the non-early responders ( 0% versus 26% ; p = 0024 ) .
13 Early tumour response was jointly predicted by chronomodulation-odds ratio ( OR ) : 6.0 ( 12-298 ; p = 0029 ) -and LM diameter
14 Early tumour response predicted for both R0-R1 liver resection-OR : 11.8 ( 14-1002 ; p = 0024 ) and overall survival-hazard ratio : 0.39 ( 017-088 ; p = 0023 ) in multivariate analyses .
15 CONCLUSIONS :
16 Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy .
17 Confirmation is warranted for early response on HAI to guide decision making .
18 Protocol numbers : EUDRACT 2007-004632-24 NCT00852228 .



PMID: 27765849
(Cell)  
Terms: in vitro, xenograft
Sent# Symbols Sentence Mnemonics
0 Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer .
1 Oncogenic BRAFV600E mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer .
2 In BRAFV600E-mutant colorectal cancers , treatment failure may be related to BRAFV600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism .
3 We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose -dependent manner using colorectal cancer cell lines isogenic for BRAF BRAFV600E -induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate ( MCL-1Thr163 ) and stabilize MCL-1 .
4 Upregulation of MCL-1 was mediated by MEK/ERK shown by the ability of ERK siRNA to suppress MCL-1 .
5 Stabilization of MCL-1 by phosphorylation was shown by a phosphorylation-mimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover , respectively .
6 MEK/ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced proapoptotic BIM to a greater extent than did vemurafenib in BRAFV600E cell lines .
7 MCL-1 knockdown versus control shRNA significantly enhanced cobimetinib-induced apoptosis in vitro and in HT29 colon cancer xenografts .
8 The small-molecule MCL-1 inhibitor , A-1210477 , also enhanced cobimetinib-induced apoptosis in vitro that was due to disruption of the interaction of MCL-1 with proapoptotic BAK and BIM .
9 Knockdown of BIM attenuated BAX , but not BAK , activation by cobimetinib plus A-1210477 .
10 In summary , BRAFV600E -mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism combined with cobimetinib , suggesting a novel therapeutic strategy against BRAFV600E-mutant CRCs .
11 Mol Cancer Ther ; 15 ( 12 ) ; 3015-27 .
12 (c) 2016 AACR .



PMID: 27764839
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Impact of tumour RAS/BRAF status in a first - line study of panitumumab + FOLFIRI in patients with metastatic colorectal cancer .
1 BACKGROUND :
2 To investigate tumour biomarker status and efficacy of first - line panitumumab+FOLFIRI for metastatic colorectal carcinoma ( mCRC ) .
3 METHODS :
4 154 patients received first - line panitumumab + FOLFIRI every 14 days .
5 Primary end point was objective response rate ( ORR ) .
6 Data were analysed by tumour RAS ( KRAS/NRAS ) and BRAF status , and baseline amphiregulin (AREG) expression .
7 RESULTS :
8 Objective responses occurred more frequently in RAS wild type ( WT ) ( 59% ) versus RAS mutant ( MT ) ( 41% ) mCRC and in RAS WT/BRAF WT ( 68% ) versus RAS or BRAF MT ( 37% ) disease .
9 Median response duration was longer in RAS WT ( 130 months ) versus RAS MT ( 58 months ) ( hazard ratio ( HR ) : 0.16 ) .
10 Median progression-free survival was longer in RAS WT versus MT ( 112 versus 73 months ; HR , 037 ) and was also longer in RAS WT/BRAF WT versus RAS or BRAF MT ( 132 versus 69 months ; HR , 025 ) .
11 Incidence of adverse events was similar regardless of RAS/BRAF status , and no new safety signals were noted .
12 Among patients with RAS WT tumours , ORR was 67% with high AREG expression and 38% with low AREG expression .
13 CONCLUSIONS :
14   First - line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT versus MT mCRC tumours and was well tolerated .



PMID: 27764698
(Cell)  
Terms: in vitro, in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase .
1 A number of clinical trials have shown that KRAS mutations of colorectal cancer ( CRC ) can predict a lack of responses to anti-epidermal growth factor receptor -based therapy .
2 Recently , there have been several studies to elucidate metabolism reprogramming in cancer .
3 However , it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth .
4 Μ In this study , we found that KRAS mutation in CRC caused alteration in amino acid metabolism .
5 KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC .
6 Μ Using several human CRC cell lines and clinical specimens of primary CRC , we demonstrated that the expression of asparagine synthetase ( ASNS ) , an enzyme that synthesizes asparagine from aspartate , was upregulated by mutated KRAS and that ASNS expression was induced by KRAS -activated signaling pathway , in particular PI3K-AKT-mTOR pathway .
7 Importantly , we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro .
8 Μ Notably , a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo .
9 Furthermore , combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo , whereas either L-asparaginase or rapamycin alone was not effective .
10 These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS .



PMID: 27756406
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing .
1 BACKGROUND :
2 Targeted next generation sequencing ( tNGS ) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer ( CRC ) patients as predictive tool for decision on EGFR-targeted therapy .
3 Μ Here , we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC , to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases .
4 METHODS :
5 Case-matched formalin-fixed and paraffin-embedded ( FFPE ) resection specimens ( n = 70 ; primary tumours , synchronous and/or metachronous liver and/or lung metastases ) of 14 CRC cases were subjected to microdissection of normal colonic epithelial , primary and metastatic tumour cells , their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer PanelTM , MiSeq sequencing and data analyses ( Illumina ) .
6 RESULTS :
7 By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 ( 8/9 KRAS exon 2 ; 1/9 NRAS Exon 3 ) of cases .
8 RAS mutation status was maintained in case-matched metastases throughout the disease course , albeit with altered allele frequencies .
9 Μ Case-matched analyses further identified a maximum of three sequence variants ( mainly in APC , KRAS , NRAS , TP53 ) shared by all tumour specimens throughout the disease course per individual case .
10 Μ In addition , further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases ( e.g. in APC , ATM , FBXW7 , FGFR3 , GNAQ , KIT , PIK3CA , PTEN , SMAD4 , SMO , STK11 , TP53 , VHL ) .
11 Moreover , several de novo mutations were more frequent in synchronous ( e.g . ATM , KIT , PIK3CA , SMAD4 ) or metachronous ( e.g . FBXW7 , SMO , STK11 ) lung metastases .
12 Μ Finally , some de novo mutations occurred only in metachronous lung metastases ( CDKN2A , FGFR2 , GNAS , JAK3 , SRC ) .
13 CONCLUSION :
14 Together , this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients .
15 Μ Moreover , it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases , several of which might be actionable by targeted therapies .



PMID: 27756306
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Adaptation of a RAS pathway activation signature from FF to FFPE tissues in colorectal cancer .
1 XPO1 -dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer .



PMID: 27753661
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pulmonary Adenocarcinoma With Enteric Differentiation : Immunohistochemistry and Molecular Morphology .
1 Pulmonary adenocarcinoma with enteric differentiation ( PAED ) is a rare subtype of lung adenocarcinoma recently recognized in the WHO classification .
2 It is defined as an adenocarcinoma in which the enteric component exceeds 50% and have to show the expression of atleast 1 immunohistochemical marker of enteric differentiation .
3 Although the definition of this tumor type is very important , above all in the differential diagnosis between a primary lung tumor and a metastasis of colorectal adenocarcinoma , this cancer still lacks a distinctive immunohistochemical and molecular signature .
4 We recruited the largest series in the literature of PAEDs according to the morphology and the positivity for intestinal markers .
5 Then , we evaluated the immunohistochemical and molecular profile of these adenocarcinomas .
6 In our series , CDX-2 and CK7 were the immunohistochemical markers mostly expressed by PAEDs .
7 There was an inverse relationship between the expression of pnuemocytes markers , such as TTF-1 , and intestinal markers .
8 Μ Molecular analysis revealed KRAS as the most frequently mutated gene ( >60% of cases ) , with very few cases harboring abnormalities affecting EGFR , BRAF , and ALK genes .
9 PAEDs are morphologically very heterogenous .
10 The immunohistochemical profile based on CDX-2 and CK7 positivity of PAEDs appears very robust to support this diagnosis , and it is applicable also on small biopsies .
11 KRAS appears as the most important mutated gene in such tumors .



PMID: 27753016
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Screening of KRAS Mutation in Pre - and Post-Surgery Serum of Patients Suffering from Colon Cancer by COLD-PCR HRM .
1 Genomic characterization of cell -free circulating tumour DNA ( ctDNA ) may offer an opportunity to assess clonal dynamics throughout the course of a patient's illness .
2 The existence of KRAS driver mutations in colon cancer patients is determinant to decide their treatment and to predict their outcome .
3 DNA is extracted automatically from 400 muL of serum using the MagNa Pure Compact with the Nucleic Acid Isolation Kit I .
4 DNA amplification , COLD-PCR and HRM were performed in the same run in the Light Cycler 480 .
5 We found three different situations : pre - and post-surgical samples grouped with the negative control , pre-surgical samples appear to group with the positive control and the post-surgical samples appear to group with the negative control and finally both samples , pre - and post-surgical ones , appear to be grouped with the positive control .
6 Μ COLD-PCR HRM is a cost-effective way for screening one of the most common driver mutations to predict the worst prognosis in colorectal cancer .



PMID: 27750444
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Cost-effectiveness of cetuximab for colorectal cancer .
1 INTRODUCTION :
2 Cetuximab is a novel biological agent with superior therapeutic efficacy for colorectal cancer treatment .
3 This study aimed to systematically review the existing evidence related to the cost-effectiveness of cetuximab .
4 Areas covered : Using Medline and Cochrane Database of Systematic Reviews , a total of 12 articles were identified .
5 Previous studies have shown mixed results on the cost-effectiveness of first - line cetuximab combined with FOLFIRI ( 5-Fluorouracil , leucovorin , irinotecan ) .
6   However , cetuximab-irinotecan therapy as third - line treatment has consistently been found to be cost-ineffective compared to best supportive care or no third - line therapy .
7 The Kristen-rat-Sarcoma-viral-oncogene ( KRAS ) testing strategy prior to cetuximab use has been reported as cost-effective compared with the cetuximab-containing strategy without KRAS testing .
8 Expert commentary : The results should be interpreted with consideration of the specific healthcare settings in which cetuximab use was evaluated .
9 Future studies are expected to examine the economic value of cetuximab compared with other newly approved biologic products .



PMID: 27750112
(None)  
Terms: in vivo, mouse models, mouse, transgenic and knockout mouse, mice
Sent# Symbols Sentence Mnemonics
0 The role of S100a4 ( Mts1 ) in Apc- and Smad4-driven tumour onset and progression .
1 INTRODUCTION :
2 S100a4 is a calcium-binding protein belonging to the family of S100-proteins , highly expressed in different stromal cell types .
3 S100A4 has been reported as a prognostic marker in colorectal cancer in association with tumour progression and metastasis .
4 METHODS :
5 In this study , we analysed the in vivo role of S100a4 in intestinal tumour initiation and progression using different transgenic and knockout mouse models .
6 RESULTS :
7 We found that genetic ablation or overexpression of S100a4 in both Apc- and Smad4-mutant mice do not affect tumour initiation in the intestinal tract .
8 In contrast , S100a4 epithelial overexpression in Apc1638N/+/KRASV12G mice increases the dissemination of intestinal tumour cells to the liver , in agreement with its role in tumour metastasis .
9 Moreover , we report a novel role for S100a4 in desmoid formation where S100a4 deficiency results in a significant reduction of the tumour burden characteristic of the Apc1638N model .
10 In agreement with these results , S100a4 appears to be co-expressed together with mesenchymal stem cell ( MSC ) markers in desmoid tumours from Apc1638N/+ mice , as well as from sporadic and hereditary human desmoids .
11 CONCLUSION :
12 Our data provide the first report on the in vivo role of S100a4 in intestinal tumourigenesis and describe a new role for S100a4 in the aetiology of desmoids formation .



PMID: 27747085
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarkers for immune therapy in colorectal cancer : mismatch-repair deficiency and others .
1 Colorectal cancer ( CRC ) is a heterogeneous disease for which the treatment backbone has primarily been cytotoxic chemotherapy .
2 With better understanding of the involved molecular mechanisms , it is now known that there are a number of epigenetic and genetic events , which are involved in CRC pathogenesis .
3   Specific biomarkers have been identified which can be used to determine the clinical outcome of patients beyond tumor staging and predict for treatment efficacy .
4   Molecular testing is now routinely performed to select for patients that will benefit the most from targeted agents and immunotherapy .
5   Μ In addition to KRAS , NRAS , and BRAF mutation ( MT ) , analysis of DNA mismatch repair ( MMR ) status , tumor infiltrating lymphocytes , and checkpoint protein expression may be helpful to determine whether patients are eligible for certain therapies .
6   The focus of this article is to discuss present and upcoming biomarkers for immunotherapy in CRC .



PMID: 27747084
(None)  
Terms: This review, rat
Sent# Symbols Sentence Mnemonics
0 Beyond RAS and BRAF : a target rich disease that is ripe for picking .
1 Despite numerous breakthroughs in the understanding of colorectal cancer and identification of many oncogenic mutations , the treatment of metastatic colorectal cancer remains relatively more empiric than targeted .
2 Testing for mutations in rat sarcoma virus ( RAS ) and rapidly growing fibrosarcoma ( RAF ) are routinely performed , though identification of these mutations currently offers little more than a negative predictive marker for response to EGFR inhibitor treatment and , in the case of RAF mutation , a poor prognostic indicator .
3   Μ Next-generation sequencing has identified both common and rare mutations in colorectal cancer that offer options for more advanced , targeted therapy .
4 With so much research invested in these targets , the treatment of metastatic colorectal cancer stands to become much more personalized in the near future .
5 This review describes several of the more promising targets that are currently being investigated in advanced colorectal cancer .



PMID: 27747083
(None)  
Terms: Clinical trial, clinical trial
Sent# Symbols Sentence Mnemonics
0 RAS and BRAF in metastatic colorectal cancer management .
1 The treatment of metastatic colorectal cancer ( mCRC ) has been further refined with the development of monoclonal antibodies , cetuximab and panitumumab , towards the epidermal growth factor receptor ( EGFR ) .
2 Anti-EGFR therapy has afforded improved survival in those with wild-type RAS mCRC but provides no benefit and even harm in those with RAS-mutant tumors .
3 BRAF mutations have also been shown to predict lack of clinically meaningful benefit to anti-EGFR therapy in mCRC .
4 Mechanisms of resistance to EGFR blockade in wild-type RAS or BRAF metastatic colorectal tumors appear to converge on the mitogen -activated protein kinase ( MAPK ) signaling pathway .
5 Clinical trials involving combined BRAF , EGFR , and/or MAPK kinase ( MEK ) inhibition have shown promising activity in BRAF-mutant mCRC .
6   Here , we review pivotal clinical trials that have redefined our treatment approach in mCRC with respect to anti-EGFR therapy based on RAS and BRAF mutation status .
7 Future studies will likely focus on improving efficacy of anti-EGFR-based therapy in mCRC through sustained MAPK pathway inhibition .



PMID: 27681944
(Patient)  
Terms: phase II/III, phase II/III study
Sent# Symbols Sentence Mnemonics
0 Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer : Results from a randomised phase II/III trial .
1 Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer ( CRC ) .
2 We analysed the outcome of 69 chemorefractory , KRAS exon 2 mutant CRC patients who were enrolled in a double-blind , randomised , phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly ( arm A ) , dalotuzumab 7.5 mg/kg every second week ( arm B ) or placebo ( arm C ) .
3 Objective response rate ( 56% vs. 31% vs. 48% ) , median progression-free survival ( 27 vs. 26 vs. 14 months ) and overall survival ( 78 vs. 103 vs. 78 months ) were not statistically significantly different between treatment groups .
4 Most common grade >/ = 3 treatment-related toxicities included neutropenia , diarrhoea , hyperglycaemia , fatigue and dermatitis acneiform .
5 Expression of IGF-1R , IGF-1 , IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status .
6 Median cycle threshold values for all biomarkers were significantly lower ( i.e. , higher expression , p <005 ) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours .
7 No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers ( p = 006 ) .
8 Albeit limited by the small sample size , this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC .
9   Data on IGF-1R , IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway .



PMID: 27743922
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy : an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System ( ARCAD ) database .
1 Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer .



PMID: 27743339
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutant KRAS Status Is Associated with Increased KRAS Copy Number Imbalance : a Potential Mechanism of Molecular Heterogeneity .
1 Mutation rates determined by allele -specific PCR can be highly different in KRAS exon 2 mutant colorectal carcinoma ( CRC ) samples suggesting intratumoural heterogeneity .
2 To address the effect of KRAS gene copy number on the relative mutant allele frequency the KRAS locus was individually quantified following FISH analysis in 36 cases .
3 We observed , that mutant KRAS status was associated with an elevated KRAS locus number ( 236 +/- 042 versus 263 +/- 075 ; p = 0037 ) reflecting an increased aneuploidy status but no true amplification of the locus .
4 In parallel , KRAS locus copy numbers showed significant intercellular variability ( 1-16 copies/cell nucleus ) within individual tumours also indicating to a dynamic intratumoural oscillation of the mutant allele copy number .
5 Μ In conclusion , aneusomy is a common feature of KRAS mutant CRC and KRAS copy number variations may have an impact on the relative mutant allele frequency detected by allele specific PCR/sequencing ) , potentially leading to subclonal diversity and influencing tumour behaviour .



PMID: 27738330
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer .
1 OBJECTIVES :
2 The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response ( SIR ) , in particular C-reactive protein ( CRP ) , in metastatic colorectal cancer ( mCRC ) patients , in the total study population and according to RAS and BRAF mutation status .
3 RESULTS :
4 High levels of pretreatment serum IL-6 or CRP were associated with impaired outcome , in terms of reduced PFS and OS .
5 Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months , respectively ( P <0001 ) .
6 Stratified according to increasing CRP levels , median OS varied from 24.3 months to 12.3 months , ( P <0001 ) .
7 IL-6 and CRP levels affected overall prognosis also in adjusted analyses .
8 The effect of IL-6 was particularly pronounced in patients with BRAF mutation ( interaction P = 0004 ) .
9 MATERIALS AND METHODS :
10 IL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial , in which patients with mCRC received first line treatment .
11 The effect of serum IL-6 and CRP on progression-free survival ( PFS ) and overall survival ( OS ) was estimated .
12 CONCLUSIONS :
13 High baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC .
14 IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status .



PMID: 27737711
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic impact of KRAS , NRAS , BRAF , and PIK3CA mutations in primary colorectal carcinomas : a population-based study .
1 BACKGROUND :
2 Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments .
3 The aim of this study was to evaluate the prognostic value of KRAS , BRAF , NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population .
4 METHODS :
5 A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma ( CRC ) and presenting with metastatic disease were included into the study .
6 Μ Genomic DNA was isolated from formalin-fixed , paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes , using pyrosequencing assays , and in PIK3CA gene , using automated DNA sequencing assays .
7 RESULTS :
8 Overall , mutation rates were 35.6 % for KRAS , 4.1 % for NRAS , and 2.1 % for BRAF .
9 Μ Among available DNA samples , 114/796 ( 143 % ) primary CRCs were found to carry a mutation in the PIK3CA gene .
10 Μ In this subset of patients analysed in all four genes , a pathogenetic mutation of atleast one gene was discovered in about half ( 378/796 ; 475 % ) of CRC cases .
11 Μ A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease ( from detection of primary CRC to diagnosis of first distant metastasis ; p = 0009 ) or partial survival ( from diagnosis of advanced disease to the time of death or last control ; p = 0006 ) or overall survival ( p <0001 ) .
12 Μ No significant impact on prognosis was observed for mutated KRAS , NRAS , and PIK3CA genes or combined RAS mutations (all RAS) .
13 CONCLUSIONS :
14 Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients .



PMID: 27736842
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer .
1 Colorectal cancer ( CRC ) is one of the most common malignancies worldwide and it still represents a major cause of cancer-related death .
2 Postsurgical Tumor Node Metastasis ( pTNM ) stage is the main prognostic factor in CRC and it currently drives therapeutic protocols after surgery .
3 However , CRC outcome is not always predictable on the basis of pTNM stage .
4 Hence , there is the need to find additional prognostic factors that may allow to predict the clinical course of CRC regardless of pTNM stage , so that patients may receive the most appropriate treatment for their tumor .
5 In recent years , the prognostic value of a novel grading system based on the counting of poorly differentiated clusters ( PDCs ) of neoplastic cells in tumor tissue was documented in CRC .
6 In this article , we review the clinical relevance of grading based on PDC counting in CRC .
7 In view of its high prognostic value and reproducibility , PDC grading could be introduced in routine histopathological report of CRC and used for therapeutic decision making .
8 Although there is initial evidence that PDC may be correlated with biomolecular profile of CRC , whether their presence is associated with response to targeted therapies is still unknown and deserves further investigation .



PMID: 27729614
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients . GM-ASS-RO
1 Tumor profiling of DNA alterations , i.e.gene point mutations , somatic copy number aberrations ( CNAs ) and structural variants ( SVs ) , improves insight into the molecular pathology of cancer and clinical outcome .
2 Here , associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated .
3 A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization ( array-CGH ) to detect CNAs and CNA-associated chromosomal breakpoints ( SVs ) .
4 For 60 of these samples mutation status of APC , TP53 , KRAS , PIK3CA , FBXW7 , SMAD4 , BRAF and NRAS was determined using targeted massive parallel sequencing .
5 Loss of chromosome 18q12.1-18q12.2 occurred more frequently in tumors that relapsed than in relapse-free tumors ( p <0001 ; FDR = 013 ) .
6 In total , 267 genes were recurrently affected by SVs ( FDR <01 ) .
7 CNAs and SVs were not associated with disease-free survival ( DFS ) .
8 Mutations in APC and TP53 were associated with increased CNAs .
9 ✓ APC mutations were associated with poor prognosis in ( 5-fluorouracil treated ) stage III colon cancers ( p = 0005 ; HR = 41 ) , an effect that was further enhanced by mutations in MAPK pathway ( KRAS , NRAS , BRAF ) genes . GM-ASS-RO
10 Μ We conclude that among multiple genomic alterations in CRC , strongest associations with clinical outcome were observed for common mutations in APC .



PMID: 27729313
(Patient)  
Terms: Phase I, in vivo, In vivo
Sent# Symbols Sentence Mnemonics
0 Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation .
1 In vitro , EGFR inhibition , combined with the BRAF inhibitor vemurafenib , causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer , further augmented by irinotecan .
2 The safety and efficacy of vemurafenib , irinotecan , and cetuximab in BRAF-mutated malignancies are not defined .
3 In this 3+3 phase I study , patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib .
4 Nineteen patients ( 18 with metastatic colorectal cancer and 1 with appendiceal cancer ) were enrolled .
5 Three patients experienced dose-limiting toxicities .
6 The MTD of vemurafenib was 960 mg twice daily .
7 Six of 17 evaluable patients ( 35% ) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria , consistent with in vivo models demonstrating tumor regressions with the triplet regimen .
8 Median progression-free survival was 7.7 months .
9 Μ BRAFV600E circulating cell -free DNA ( cfDNA ) trends correlated with radiographic changes , and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression .
10 SIGNIFICANCE :
11 Vemurafenib , in combination with irinotecan and cetuximab , was well tolerated in patients with refractory , BRAF-mutated metastatic colorectal cancer , and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer .
12 In vivo models demonstrated regressions with the triplet , in contrast with vemurafenib and cetuximab alone .
13 Μ cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression .
14 Cancer Discov ; 6 ( 12 ) ; 1352-65 .
15 (c) 2016 AACR .
16 This article is highlighted in the In This Issue feature , p. 1293 .



PMID: 27725862
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel E1B55kDa-deleted oncolytic adenovirus carrying microRNA-143 exerts specific antitumor efficacy on colorectal cancer cells .
1 Μ The KRAS is an important and frequently mutated gene during colorectal carcinogenesis .
2 The expression of miR-143 is often down-regulated and it might play an important role by targeting KRAS in colorectal cancer ( CRC ) .
3 The purpose of this study was to investigate the antitumor effects of miR-143 with an intermediate oncolytic adenovirus ( Ad ) in CRC .
4 We constructed the recombinant virus Ad-ZD55-miR-143 and verified its expression by qPCR and western blot assays .
5 Oncolytic potency of Ad-ZD55-miR-143 was determined by cytopathic effect assays using human SW480 CRC cells and L-02 normal liver cells .
6 MTT and cell apoptosis assays were applied to explore the biological functions of Ad-ZD55-miR-143 within SW480 cells .
7 Dual-luciferase reporter assays were performed to validate whether KRAS was regulated by miR-143 .
8 The expression level of KRAS was measured by qPCR and western blot assays .
9 Μ Results showed that infection of SW480 cells with Ad-ZD55-miR-143 induced high level expression of miR-143 .
10 Furthermore , Ad-ZD55-miR-143 significantly suppressed the viability of SW480 cells in a dose -dependent pattern , but did not influence L-02 cells .
11 Ad-ZD55-miR-143 also inhibited cell growth and induced cell apoptosis in SW480 cells .
12 Dual-luciferase assays indicated that KRAS was a direct target of miR-143 , as subsequently demonstrated by qPCR and western blot analysis showing that infection of SW480 cells with Ad-ZD55-miR-143 resulted in the down-regulation of KRAS at both mRNA and protein levels .
13   Taken together , the recombinant virus Ad-ZD55-miR-143 exhibited specific antitumor effects by targeting KRAS , and might be a promising agent for the treatment of CRC .



PMID: 27722750
(Patient)  
Terms: Retrospective, retrospective, NCT00433927, NCT00154102
Sent# Symbols Sentence Mnemonics
0 Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer : Retrospective Analyses of the CRYSTAL and FIRE-3 Trials .
1 Importance : Metastatic colorectal cancer ( mCRC ) is heterogeneous , and primary tumors arising from different regions of the colon are clinically and molecularly distinct .
2 Objective : To examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type ( wt ) mCRC treated with first - line fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) plus cetuximab in the Cetuximab Combined With Irinotecan in First - line Therapy for Metastatic Colorectal Cancer ( CRYSTAL ) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First - Line Treatment For Patients With Metastatic Colorectal Cancer ( FIRE-3 ) trial .
3 Design , Setting , and Participants : In this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC , defined , respectively , as patients whose tumors originated in the splenic flexure , descending colon , sigmoid colon , or rectum versus appendix , cecum , ascending colon , hepatic flexure , or transverse colon .
4 Main Outcomes and Measures : Progression-free survival ( PFS ) , overall survival ( OS ) , and objective response rate ( ORR ) were assessed according to tumor location and treatment arm .
5 Results : In the RAS wt populations of the CRYSTAL and FIRE-3 trials , patients with left-sided tumors ( n = 142 and n = 157 , respectively ) had markedly superior PFS , OS , and ORR compared with patients with right-sided tumors ( n = 33 and n = 38 , respectively ) .
6   Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors , FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators ( FOLFIRI and FOLFIRI plus bevacizumab ) ; in contrast , in RAS wt patients with poor-prognosis right-sided tumors , limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL , and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3 .
7   A significant interaction was observed between primary tumor location and treatment for OS ( CRYSTAL : hazard ratio [HR] , 1.95 ; 95% CI , 1.09-3.48 and FIRE-3 : HR , 0.40 ; 95% CI , 0.23-0.70 ) within the RAS wt populations of both studies in multivariable models that also included sex , prior adjuvant therapy , and BRAF mutational status .
8 Conclusions and Relevance : In the RAS wt populations of CRYSTAL and FIRE-3 , patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors .
9   First - line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors ( vs FOLFIRI or FOLFIRI plus bevacizumab , respectively ) , whereas patients with right-sided tumors derived limited benefit from standard treatments .
10 Trial Registration : clinicaltrials .
11 gov Identifiers : CRYSTAL , NCT00154102 , and FIRE-3 , NCT00433927 .



PMID: 27718155
(Patient)  
Terms: retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 Effectiveness and safety of aflibercept for metastatic colorectal cancer : retrospective review within an early access program in Spain .
1 PURPOSE :
2 In the VELOUR study , aflibercept + FOLFIRI regimen resulted in improved survival in metastatic colorectal cancer ( mCRC ) patients who progressed after oxaliplatin .
3 The use of aflibercept outside the clinical trial framework needs to be further assessed in terms of effectiveness and tolerability .
4 METHODS :
5 Early access to aflibercept through a named patient programme ( NPP ) was provided to mCRC patients receiving FOLFIRI as second - line treatment in Spain .
6 The effectiveness of aflibercept was assessed as progression-free survival ( PFS ) achieved within the NPP population .
7 Μ Post hoc analyses on PFS were done according to certain baseline characteristics ( K-RAS mutation , prior targeted therapy ) or prognostic factors .
8 RESULTS :
9 Registries from 71 mCRC patients included in the NPP were reviewed retrospectively .
10 The median age for the NPP population was 64 years ( 197 % aged >/ = 70 years ) and 63.4 % patients had >/ = 2 metastases .
11 A median PFS of 5.3 months ( 95 % CI , 36-85 months ) was achieved , which did not depend on K-RAS mutation status or prior targeted therapy received .
12 The risk of progression or death increased in patients with a poor prognosis as per the GERCOR score ( performance status [PS] 1-2 and increased baseline lactate dehydrogenase [LDH] level ) compared with patients with a good prognosis ( PS 0 and normal LDH level ) ( median PFS : 2.6 vs. 8.3 months , respectively ; p = 0.0124 ) .
13 Aflibercept was well tolerated , with a manageable toxicity profile .
14 CONCLUSIONS :
15 Bearing in mind the differences in sample size , the PFS achieved with the aflibercept + FOLFIRI regimen in the real-life practice setting is comparable to that observed in the clinical trial setting .



PMID: 27716478
(Patient)  
Terms: NCT01001377
Sent# Symbols Sentence Mnemonics
0 Economic analysis of ALK testing and crizotinib therapy for advanced non-small - cell lung cancer .
1 PURPOSE :
2 The primary analysis of the ASPECCT study demonstrated that panitumumab was non-inferior to cetuximab for overall survival ( OS ) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer ( mCRC ) .
3 Here , we report the final analysis results of ASPECCT .
4 PATIENTS AND METHODS :
5 Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan - or oxaliplatin-based chemotherapy were randomised to receive panitumumab 6 mg/kg once every 2 weeks or cetuximab ( 400 mg/m2 ) followed by 250 mg/m2 weekly .
6 The primary end-point was OS assessed for non-inferiority .
7 Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted .
8 No formal hypothesis testing was done .
9 Post hoc analyses of outcomes by prior bevacizumab exposure , worst-grade skin toxicity ( 0-1 versus 2-4 ) and worst-grade hypomagnesaemia ( 0 versus 1-4 ) were conducted .
10 RESULTS :
11   Nine hundred ninety-nine patients were randomised and received >/ = 1 treatment dose ( panitumumab , n = 499 ; cetuximab , n = 500 ) .
12 Median OS was 10.2 months with panitumumab versus 9.9 months with cetuximab ( hazard ratio = 094 ; 95% confidence interval = 082-107 ) .
13 Median progression-free survival was 4.2 months with panitumumab and 4.4 months with cetuximab ( hazard ratio = 098 ; 95% confidence interval = 087-112 ) .
14 Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms .
15 Furthermore , OS was longer for patients with prior bevacizumab exposure treated with panitumumab than with cetuximab .
16 The observed safety profiles were consistent with previous studies .
17 CONCLUSION :
18   Consistent with the primary analysis , the final analysis of ASPECCT showed panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory , wild-type KRAS exon 2 mCRC .
19 TRIAL REGISTRATION : ClinicalTrials .
20 gov , NCT01001377 .



PMID: 27712015
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild-type KRAS colorectal cancer-WJOG 6210G .
1 This randomized phase II trial compared panitumumab plus fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) with bevacizumab plus FOLFIRI as second - line chemotherapy for wild-type ( WT ) KRAS exon 2 metastatic colorectal cancer ( mCRC ) and to explore the values of oncogenes in circulating tumor DNA ( ctDNA ) and serum proteins as predictive biomarkers .
2 Patients with WT KRAS exon 2 mCRC refractory to first - line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI .
3 Of 121 randomly assigned patients , 117 were eligible .
4 Median overall survival ( OS ) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio ( HR ) , 1.16 ; 95% CI , 0.76-1.77] , respectively .
5 Progression-free survival ( PFS ) was also similar ( HR , 114 ; 95% CI , 078-166 ) .
6 Μ KRAS , NRAS , and BRAF status using ctDNA was successfully examined in 109 patients , and mutations were identified in 19 patients ( 174% ) .
7 Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations ( P for interaction = 0026 in OS and 0054 in PFS ) .
8 OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A ( VEGF-A ) levels and worse in those with low levels ( P for interaction = 0016 ) .
9   Second - line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC .
10 RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab .



PMID: 27694612
(None)  
Terms: , mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Establishing the colitis-associated cancer progression mouse models .
1 [ Advances in the Research of Autophagy in EGFR-TKI Treatment and Resistance in Lung Cancer ] .



PMID: 27693244
(Patient)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens .
1 Colorectal cancer ( CRC ) is one of the most frequently diagnosed cancers , which is causally linked to dietary habits , notably the intake of processed and red meat .
2 Processed and red meat contain dietary carcinogens , including heterocyclic aromatic amines ( HCAs ) and N-nitroso compounds ( NOC ) .
3 NOC are agents that induce various N-methylated DNA adducts and O6-methylguanine ( O6-MeG ) , which are removed by base excision repair ( BER ) and O6-methylguanine-DNA methyltransferase ( MGMT ) , respectively .
4 HCAs such as the highly mutagenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) cause bulky DNA adducts , which are removed from DNA by nucleotide excision repair ( NER ) .
5 Both O6-MeG and HCA -induced DNA adducts are linked to the occurrence of KRAS and APC mutations in colorectal tumors of rodents and humans , thereby driving CRC initiation and progression .
6 In this review , we focus on DNA repair pathways removing DNA lesions induced by NOC and HCA and assess their role in protecting against mutagenicity and carcinogenicity in the large intestine .
7 We further discuss the impact of DNA repair on the dose-response relationship in colorectal carcinogenesis in view of recent studies , demonstrating the existence of 'no effect' point of departures ( PoDs ) , i.e.thresholds for genotoxicity and carcinogenicity .
8 The available data support the threshold concept for NOC with DNA repair being causally involved .



PMID: 27685445
(None)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 ✓ FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer . GE-REG-RO
1 BACKGROUND :
2 Cetuximab , a monoclonal antibody against EGFR used for the treatment of colorectal cancer ( CRC ) , is ineffective in many patients .
3 The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response .
4 METHODS :
5 We used in vitro , in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action .
6 RESULTS :
7 We show that cetuximab activates the MAPK p38 .
8 Specifically , p38 inhibition reduced cetuximab efficacy on cell growth and cell death .
9 At the molecular level , cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation , leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation .
10   Μ Finally , we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS .
11 CONCLUSIONS :
12 We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context .
13 ✓ Moreover , high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS . GE-REG-RO



PMID: 27685259
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Multi-Center Evaluation of the Fully Automated PCR-Based Idylla KRAS Mutation Assay for Rapid KRAS Mutation Status Determination on Formalin-Fixed Paraffin-Embedded Tissue of Human Colorectal Cancer .
1 Since the advent of monoclonal antibodies against epidermal growth factor receptor ( EGFR ) in colorectal cancer therapy , the determination of RAS mutational status is needed for therapeutic decision-making .
2 Μ Most prevalent in colorectal cancer are KRAS exon 2 mutations ( 40% prevalence ) ; lower prevalence is observed for KRAS exon 3 and 4 mutations ( 6% ) and NRAS exon 2 , 3 , and 4 mutations ( 5% ) .
3 The Idylla KRAS Mutation Test on the molecular diagnostics Idylla platform is a simple ( <2 minutes hands-on time ) , highly reliable , and rapid ( approximately 2 hours turnaround time ) in vitro diagnostic sample-to-result solution .
4 This test enables qualitative detection of 21 mutations in codons 12 , 13 , 59 , 61 , 117 , and 146 of the KRAS oncogene being clinically relevant according to the latest clinical guidelines .
5 Here , the performance of the Idylla KRAS Mutation Assay , for Research Use Only , was assessed on archived formalin-fixed paraffin-embedded ( FFPE ) tissue sections by comparing its results with the results previously obtained by routine reference approaches for KRAS genotyping .
6 In case of discordance , samples were assessed further by additional methods .
7 Μ Among the 374 colorectal cancer FFPE samples tested , the overall concordance between the Idylla KRAS Mutation Assay and the confirmed reference routine test results was found to be 98.9% .
8 Μ The Idylla KRAS Mutation Assay enabled detection of 5 additional KRAS-mutated samples not detected previously with reference methods .
9   As conclusion the Idylla KRAS Mutation Test can be applied as routine tool in any clinical setting , without needing molecular infrastructure or expertise , to guide the personalized treatment of colorectal cancer patients .



PMID: 27682134
(Patient)  
Terms: prospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 ✓ Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer .
1 INTRODUCTION :
2 A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor ( EGFR ) antibody therapy in advanced colorectal cancer ( CRC ) .
3 Expanded RAS testing has further refined the treatment approach , but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed .
4 MATERIALS AND METHODS :
5 We prospectively analyzed 4,422 clinical samples from patients with advanced CRC , using hybrid -capture based comprehensive genomic profiling ( CGP ) at the request of the individual treating physicians .
6 Comparison with prior molecular testing results , when available , was performed to assess concordance .
7 RESULTS :
8 Μ We identified a RAS/RAF pathway mutation or amplification in 62% of cases , including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases .
9 Among cases with KRAS non - codon 12/13 alterations for which prior test results were available , 79 of 90 ( 88% ) were not identified by focused testing .
10   Μ Of 1,644 RAS/RAF wild-type cases analyzed by CGP , 31% harbored a genomic alteration ( GA ) associated with resistance to anti-EGFR therapy in advanced CRC including mutations in PIK3CA , PTEN , EGFR , and ERBB2 .
11 Μ We also identified other targetable GA , including novel kinase fusions , receptor tyrosine kinase amplification , activating point mutations , as well as microsatellite instability .
12 CONCLUSION :
13   Μ Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC , while simultaneously identifying alterations potentially important in guiding treatment .
14   The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials , increasing the chance of clinical benefit and avoiding therapeutic futility .
15 IMPLICATIONS FOR PRACTICE :
16   Μ Comprehensive genomic profiling ( CGP ) detects diverse genomic alterations associated with lack of benefit to anti-epidermal growth factor receptor therapy in advanced colorectal cancer ( CRC ) , as well as targetable alterations in many other genes .
17 Μ This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing , as well as other RAS/RAF pathway alterations , mutations shown to disrupt antibody binding , RTK activating point mutations , amplifications , and rearrangements , and activating alterations in downstream effectors including PI3K and MEK1 .
18   The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC .



PMID: 27681846
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 How close are we to standardised extended RAS gene mutation testing? The UK NEQAS evaluation .
1 AIMS :
2 Since 2008 , KRAS mutation status in exon 2 has been used to predict response to anti-EGFR therapies .
3 Recent evidence has demonstrated that NRAS status is also predictive of response .
4 Several retrospective 'extended RAS' analyses have been performed on clinical trial material .
5 Despite this , are we really moving towards such extended screening practice in reality? METHODS : Data were analysed from four consecutive UK National External Quality Assessment Service for Molecular Genetics Colorectal cancer External Quality Assessment schemes ( during the period 2014-2016 ) , with up to 110 laboratories ( worldwide ) participating in each scheme .
6 Testing of four or five tumour samples is required per scheme .
7 Laboratories provided information on which codons were routinely screened , and provided genotyping and interpretation results for each sample .
8 RESULTS :
9 At least 85% of laboratories routinely tested KRAS codons 12 , 13 and 61 .
10 Over the four schemes , an increasing number of laboratories routinely tested KRAS codons 59 , 117 and 146 .
11 Furthermore , more laboratories were introducing next generation sequencing technologies .
12 The pattern of 'extended testing' was reassuringly similar for NRAS , although fewer laboratories currently test for mutations in this gene .
13 Alarmingly , still only 36.1% and 24.1% of participating laboratories met the ACP Molecular Pathology and Diagnostics Group and American Society of Clinical Oncology guidelines , respectively , for extended RAS testing in the latest assessment .
14 CONCLUSIONS :
15 Despite recommendations in the UK and USA on extended RAS testing , there has clearly been , based on these results , a delay in implementation .
16   Inadequate testing results in patients being subjected to harmful treatment regimens , which would not be the case , were routine practice altered , in line with evidence-based guidelines .



PMID: 27672422
(None)  
Terms: retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 Role of targeted therapy in metastatic colorectal cancer .
1 Colorectal cancer ( CRC ) is a significant cause of cancer-related morbidity and mortality all over the world .
2 Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC ( mCRC ) , with a median overall survival of approximately 2 years and more in the past two decades .
3 The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor ( VEGF ) and epidermal growth factor receptor ( EGFR ) .
4 In particular , bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first - line , second - line , or salvage setting .
5 Aflibercept , ramucirumab , and regorafenib are also used in second - line or salvage therapy .
6 Μ Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy .
7   Based on the evidence from large randomized clinical trials , personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics .
8   The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC .



PMID: 27672042
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic value of BRAF V600E mutation and microsatellite instability in Japanese patients with sporadic colorectal cancer .
1 The BRAF proto - oncogene serine/threonine-protein kinase , known as BRAF , belongs to the RAF kinase family .
2 It regulates the MAPK/ERK signalling pathway affecting several cellular processes such as growth , survival , differentiation , and cellular transformation .
3 BRAF is mutated in ~8% of all human cancers with the V600E mutation constituting ~90% of mutations .
4 Here , we have used quantitative mass spectrometry to map and compare phosphorylation site patterns between BRAF and BRAF V600E .
5 We identified sites that are shared as well as several quantitative differences in phosphorylation abundance .
6 The highest difference is phosphorylation of S614 in the activation loop which is ~5fold enhanced in BRAF V600E .
7 Mutation of S614 increases the kinase activity of both BRAF and BRAF V600E and the transforming ability of BRAF V600E .
8 The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation .
9 These data suggest that phosphorylation at this site is inhibitory , and part of the physiological shut-down mechanism of BRAF signalling .



PMID: 27670892
(Patient)  
Terms: Retrospective, retrospective
Sent# Symbols Sentence Mnemonics
0 Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer : A Retrospective Comparison .
1 BACKGROUND :
2 Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer .
3 However , it is unclear which drug should be administered first .
4 MATERIALS AND METHODS :
5 We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015 .
6 The inclusion criteria were disease refractory or intolerant to fluoropyrimidines , oxaliplatin , irinotecan , anti-vascular endothelial growth factor antibodies , and anti-epidermal growth factor receptor ( EGFR ) antibodies ( if KRAS exon 2 wild-type ) , and no previous treatment with regorafenib or TAS-102 .
7 RESULTS :
8 A total of 146 and 54 patients received regorafenib and TAS-102 , respectively .
9 The baseline characteristics were similar between the 2 groups , except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels .
10 The median progression-free survival and overall survival were 2.1 months and 6.7 months , respectively , with regorafenib and 2.1 months and 6.5 months , respectively , with TAS-102 ( progression-free survival hazard ratio 120 , P = 27 ; overall survival hazard ratio , 101 , P = 97 ) .
11 The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population .
12 The frequency of hand-foot syndrome and increased aspartate aminotransferase , alanine aminotransferase , and bilirubin levels was higher and the frequency of neutropenia , leukopenia , anemia , nausea , and febrile neutropenia was lower with regorafenib than with TAS-102 .
13 No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa .
14 CONCLUSION :
15 Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities , which could guide the agent choice .



PMID: 27670890
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Radiosensitivity of Colon and Rectal Lung Oligometastasis Treated With Stereotactic Ablative Radiotherapy .
1 INTRODUCTION :
2 Patients with metastatic colorectal cancer ( CRC ) may present with oligometastatic lung lesions for which stereotactic ablative radiotherapy ( SABR ) can be utilized .
3 This study aims to report efficacy and prognostic factors associated with colorectal lung metastases treated with SABR .
4 MATERIAL AND METHODS :
5 This is a retrospective study including patients who presented with lung oligometastasis from CRC treated with SABR from September 2007 to November 2014 .
6 RESULTS :
7 We identified 53 oligometastatic patients with 87 lung lesions .
8 The median prescription dose was 60 Gy in 3 fractions ( median biological effective dose of 180 Gy ) .
9 The median follow up was 33 months .
10 The 1 - and 2-year local control , metastasis-free survival , and overall survival were 79.8% and 78.2% , 29.2% and 16.2% , and 83.8% and 69.3% , respectively .
11 On multivariate analysis , rectal primary site ( P = 001 ) and >2 metastases ( P = 02 ) were significantly associated with a lower local control rate .
12 Rectal lesions were associated with higher radiation dose ( 1693 Gy vs. 1533 Gy ; P = 01 ) and higher rate of KRAS mutations ( 733% vs. 404% ; P = 02 ) .
13 ✓ KRAS mutation did not predict for local control , but predicted for a 1-year metastasis-free survival detriment ( 0% vs. 375% ; P = 04 ) , when compared with KRAS wild-type . GM-REG-RO
14 On multivariate analysis , there is an overall survival detriment associated with gross tumor volume >/= 3266 mm3 ( P = 03 ) and >2 metastases ( P = 04 ) .
15 CONCLUSION :
16 In CRC , oligometastatic lung lesions treated with SABR had a worse outcome in patients presenting with a rectal primary , >2 metastases , or treated with a larger gross tumor volume .
17   More aggressive treatment may be considered in this subset of patients to improve outcome .



PMID: 27670374
(Cell)  
Terms: in vivo, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 Inhibition of RAF1 kinase activity restores apicobasal polarity and impairs tumour growth in human colorectal cancer .
1 BACKGROUND AND AIM :
2 Colorectal cancer ( CRC ) remains one of the leading causes of cancer-related death .
3 Novel therapeutics are urgently needed , especially for tumours with activating mutations in KRAS ( approximately 40% ) .
4 Here we investigated the role of RAF1 in CRC , as a potential , novel target .
5 METHODS :
6 Colonosphere cultures were established from human tumour specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma .
7 The role of RAF1 was tested by generating knockdowns ( KDs ) using three independent shRNA constructs or by using RAF1-kinase inhibitor GW5074 .
8 Clone -initiating and tumour-initiating capacities were assessed by single - cell cloning and injecting CRC cells into immune-deficient mice .
9 Expression of tight junction ( TJ ) proteins , localisation of polarity proteins and activation of MEK-ERK pathway was analysed by western blot , immunohistochemistry and immunofluorescence .
10 RESULTS :
11 KD or pharmacological inhibition of RAF1 significantly decreased clone -forming and tumour-forming capacity of all CRC cultures tested , including KRAS-mutants .
12 This was not due to cytotoxicity but , atleast in part , to differentiation of tumour cells into goblet-like cells .
13 Inhibition of RAF1-kinase activity restored apicobasal polarity and the formation of TJs in vitro and in vivo , without reducing MEK-ERK phosphorylation .
14 MEK-inhibition failed to restore polarity and TJs .
15 Moreover , RAF1-impaired tumours were characterised by normalised tissue architecture .
16 CONCLUSIONS :
17 RAF1 plays a critical role in maintaining the transformed phenotype of CRC cells , including those with mutated KRAS .
18 The effects of RAF1 are kinase -dependent , but MEK-independent .
19 Despite the lack of activating mutations in RAF1 , its kinase domain is an attractive therapeutic target for CRC .



PMID: 27661107
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis .
1 Serrated pathway colorectal cancers ( CRCs ) are characterised by a BRAF mutation and half display microsatellite instability ( MSI ) .
2 The Wnt pathway is commonly upregulated in conventional CRC through APC mutation .
3 By contrast , serrated cancers do not mutate APC .
4 We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia .
5 RNF43 was mutated in 47/54 ( 87% ) BRAF mutant/MSI and 8/33 ( 24% ) BRAF mutant/microsatellite stable cancers compared to only 3/79 ( 4% ) BRAF wildtype cancers ( p<00001 ) .
6 ZNRF3 was mutated in 16/54 ( 30% ) BRAF mutant/MSI and 5/33 ( 15% ) BRAF mutant/microsatellite stable compared to 0/27 BRAF wild type cancers ( p = 0004 ) .
7 Μ An RNF43 frameshift mutation ( X659fs ) occurred in 80% BRAF mutant/MSI cancers .
8 This high rate was verified in a second series of 25/35 ( 71% ) BRAF mutant/MSI cancers .
9 RNF43 and ZNRF3 had lower transcript expression in BRAF mutant compared to BRAF wildtype cancers and less cytoplasmic protein expression in BRAF mutant/MSI compared to other subtypes .
10 Treatment with a porcupine inhibitor reduced RNF43/ZNRF3 mutant colony growth by 50% and synergised with a MEK inhibitor to dramatically reduce growth .
11 This study suggests inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype .



PMID: 27656095
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogene Mutations in Colorectal Polyps Identified in the Norwegian Colorectal Cancer Prevention ( NORCCAP ) Screening Study .
1 Data are limited on oncogene mutation frequencies in polyps from principally asymptomatic participants of population-based colorectal cancer screening studies .
2 Μ In this study , DNA from 204 polyps , 5 mm or larger , were collected from 176 participants of the NORCCAP screening study and analyzed for mutations in KRAS , BRAF , and PIK3CA including the rarely studied KRAS exons 3 and 4 mutations .
3 Μ KRAS mutations were identified in 23.0% of the lesions and were significantly associated with tubulovillous adenomas and large size .
4 A significantly higher frequency of KRAS mutations in females was associated with mutations in codon 12 .
5 The KRAS exon 3 and 4 mutations constituted 23.4% of the KRAS positive lesions , which is a larger proportion compared to previous observations in colorectal cancer .
6 Μ BRAF mutations were identified in 11.3% and were associated with serrated polyps .
7 None of the individuals were diagnosed with de novo or recurrent colorectal cancer during the follow-up time ( median 112 years ) .
8 Revealing differences in mutation-spectra according to gender and stages in tumorigenesis might be important for optimal use of oncogenes as therapeutic targets and biomarkers .



PMID: 27655129
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling .
1 MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway -dependent cancers due to feedback pathway compensation and dose-limiting toxicities .
2 Combining MEK inhibitors with other targeted agents may enhance efficacy .
3 Here , codependencies of MEK , TAK1 , and KRAS in colon cancer were investigated .
4 Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS -dependent cells .
5 Pharmacologic studies and cell -cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death , as assessed by sub-G1 accumulation , in a distinct subset of cell lines .
6 Furthermore , TAK1 inhibition causes G2-M cell -cycle blockade and polyploidy in many of the cell lines .
7 MEK plus TAK1 inhibition causes reduced G2-M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1 -dependent cell lines as well as a subset of BRAF-mutant cells .
8 Mechanistically , sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation , which promote expression of NF-kappaB -dependent proinflammatory cytokines , driving tumor cell survival and proliferation .
9 MEK/TAK1 inhibition causes reduced mTOR , Wnt , and NF-kappaB signaling in TAK1/MEK -dependent cell lines concomitant with apoptosis .
10 A Wnt/NF-kappaB transcriptional signature was derived that stratifies primary tumors into three major subtypes : Wnt-high/NF-kappaB-low , Wnt-low/NF-kappaB-high and Wnt-high/NF-kappaB-high , designated W , N , and WN , respectively .
11 These subtypes have distinct characteristics , including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype .
12 Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines .
13 Therefore , N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics .
14 IMPLICATIONS :
15 This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways , which are currently difficult to block with selective agents .
16 Mol Cancer Res ; 14 ( 12 ) ; 1204-16 .
17 (c) 2016 AACR .



PMID: 27650277
(Patient)  
Terms: phase I
Sent# Symbols Sentence Mnemonics
0 A phase I dose-escalation study of TAK-733 , an investigational oral MEK inhibitor , in patients with advanced solid tumors .
1 Purpose TAK-733 , an investigational , selective , allosteric MEK1/2 inhibitor , has demonstrated antitumor effects against multiple cancer cell lines and xenograft models .
2 This first-in-human study investigated TAK-733 in patients with solid tumors .
3 Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles .
4 Adverse events ( AEs ) were graded using the Common Terminology Criteria for AEs version 3.0 .
5 Response was assessed using RECIST v1.1 .
6 Blood samples for TAK-733 pharmacokinetics and pharmacodynamics ( inhibition of ERK phosphorylation ) were collected during cycle 1 .
7 Results Fifty-one patients received TAK-733 0.2-22 mg .
8 Primary diagnoses included uveal melanoma ( 24 % ) , colon cancer ( 22 % ) , and cutaneous melanoma ( 10 % ) .
9 Four patients had dose-limiting toxicities of dermatitis acneiform , plus fatigue and pustular rash in one patient , and stomatitis in one patient .
10 The maximum tolerated dose was 16 mg .
11 Common drug -related AEs included dermatitis acneiform ( 51 % ) , diarrhea ( 29 % ) , and increased blood creatine phosphokinase ( 20 % ) ; grade >/= 3 AEs were reported in 27 ( 53 % ) patients .
12 Median Tmax was 3 h ; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg .
13 On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 >/= 8.4 mg .
14 Among 41 response-evaluable patients , 2 ( 5 % ) patients with cutaneous melanoma ( one with BRAF L597R mutant melanoma ) had partial responses .
15 Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose , and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation .
16 Limited antitumor activity was demonstrated .
17 Further investigation is not currently planned .



PMID: 27638675
(Patient)  
Terms: Phase II Study, phase II trial
Sent# Symbols Sentence Mnemonics
0 The COMET Open-label Phase II Study of Neoadjuvant FOLFOX or XELOX Treatment Combined with Molecular Targeting Monoclonal Antibodies in Patients with Resectable Liver Metastasis of Colorectal Cancer .
1 BACKGROUND :
2 Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis ( CLM ) have not been established .
3 The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen ( FOLFOX or XELOX ) plus monoclonal antibodies ( cetuximab or bevacizumab ) treatment in patients with resectable CLM .
4 METHODS :
5 A single-arm , open-label , multicenter , phase II trial was conducted for patients aged >/= 20 years with resectable and untreated CLM .
6 Patients received preoperative FOLFOX ( 6 cycles ) or XELOX ( 4 cycles ) .
7 Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13 , respectively .
8 The primary endpoint was progression-free survival ( PFS ) .
9 RESULTS :
10 Between January 2010 and June 2012 , 47 patients were enrolled from 12 institutions .
11 Wild-type or mutant KRAS sequences were examined in 32 and 15 patients , respectively .
12   Twenty-one ( 45 % ) patients experienced Grades 3/4 adverse events , and 55 % of all patients responded to therapy .
13 The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group .
14 The overall rates of liver resection and postoperative morbidity were 83 and 14 % , respectively , and the median PFS was 15.6 months .
15 The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months , respectively .
16 CONCLUSIONS :
17 Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS , although it was administered safely and had less adverse effects after liver resection .



PMID: 27638535
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Pathogenetic aspects in precursor lesions of gastrointestinal tumors ] .
1 The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways .
2 In the esophagus an aberrant genetic expression of intestinal transcription factors , such as CDX2 is initiated by local environment factors .
3 During the subsequent dysplasia to carcinoma sequence , chromosomal gain and loss of genes occurs .
4 A 4-color fluorescence in situ hybridization ( FISH ) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations .
5 In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation .
6 In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression .
7 This event is accompanied by an increase of intraepithelial lymphocytes , which is an easy to use tool for routine diagnostics using H& ; E sections .
8 Μ Next generation sequencing ( NGS ) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene .
9 An individual risk stratification for penetration of these germline mutations is necessary .
10 In conclusion , genetics , phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine .



PMID: 27638531
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Prognostic biomarkers for metastatic colorectal cancer ] .
1 In colorectal cancer ( CRC ) distant metastases essentially determine the overall survival and prognosis .
2 Biomarkers that correlate with the presence of distant metastases are therefore of great clinical importance for risk stratification and clinical treatment decisions .
3 As part of the habilitation project various prognostic biomarkers were analyzed and correlated with the occurrence of distant metastases and different patterns of distant spread in CRC .
4 Μ It could be demonstrated that CRC with microsatellite instability ( MSI ) , as detected by a loss of hMLH1 protein expression , have a very low risk of distant metastases .
5 In contrast , microsatellite stable ( MSS ) CRC ( with positive hMLH1 expression ) with concurrent activation of the Wnt-beta catenin signaling pathway and strong expression of the cancer stem cell marker CD133 , exhibit a very high risk for liver metastases .
6 From these observations a two-step immunohistochemical algorithm based on three immunohistochemical stains could be derived , allowing CRC to be classified according to the risk of distant metastases .
7 Further studies demonstrated that a deregulation of the Wnt-beta catenin signaling pathway and the expression of cancer stem cell markers , such as CD133 and CD44 correlated with hematogenous metastasis to the liver but not with peritoneal carcinomatosis or hematogenous metastasis to the central nervous system ( CNS ) .
8 Finally , in CRC patients with CNS metastases , increased rates of mutations in the mitogen -activated protein kinases ( MAPK ) pathway ( KRAS and BRAF mutations ) in combination with a low beta catenin expression could be detected .
9 It can be concluded from these results that for CRC with different patterns of distant spread alternative molecular mechanisms must play a role .



PMID: 27636997
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer .
1 KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer ( mCRC ) .
2 However , little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC .
3 Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K , we aimed to elucidate the mechanisms by which mutant NRAS blocks cetuximab from inhibiting mCRC growth .
4 NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition .
5 Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells .
6 We therefore employed four representative MEK1/2 inhibitors ( binimetinib , trametinib , selumetinib , and pimasertib ) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC .
7 Co-treatment with an ineffective dose of cetuximab augmented , up to more than 1,300-fold , the cytotoxic effects of pimasertib against NRASQ61K/+ cells .
8 Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose -dependent synthetic lethal effects , which were executed , atleast in part , by exacerbated apoptotic cell death .
9 Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition .
10 Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors .



PMID: 27630355
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Efficacy and Toxicity of Panitumumab After Progression on Cetuximab and Predictive Value of MiR-31-5p in Metastatic Wild-type KRAS Colorectal Cancer Patients .
1 BACKGROUND :
2 In metastatic colorectal cancer ( mCRC ) , panitumumab is generally considered to be ineffective after the progression on cetuximab therapy .
3 However , few studies have demonstrated that a small subset of mCRC patients may benefit from panitumumab in this setting .
4 PATIENTS AND METHODS :
5 In our study , wild-type KRAS mCRC patients , enrolled into the nationwide Czech registry CORECT between January 2007 and December 2012 , were screened for panitumumab therapy after progression on cetuximab .
6 RESULTS :
7 We identified 26 mCRC in the registry with well documented progression on cetuximab in combination with irinotecan-based chemotherapy ( FOLFIRI or irinotecan alone ) who received panitumumab monotherapy .
8   Partial response ( PR ) was achieved in 3 ( 115% ) patients and stable disease ( SD ) in 7 ( 269% ) patients after 8 weeks of therapy .
9 Thirteen ( 500% ) patients had evidence of progressive disease ( PD ) and in 3 ( 115% ) cases response was not available .
10   Furthermore , we confirmed that higher expression levels of newly described biomarker , miR-31-5p , in tumor are significantly associated with shorter progression-free survival ( PFS ) in patients treated with cetuximab ( p = 0038 ) ; however , we did not observe association between miR-31-5p and response to panitumumab in mCRC patients after progression on cetuximab .
11 CONCLUSION :
12   It remains possible that a subset of mCRC patients may benefit from panitumumab after progression on cetuximab .



PMID: 27630332
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic Role of BRAF Mutations in Colorectal Cancer Liver Metastases .
1 BACKGROUND/AIMS :
2 The impact of tumor biology on prognosis in patients with colorectal liver metastasis ( CRLM ) has been the topic of intense research .
3 Specifically , the presence of BRAF mutations has been recently associated with adverse long-term outcomes .
4 We examined the existing literature on the prognostic implications of BRAF mutations in patients with CRLM .
5 MATERIALS AND METHODS :
6 A structured review of the literature was performed between 5/1/2016 and 6/1/2016 using the PubMed database .
7 Original research articles published between 1/1/2010 and 4/01/2016 were considered eligible .
8 The primary end-points were overall survival ( OS ) /disease-specific survival ( DSS ) and recurrence-free survival ( RFS ) among patients with BRAF mutated CRLM who underwent resection .
9 RESULTS :
10 Eight studies were included .
11 All studies reported on OS/DSS , while 6 reported on RFS .
12 BRAF mutant status was a strong independent predictor of both worse OS/DSS and RFS in 7 and 4 studies , respectively .
13 CONCLUSION :
14 BRAF-mutant lesions are consistently associated with poor prognosis .
15 Consequently , the indications of CRLM resection in this patient group should be reconsidered .



PMID: 27630331
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prediction of KRAS Mutation in Rectal Cancer Using MRI .
1 AIM :
2 The purpose of the study was to investigate imaging predictors of Kirsten-ras ( KRAS ) mutations using magnetic resonance imaging ( MRI ) in patients with rectal cancer .
3 PATIENTS AND METHODS :
4 A total of 275 patients with rectal cancer were enrolled .
5 They underwent pretreatment rectal MRI , and then KRAS mutation evaluation following surgery .
6 Two reviewers assessed diverse MRI findings associated with rectal cancer .
7 RESULTS :
8 Μ KRAS mutations were detected in 107 ( 389% ) .
9 KRAS mutations were associated with N stage , gross tumor pattern , axial length of the tumor , and the ratio of the axial to the longitudinal dimensions of the tumor ( p = 00064 , p<00001 , p = 00003 and p = 00090 ) .
10 The frequency of KRAS mutations was higher in N2 stage ( 5370% ) , and polypoid tumors ( 5909% ) .
11 Tumors with KRAS mutations exhibited a longer axial length , as well as a larger ratio of the axial to the longitudinal dimensions .
12 CONCLUSION :
13 KRAS mutations were associated with N stage , a polypoid pattern , axial tumor length , and the ratio of the axial to the longitudinal dimensions of the tumor .



PMID: 27630318
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients .
1 AIM :
2 This study focuses on the plasma disposition and metabolic activation of capecitabine ( CCB ) when administered alone or when combined with cetuximab ( CTX ) .
3 PATIENTS AND METHODS :
4 Twenty-four chemo-naive patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone ( 1,000 mg/m(2) bid po ) , followed by CCB plus CTX ( loading dose ( LD ) =400 mg/m(2) followed by 250 mg/m(2) weekly i .
5 v .
6 maintenance dose ) ( Arm A ; n = 12 patients ( patients ) ) or CCB plus CTX followed by CCB alone ( Arm B ; n = 12 patients ) .
7 Plasma samples were collected from the cubital vein and CCB , 5'-desoxy-5-fluorocytidine ( 5'-DFCR ) and 5'-desoxy-5 fluorouridine ( 5'-DFUR ) were quantified by a sensitive , selective reversed phase high-performance liquid chromatography ( HPLC ) assay .
8 Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin .
9 RESULTS :
10 No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation ( ANOVA ) .
11 CONCLUSION :
12 From the pharmacokinetic point of view , co-administration of CTX to CCB seems to be safe .



PMID: 27629291
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Study of apoptosis-related interactions in colorectal cancer .
1 Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer .
2 In this study , molecular interactions behind the apoptotic regulation have been explored .
3 For this purpose , enrichment analysis was performed considering microRNAs ( miRNAs ) that putatively target TP53 and altered during colon cancer .
4 This revealed gene associated with both TP53 and miRNAs .
5 Further analysis showed that a significant molecular interaction between the shortlisted candidates ( TP53 , miR-143 , KRAS , BCL2 , and PLK1 ) exists .
6 Mutation study was conducted to confirm the clinical relevance of candidates .
7 Μ It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets .
8 Overall , we showed the importance of interactions between TP53 , miR-143 , KRAS , BCL2 , and PLK1 with respect to colorectal cancer using bioinformatics approach .



PMID: 27626067
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Testing ERBB2 p.L755S kinase domain mutation as a druggable target in a patient with advanced colorectal cancer .
1 Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified .
2 The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinical outcomes will be achieved by inhibiting these discovered genetic driver events with matched targeted drugs .
3 This hypothesis is currently being tested in oncology clinics with variable early results .
4 Herein , we present our experience with a case of advanced colorectal cancer ( CRC ) with an ERBB2 p.L755S kinase domain mutation , a BRAF p.N581S mutation , and an APC p.Q1429fs mutation , together with a brief review of the literature describing the biological and clinical significance of ERRB2 kinase domain mutations in CRC .
5   The patient was treated with trastuzumab combined with infusional 5-fluorouracil and leucovorin based on the presence of ERBB2 p.L755S kinase mutation in the tumor and based on the available evidence at the time when standard treatment options had been exhausted .
6   However , there was no therapeutic response illustrating the challenges we face in managing patients with potentially targetable mutations where results from functional in vitro and in vivo studies lag behind those of genomic sequencing studies .
7 Also lagging behind are clinical utility data from oncology clinics , hampering rapid therapeutic advances .
8   Our case also highlights the logistical barriers associated with getting the most optimal therapeutic agents to the right patient in this era of personalized therapeutics based on cancer genomics .



PMID: 27624806
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Identification and Characterization of Small-Molecule Inhibitors to Selectively Target the DFG-in over the DFG-out Conformation of the B-Raf Kinase V600E Mutant in Colorectal Cancer .
1 V600E is the most common mutation in the B-Raf kinase domain and the B-RafV600E mutant has been recognized as an attractive target of colorectal cancer .
2 Here , the structural dynamics of V600E -induced conformational conversion in the B-Raf activation loop ( A-loop ) was characterized in detail using a computational simulation strategy .
3 Μ The simulations revealed that the V600E mutation would induce A-loop flipping from DFG-out to DFG-in , and the approved B-Raf inhibitor vemurafenib exhibits strong selectivity for the mutant over the wild-type kinase .
4 The selectivity is closely associated with the kinase conformation , which can be influenced directly by the V600E mutation .
5 Μ The molecular structure of vemurafenib was applied to a chemical similarity search against a large library of drug/lead-like compounds , from which three hits with high structural similarity were identified , and their inhibitory activities against both the wild-type and mutant kinases were measured by in vitro kinase assay , from which two compounds were determined to possess higher selectivity for the B-RafV600E mutant than for the wild type ( 52 - and 31-fold , respectively ) .
6 They can potently inhibit the kinase mutant with IC50 = 54 and 76 nM , respectively .
7 Structural analysis suggested that specific noncovalent interactions play a crucial role in the selectivity of B-Raf inhibitors .



PMID: 27621654
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Efficacy and safety of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer in first - line and second - line therapies : a meta-analysis .
1 AIM :
2 This study aimed to compare anti-epidermal growth factor receptor ( anti-EGFR ) therapy and anti-vascular endothelial growth factor therapy as first - line and second - line therapies in patients with KRAS exon 2 codon 12/13 wild-type ( KRAS-WT ) metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 Major databases were systematically searched .
5 The hazard ratio ( HR ) , odds ratio ( OR ) , and 95% confidence intervals ( 95% CIs ) were used to estimate the effect measures .
6 Review Manager software version 5.3 was used for statistical analysis .
7 RESULTS :
8 Seven trials including ten articles were eligible in the meta-analysis .
9   The patients treated with anti-EGFR as first - line therapy showed a longer overall survival ( OS ) for KRAS-WT and all RAS wild-type ( RAS-WT ) mCRC ( HR =0.81 , 95% CI : 0.72-0.92 , P<0.01 , n = 5 ; HR =0.78 , 95% CI : 0.66-0.93 , P<0.01 , n = 3 , respectively ) .
10 The objective response rate ( ORR ) was better with the anti-EGFR therapy for KRAS-WT and all RAS-WT mCRC ( OR =1.32 , 95% CI : 1.11-1.56 , P<0.01 , n = 5 ; OR =1.55 , 95% CI : 1.21-2.00 , P<0.01 , n = 3 , respectively ) .
11 There was no difference in progression-free survival ( PFS ) for KRAS-WT mCRC and all RAS-WT mCRC between the two groups ( HR =1.00 ; 95% CI : 0.92-1.09 , P = 0.99 , n = 4 ; HR =0.92 , 95% CI : 0.71-1.19 , P = 0.52 , n = 3 , respectively ) .
12   In addition , two trials provided data on the second - line therapy ; there was no significant difference in OS and PFS for the second - line therapy , but a significant improvement in ORR was found in the anti-EGFR group ( OR =1.91 , 95% CI : 1.16-3.16 , P = 0.01 , n = 2 ) .
13 No difference in the conversion therapy ( OR =1.34 ; 95% CI : 0.91-1.99 ; P = 0.14 , n = 4 ) was observed between the two therapies .
14 CONCLUSION :
15 Our results indicate that anti-EGFR therapy is superior to anti-vascular endothelial growth factor therapy for OS and ORR as a first - line therapy for KRAS-WT mCRC .
16 In the second - line therapy , there was no significant difference in the survival outcomes on the basis of OS and PFS between the two groups .
17 However , ORR improved significantly in the anti-EGFR group .



PMID: 27610020
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Current understanding concerning intestinal stem cells .
1 In mammals , the intestinal epithelium is a tissue that contains two distinct pools of stem cells : active intestinal stem cells and reserve intestinal stem cells .
2 The former are located in the crypt basement membrane and are responsible for maintaining epithelial homeostasis under intact conditions , whereas the latter exhibit the capacity to facilitate epithelial regeneration after injury .
3 These two pools of cells can convert into each other , maintaining their quantitative balance .
4 In terms of the active intestinal stem cells , their development into functional epithelium is precisely controlled by the following signaling pathways : Wnt/beta-catenin , Ras/Raf/Mek/Erk/MAPK , Notch and BMP/Smad .
5 However , mutations in some of the key regulator genes associated with these signaling pathways , such as APC , Kras and Smad4 , are also highly associated with gut malformations .
6 At this point , clarifying the biological characteristics of intestinal stem cells will increase the feasibility of preventing or treating some intestinal diseases , such as colorectal cancer .
7   Moreover , as preclinical data demonstrate the therapeutic effects of colon stem cells on murine models of experimental colitis , the prospects of stem cell -based regenerative treatments for ulcerous lesions in the gastrointestinal tract will be improved all the same .



PMID: 27609830
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates .
1 OBJECTIVE AND DESIGN :
2 The goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour .
3 The growth of small polyps ( 6-9 mm ) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography .
4 Μ Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing .
5 The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness .
6 RESULTS :
7 The mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour .
8 Polyps carried 0-3 pathogenic mutations with the most frequent being in APC , KRAS/NRAS , BRAF , FBXW7 and TP53 .
9 In polyps with two or more pathogenic mutations , allele frequencies were often variable , indicating the presence of multiple populations within a single tumour .
10 Μ Based on computer modelling , detectable mutations occurred at a mean polyp size of 30+/-35 crypts , well before the tumour is of a clinically detectable size .
11 CONCLUSIONS :
12 These data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour .
13 Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease .



PMID: 27605871
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer .
1 The prognosis of patients with metastatic colorectal cancer ( mCRC ) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo , with the only best supportive care , to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents .
2 The monoclonal antibodies ( moAbs ) cetuximab and panitumumab , directed against the epidermal growth factor receptor ( EGFR ) , undoubtedly represent a major step forward in the treatment of mCRC , given the relevant efficacy in terms of progression-free survival , overall survival , response rate , and quality of life observed in several phase III clinical trials among different lines of treatment .
3 However , the anti-EGFR moAbs were shown only to be effective in a subset of patients .
4 ✓ Μ For instance , KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs , improving the selection of patients who might derive a benefit from these treatments .
5 ✓ Nevertheless , several other alterations might affect the response to these drugs , and unfortunately , even the responders eventually become resistant by developing secondary ( or acquired ) resistance in approximately 13-18 mo . GM-INV-RO
6 ✓ Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways .
7 In this review , we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent , overcame or revert them .



PMID: 27602501
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Specific inhibition of p110alpha subunit of PI3K : putative therapeutic strategy for KRAS mutant colorectal cancers .
1 Colorectal cancer ( CRC ) is a leading cause of cancer mortality worldwide .
2 It is often associated with activating mutations in KRAS leading to deregulation of major signaling pathways as the RAS-RAF-MAPK and PI3K-Akt .
3 However , the therapeutic options for CRC patients harboring somatic KRAS mutations are still very limited .
4 It is therefore urgent to unravel novel therapeutic approaches for those patients .
5 In this study , we have awarded PI3K p110alpha a key role in CRC cells harboring KRAS/PIK3CA mutations or KRAS mutations alone .
6 Specific silencing of PI3K p110alpha by small interfering RNA ( siRNA ) reduced viability and induced apoptosis or cell cycle arrest .
7 In agreement with these cellular effects , PI3K p110alpha silencing led to alterations in the expression levels of proteins implicated in apoptosis and cell cycle , namely XIAP and pBad in KRAS/PIK3CA mutant cells and cyclin D1 in KRAS mutant cells .
8 To further validate our data , a specific PI3K p110alpha inhibitor , BYL719 , was evaluated .
9 BYL719 mimicked the in vitro siRNA effects on cellular viability and on the alterations of apoptotic- and cell cycle-related proteins in CRC mutant cells .
10 Overall , this study demonstrates that specific inhibition of PI3K p110alpha could provide an alternative therapeutic approach for CRC patients , particularly those harboring KRAS mutations .



PMID: 27602102
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 ✓ Low expression of PKCalpha and high expression of KRAS predict poor prognosis in patients with colorectal cancer . GE-REG-RO
1 The current study aimed to determine the association between protein kinase Calpha ( PKCalpha ) and rat Kirsten sarcoma viral oncogene homolog ( KRAS ) expression and the response to folinic acid , 5-fluorouracil and oxaliplatin ( FOLFOX regimen ) in patients with colorectal cancer ( CRC ) .
2 The protein levels of PKCalpha and KRAS were analyzed by immunohistochemistry in tissue samples from patients with CRC and in non-cancerous tissues , including 152 cases of colorectal adenocarcinoma , 30 cases of colorectal adenoma and 20 normal colonic mucosa samples .
3 The association between PKCalpha and KRAS expression and clinicopathological features was analyzed .
4 The rates of positive PKCalpha protein expression in patients with poorly , moderately and well-differentiated adenocarcinoma were 16.7% ( 6/36 ) , 40.0% ( 24/60 ) , and 57.1% ( 32/56 ) , respectively ( P<0013 ) .
5 The rate of positive KRAS expression in CRC patients was significantly higher than in patients with colon adenoma and normal colon mucosa ( P<0001 ) .
6 Expression levels of KRAS were associated with the degree of differentiation of CRC ( P<0001 ) .
7 Expression of PKCalpha was negatively correlated with KRAS expression in CRC tissues .
8 The mean progression-free survival ( PFS ) times in patients with high and low expression of PKCalpha were 43.9 and 38.8 months , respectively ( P<0001 ) .
9 ✓ The mean PFS times were 38.5 and 45.5 months in patients with high and low expression of KRAS , respectively ( P = 0001 ) . GN-ASS-RO
10 ✓ In conclusion , low PKCalpha and high KRAS expression predicted relatively poor prognosis in patients with CRC . GE-REG-RO



PMID: 27600383
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Connecting cancer biology and clinical outcomes to imaging in KRAS mutant and wild-type colorectal cancer liver tumors following selective internal radiation therapy with yttrium-90 .
1 PURPOSE :
2 To determine whether pathologic colorectal tumor KRAS mutation status is correlated with progression-free survival ( PFS ) by imaging after selective internal radiation therapy with Yttrium-90 ( SIRT Y90 ) for metastatic colorectal cancer in the liver ( mCRC ) .
3 MATERIALS AND METHODS :
4 This was an IRB approved , HIPAA compliant retrospective cohort study .
5 Consecutive patients with unresectable mCRC with documented KRAS mutation status treated at a single center from 2002 to 2013 with SIRT Y90 were investigated .
6 Treatment response was compared between KRAS wild-type ( wt ) and mutant ( mut ) using an anatomic tumor response criteria based on RECIST 1.0 .
7 Kaplan-Meier estimation and Cox regression analysis were used to measure progression-free survival ( PFS ) and to assess independent prognostic factors for PFS .
8 RESULTS :
9 82 of 186 patients met review criteria. 33 ( 402% ) patients were identified as KRAS mut .
10 PFS was longer in KRAS wt ( median 166 days [95% CI 96-258 days] ) vs . mut ( median 91 days [95% CI 79-104 days] , p = 0.002 ) .
11 KRAS mut patients were 1.48 times more likely to progress at first follow-up imaging than wt ( 95% CI 106-208 , p = 0024 ) .
12   Μ Univariate analysis identified high pre-SIRT Y90 INR , KRAS wt , any use of anti-EGFR therapy , and post-SIRT Y90 chemotherapy as prognostic factors for longer PFS .
13 ✓ In multivariate analysis , only KRAS wt was an independent prognostic factor for longer PFS ( RR : 1.80 [95% CI 108-299] , p = 0.024 ) . GE-ASS-RO
14 CONCLUSION :
15 Longer PFS is associated with KRAS wt vs . mut following SIRT Y90 .



PMID: 27592068
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 A study-level meta-analysis of efficacy data from head-to-head first - line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer .
1 BACKGROUND :
2 Head-to-head trials comparing first - line epidermal growth factor receptor inhibitor ( EGFRI ) versus vascular endothelial growth factor inhibitor ( bevacizumab ) therapy yielded differing results , and debate remains over optimal first - line therapy for patients with RAS wild-type ( WT ) metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 A PubMed search identified first - line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy ; data were subsequently updated using recent congress presentations .
5 This study-level meta-analysis estimated the overall survival ( OS ) treatment effect of first - line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC .
6 Secondary end-points were progression-free survival ( PFS ) , objective response rate ( ORR ) , resection rate and safety .
7 Early tumour shrinkage ( ETS ) of >/ = 20% at week 8 was an exploratory end-point .
8 RESULTS :
9 Three trials comprising data from 1096 patients with RAS WT mCRC were included .
10 OS ( hazard ratio [HR] : 0.80 [95% confidence interval : 0.68-0.93] ) , ORR ( odds ratio [OR] : 0.57 ) and ETS ( OR : 0.48 ) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy .
11 PFS ( HR :
12 0.98 ) and resections ( OR : 0.93 ) were similar between treatments .
13 For patients with KRAS exon 2 WT/'other' RAS mutant mCRC the OS HR was 0.70 .
14 A safety meta-analysis was not possible due to a lack of data ; in the individual studies , skin toxicities and hypomagnesaemia were more common with EGFRIs , nausea and hypertension were more common with bevacizumab .
15 CONCLUSIONS :
16   This meta-analysis supports a potential benefit for first - line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS , ORR and ETS in patients with RAS WT mCRC .
17 A patient-level meta-analysis is awaited .



PMID: 27591037
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effect of treatment of rectal cancer metastasis with intravitreal bevacizumab ( Avastin ) in patient with subretinal fluid and macular oedema : short-term follow-up .
1 We describe the management of subretinal fluid and macular oedema due to colorectal cancer metastasis to the choroid using intravitreal bevacizumab .
2 A patient with grade VI KRAS mutation rectal cancer with metastasis to the lung and cerebellum presented with left eye choroidal metastasis 1 week after being started on the experimental medication KTN3379 .
3   After intravitreal bevacizumab administration , the patient had improvement in macular subretinal fluid , but eventually progressed to severe cystoid macular oedema despite monthly intravitreal bevacizumab treatment .



PMID: 27590223
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gene heterogeneity in metastasis of colorectal cancer to the lung .
1 Colorectal cancer ( CRC ) as a heterogeneous disease , is one of the most common and serious cancers with high metastases and mortality .
2 Lung is one of the most common sites of CRC metastases with high heterogeneity between cells , pathways , or molecules .
3 The present review will focus on potential roles of gene heterogeneity in KRAS pathway in the development of CRC metastasis to lung and clinical therapies , which would lead to better understanding of the metastatic control and benefit to the treatment of metastases .
4 KRAS is the central relay for pathways originating at the epidermal growth factor receptor ( EGFR ) family .
5 KRAS mutation exists in about 40% CRC , associated with higher cumulative incidence of CRC lung metastasis , and acts as an independent predictor of metastasis to lung .
6 Mutations in KRAS can lead to poor response of patients to panitumumab , and inferior progression-free survival .
7 However , most patients with KRAS wild-type tumors still do not respond , which indicates other mutations .
8 LONGTOKEN mutation was associated with lung metastases in metastatic colorectal cancer .
9 ✓ Μ PIK3CA mutation in exon 20 was found to be correlated with patient survival in the metastatic setting after the treatment with cetuximab and chemotherapy . GM-ASS-RO
10 The heterogeneity of KRAS pathway was found in the phosphatase and tensin homologue deleted on chromosome ten loss , disheveled binding antagonist of beta catenin 2 overexpression and increased dual-specificity protein phosphatase 4 expression of CRC lung metastasis .



PMID: 27589875
(Cell)  
Terms: , Syngeneic Model, syngeneic murine tumor, mice, tumor models
Sent# Symbols Sentence Mnemonics
0 Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation , CD4 , and CD8 T Cells .
1 The programmed cell death protein 1 ( PD-1 ) limits effector T - cell functions in peripheral tissues , and its inhibition leads to clinical benefit in different cancers .
2 To better understand how PD-1 blockade therapy modulates the tumor-host interactions , we evaluated three syngeneic murine tumor models , the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas , and the carcinogen-induced murine colon adenocarcinoma MC38 .
3 The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss ( BRAFV600E/PTEN-/- ) .
4 Anti-PD-1 or anti-PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1 , but not YUMM1.1 .
5 PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation .
6 Whereas mutational load was high in MC38 , it was lower in both YUMM models .
7 In YUMM2.1 , the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells , as well as CD28 and CD80/86 costimulation , with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade .
8 Compared with YUMM1.1 , YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis , with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T - cell priming .
9 In conclusion , response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages .
10 Cancer Immunol Res ; 4 ( 10 ) ; 845-57 .
11 (c) 2016 AACR .



PMID: 27589478
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer .
1 EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases .



PMID: 27586204
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components .
1 Neuroendocrine carcinomas ( NECs ) of the colorectum are rare but highly aggressive neoplasms .
2 These tumors show some shared genetic alterations with colorectal adenocarcinomas , and most of them have adjacent glandular adenoma or adenocarcinoma components .
3 However , genetic data on colorectal NECs still are sparse and insufficient for definite conclusions regarding their molecular origin .
4 Based on morphological characterization , panel and whole-exome sequencing , we here present results from an in-depth analysis of a collection of 15 colorectal NECs with glandular components , 10 of which by definition were mixed adenoneuroendocrine carcinomas ( MANECs ) .
5 Μ Among shared genetic alterations of both tumor components , we most frequently found TP53 , KRAS and APC mutations that also had highest allele frequencies .
6 Mutations exclusive to glandular or neuroendocrine components outnumbered shared mutations but occurred at lower allele frequencies .
7 Our findings not only provide additional evidence for a common clonal origin of colorectal NECs and adjacent glandular tumor components , but strongly suggest their development through the classical adenoma-carcinoma sequence .
8 Moreover , our data imply early separation of glandular and neuroendocrine components during malignant transformation with subsequent independent mutational evolution .



PMID: 27582544
(Cell)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development .
1 A major risk factor of developing colorectal cancer ( CRC ) is the presence of chronic inflammation in the colon .
2 In order to understand how inflammation contributes to CRC development , the present study focused on SHP-2 , a tyrosine phosphatase encoded by PTPN11 gene in which polymorphisms have been shown to be markers of colitis susceptibility .
3 Μ Conversely , gain-of-function mutations in PTPN11 gene (E76 residue) have been found in certain sporadic CRC .
4 Results shown herein demonstrate that SHP-2 expression was markedly increased in sporadic human adenomas but not in advanced colorectal tumors .
5 SHP-2 silencing inhibited proliferative , invasive and tumoral properties of both intestinal epithelial cells ( IECs ) transformed by oncogenic KRAS and of human CRC cells .
6 IEC-specific expression of a SHP-2E76K activated mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background .
7 Conversely , mice with a conditional deletion of SHP-2 in IECs developed colitis-associated adenocarcinomas with age , associated with sustained activation of Wnt/beta-catenin , NFkappaB and STAT3 signalings in the colonic mucosae .
8 Moreover , SHP-2 epithelial deficiency considerably increased tumor load in ApcMin/+ mice , shifting tumor incidence toward the colon .
9 Overall , these results reveal that SHP-2 can exert opposing functions in the large intestine : it can promote or inhibit tumorigenesis depending of the inflammatory context .



PMID: 27578453
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of the molecular profile of brain metastases from colorectal cancer and corresponding primary tumors .
1 AIM :
2 Little is known about molecular biology of brain metastasis ( BM ) from colorectal cancer and its concordance with matched primary tumors .
3 MATERIALS & ; METHODS : We identified 56 consecutive colorectal cancer patients who underwent neurosurgical resection of BM .
4 Tumor samples were tested for KRAS , NRAS , BRAF and PIK3CA .
5 The molecular profile of the brain lesion was compared with the corresponding primary tumor .
6 RESULTS :
7 The molecular profile concordance rate was 95.1% .
8 Median survival after neurosurgery was 5.5 months ( 95% CI : 4.7-6.3 ) ; median overall survival was 24.0 months ( 95% CI : 15.6-32.4 ) .
9 CONCLUSION :
10 In this cohort , we report a high frequency of KRAS mutations and a very high concordance rate between the molecular status of BM and that of matched primary tumors .



PMID: 27578007
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer heterogeneity and targeted therapy : Clinical implications , challenges and solutions for treatment resistance .
1 Precision medicine is becoming considerably critical in colorectal cancer therapy .
2 Particularly for targeted therapies , the response to anti-EGFR therapy largely varies among individual patients .
3 Μ The mechanisms of anti-EGFR-based regimens resistance have been revealed , for instance , mutations in KRAS , BRAF , and PIK3CA .
4 It is well known that colorectal cancer is a heterogeneous disease , massive evidences indicate that there are intertumour and intratumour heterogeneities in colorectal cancer .
5 Recently , the integrative factor of the genetic , epigenetic and microenvironmental alterations that attribute to CRC heterogeneity is associated with the response to targeted therapies .
6   We review here the possible mechanisms of heterogeneity that influence the anti-EGFR therapy , and mainly focus on the enhancive biomarkers detection to predict the therapy efficiency and select appropriate patients who are most likely to benefit from special targeted therapies , and take advantage of simultaneously blocked the multiple molecules involved in activation of independent of ligands induced EGFR signaling pathway to overcome the resistance to anti-EGFR therapies .



PMID: 27575968
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 FOLFIRI plus cetuximab in patients with liver-limited or non-liver-limited RAS wild-type metastatic colorectal cancer : A retrospective subgroup analysis of the CRYSTAL study .
1 BACKGROUND :
2 Adding cetuximab to first - line FOLFIRI in the phase 3 CRYSTAL trial significantly improved progression-free survival ( PFS ) , overall survival ( OS ) , and objective response rate ( ORR ) in patients with KRAS wild-type ( wt ) or RAS wt metastatic colorectal cancer ( mCRC ) .
3 In this retrospective subgroup analysis of CRYSTAL , we investigated benefit of treatment in patients with KRAS wt or RAS wt tumors according to whether patients had liver-limited disease ( LLD ) or non-LLD , including assessing the role of cetuximab in downsizing metastases and conversion rates from initially unresectable to resectable disease .
4 METHODS :
5 PFS , OS , ORR , and R0 resection rates were analyzed according to treatment arm for the LLD and non-LLD subgroups .
6 RESULTS :
7 Of the 367 patients with RAS wt tumors , 89 ( 24% ) had LLD and 278 ( 76% ) had non-LLD .
8 Within the RAS wt LLD and non-LLD subpopulations , demographic and baseline characteristics were comparable between treatment arms .
9 In patients with RAS wt LLD , adding cetuximab to FOLFIRI significantly improved PFS ( hazard ratio [HR] [95% CI] = 0.21[0.09-0.49] ) and ORR ( odds ratio [OR] [95% CI] = 8.99[3.17-25.52] ) , and numerically improved OS ( HR[95% CI] = 0.65[0.38-1.10] ) and R0 resection rate ( OR[95% CI] = 2.68[0.63-11.43] ) relative to FOLFIRI alone .
10 In patients with RAS wt non-LLD , adding cetuximab to FOLFIRI significantly improved PFS ( HR[95% CI] = 0.65[0.46-0.93] ) , OS ( HR[95% CI] = 0.71[0.54-0.93] ) , ORR ( OR[95% CI] = 2.44[1.49-3.98] ) , and-numerically-R0 resection rate ( OR[95% CI] = 5.94[0.79-44.88] ) .
11 Similar results were obtained from the KRAS wt population .
12 CONCLUSIONS :
13   Adding cetuximab to first - line FOLFIRI appears to improve clinical outcomes and R0 resection rates in KRAS wt and RAS wt mCRC patients with LLD as well as in those with non-LLD .



PMID: 27575851
(Cell)  
Terms: xenograft, in vivo, in vitro, mouse, mouse xenograft, mouse xenograft model
Sent# Symbols Sentence Mnemonics
0 gamma-Tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by down-regulating multiple molecules .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is one of the most common malignancies worldwide and even develops resistance to chemotherapeutic agents over time .
3 As a result survival for patients with CRC remains poor .
4 METHOD :
5 We investigated both in vitro and in vivo effects of gamma-tocotrienol ( gamma-T3 ) alone and in combination with capecitabine .
6 Apoptosis and cytotoxicity assays were performed by MTT and FACS analysis , whereas expression of proteins was investigated using western blotting and immunohistochemistry .
7 RESULTS :
8 The gamma-T3 inhibited the proliferation of CRC cells with wild-type or mutated KRAS .
9 It also induced apoptosis , inhibited colony formation , and suppressed key regulators of cell survival , cell proliferation , invasion , angiogenesis , and metastasis .
10 Furthermore , gamma-T3 enhanced the anticancer effects of capecitabine in CRC cells .
11 In a nude mouse xenograft model of human CRC , oral administration of gamma-T3 inhibited tumour growth and enhanced the antitumour efficacy of capecitabine .
12 Western blot and immunohistochemical analysis results indicated that expression of Ki-67 , cyclin D1 , MMP-9 , CXCR4 , NF-kappaB/p65 , and VEGF was lower in tumour tissue from the combination treatment group .
13 Combination treatment also downregulated NF-kappaB and NF-kappaB -regulated gene products .
14 CONCLUSIONS :
15 Our findings suggest that gamma-T3 inhibited the growth of human CRC and sensitised CRC to capecitabine by regulating proteins linked to tumourigenesis .



PMID: 27575024
(Patient)  
Terms: NCT00433927
Sent# Symbols Sentence Mnemonics
0 FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer ( FIRE-3 ) : a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial .
1 BACKGROUND :
2 FIRE-3 compared first - line 5-fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer .
3 The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2-4 ) .
4 We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2-4 ) wild-type subgroup .
5 Moreover , new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival .
6 METHODS :
7   FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first - line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer .
8 The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors ( RECIST ) 1.0 in the intention-to-treat population .
9 A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1 , early tumour shrinkage , depth of response , duration of response , and time to response in the final RAS wild-type subgroup .
10 Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test ( two-sided ) , while differences in depth of response were investigated with a two-sided Wilcoxon test .
11 This trial is registered at ClinicalTrials .
12 gov , number NCT00433927 .
13 FINDINGS :
14 In the final RAS wild-type population ( n = 400 ) , median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group ( 33.1 months [95% CI 245-394] versus 25.0 months [230-281] ; hazard ratio 0.70 [054-090] ; p = 0.0059 ) , although investigator-assessed objective response and progression-free survival were comparable between treatment groups .
15 Centralised radiological review of CT-assessable patients ( n = 330 ) showed that the proportion of patients achieving an objective response ( 113 of 157 , 72.0% [95% CI 643-788] versus 97 of 173 , 56.1% [483-636] ; p = 0.0029 ) , frequency of early tumour shrinkage ( 107 of 157 , 68.2% [603-754] versus 85 of 173 , 49.1% [415-568] ; p = 0.0005 ) , and median depth of response ( -48.9% [-543 to -420] versus -32.3% [-382 to -292] ; p<0.0001 ) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab .
16 No differences in duration of response and time to response were observed between treatment groups .
17 INTERPRETATION :
18 This analysis provides a new framework that connects alternative metrics of response to overall survival .
19 Superior response-related outcome parameters , such as early tumour shrinkage and depth of response , obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup .
20 FUNDING :
21 Merck KGaA and Pfizer .



PMID: 27570430
(Patient)  
Terms: meta-analysis, This review
Sent# Symbols Sentence Mnemonics
0 Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy .
1 AIM :
2 To reviewing genetic and epigenetic make-up of metastatic colorectal cancers ( mCRCs ) addicted to epidermal growth factor receptor ( EGFR ) signalling .
3 METHODS :
4 The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy .
5 A meta-analysis was performed using a systematic search of PubMed , Medline and Web of Science to identify eligible papers until March 21 ( st ) , 2016 using these following terms : ''colorectal cancer'' , "predictive biomarkers'' , "anti-EGFR therapy" , "KRAS" , "NRAS'' , "PIK3CA" , "TP53" , "PTEN" , ''EGFR" , "MET" , "HER2" , "epiregulin" , "amphiregulin" , "prognostic biomarkers" , "BRAF" , "miRNA" and "antibody-dependent cell -mediated cytotoxicity ( ADCC ) activity" .
6 Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion .
7 RESULTS :
8 The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs .
9 Nevertheless , it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30% .
10 Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers .
11 So far the identification of predictive biomarkers have generated interesting , though preliminary and , at times , conflicting data on the importance of tumour mRNA levels of EGFR ligands , of activating mutations in other genes such as NRAS and PIK3CA .
12 The prognostic value of selected microRNAs level and ADCC activity is under investigation , while the prognostic impact of BRAF status remains controversial .
13 CONCLUSION :
14   This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy .



PMID: 27569082
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Diagnostic value of immunohistochemistry for the detection of the BRAF V600E mutation in colorectal carcinoma .
1 PURPOSE :
2 V600E is the most common activating BRAF mutation in colorectal carcinomas ( CRCs ) .
3 It is a crucial biomarker for patient selection and response to targeted therapy with BRAF V600E inhibitors .
4 Previous studies using immunohistochemistry ( IHC ) have shown different results .
5 In this study , we evaluated the IHC expression of the mutated BRAF protein in archival material from CRC specimens and correlated it with DNA sequence analysis .
6 METHODS :
7 51 cases of primary colon adenocarcinoma were stained with BRAF V600E-specific clone VE1 antibody against mutated BRAF protein .
8 DNA sequence analysis was performed and the results were compared .
9 RESULTS :
10 BRAF V600E protein was detected in the cytoplasm of neoplastic cells in 15 of the 51 examined cases ( 294% ) .
11 The correlation between IHC staining and DNA sequence analysis showed 93.75% sensitivity and 100% specificity .
12 CONCLUSIONS :
13 Our data show that IHC could be used in routine clinical practice as a screening method for BRAF V600E mutant protein detection in CRC patients .



PMID: 27566041
(None)  
Terms: This review, meta-analysis, retrospective, retrospective studies
Sent# Symbols Sentence Mnemonics
0 From bench to bedside : Clinical implications of KRAS status in patients with colorectal liver metastasis .
1 INTRODUCTION :
2 While the role of KRAS in the molecular genetics of colorectal cancer has been studied extensively , its prognostic impact in colorectal liver metastases ( CRLM ) has only recently been examined .
3 This review aimed to summarize currently reported findings on the clinical implications of KRAS mutant ( mut-KRAS ) status for patients with CRLM .
4 MATERIALS AND METHODS :
5 The Pubmed database was searched for relevant articles published from 01/01/2010 to 02/01/2016 .
6 Overall survival ( OS ) and recurrence free survival ( RFS ) as well as patterns of recurrence were the primary endpoints , but consideration was given to secondary outcomes when the respective findings were of clinical interest .
7 RESULTS :
8 Out of the 266 studies screened , 15 were included in our review .
9 Fourteen studies were retrospective cohorts while one was a systematic review/meta-analysis .
10 ✓ Among the 14 retrospective studies , 12 reported OS with 9 detecting a negative association with mut-KRAS status . RO-ASS-GE
11 ✓ Similarly , 11 out of 14 retrospective cohorts reported RFS with 6 detecting a negative association with mut-KRAS status . RO-ASS-GE
12 Five studies examined patterns of recurrence , with 4 detecting increased extrahepatic recurrence in the mut-KRAS group .
13 ✓ One study examined the different effects of codon -specific KRAS mutations on prognosis . GM-INV-RO
14 CONCLUSION :
15 mut-KRAS status predisposes to worse RFS and OS in patients with CRLM , possibly as a result of aggressive tumor biology .
16 Early unresectable extrahepatic recurrence is more frequent in this patient group and may underlie the unfavorable prognosis .
17 Future research should focus on characterizing the distinct effects of codon -specific KRAS mutations as well their interplay with other less common genetic mutations .



PMID: 27566022
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular markers of prognosis and therapeutic targets in metastatic colorectal cancer .
1 Metastatic disease ultimately occurs in approximately 50-70% of patients presenting with colorectal cancer .
2 In patients with advanced disease , there is significant variability in individual patient outcomes .
3 To improve understanding of tumor behavior , markers such as KRAS and BRAF mutation status are increasingly utilized .
4 Additionally , newer surrogates of tumor biology , such as telomerase activity and the prevalence of circulating tumor cells and circulating tumor DNA , have generated increasing interest due to clinical potential .
5 While the extent to which these newer markers can predict outcome and guide therapy is yet to be determined , KRAS mutation status is currently used to guide systemic therapy in selected patients .
6 Furthermore , advances in our understanding of various tumorigenic pathways ( such as the mitogen activated protein kinase pathway ) have enabled newer targeted agents , including BRAF inhibitors .
7 Interestingly , although inhibition of BRAF in patients has not translated into improved outcomes , characterization of BRAF mutations led to an association with microsatellite instability .
8 A unique histologic characteristic of certain tumors in patients with microsatellite instability is the infiltration by lymphocytes at the tumor-stromal interface .
9 This feature highlights the biology of the tumor in its microenvironment and underlies the efficacy of the programmed-death inhibitor , pembrolizumab , in patients with microsatellite unstable metastatic colorectal cancer .
10   With an increasing number of prognostic markers and therapeutic options in metastatic colorectal cancer , the multidisciplinary approach becomes critical for appropriate treatment decisions .



PMID: 27563825
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis .
1 While sporadic colorectal cancer ( CRC ) is classified into several molecular subtypes , stratification of familial colorectal tumors is yet to be well investigated .
2 We previously established two groups of methylation markers through genome -wide DNA methylation analysis , which classified sporadic CRC and adenoma into three distinct subgroups : high - , intermediate - , and low-methylation epigenotypes .
3 Μ Here , we investigated familial adenomatous polyposis ( FAP ) , through quantitative methylation analysis of 127 samples ( 16 cancers , 96 adenomas , and 15 benign mucosa from 14 patients with FAP ) using six Group-1 and 14 Group-2 methylation markers , APC , BRAF , and KRAS mutation analysis , and CTNNB1 and TP53 immunohistochemical analysis .
4 All the 14 patients presented with APC germline mutation .
5 Three were from the same family and presented the same APC mutation .
6 FAP tumors lacked BRAF-mutation(+) high-methylation epigenotype and were classified into two methylation epigenotypes .
7 Μ While 24 of 112 tumor samples showed intermediate-methylation epigenotype significantly correlating with KRAS-mutation(+) ( P = 3x10-4 ) , 88 tumor samples showed low-methylation epigenotype correlating with the absence of KRAS - and BRAF-mutations .
8 Μ Similar to sporadic CRC , CTNNB1 was frequently activated at the adenoma stage , and TP53 mutation occurred during cancer development from adenoma .
9 Whereas some patients showed a single epigenotype in all tumors throughout the colon , tumors with two distinct epigenotypes developed within a family with the same APC mutation or even within one patient .
10 Methylation accumulation significantly correlated with proximal location and older age .
11 These results indicate that there are atleast two distinct molecular subtypes of FAP tumors , resembling sporadic CRC and independent from the APC germline mutation status .



PMID: 27562229
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer .
1 BACKGROUND :
2 The progression of colorectal cancer ( CRC ) involves recurrent amplifications/mutations in the epidermal growth factor receptor ( EGFR ) and downstream signal transducers of the Ras pathway , KRAS and BRAF .
3 Whether genetic events predicted to result in increased and constitutive signaling indeed lead to enhanced biological activity is often unclear and , due to technical challenges , unexplored .
4 Here , we investigated proliferative signaling in CRC using a highly sensitive method for protein detection .
5 The aim of the study was to determine whether multiple changes in proliferative signaling in CRC could be combined and exploited as a "complex biomarker" for diagnostic purposes .
6 METHODS :
7 We used robotized capillary isoelectric focusing as well as conventional immunoblotting for the comprehensive analysis of epidermal growth factor receptor signaling pathways converging on extracellular regulated kinase 1/2 ( ERK1/2 ) , AKT , phospholipase Cgamma1 ( PLCgamma1 ) and c-SRC in normal mucosa compared with CRC stage II and IV .
8 Computational analyses were used to test different activity patterns for the analyzed signal transducers .
9 RESULTS :
10 Signaling pathways implicated in cell proliferation were differently dysregulated in CRC and , unexpectedly , several were downregulated in disease .
11 Thus , levels of activated ERK1 ( pERK1 ) , but not pERK2 , decreased in stage II and IV while total ERK1/2 expression remained unaffected .
12 ✓ In addition , c-SRC expression was lower in CRC compared with normal tissues and phosphorylation on the activating residue Y418 was not detected . GE-ASS-DS
13 In contrast , PLCgamma1 and AKT expression levels were elevated in disease .
14 Immunoblotting of the different signal transducers , run in parallel to capillary isoelectric focusing , showed higher variability and lower sensitivity and resolution .
15 Computational analyses showed that , while individual signaling changes lacked predictive power , using the combination of changes in three signaling components to create a "complex biomarker" allowed with very high accuracy , the correct diagnosis of tissues as either normal or cancerous .
16 CONCLUSIONS :
17 We present techniques that allow rapid and sensitive determination of cancer signaling that can be used to differentiate colorectal cancer from normal tissue .



PMID: 27558481
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer in the very young : a comparative study of tumor markers , pathology and survival in early onset and adult onset patients .
1 INTRODUCTION :
2 Colorectal cancer ( CRC ) diagnosed before age 30 years is a fatal disease whose biology remains poorly understood .
3 To understand its pathogenesis , we compared molecular and clinical data in surgically treated early-age onset and adult onset patients .
4 MATERIALS AND METHODS :
5 Clinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC ( age CRC patients ( age >/ = 50 years ) .
6 Tumor morphology , microsatellite instability ( MSI ) and stability ( MSS ) , KRAS and BRAF mutations , and mismatch repair ( MMR ) expression ( MSH2 , MLH1 , MSH6 , PMS2 ) were assessed .
7 RESULTS :
8 Early-age CRC was distinguished from adult CRC by advanced stage presentation ( P<0001 ) , frequent high grade cancers ( P<0001 ) , and poor prognosis ( P<0001 ) .
9 MSI was associated with favorable survival and MMR loss in both groups .
10 Compared to adults , MSI in early-onset CRC was more prevalent ( P<001 ) , not tightly linked to MLH1/PMS2 loss , and never associated with BRAFV600E mutations ( P<001 ) .
11 ✓ MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC ( 9% vs. 3% ) . GM-ASS-RO
12 DISCUSSION : Specific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC .
13 Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC .



PMID: 27555788
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy .
1 PURPOSE :
2 Although several molecular markers predicting resistance to cetuximab - or panitumumab-based therapy of metastatic colorectal cancer were described , mutations in RAS proto-oncogenes remain the only predictors being used in daily clinical practice .
3 However , 35%-45% of wild-type RAS patients still do not respond to this anti-epidermal growth factor receptor ( anti-EGFR ) monoclonal antibody -based therapy , and therefore the definition of other predictors forms an important clinical need .
4 Μ The aim of the present retrospective single-institutional study was to evaluate potential genes responsible for resistance to anti-EGFR therapy in relation to mutational analysis of primary versus metastatic lesions .
5 PATIENTS AND METHODS :
6 Twenty-four paired primary and corresponding metastatic tissue samples from eight nonresponding and four responding metastatic colorectal cancer patients treated with cetuximab-based therapy were sequenced using a next-generation sequencing panel of 26 genes involved in EGFR signaling pathway and colorectal carcinogenesis .
7 RESULTS :
8 Mutational status of primary tumors and metastatic lesions was highly concordant in TP53 , APC , CTNNB1 , KRAS , PIK3CA , PTEN , and FBXW7 genes .
9 Metastatic samples harbor significantly more mutations than primary tumors .
10 Potentially negative predictive value of FBXW7 mutations in relationship to anti-EGFR treatment outcomes was confirmed .
11 Μ Finally , new occurrences of activating KRAS mutations were identified in a group of patients initially determined as wild-type RAS by routinely used qPCR-based RAS mutational tests .
12 ✓ Μ All newly detected activating KRAS mutations most likely led to cetuximab treatment failure . GM-REG-RO
13 CONCLUSION :
14   The results of the present study suggest a need of careful consideration of previously published results of anti-EGFR-targeted therapy with regard to potentially inaccurate diagnostic tools used in the past .
15 Based on our findings , we recommend more extensive use of next-generation sequencing testing in daily clinical practice , as it brings a significant added value in terms of validity of the diagnostic procedure .



PMID: 27549777
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer : the effect on the outcome and the response to chemotherapy plus bevacizumab .
1 PURPOSE :
2 We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer ( CRC ) who underwent bevacizumab-containing chemotherapy .
3 METHODS :
4 In this retrospective study , the pretreatment serum IL-6 and plasma vascular endothelial growth factor ( VEGF ) levels were measured in 113 patients with metastatic CRC .
5 The cut-off values for these measurements , as determined by a receiver operating characteristic curve analysis , were 4.3 and 66 pg/mL , respectively .
6 The median follow-up period was 19 months ( range 1-40 months ) .
7 Sixty-three patients had primary cancer , and 38 had a metachronous recurrence .
8 Thirty patients underwent curative resection , and 71 underwent chemotherapy , 53 of whom received bevacizumab-containing chemotherapy .
9 Overall survival ( OS ) and progression-free survival ( PFS ) were estimated using Kaplan-Meier and multivariate Cox proportional hazards regression analyses .
10 RESULTS :
11 ✓ The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes . GM-ASS-RO
12 However , high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels .
13 Μ A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome .
14 CONCLUSION :
15   In patients with metastatic CRC , high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance .



PMID: 27548393
(None)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 ✓ Early 18F-FDG-PET/CT as a predictive marker for treatment response and survival in patients with metastatic colorectal cancer treated with irinotecan and cetuximab . GM-MRK-RO
1 BACKGROUND :
2 To clarify if early reduction in standard uptake value ( SUV ) could predict metabolic response , radiologic response and overall survival ( OS ) in patients with metastatic colorectal cancer receiving third - line treatment .
3 MATERIAL AND METHODS :
4 Patients were regardless of KRAS status , included in this phase II trial .
5 They were treated with the monoclonal antibody , cetuximab , and the chemotherapeutic drug , irinotecan , every second week .
6 A LONGTOKEN was scheduled before the first and second treatment , respectively , and then after every fourth treatment .
7 Early metabolic response after one treatment and best overall metabolic response was calculated according to EORTC criteria ( responders : >/ = 15% decrease in summation operatorSUVmax ) and PERCIST ( responders : >/ = 30% decrease in SULpeak ) .
8 Best overall radiologic response was calculated according to RECIST 1.0 .
9 RESULTS :
10 By EORTC criteria , early metabolic response predicted partial metabolic response ( PMR ) with a high positive predictive value ( PPV ) of 0.875 and a high negative predictive value ( NPV ) of 0.714 .
11 Partial radiologic response was predicted with a low PPV of 0.368 but a high NPV of 1.0 .
12 By PERCIST , PMR was predicted with a high PPV of 0.826 and an intermediate NPV of 0.667 and partial radiologic response was predicted with a low PPV of 0.5 but a high NPV of 1.0 .
13 Median OS was nearly the same with the two criteria sets ; 14.1 months for early metabolic responders and 9.9 months for non-responders using EORTC criteria and 13.5 and 10.1 months , respectively , using PERCIST .
14 CONCLUSIONS :
15 With both EORTC criteria and PERCIST , early reduction in FDG uptake was predictive of a later partial metabolic and partial radiologic response to treatment .
16 It was also predictive of significantly longer survival of early metabolic responders compared to non-responders .
17 However , the sensitivities and specificities were not high enough to support clinical routine use .



PMID: 27540971
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS , BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2 , DAPK1 , MGMT , HIC1 and p16 genes in colorectal cancer patients .
1 BACKGROUND :
2 Colorectal cancer is a serious disease that causes significant morbidity and mortality in developed countries .
3 Genetic changes , such as mutations in proto - oncogenes and DNA repair genes , and loss of function in the tumor suppressor genes cause colorectal cancer development .
4 Abnormal DNA methylation is also known to play a crucial role in colorectal carcinogenesis .
5 OBJECTIVE :
6 In this study , frequencies of KRAS and BRAF mutations , promoter hypermethylation profiles of SFRP2 , DAPK1 , MGMT , HIC1 and p16 genes , and possible associations between hypermethylation of these genes and KRAS and BRAF mutations were aimed to find out .
7 METHODS :
8 Ninety three colorectal cancer tissues and 14 normal colon mucosas were included in the study .
9 Common twelve KRAS gene mutation were investigated with using reverse-hybridization strip assay method .
10 BRAF V600E mutations were investigated with RFLP method .
11 Hypermethylation status of five tumor suppressor genes were detected by using reverse-hybridization strip assay method after bisulfite modification of DNA .
12 RESULTS :
13 KRAS and BRAF mutation frequencies were determined as 54.84% and 12.9% , respectively .
14 Promoter hypermethylation frequencies of tumor suppressor genes SFRP2 , DAPK1 , MGMT , HIC1 and p16 were determined as 66.7% , 45.2% , 40.9% , 40.9% and 15.1% , respectively .
15 Μ Statistically significant associations were found between BRAF mutation and SFRP2 and p16 tumor suppressor genes hypermethylation ( SFRP2 ; p= 0005 , p16 ; p= 0016 ) .
16 Compared to rectum , SFRP2 ( p= 0017 ) and MGMT ( p= 0013 ) genes have statistically significantly higher promoter hypermethylation in colon .
17 CONCLUSIONS :
18 ✓ Results of the current study have confirmed that KRAS mutations and SFRP2 hypermethylation can be used as genetic markers in colorectal cancer . GM-MRK-DS



PMID: 27539046
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Rectal Neuroendocrine Carcinoma with Metachronous Liver Metastasis Treated with Multimodality Therapy ] .
1 A 6 2-year-old woman visited our hospital with a complaint of anal bleeding and was diagnosed with rectal cancer .
2 She underwent low anterior resection and D3 lymphadenectomy .
3 The pathological diagnosis was shown as follows : Ra , Circ , type 2 , por1 , pSS , ly3 , v1 , pN2 , pStage III b , and KRAS wild type .
4 UFT/UZEL with polysaccharide K ( PSK ) was initiated as adjuvant chemotherapy after the operation .
5 However , multiple liver metastases were found on CT after 3 courses of UFT/UZEL with PSK , and pathological reexamination revealed that the primary tumor was a neuroendocrine carcinoma .
6   She underwent chemotherapy with CBDCA combined with CPT-11 , but bone marrow suppression was observed after 4 courses of the treatment .
7 As second - line chemotherapy , FOLFOX4 plus panitumumab ( Pmab ) was administered .
8 Although the disease remained stable through 10 courses of FOLFOX4 plus Pmab , Grade 3 peripheral neuropathy was observed .
9 Hence , FOLFIRI plus bevacizumab ( Bmab ) was administered as third - line chemotherapy .
10 Twenty-eight courses of FOLFIRI plus Bmab were administered , and transcatheter arterial chemoembolization ( TACE ) was performed during chemotherapy .
11 However , her general condition worsened after the therapies , and she died 2 years 3 months after the initial chemotherapy .



PMID: 27526306
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Carrier molecules and extraction of circulating tumor DNA for next generation sequencing in colorectal cancer .
1 Μ The aims of the study were : i ) to compare circulating tumor DNA ( ctDNA ) yields obtained by different manual extraction procedures , ii ) to evaluate the addition of various carrier molecules into the plasma to improve ctDNA extraction recovery , and iii ) to use next generation sequencing ( NGS ) technology to analyze KRAS , BRAF , and NRAS somatic mutations in ctDNA from patients with metastatic colorectal cancer .
2 Venous blood was obtained from patients who suffered from metastatic colorectal carcinoma .
3 For plasma ctDNA extraction , the following carriers were tested : carrier RNA , polyadenylic acid , glycogen , linear acrylamide , yeast tRNA , salmon sperm DNA , and herring sperm DNA .
4 Each extract was characterized by quantitative real-time PCR and next generation sequencing .
5 The addition of polyadenylic acid had a significant positive effect on the amount of ctDNA eluted .
6 Μ The sequencing data revealed five cases of ctDNA mutated in KRAS and one patient with a BRAF mutation .
7 An agreement of 86% was found between tumor tissues and ctDNA .
8 Testing somatic mutations in ctDNA seems to be a promising tool to monitor dynamically changing genotypes of tumor cells circulating in the body .
9 The optimized process of ctDNA extraction should help to obtain more reliable sequencing data in patients with metastatic colorectal cancer .



PMID: 27526107
(Cell)  
Terms: , mouse models, mouse, mouse model
Sent# Symbols Sentence Mnemonics
0 KRAS mutation leads to decreased expression of regulator of calcineurin 2 , resulting in tumor proliferation in colorectal cancer .
1 KRAS mutations occur in 30-40% of all cases of human colorectal cancer ( CRC ) .
2 However , to date , specific therapeutic agents against KRAS-mutated CRC have not been developed .
3 We previously described the generation of mouse models of colon cancer with and without Kras mutations ( CDX2P-G22Cre ; Apc ( flox/flox ) ; LSL-Kras (G12D) and CDX2P-G22Cre ; Apc ( flox/flox ) mice , respectively ) .
4 Here , the two mouse models were compared to identify candidate genes , which may represent novel therapeutic targets or predictive biomarkers .
5 Μ Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis , and their expression was compared by quantitative reverse transcription-PCR ( qRT-PCR ) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC , with or without KRAS mutations , respectively .
6 Furthermore , the functions of candidate genes were studied using human CRC cell lines .
7 Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes .
8 qRT-PCR analysis data showed that four of these candidate genes ( Clps , Irx5 , Bex1 and Rcan2 ) exhibited decreased expression in the Kras-mutated mouse model .
9 Μ The expression of the regulator of calcineurin 2 ( RCAN2 ) was also observed to be lower in KRAS-mutated human CRC .
10 Moreover , inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines .
11 KRAS mutations in CRC lead to a decrease in RCAN2 expression , resulting in tumor proliferation due to derepression of calcineurin-nuclear factor of activated T cells ( NFAT ) signaling .
12   Our findings suggest that calcineurin-NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC .



PMID: 27525719
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 G9a/RelB regulates self-renewal and function of colon-cancer-initiating cells by silencing Let-7b and activating the K-RAS/beta-catenin pathway .
1 Epigenetic reprogramming has been associated with the functional plasticity of cancer-initiating cells ( CICs ) ; however , the regulatory pathway has yet to be elucidated .
2 A siRNA screen targeting known epigenetic genes revealed that G9a profoundly impairs the chemo-resistance , self-renewal and metastasis of CICs obtained from patients with colorectal cancer ( CRC ) .
3 Patients with elevated G9a were shown to face a high risk of relapse and poor survival rates .
4 From a mechanistic perspective , G9a binds with and stabilizes RelB , thereby recruiting DNA methyltransferase 3 on the Let-7b promoter and repressing its expression .
5 This leads to the activation of the K-RAS/beta-catenin pathway and regulates self-renewal and function of CICs .
6 These findings indicate that the G9a/RelB/Let-7b axis acts as a critical regulator in the maintenance of CIC phenotypes and is strongly associated with negative clinical outcomes .
7   Thus , these findings may have diagnostic as well as therapeutic implications for the treatment of chemotherapy-resistant or metastatic CRC .



PMID: 27522626
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102 .
1 BACKGROUND :
2 TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer .
3 The most common treatment-related adverse event of TAS-102 is bone marrow suppression , which leads to neutropenia .
4 The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer .
5 METHODS :
6 We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS-102 at 2 Japanese institutions between May 2014 and May 2015 .
7 To evaluate the association between efficacy and neutropenia , patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102 : Category A ( grade 0-1 ) , B ( grade 2-4 ) , C ( grade 0-2 ) , and D ( grade 3-4 ) .
8 RESULTS :
9 Patient characteristics were as follows : median age , 64 years ; male , 58% ; Eastern Cooperative Oncology Group performance status 0 to 1 , 91% ; primary site colon , 49% ; KRAS exon 2 wild , 57% ; and number of metastatic site >/= 3 , 55% .
10 The disease control rate was significantly different between Category A and B ( 292% vs. 526% ; P = 045 ) and between Category C and D ( 309% vs. 722% ; P = 002 ) .
11 In multivariate analysis , Category D remained a significant predictive factor for progression-free survival compared with Category C ( 43 vs. 20 months ; hazard ratio , 045 ; P = 01 ) .
12 CONCLUSION :
13 Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy .
14 Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102 .



PMID: 27521480
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Epigenetic Homogeneity Within Colorectal Tumors Predicts Shorter Relapse-Free and Overall Survival Times for Patients With Locoregional Cancer .
1 BACKGROUND & ; AIMS : There are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer .
2 Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients , but also within tumors .
3 We have explored intratumor heterogeneity at the epigenetic level , due to its dynamic nature .
4 We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors .
5 METHODS :
6 We determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases , obtained from 2 hospitals in Spain .
7 Μ We also analyzed samples for KRAS and BRAF mutations , 499,170 single nucleotide polymorphisms , and performed immunohistochemical analyses .
8 RESULTS :
9 We observed differences in DNA methylation among the 3 tumor sections ; regions of tumor-host interface differed the most from the other tumor sections .
10 Interestingly , tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases .
11 When we calculated individual coefficients to quantify heterogeneity , we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival ( log-rank P = 037 ) and short time of overall survival ( log-rank P = 026 ) in patients with locoregional colorectal cancer .
12 CONCLUSIONS :
13 In an analysis of 79 colorectal tumors , we found significant heterogeneity in patterns of DNA methylation within each tumor ; the level of heterogeneity correlates with times of relapse-free and overall survival .



PMID: 27520705
(None)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State .
1 BACKGROUND :
2 High expression levels of Inhibitors of Apoptosis Proteins ( IAPs ) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation .
3 SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs .
4 METHODS :
5 In this study , anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2 , or with the TRAIL are further exploited towards rational combined protocols .
6 RESULTS :
7 It is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability , migration and can very efficiently sensitize colorectal tumour cells to apoptosis .
8 Moreover , co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically , as shown by median effect analysis .
9 Finally , Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression .
10 CONCLUSIONS :
11 Proposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo , from precision tumour biology to precision medical oncology .



PMID: 27517624
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer .
1 The tumor suppressor microRNA-199b ( miR-199b ) is a negative SET regulator associated with poor outcome in some human cancers .
2 However , its expression levels as well as potential biological and clinical significance in colorectal cancer ( CRC ) remain completely unexplored .
3 The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC ( mCRC ) but the molecular mechanisms underlying SET deregulation are currently unknown .
4 We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients .
5 Moreover , miR-199b led to PP2A activation through a direct SET inhibition , impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells .
6 MiR-199b was found downregulated in 25% of cases , and associated with lymph metastasis ( p = 0049 ) , presence of synchronous metastasis at diagnosis ( p = 0026 ) and SET overexpression ( p <0001 ) .
7 Furthermore , low miR-199b levels determined shorter overall ( p <0001 ) , progression-free survival ( p = 0003 ) and predicted clinical benefit to oxaliplatin treatment .
8 The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups .
9 Multivariate analyses confirmed its independent prognostic impact .
10 Altogether , our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patients .



PMID: 27516017
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Histoprognostic markers role in colorectal cancer .
1 Malignant tumors with digestive location are , according to the World Health Organization ( WHO ) , a major cause of morbidity and mortality worldwide .
2 In Romania , the constant increase of prevalence and incidence of colorectal cancer awarded it the status of priority public health problem .
3 The study aimed to identify specific aspects of colorectal cancer histoprognosis that may be associated with a higher frequency of the disease .
4 Data were collected from records and registers within Clinic of Medical Oncology , Emergency County Hospital , Craiova , Romania .
5 Were analyzed and associated demographics and epidemiological data , clinical features , anatomotopographical , histopathological and immunohistochemical .
6 The cases studied were adenocarcinomas with a balanced gender distribution and a worrying incidence for Craiova .
7 The age group with the highest incidence was that of 55-64 years .
8 Topographic , rectum and rectosigmoidian junction are the first two locations .
9 Μ More than half of the cases ( 5555% ) are adenocarcinomas with moderate differentiation and belong to the pT3 category , as extension of colorectal tumor degree. 32.5% of patients were identified with mutations in the K-Ras oncogenes and were found Ki67 positive immunoreacted and heterogeneity of antigen expression in tumor areas studied .
10 Colorectal cancer recorded a worldwide steady increase in the incidence ; growth trend in our country is above the European average .
11 Dolj County faces with an increased incidence and mortality rates by this disease .
12 To limit the disease at the population level and pre-malignant diagnosis is necessary to establish histoprognostic value and predictive of tumor markers .



PMID: 27511199
(None)  
Terms: in vivo, mouse model, mouse, transgenic mouse, mice
Sent# Symbols Sentence Mnemonics
0 RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis .
1 OBJECTIVE :
2 The gross majority of colorectal cancer cases results from aberrant Wnt/beta-catenin signalling through adenomatous polyposis coli ( APC ) or CTNNB1 mutations .
3 However , a subset of human colon tumours harbour , mutually exclusive with APC and CTNNB1 mutations , gene fusions in RSPO2 or RSPO3 , leading to enhanced expression of these R-spondin genes .
4 This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer .
5 Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models .
6 The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct , causal fashion , and addresses the in vivo activities of RSPO3 in parallel .
7 DESIGN :
8 We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity .
9 Cre is provided by cross-breeding with Lgr5-GFP-CreERT2 mice .
10 RESULTS :
11 Upon in vivo Rspo3 expression , mice rapidly developed extensive hyperplastic , adenomatous and adenocarcinomatous lesions throughout the intestine .
12 RSPO3 induced the expansion of Lgr5+ stem cells , Paneth cells , non-Paneth cell label-retaining cells and Lgr4+ cells , thus promoting both intestinal stem cell and niche compartments .
13 Wnt/beta-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth .
14 CONCLUSIONS :
15 We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis .
16   This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions .



PMID: 27509985
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathological Features and Survival Rate of Colorectal Adenocarcinoma Patients with and without a KRAS Mutation : a FiveYear Study in Yazd , Iran .
1 BACKGROUND :
2 By some estimates , colorectal carcinoma is the third most common cancer worldwide .
3 The most appropriate method of treatment , especially of its metastatic form , is determined based on KRAS status .
4 The present study was conducted on patients with colorectal cancer positive or neagtive for a KRAS mutation in terms of survival rate and the response to treatment .
5 MATERIALS AND METHODS :
6 Medical records of all cases with colorectal cancer hospitalized from 2010 to 2015 and with KRAS testing results were studied .
7 Data such as gender , age , tumor ( size , grade , location , stage ) , treatment type , KRAS status and survival were considered as variables .
8 Survival analysis was performed using the KaplanMeier method and Logrank test .
9 Statistical significance level was defined as P value <0.05 .
10 RESULTS :
11 Out of 90 patients , 55 ( 612% ) were male and 35 ( 38.8% ) were female with the age range of 2287 years .
12 The overall disease specific survival was 53+/-3 ( Mean +/- SE ) months with 95%CI : 4760 , and there were statistically significant differences between the mean survival rate with tumor stage and the response to treatment ( log rank test , PV = 0007 and PV = 0001 ) respectively .
13 The risk of mortality was 2.02 times higher in patients with mutant KRAS compared to those with the wild type of the gene ; however , this difference was not statistically significant ( OR = 2.016 ; 95%CI : 0.685.9 ; PV = 0.197 ) .
14 CONCLUSIONS :
15 In our study the overall 5year disease specific survival rate was low as compared to similar studies elsewhere .
16 Significant correlations were found between survival time with treatment type and tumor stage .



PMID: 27509933
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of KRAS Gene Mutations in Metastatic Colorectal Cancer Patients in Kermanshah Province .
1 BACKGROUND :
2 Worldwide , colorectal cancer ( CRC ) is reported to be the fourth most common cancer in men and the third most common in women .
3 KRAS is a protooncogene located on the short arm of chromosome 12 .
4 The aim of this study was to evaluate the KRAS oncogene and its relationship it with clinicopathologic features in 33 Kurdish patients .
5 MATERIALS AND METHODS :
6 Μ Metastatic CRC between 2012 and 2016 that came to Imam Reza hospital , Kermanshah province , Iran , were analysed for KRAS mutations using allele specific PCR primers and pyrosequencing .
7 Correlations between variables was analyzed in PASW SPSS and overall survival curves were plotted in Graph Pad prism 5 .
8 RESULTS :
9 The mean age for them at diagnosis was 51.5+/-12.6 years ( range , 2276 years ) .
10 Among the 33 patients that were sequenced , 12 samples in the KRAS gene had a nucleotide change , 11 in codon 12 and 1 in codon 13 .
11 There was no significant relationship between the mutation and clinical and pathological aspects of the disease .
12 CONCLUSIONS :
13 Knowledge of the KRAS status can help in decisionmaking to treat metastatic colorectal cancer patients more efficiently and increase survival .
14 However , many Kurdish people due to economic problems are not able to do this valuable genetic test .
15 In addition , we need more careful research of KRAS oncogene at the molecular level in young populations with more patients .



PMID: 27509333
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular differences in the microsatellite stable phenotype between left-sided and right-sided colorectal cancer .
1 Differences in the pathogenesis of microsatellite stable ( MSS ) sporadic colorectal cancers ( CRCs ) between left-sided CRC ( LC ) and right-sided CRC ( RC ) have not been clarified .
2 To identify pathogenesis-related genomic differences between MSS CRCs within the two locations , we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs .
3 Microsatellite instability ( MSI ; high and low/negative ) and DNA methylation status ( low methylation epigenome ; intermediate methylation epigenome [IME] or high methylation epigenome [HME] ) were determined using polymerase chain reaction ( PCR ) microsatellite analysis and PCR-bisulfite pyrosequencing , respectively .
4 Additionally , mutations in the TP53 , KRAS , BRAF and PIK3CA genes were examined using PCR-bisulfite pyrosequencing ( for KRAS and BRAF mutations ) or PCR-single conformation polymorphism ( for TP53 and PIK3CA mutations ) , followed by sequencing of aberrant bands .
5 Finally , a genome -wide study using a copy number alteration ( CNA )- targeted single nucleotide polymorphism array was performed .
6 Ninety-two CRCs were classified into 71 MSS and 21 MSI phenotypes .
7 We examined 71 CRCs with the MSS phenotype ( LC , 56 ; RC , 15 ) .
8 Mutations in KRAS were associated with RC with the MSS phenotype , whereas mutations in TP53 were more frequently found in LC with the MSS phenotype .
9 There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype .
10 Although CNA gains were associated with LC with the MSS phenotype , CNA losses were not major alterations associated with the MSS phenotype .
11 These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC .



PMID: 27509063
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells : a potential novel approach to the treatment of metastatic colorectal cancer .
1 It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor ( EGFR ) can have efficacy in KRAS wild-type advanced colorectal cancer ( CRC ) patients .
2 What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors .
3 Metalloproteinase inhibitor 1 ( TIMP-1 ) is a pleiotropic factor predictive of survival outcome of CRC patients .
4 Levels of TIMP-1 were measured in pre-treatment plasma samples ( n = 426 ) of metastatic CRC patients randomized to Nordic FLOX ( 5-fluorouracil and oxaliplatin ) +/- cetuximab ( NORDIC VII study ) .
5 ✓ Μ Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels , KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level ( >3rd quartile ) showing a significantly longer overall survival if treated with cetuximab ( HR , 048 ; 95% CI , 025 to 093 ) . GE-ASS-RO
6 To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines .
7 We show here that EGFR signaling induces TIMP-1 expression in CRC cells , and that TIMP-1 promotes a more aggressive behavior , specifically in KRAS mutated cells .
8   Μ The two sets of data , clinical and in vitro , are complementary and support each other , lending strength to our contention that TIMP - 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy .



PMID: 27507128
(Patient)  
Terms: Phase II Study, clinical trial, rat
Sent# Symbols Sentence Mnemonics
0 A Phase II Study of XELOX and Cetuximab as First - Line Therapy in Patients With KRAS Wild Type Metastatic Colorectal Cancer (FLEET2 Study) .
1 BACKGROUND :
2 Despite the comparable clinical benefit of XELOX ( capecitabine with oxaliplatin ) and FOLFOX ( 5-fluorouracil , leucovorin , and oxaliplatin ) , the value of XELOX treatment in combination with cetuximab for metastatic colorectal cancer ( mCRC ) remains largely unknown .
3 PATIENTS AND METHODS :
4 In this clinical trial we evaluated the efficacy and safety of weekly/biweekly cetuximab administration combined with biweekly XELOX in patients with previously untreated v-Ki-ras2 rat Kirsten sarcoma viral oncogene homolog ( KRAS ) wild type mCRC .
5 The primary end point was response rate ( RR ) with confirmation , and the secondary end points included progression-free survival ( PFS ) , overall survival ( OS ) , disease control rate ( DCR ) , dose intensity , and the safety of the protocol treatment .
6 RESULTS :
7 Forty patients who fulfilled the inclusion criteria participated in this study .
8 The median treatment cycle number was 8 and the median dose intensities were 218 mg/m2/wk for cetuximab , 34 mg/m2/wk for oxaliplatin , and 821 mg/m2/d for capecitabine .
9 One patient showed complete response and partial response was observed in 19 patients , giving an overall RR of 50% ( 95% confidence interval [CI] , 33.8%-66.2% ) .
10 Stable disease was obtained in 13 patients , resulting in a DCR of 82.5% ( 95% CI , 672%-927% ) .
11 The PFS was 6.5 months ( 95% CI , 35-96 months ) , and the OS was 24.3 months ( 95% CI , 149-337 months ) .
12 The safety profile revealed the common Grade 3/4 adverse events to be acneiform eruption ( 125% ) , peripheral neuropathy ( 75% ) , and elevated alanine transaminase levels ( 75% ) .
13 Grade 3/4 thrombocytopenia and neutropenia occurred only in 5.0% and 2.5% of the patients , respectively .
14 Grade 1 hand-foot syndrome ( HFS ) was not uncommon ( 20% ) , whereas Grade 2/3 HFS occurred in only 3 patients ( 75% ) .
15 No deaths were reported within 30 days of the last dose .
16 CONCLUSION :
17 Cetuximab with XELOX showed a confirmed overall RR of 50% , which was within the previously reported range of RR .
18 The safety profile showed an acceptable rate and severity of adverse events .
19 In light of the several advantages of XELOX , including convenience and the reported cost-saving aspects , further study of this combination therapy is warranted .



PMID: 27499925
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases : Identification of driver and passenger mutations .
1 The mutational profiles of primary colorectal cancers ( CRCs ) and corresponding ovarian metastases were compared .
2 Using a custom-made next generation sequencing panel , 115 cancer-driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases ( four with bilateral metastases ) .
3 Μ To obtain a complete overview of the mutational profile , low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out .
4 A subset of variants was validated using Sanger and/or hydrolysis probe assays .
5 The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series .
6 When comparing primary CRCs and their matching ovarian metastases , there was considerable overlap in the mutations of early affected genes .
7 Μ A subset of mutations demonstrated less overlap , presumably being passenger mutations .
8 Μ In particular , primary CRCs showed a substantially high number of passenger mutations .
9   We also compared the primary CRCs and matching metastases for stratifying variants of six genes ( KRAS , NRAS , BRAF , FBXW7 , PTEN and PIK3CA ) that select for established ( EGFR directed ) or future targeted therapies .
10 Μ In a total of 31 variants 12 were not found in either of the two locations .
11 Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases .
12 Half of these discordant variants were definitive class 4/5 pathogenic variants .
13 Μ However , in terms of temporal heterogeneity , no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases .
14 This suggests that dormant metastases may be present from the early days of the primary tumours .



PMID: 27499922
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 The molecular characteristics of colonic neoplasms in serrated polyposis : a systematic review and meta-analysis .
1 Serrated polyposis is a rare disorder characterised by the presence of multiple serrated polyps in the large intestine , and an increased personal and familial risk of colorectal cancer .
2 Knowledge of the molecular characteristics of colonic lesions which develop in this syndrome is fragmented , making it difficult to understand the underlying genetic basis of this condition .
3 We conducted a systematic review and meta-analysis of all studies which evaluated the molecular characteristics of colorectal neoplasms found in individuals with serrated polyposis .
4 We identified 4561 potentially relevant studies , but due to a lack of consensus in the reporting of findings , only fourteen studies were able to be included in the meta-analysis .
5 Μ BRAF mutation was found in 73% ( 95% CI 65-80% ) of serrated polyps , 0% ( 95% CI 0-3% ) of conventional adenomas and 49% ( 95%CI 33-64% ) of colorectal cancers .
6 In contrast , KRAS mutation was present in 8% ( 95% CI 5-11% ) of serrated polyps , 3% ( 95% CI 0-13% ) of conventional adenomas and 6% ( 95% CI 0-13% ) of colorectal cancers .
7 Absence of MLH1 immunostaining was found in 3% ( 95% CI 0-10% ) of serrated polyps and 53% ( 95% CI 36-71% ) of colorectal cancers .
8 Overall , microsatellite instability was found in 40% ( 95% CI 18-64% ) of colorectal cancers arising in the setting of serrated polyposis .
9 Our results indicate that diverse molecular pathways are likely to contribute to the increased predisposition for colorectal cancer in individuals with serrated polyposis .
10 We also propose a set of minimum standards for the reporting of future research in serrated polyposis as this is a rare syndrome and collation of research findings from different centres will be essential to identify the molecular mechanisms involved in the pathogenesis of this condition .



PMID: 27499921
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities , clinical parameters and phenotype-genotype correlation .
1 Studies on traditional serrated adenoma ( TSA ) and sessile serrated adenoma with dysplasia ( SSA-D ) are rare due to the low frequency of these lesions , which are well defined by the latest WHO classification .
2 However , introducing new morphological criteria such as intra-epithelial lymphocytes ( IELs ) might facilitate colorectal polyp diagnoses .
3 Additionally , the phenotype-genotype correlation needs to be updated as the terminology has repeatedly changed .
4 This study analysed 516 polyps , consisting of 118 classical adenomas ( CAD ) , 116 hyperplastic polyps ( HPP ) , 179 SSAs , 41 SSA-Ds , and 62 TSAs .
5 The lesions were analysed in relation to the patients' clinical parameters including gender , age , localisation , and size .
6 The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed .
7 In multivariate analyses , an increase in IELs was an independent and robust new criterion for the diagnosis of SSA-D ( p <0001 ) .
8 Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia .
9 KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA , respectively .
10 However , almost half of TSAs had a BRAF mutation and were KRAS wild type .
11 CDKN2A seems to precede MLH1 hyper-methylation within the serrated carcinogenesis model .
12 The genotyping of WHO-based entities - and especially SSA - has sharpened in comparison to previously published data .
13 TSAs can be sub-grouped according to their mutation status .
14 Of note , the higher number of IELs in SSA-D reflects their close relationship to colorectal cancers with micro-satellite instability .
15 Therefore , IELs might represent a new diagnostic tool for SSA-D .



PMID: 27499912
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The infiltration , and prognostic importance , of Th1 lymphocytes vary in molecular subgroups of colorectal cancer .
1 Giving strong prognostic information , T - cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer ( CRC ) .
2 With a view to further improving the tools for prognostic evaluation , we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity , but also by subsite , within CRCs with different molecular characteristics ( microsatellite instability , CpG island methylator phenotype status , and BRAF and KRAS mutational status ) .
3 We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC .
4 Μ We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC , irrespective of intratumoural subsite , and that both extent of infiltration and patient outcome differ according to molecular subgroup .
5 In brief , microsatellite instability , CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes , and the most pronounced prognostic effect of Th1 infiltration was found in these tumours .
6 Μ Interestingly , BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours .
7 Μ These differences could be explained atleast partly by our finding that BRAF mutated , in contrast to KRAS mutated , CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10 , and reduced levels of CCL22 and TGFB1 , stimulating Th2/Treg recruitment and polarisation .
8 In conclusion , the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated , and it remained significant in multivariable analyses , indicating that T-bet may be a valuable marker in the clinical setting .
9   Our results also indicate that T-bet is of value when analysed in molecular subgroups of CRC , allowing identification of patients with especially poor prognosis who are in need of extended treatment .



PMID: 27497007
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Quantitative analysis of wild-type and V600E mutant BRAF proteins in colorectal carcinoma using immunoenrichment and targeted mass spectrometry .
1 The BRAF V600E mutation is one of the most common mutations implicated in the development of several types of cancer including colorectal cancer ( CRC ) , where it is associated with aggressive disease phenotypes and poor outcomes .
2 Μ The status of the BRAF V600E mutation is frequently determined by direct DNA sequencing .
3 However , no previous study has sought to quantify the BRAF V600E protein in cancer specimens .
4 Here , we evaluated immunoenrichment coupled with two MS-based quantitative techniques , namely multiple reaction monitoring ( MRM ) and single ion monitoring conjugated accurate inclusion mass screening ( SIM-AIMS ) , to detect and precisely quantify wild-type ( WT ) and V600E mutant BRAF proteins in DNA sequence -confirmed CRC tissue specimens .
5 WT and V600E BRAF proteins were immunoprecipitated from a CRC cell line (HT-29) , and their representative peptides ( ( 592 ) IGDFGLATVK ( 601 ) and ( 592 ) IGDFGLATEK ( 601 ) , respectively ) were confirmed by LC-MS/MS analysis and then quantified by MRM or SIM-AIMS with spiked stable isotope-labeled peptide standards .
6 Both assays worked well for measuring WT BRAF from different amounts of HT-29 cell lysates , but the MRM assay was more sensitive than SIM-AIMS assay for quantifying lower levels of V600E BRAF .
7 In protein extracts ( 2 mg ) from 11 CRC tissue specimens , the MRM assay could measure WT BRAF in all 11 cases ( 032-166 ng ) and the V600E BRAF in two cases ( 01-013 ng ; mutant-to-WT ratio , 016-017 ) .
8 The SIM-AIMS assay could also detect WT and V600E BRAF in CRC specimens , but the measured levels of both targets were lower than those determined by MRM assay .
9 Collectively , this study provides an effective method to precisely quantify WT and V600E BRAF proteins in complex biological samples using immunoenrichment-coupled targeted MS .
10 Since the V600E BRAF protein has emerged as an important therapeutic target for cancer , the developed assay should facilitate future BRAF-related basic and clinical studies .



PMID: 27494869
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression .
1 The development and progression of CRC are regarded as a complicated network and progressive event including genetic and/or epigenetic alterations .
2 Recent researches revealed that MicroRNAs are biomarkers and regulators of CRC progression .
3 Analyses of published microarray datasets revealed that miR-450b-5p was highly up-regulated in CRC tissues .
4 In addition , high expression of miR-450b-5p was significantly associated with KRAS mutation .
5 However , the role of miR-450b-5p in the progression of CRC remains unknown .
6 Here , we sought to validate the expression of miR-450b-5p in CRC tissues and investigate the role and underlying mechanism of miR-450b-5p in the progression of CRC .
7 Μ The results revealed that miR-450b-5p was up-regulated in CRC tissues , high expression level of miR-450b-5p was positively associated with poor differentiation , advanced TNM classification and poor prognosis .
8 Moreover , miR-450b-5p was especially high in KRAS-mutated cell lines and could be up-regulated by KRAS/AP-1 signaling .
9 Functional validation revealed that overexpression of miR-450b-5p promoted cell proliferation and tumor growth while inhibited apoptosis of CRC cells .
10 Furthermore , we demonstrated that miR-450b-5p directly bound the 3'-UTRs of SFRP2 and SIAH1 , and activated Wnt/beta-Catenin signaling .
11 In conclusion , miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression .
12 Collectively , our work helped to understand the precise role of miR-450b-5p in the progression of CRC , and might promote the development of new therapeutic strategies against CRC .



PMID: 27493945
(None)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Treatment of Metastatic Colorectal Cancer : Standard of Care and Future Perspectives .
1 Palliative chemotherapy for metastatic colorectal cancer has undergone substantial changes in recent years .
2 The implementation of modern biologicals in the treatment has substantially improved overall survival up to 30 months .
3 With the increasing number of therapeutic options , the question of optimal treatment sequence arises , which is addressed in current studies like FIRE 4 or STRATEGIC-1 .
4 Furthermore , clinical and molecular biomarkers to predict efficacy and tolerability are urgently needed .
5 Today , the detection of activating RAS mutations is the only validated biomarker which precludes patients from anti-EGFR treatment .
6 The detection of BRAF mutation V600E is associated with a very poor prognosis corresponding to a survival of 9-12 months .
7 Prospective trials evaluating an optimal approach to this subgroup are still missing .
8 First results from strategies targeting the aberrant signal transduction are promising and require further validation .
9 Despite the advances so far , life expectancy unfortunately continues to be limited in the majority of patients with metastatic colorectal cancer .
10 New strategies are needed to improve the prognosis .
11 To this end , the identification of Her2/neu as a potential target and first experiences with checkpoint inhibition in patients with mismatch repair-deficient tumors are promising and also require further validation .



PMID: 27489542
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Successful Multidisciplinary Treatment with Secondary Metastatic Liver Resection after Downsizing by Palliative Second - Line Treatment of Colorectal Cancer : A Curative Option .
1 INTRODUCTION :
2 The prognostic outcome following progression after palliative first - line treatment for patients suffering from metastatic colorectal adenocarcinoma is generally poor .
3 Long-term relapse-free survival with palliative second - line treatment may be achieved in only a limited number of individual cases .
4 CASE REPORT :
5 A 37-year-old patient presented with bilobar liver metastases of colon cancer confirmed by histology with wild-type K-RAS ( exon 2 ) .
6 Due to progressive disease after eight cycles of first - line therapy with FOLFIRI plus cetuximab , second - line chemotherapy with modified FOLFOX4 ( mFOLFOX4 ) plus bevacizumab was initiated .
7 During four cycles of mFOLFOX4 plus bevacizumab ( 2 months ) , no higher-grade toxicity occurred .
8 Liver MRI with contrast medium revealed downsizing of the segment II/III metastases , as well as regressive , small , faint , hardly definable lesions in segments VI and IVb .
9 The interdisciplinary tumor board of the University of Erlangen thus decided to perform resection of the liver metastases .
10 Segments II and III were resected , and the liver metastases in segments IVa and VI were excised ( R0 ) .
11 Histopathology confirmed three of the R0-resected metastases to be completely necrotic , with residual scarring .
12 As perioperative therapy , four additional cycles of mFOLFOX4 plus bevacizumab were administered postoperatively .
13 No higher-grade toxicity was observed .
14 Three years after the initial diagnosis , the patient is relapse free , professionally fully reintegrated , and has an excellent performance status .
15 CONCLUSION :
16   Patients suffering from metastatic colorectal cancer may benefit from multidisciplinary treatment with secondary metastatic liver resection after downsizing by palliative second - line treatment .
17 In individual cases , patients may even have a curative treatment option , provided that close interdisciplinary collaboration exists .



PMID: 27485514
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A rational two-step approach to KRAS mutation testing in colorectal cancer using high resolution melting analysis and pyrosequencing .
1 BACKGROUND :
2 KRAS mutation testing is mandatory in the management of metastatic colorectal cancer prior to treatment with anti-EGFR antibodies as patients whose tumors express mutant KRAS do not benefit from these agents .
3 Although the U .
4 S .
5 Food and Drug Administration has recently approved two in-vitro diagnostics kits for determination of KRAS status , there is generally no consensus on the preferred method and new tests are continuously being developed .
6 Most of these techniques focus on the hotspot mutations at codons 12 and 13 of the KRAS gene .
7 METHODS :
8 Μ We describe a two-step approach to KRAS codon 12/13 mutation testing involving high resolution melting analysis ( HRM ) followed by pyrosequencing using the Therascreen KRAS Pyro kit ( Qiagen ) of only those samples that are not clearly identified as KRAS wildtype or mutant by HRM .
9 First , we determined KRAS status in a panel of 61 colorectal cancer samples using both methods to compare technical performance and concordance of results .
10 Subsequently , we evaluated practicability and costs of our concept in an independent set of 120 colorectal cancer samples in a routine diagnostic setting .
11 RESULTS :
12 HRM and pyrosequencing appeared to be equally sensitive , allowing for clear detection of mutant alleles at a mutant allele frequency >/ = 12.5 % .
13 Pyrosequencing yielded more exploitable results due to lower input requirements and a lower rate of analysis failures .
14 KRAS codon 12/13 status was called concordantly for 98.2 % ( 56/57 ) of all samples that could be successfully analysed by both methods and 100 % ( 19/19 ) of samples that were identified mutant by HRM .
15 Μ Reviewing the actual effort and expenses for KRAS mutation testing in our laboratory revealed , that the selective use of pyrosequencing for only those samples that could not be analysed by HRM increased the fraction of valid results from 87.5 % for HRM alone to 99.2 % ( 119/120 ) while allowing for a net reduction of operational costs of >75 % compared to pyrosequencing alone .
16 CONCLUSIONS :
17 Combination of HRM and pyrosequencing in a two-step diagnostic procedure constitutes a reliable and economic analysis platform for KRAS mutation testing in colorectal cancer in a clinical setting .



PMID: 27482709
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan .
1 Patients with Lynch syndrome ( LS ) have a significantly increased risk of developing colorectal cancer ( CRC ) and other cancers .
2 Μ Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes ( i.e. , the DNA mismatch repair genes ) in the patients , to offer genetic testing for relatives of the patients with the mutations , and then to provide early prevention for the relatives with the mutations .
3 Several genetic tests are available for LS , such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses .
4 Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany .
5 However , a cost-effectiveness analysis for the testing has not yet been performed in Taiwan .
6 In this study , we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies , while population-specific parameters , such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan , were used .
7 The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy .
8 Using the World Health Organization standard , which was defined based on Taiwan's Gross Domestic Product per capita , the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening .
9 Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness .
10 To the best of our knowledge , this is the first cost-effectiveness analysis for evaluating different genetic testing strategies for LS in Taiwan .
11 The results will be informative for the government when considering offering screening for LS in patients newly diagnosed with CRC .



PMID: 27475305
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes .
1 BACKGROUND & ; AIMS : Aspirin use reduces colorectal cancer risk .
2 Aspirin , a nonsteroidal anti-inflammatory drug , inhibits prostaglandin-endoperoxide synthase 2 ( PTGS2 or cyclooxygenase-2 ) ; PTGS2 promotes inflammation and suppresses T-cell -mediated adaptive immunity .
3 We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates .
4 METHODS :
5 We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study .
6 Participants were asked whether they took aspirin in most weeks , the number of tablets taken per week , and years of aspirin use .
7 We collected available tumor specimens ( n = 1458 ) from pathology laboratories in the United States .
8 A pathologist confirmed the diagnosis of colorectal adenocarcinoma ( excluding anal squamous cell carcinoma ) , and evaluated histopathology features , including patterns and degrees of lymphocytic infiltrates within and around tumor areas .
9 Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis , death , or the end of follow-up evaluation ( June 2010 ) .
10 Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes ( TILs ) , intratumoral periglandular reaction , peritumoral reaction , or Crohn's-like reaction .
11 RESULTS :
12 We documented 1458 rectal and colon cancers .
13 The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs ( Pheterogeneity = 007 ) .
14 Compared with nonregular use , regular aspirin use was associated with a lower risk of tumors that had low levels of TILs ( relative risk , 072 ; 95% confidence interval , 063-081 ) , and strength of the association depended on aspirin dose and duration ( both Ptrend <001 ) .
15 In contrast , aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs .
16 This differential association was consistent regardless of the status of tumor microsatellite instability , mutations in BRAF , or expression of PTGS2 .
17 Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells , CD8+ T cells , or CD45RO (PTPRC) + T cells ( measured by immunohistochemistry and computer-assisted image analysis ) .
18 CONCLUSIONS :
19 Based on data from the prospective cohort studies , regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs .
20 These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin .



PMID: 27472952
(Cell)  
Terms: in vivo, in vitro, xenograft, mouse model, mouse, mice
Sent# Symbols Sentence Mnemonics
0 Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer .
1 Oxaliplatin is a key drug in chemotherapy of colorectal cancer ( CRC ) .
2 However , its efficacy is unsatisfied due to drug resistance of cancer cells .
3 In this study , we tested whether a natural agent , ursolic acid , was able to enhance the efficacy of oxaliplatin for CRC .
4 Four CRC cell lines including SW480 , SW620 , LoVo , and RKO were used as in vitro models , and a SW620 xenograft mouse model was used in further in vivo study .
5 We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin .
6 This effect was associated with down-regulation of Bcl-xL , Bcl-2 , survivin , activation of caspase-3 , 8 , 9 , and inhibition of KRAS expression and BRAF , MEK1/2 , ERK1/2 , p-38 , JNK , AKT , IKKalpha , IkappaBalpha , and p65 phosphorylation of the MAPK , PI3K/AKT , and NF-kappaB signaling pathways .
7 The two agents also showed synergistic effects against tumor growth in vivo .
8 In addition , ursolic acid restored liver function and body weight of the mice treated with oxaliplatin .
9 Thus , we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo , which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC .



PMID: 27470214
(None)  
Terms: in vivo, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 Simultaneous destabilization of beta-catenin and Ras via targeting of the axin-RGS domain as a potential therapeutic strategy for colorectal cancer .
1 Μ Mutations of APC and KRAS are frequently observed in human colorectal cancers ( CRCs ) and the Wnt/beta-catenin and Ras pathways are consequently activated in a significant proportion of CRC patients .
2 Mutations in these two genes are also known to synergistically induce progression of CRCs .
3 Through a series of studies , we have demonstrated that inhibition of the Wnt/beta-catenin signaling pathway negatively regulates Ras stability , therefore , Ras abundance is increased together with beta-catenin in both mice and human CRCs harboring adenomatous polyposis coli ( APC ) mutations .
4 In a recent study , we identified KY1220 , a small molecule that simultaneously degrades beta-catenin and Ras by inhibition of the Wnt/beta-catenin pathway , and obtained its derivative KYA1797K , which has improved activity and solubility .
5 We found that KYA1797K binds the RGS domain of axin and enhances the binding affinity of beta-catenin or Ras with the beta-catenin destruction complex components , leading to simultaneous destabilization of beta-catenin and Ras via GSK3beta activation .
6 By using both in vitro and in vivo studies , we showed that KYA1797K suppressed the growth of CRCs harboring APC and KRAS mutations through destabilization of beta-catenin and Ras .
7 Therefore , our findings indicate that the simultaneous destabilization of beta-catenin and Ras via targeting axin may serve as an effective strategy for inhibition of CRCs. [BMB Reports 2016 ; 49(9) : 455-456] .



PMID: 27469030
(Cell)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 Sur8 mediates tumorigenesis and metastasis in colorectal cancer .
1 Sur8 , a scaffold protein of the Ras pathway , interacts with Ras and Raf and modulates the Ras-extracellular signal-regulated kinase ( ERK ) pathway .
2 Here we show that Sur8 is overexpressed in established human colorectal cancer ( CRC ) cell lines and CRC patient tissues .
3 Moreover , Sur8 expression is increased during liver metastasis in CRC patients .
4 Sur8 knockdown decreases ERK and Akt activities in CRC cell lines , regardless of their K-Ras , B-Raf or PI3K mutation status .
5 Overexpression or knockdown of Sur8 increases or decreases , respectively , the proliferation or transformation of CRC cell lines .
6 Sur8 knockdown attenuates the migration and invasion of HCT116 CRC cells .
7 Subcutaneous or orthotopic injection of HCT116 cells harboring a doxycycline ( Dox )- mediated Sur8 knockdown system in nude mice resulted in decreased tumorigenic potential and inhibited the liver metastatic potential of HCT116 cells .
8 Taken together , our data support the role of Sur8 as a promoter of tumorigenesis and liver metastasis in CRC through its modulation of the Ras-ERK and PI3K-Akt signaling pathways .



PMID: 27468967
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Association of KRAS gene mutations with depression in older metastatic colorectal cancer patients . GM-ASS-DS
1 BACKGROUND :
2 Cancer patients with depression or anxiety have poor survival , and the interaction between mental and physical problems in older patients may exacerbate this problem .
3 K-ras oncogene ( KRAS ) mutation may play a role in the development of psychosocial distress and may be associated with poor survival of metastatic colorectal cancer ( mCRC ) patients .
4 This study investigated the association between KRAS gene mutations and psychosocial morbidity to explore the possible cancer/psychosis relationship in older mCRC patients .
5 METHODS :
6 In this study , 62 newly diagnosed mCRC patients were recruited and completed the Hospital Anxiety and Depression Scale ( HADS ) .
7 Demographic data were also collected , and clinicopathological data were retrieved from medical records .
8 Μ KRAS mutations were assessed via PCR analysis of tissue specimens from the patients .
9 RESULTS :
10 Μ The results showed that 28 of the 62 participants ( 452% ) had positive screens for possible depression , and 45 of the 62 participants ( 726% ) had positive screens for anxiety .
11 The KRAS mutation rate was 40.3% ( 25/62 ) , and 19 of the 25 patients with KRAS mutations ( 760% ) had probable depression , whereas only 24.3% of the patients with wild-type KRAS were probably depressed ( p <005 ) .
12 The KRAS mutation was associated with higher HADS depression scores , independent of gender and performance status ( p <005 ) , but not with higher HADS anxiety or total scores .
13 CONCLUSIONS :
14 KRAS mutations were associated with depression severity and higher rates of probable depression in older mCRC patients .
15 Depression should be assessed and treated as early as possible in older mCRC patients with the KRAS mutation .
16 Further studies are needed to verify our current findings using a larger sample size .



PMID: 27468920
(Patient)  
Terms: phase II study, phase II
Sent# Symbols Sentence Mnemonics
0 Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan , oxaliplatin , and fluoropyrimidines ( KSCC 0901 study ) .
1 PURPOSE :
2 Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third - line treatment for KRAS wild-type unresectable metastatic colorectal cancer .
3 However , in some cases , it is difficult to administer irinotecan after third - line treatment .
4 Therefore , we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan , oxaliplatin , and fluoropyrimidines .
5 METHODS :
6 The study was designed as a phase II , non-randomized , open-label , multicenter trial .
7 Cetuximab was initially administered at 400 mg/m(2) , followed by weekly infusion at 250 mg/m(2) .
8 S-1 was administered at a fixed dose of 80 mg/m(2) orally twice daily for 28 days followed by a 14-day break , resulting in a 6-week treatment course .
9 The primary endpoint was progression-free survival ( PFS ) .
10 The secondary endpoints were the overall response rate ( ORR ) , overall survival ( OS ) , disease control rate ( DCR ) , time to treatment failure , dose intensity , safety , and BRAF mutation status .
11 RESULTS :
12 Thirty-seven patients were eligible .
13 The median PFS was 5.5 months , the median OS was 13.5 months , the ORR was 29.7 % , and the DCR was 73.0 % .
14 The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1 .
15 Grade 3-4 adverse events that occurred in >10 % of the patient population included rash , dry skin , diarrhea , paronychia , anorexia , fatigue , mucositis , and neutropenia .
16 CONCLUSIONS :
17   Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan - , oxaliplatin - , and fluoropyrimidine-refractory metastatic colorectal cancer .



PMID: 27466537
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Lack of Relationship Between Clinical Features and KRAS Mutations in Patients with Metastatic Colorectal Cancer .
1 BACKGROUND/AIM :
2 We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan .
3 Μ Here , we analyzed the clinical characteristics of patients with metastatic colorectal cancer ( CRC ) in order to detect potent correlations with KRAS mutations .
4 PATIENTS AND METHODS :
5 We conducted a retrospective , multicenter study between 2008 and 2012 .
6 We included patients with metastatic colorectal adenocarcinomas , previously treated by irinotecan , and with an available KRAS mutation test .
7 RESULTS :
8 We included 299 patients .
9 The median age was 60 years ; the median number of metastatic sites was 2 .
10 One hundred and eight patients ( 361% ) had a previous objective response to irinotecan .
11 The median interval between diagnosis and irinotecan discontinuation was 1.94 years .
12 Μ A KRAS mutation was detected in 133 patients ( 445% ) .
13 Μ In univariate and multivariate analyses , none of the assessed factors was associated with the presence of a KRAS mutation .
14 CONCLUSION :
15 No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer .



PMID: 27465221
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer : results from CALGB 80203 ( Alliance ) .
1 Circulating protein markers were assessed in patients with colorectal cancer ( CRC ) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers .
2 Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy ( chemo ) or chemo in combination with cetuximab .
3 Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF) , heparin-binding EGF ( HBEGF ) , epidermal growth factor receptor ( EGFR ) , HER2 , HER3 , and CD73] .
4 Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models .
5 Μ Predictive markers were identified using a treatment-by-marker interaction term in the Cox model .
6 Plasma levels of EGF , HBEGF , HER3 , and CD73 were prognostic for overall survival ( OS ) across all patients ( KRAS mutant and wild-type ) .
7   High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type ( WT ) patients ( chemo HR = 098 , 95% CI = 074-129 ; chemo+cetuximab HR = 154 , 95% CI = 105-225 ; interaction P = 0045 ) and benefit from cetuximab in KRAS mutant patients ( chemo HR = 172 , 95% CI = 102-292 ; chemo+cetuximab HR = 090 , 95% CI = 067-121 ; interaction P = 0026 ) .
8   Across all patients , higher HER3 levels were associated with significant OS benefit from cetuximab treatment ( chemo HR = 482 , 95% CI = 168-1384 ; chemo+cetuximab HR = 095 , 95% CI = 031-295 ; interaction P = 0046 ) .
9 CD73 was also identified as predictive of OS benefit in KRAS WT patients ( chemo HR = 128 , 95% CI = 088-184 ; chemo+cetuximab HR = 060 , 95% CI = 032-113 ; interaction P = 0049 ) .
10 Although these results are preliminary , and confirmatory studies are necessary before clinical application , the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab .



PMID: 27461835
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Development of a High-Throughput Gene Expression Screen for Modulators of RAS-MAPK Signaling in a Mutant RAS Cellular Context .
1 The RAS-MAPK pathway controls many cellular programs , including cell proliferation , differentiation , and apoptosis .
2 In colorectal cancers , recurrent mutations in this pathway often lead to increased cell signaling that may contribute to the development of neoplasms , thereby making this pathway attractive for therapeutic intervention .
3 To this end , we developed a 26-member gene signature of RAS-MAPK pathway activity utilizing the Affymetrix QuantiGene Plex 2.0 reagent system and performed both primary and confirmatory gene expression-based high-throughput screens ( GE-HTSs ) using KRAS mutant colon cancer cells (SW837) and leveraging a highly annotated chemical library .
4 The screen achieved a hit rate of 1.4% and was able to enrich for hit compounds that target RAS-MAPK pathway members such as MEK and EGFR .
5 Sensitivity and selectivity performance measurements were 0.84 and 1.00 , respectively , indicating high true-positive and true-negative rates .
6 Active compounds from the primary screen were confirmed in a dose-response GE-HTS assay , a GE-HTS assay using 14 additional cancer cell lines , and an in vitro colony formation assay .
7 Altogether , our data suggest that this GE-HTS assay will be useful for larger unbiased chemical screens to identify novel compounds and mechanisms that may modulate the RAS-MAPK pathway .



PMID: 27461218
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR -mediated signaling in hypoxic colorectal carcinoma cells .
1 BACKGROUND :
2 The use of targeted agents to impel dual inhibition of anti-apoptotic mechanisms and mTOR -mediated pro-survival signaling in colorectal carcinoma ( CRC ) cell lines with KRAS or BRAF mutation has been shown to induce apoptosis , a timely result given CRC entities harboring such mutations are in need of new therapies .
3 Since CRC comprises heterogeneous tumors with predominant hypoxic components , we investigated effects of an inhibitor of anti-apoptotic Bcl-2 family proteins ( ABT-737 ) in combination with an mTOR inhibitor (AZD8055) -collectively referred to as combo-Rx , in hypoxic CRC cell lines .
4 METHODS :
5 Cell viability measures , expression of proteins implicated in apoptosis and MAPK/PI3K-AKT/mTOR pathway signaling , and profiling of composite kinase activities were undertaken in a panel of 14 cell lines .
6 RESULTS :
7 In hypoxic conditions , combo-Rx suppressed viability of 13 of the cell lines , albeit ABT-737 did not significantly potentiate the inhibitory effect of single-agent AZD8055 in six of the models .
8 Hypoxic KRAS/PIK3CA-mutant HCT-116 and HCT-15 cell lines ( both with low endogenous expression of the anti-apoptotic Mcl-1 protein and showing augmented inhibition of viability following the addition of ABT-737 to AZD8055 ) responded to combo-Rx by induction of apoptosis but with the simultaneous strong Mcl-1 up-regulation and activation of MAPK/PI3K-conducted signaling .
9 In contrast , in hypoxic KRAS-mutant LoVo ( devoid of PIK3CA mutation ) , BRAF/PIK3CA-mutant RKO , and wild-type Colo320DM cell lines ( all with high endogenous Mcl-1 expression and being resistant to the additional effect of ABT-737 to AZD8055 ) , combo-Rx did not elicit apoptotic or pro-survival responses .
10 CONCLUSIONS :
11 ✓ The concurrent inhibition of anti-apoptotic proteins and mTOR -mediated signaling in hypoxic KRAS/PIK3CA-mutant CRC cell lines resulted in pro-survival responses in parallel with the intended anti-proliferative effects , a finding that should be of note if considering combinatory targeting of multiple pathways in this CRC entity . GE-REG-RO



PMID: 27460045
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 GATA binding protein 2 overexpression is associated with poor prognosis in KRAS mutant colorectal cancer .
1 Colorectal cancer ( CRC ) is one of the most lethal cancers worldwide .
2 Mutations in KRAS occur with the frequency of 30-50% in CRC leading to decreased therapeutic response to anti-epidermal growth factor receptor ( EGFR ) agents .
3 Recently GATA2 was proven to be essential in the survival of KRAS mutant non-small cell lung cancer ( NSCLC ) cells .
4 However , the association between KRAS mutation and GATA2 expression in CRC remains largely unknown .
5 In the present study , dideoxy sequencing and immunohistochemistry were used to determine KRAS mutation and GATA2 expression , respectively , in a cohort of 236 patients .
6 Cox proportional hazard regression and Kaplan-Meier survival analysis were performed to study the association between KRAS mutation or GATA2 expression and clinical outcomes .
7 ✓ Μ Kaplan-Meier analysis revealed that KRAS mutant patients with high expression of GATA2 had significantly worse long-term clinical outcomes than those with low expression of GATA2 ( P<0001 ) . GE-ASS-RO, RO-ASS-GE
8 ✓ Μ Further analysis showed that patients with both KRAS mutation and high GATA2 expression experienced significantly more unfavorable 5-year outcomes than patients with wild - type KRAS and low GATA2 expression ( P = 0001 ) . GM-ASS-RO, RO-ASS-GM
9 Μ Univariate and multivariate Cox proportional hazard regression demonstrated the GATA2 expression level was an independent risk factor for overall survival of CRC patients ( HR 1645 ; 95% CI 1004-2696 ; P = 0048 ) .
10 Μ In conclusion , the results of this study demonstrated that high expression of GATA2 is correlated with worse survival outcomes in KRAS mutant CRC patients , suggesting that GATA2 may serve as a novel biomarker for the survival of CRC patients harboring KRAS mutation .



PMID: 27454043
(None)  
Terms: , mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model .
1 Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence .
2 Here , we demonstrate that the combination of gene , drug and phototherapy delivered through a prophylactic hydrogel patch leads , in a colon cancer mouse model , to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection .
3 The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles .
4   Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras , a key oncogene driver , and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat , causing the release of a chemotherapeutic as well as thermally induced cell damage .
5 This local , triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression .



PMID: 27451147
(Cell)  
Terms: Xenograft, xenograft, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 SLC25A22 Promotes Proliferation and Survival of Colorectal Cancer Cells With KRAS Mutations and Xenograft Tumor Progression in Mice via Intracellular Synthesis of Aspartate .
1 BACKGROUND & ; AIMS : Many colorectal cancer ( CRC ) cells contain mutations in KRAS .
2 Μ Analyses of CRC cells with mutations in APC or CTNNB1 and KRAS identified SLC25A22 , which encodes mitochondrial glutamate transporter , as a synthetic lethal gene .
3 We investigated the functions of SLC25A22 in CRC cells with mutations in KRAS .
4 METHODS :
5 We measured levels of SLC25A22 messenger RNA and protein in paired tumor and nontumor colon tissues collected from 130 patients in Hong Kong and 17 patients in China and compared protein levels with patient survival times .
6 Expression of SLC25A22 was knocked down in KRAS mutant CRC cell lines ( DLD1 , HCT116 , LOVO , SW480 , SW620 , and SW1116 ) and CRC cell lines without mutations in KRAS ( CACO-2 , COLO205 , HT29 , and SW48 ) ; cells were analyzed for colony formation , proliferation , glutaminolysis and aspartate synthesis , and apoptosis in Matrigel and polymerase chain reaction array analyses .
7 DLD1 and HCT116 cells with SLC25A22 knockdown were grown as xenograft tumors in nude mice ; tumor growth and metastasis were measured .
8 SLC25A22 was expressed ectopically in HCT116 cells , which were analyzed in vitro and grown as xenograft tumors in nude mice .
9 RESULTS :
10 Levels of SLC25A22 messenger RNA and protein were increased in colorectal tumor tissues compared with matched nontumor colon tissues ; increased protein levels were associated with shorter survival times of patients ( P = 01 ) .
11 ✓ Knockdown of SLC25A22 in KRAS mutant CRC cells reduced their proliferation , migration , and invasion in vitro , and tumor formation and metastasis in mice , compared with cells without SLC25A22 knockdown . GE-REG-RO, RO-ASS-GE
12 Knockdown of SLC25A22 reduced aspartate biosynthesis , leading to apoptosis , decreased cell proliferation in KRAS mutant CRC cells .
13 Incubation of KRAS mutant CRC cells with knockdown of SLC25A22 with aspartate increased proliferation and reduced apoptosis , which required GOT1 , indicating that oxaloacetate is required for cell survival .
14 Decreased levels of oxaloacetate in cells with knockdown of SLC25A22 reduced regeneration of oxidized nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate .
15 Reduced oxidized nicotinamide adenine dinucleotide inhibited glycolysis and decreased levels of adenosine triphosphate , which inactivated mitogen -activated protein kinase kinase and extracellular signal-regulated kinase signaling via activation of AMP -activated protein kinase .
16 An increased ratio of oxidized nicotinamide adenine dinucleotide phosphate to reduced nicotinamide adenine dinucleotide phosphate induced oxidative stress and glutathione oxidation , which suppressed cell proliferation .
17 Asparagine synthetase mediated synthesis of asparagine from aspartate to promote cell migration .
18 CONCLUSIONS :
19 SLC25A22 promotes proliferation and migration of CRC cells with mutations KRAS , and formation and metastasis of CRC xenograft tumors in mice .
20 Patients with colorectal tumors that express increased levels of SLC25A22 have shorter survival times than patients whose tumors have lower levels .
21 SLC25A22 induces intracellular synthesis of aspartate , activation of mitogen -activated protein kinase kinase and extracellular signal-regulated kinase signaling and reduces oxidative stress .



PMID: 27449290
(Cell)  
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0 KRASG12 mutant induces the release of the WSTF/NRG3 complex , and contributes to an oncogenic paracrine signaling pathway .
1 It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation .
2 We identified that Williams-Beuren syndrome transcription factor ( WSTF ) , a non-secretory protein , was released in complex with secretory protein-neuregulin-3 ( NRG3 ) .
3 The KRASG12 mutant activates the transcription of NRG3 .
4 The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3 .
5 Extracellular WSTF/NRG3 promotes the formation of colon tumors .
6 Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS .
7 The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant .
8 In summary , our demonstration provides a new pathway to our understanding of the biological development of complex diseases .



PMID: 27448974
(Patient)  
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0 Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma .
1 The circulating free tumor DNA ( ctDNA ) represents an alternative , minimally invasive source of tumor DNA for molecular profiling .
2 Targeted sequencing with next generation sequencing ( NGS ) can assess hundred mutations starting from a low DNA input .
3 We performed NGS analysis of ctDNA from 44 patients with metastatic non-small-cell lung carcinoma ( NSCLC ) and 35 patients with metastatic colorectal carcinoma ( CRC ) .
4 Μ NGS detected EGFR mutations in 17/22 plasma samples from EGFR-mutant NSCLC patients ( sensitivity 773% ) .
5 The concordance rate between tissue and plasma in NSCLC was much lower for other mutations such as KRAS that , based on the allelic frequency and the fraction of neoplastic cells , were likely to be sub-clonal .
6 Μ NGS also identified EGFR mutations in plasma samples from two patients with EGFR wild type tumor tissue .
7 Both mutations were confirmed by droplet digital PCR ( ddPCR ) in both plasma and tissue samples .
8 In CRC , the sensitivity of the NGS plasma analysis for RAS mutations was 100% ( 6/6 ) in patients that had not resection of the primary tumor before blood drawing , and 46.2% ( 6/13 ) in patients with primary tumor resected before enrollment .
9 Our study showed that NGS is a suitable method for plasma testing .
10 However , its clinical sensitivity is significantly affected by the presence of the primary tumor and by the heterogeneity of driver mutations .



PMID: 27447549
(None)  
Terms:
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0 Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling .
1 Here we study the effects of inducible oncogenic K-Ras ( G12V ) expression on the polarized morphogenesis of colonic epithelial cells .
2 We provide evidence that the autocrine production of heregulins , ligands for the ErbB3 receptor tyrosine kinase , is responsible for the hyperproliferation and aberrant 3D morphogenesis upon oncogenic K-Ras expression .
3 This is in line with results obtained in primary intestinal organoid cultures , in which exogenous heregulin is shown to interfere with normal tissue architecture .
4 Importantly , ErbB3 inhibition and heregulin gene silencing rescued K-RasG12V -induced features of cell transformation .
5 Μ Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers , our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression .



PMID: 27446583
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 First - line cetuximab-based chemotherapies for patients with advanced or metastatic KRAS wild-type colorectal cancer .
1 IMPORTANCE : The abrupt appearance of melanocytic lesions is a unique phenomenon that can occur in the setting of eruptive nevi or epidermotropic melanoma metastases .
2 OBJECTIVE :
3 To examine the immunohistochemical and genetic mutative features of a novel case of an eczematous reaction followed by the abrupt appearance of melanocytic lesions .
4 DESIGN , SETTING , AND PARTICIPANT : Case report of a 48-year-old woman with no significant medical history who first presented with an eczematous dermatitis on her torso , extremities , and buttocks and who subsequently developed thousands of pinpoint , histologically atypical melanocytic tumors and invasive melanoma within the areas of inflammation .
5 Μ MAIN OUTCOMES AND MEASURES : Immunohistochemical and mutational analyses of the patient's melanocytic tumors were conducted .
6 RESULTS :
7 Μ Mutational analysis of the pigmented lesions did not identify any activating mutations in BRAF , PTEN , NRAS , KRAS , and HRAS .
8 Μ Immunohistochemical analyses of 9 biopsied pigmented lesions all showed normal expression of the tumor suppressors p16 and PTEN and no expression of mutated BRAF V600E protein .
9 CONCLUSIONS AND RELEVANCE : To our knowledge , this is a previously unreported eruption comprising 2 distinct components : an eczematous reaction and a wave of melanocytic proliferations within the inflammatory regions .
10 Possible explanations for this patient's condition , include immune stimulation leading to nevogenesis , benign "nevic" metastases , eruptive nevi , and epidermotropic metastatic melanoma .



PMID: 27446446
(Patient)  
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Sent# Symbols Sentence Mnemonics
0 Prognostic role of KRAS mutations in Sardinian patients with colorectal carcinoma .
1 The presence of mutations in the KRAS gene is a predictor of a poor clinical response to EGFR-targeted agents in patients affected by colorectal cancer ( CRC ) , but its significance as a global prognostic factor remains unclear .
2 The aim of the present study was to evaluate the impact of the KRAS mutational status on time to first metastasis ( TTM ) and overall survival ( OS ) in a cohort of Sardinian CRC patients .
3 A total of 551 patients with metastatic CRC at the time of enrolment were included .
4 Clinical and pathological features of the disease , including follow-up information , were obtained from medical records and cancer registry data .
5 Μ For mutational analysis formalin-fixed paraffin-embedded tissue samples were processed using a standard protocol .
6 Μ The coding sequence and splice junctions of exons 2 and 3 of the KRAS gene were screened for mutations by direct automated sequencing .
7 Μ Overall , 186 KRAS mutations were detected in 183/551 ( 33% ) patients : 125 ( 67% ) were located in codon 12 , 36 ( 19% ) in codon 13 , and 18 ( 10% ) in codon 61 .
8 Μ The remaining mutations ( 7 ; 4% ) were detected in uncommonly-affected codons .
9 No significant correlation between KRAS mutations and gender , age , anatomical location and stage of the disease at the time of diagnosis was identified .
10 Μ Furthermore , no prognostic value of KRAS mutations was found considering either TTM or OS .
11 When patients were stratified by KRAS mutational status and gender , males were significantly associated with a longer TTM .
12 ✓ The results of the present study indicate that KRAS mutation correlated with a slower metastatic progression in males with CRC from Sardinia , irrespective of the age at diagnosis and the codon of the mutation . GM-ASS-RO



PMID: 27444718
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Poorly Differentiated Clusters : Clinical Impact in Colorectal Cancer .
1 Colorectal cancer ( CRC ) is one of the most common malignancies worldwide and it still represents a major cause of cancer-related death .
2 Postsurgical Tumor Node Metastasis ( pTNM ) stage is the main prognostic factor in CRC and it currently drives therapeutic protocols after surgery .
3 However , CRC outcome is not always predictable on the basis of pTNM stage .
4 Hence , there is the need to find additional prognostic factors that may allow to predict the clinical course of CRC regardless of pTNM stage , so that patients may receive the most appropriate treatment for their tumor .
5 In recent years , the prognostic value of a novel grading system based on the counting of poorly differentiated clusters ( PDCs ) of neoplastic cells in tumor tissue was documented in CRC .
6 In this article , we review the clinical relevance of grading based on PDC counting in CRC .
7 In view of its high prognostic value and reproducibility , PDC grading could be introduced in routine histopathological report of CRC and used for therapeutic decision making .
8 Although there is initial evidence that PDC may be correlated with biomolecular profile of CRC , whether their presence is associated with response to targeted therapies is still unknown and deserves further investigation .



PMID: 27444698
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic relevance of autophagy-related markers LC3 , p62/sequestosome 1 , Beclin-1 and ULK1 in colorectal cancer patients with respect to KRAS mutational status .
1 BACKGROUND :
2 Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation .
3 Autophagy is involved in both tumorigenesis and tumour suppression .
4 Here we investigated the potential prognostic value of the autophagy-related proteins Beclin-1 , p62 , LC3 and uncoordinated ( UNC ) 51-like kinase 1 ( ULK1 ) in a cohort of colorectal cancer ( CRC ) specimens .
5 METHODS :
6 In this study , we analysed the immunoexpression of the autophagy-related proteins p62 , LC3 , Beclin-1 and ULK1 in 127 CRC patients with known KRAS mutational status and detailed clinical follow-up.RESULTS :
7 Μ Survival analysis of p62 staining showed a significant correlation of cytoplasmic ( not nuclear ) p62 expression with a favourable tumour-specific overall survival ( OS ) .
8 Μ The prognostic power of cytoplasmic p62 was found in the KRAS-mutated subgroup but was lost in the KRAS wildtype subgroup .
9 Survival analysis of Beclin-1 staining did not show an association with OS in the complete cohort .
10 LC3 overexpression demonstrated a slight , though not significant , association with decreased OS .
11 Upon stratifying cases by KRAS mutational status , nuclear ( not cytoplasmic ) Beclin-1 staining was associated with a significantly decreased OS in the KRAS-mutated subgroup but not in the KRAS wildtype CRCs .
12 In addition , LC3 overexpression was significantly associated with decreased OS in the KRAS-mutated CRC subgroup .
13 ✓ ULK1 expression was not correlated to survival . GE-ASS-RO
14 CONCLUSIONS :
15 Immunohistochemical analyses of LC3 , p62 and Beclin-1 may constitute promising novel prognostic markers in CRC , especially in KRAS-mutated CRCs .
16 This strategy might help in identifying high-risk patients who would benefit from autophagy-related anticancer drugs .



PMID: 27443823
(Patient)  
Terms:
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0 Clinical and Molecular Characteristics of Post-Colonoscopy Colorectal Cancer : A Population-based Study .
1 BACKGROUND & ; AIMS : Colonoscopy provides incomplete protection from colorectal cancer ( CRC ) , but determinants of post-colonoscopy CRC are not well understood .
2 We compared clinical features and molecular characteristics of CRCs diagnosed at different time intervals after a previous colonoscopy .
3 METHODS :
4 We performed a population-based , cross-sectional study of incident CRC cases in Denmark ( 2007-2011 ) , categorized as post-colonoscopy or detected during diagnostic colonoscopy ( in patients with no prior colonoscopy ) .
5 We compared prevalence of proximal location and DNA mismatch repair deficiency ( dMMR ) in CRC tumors , relative to time since previous colonoscopy , using logistic regression and cubic splines to assess temporal variation .
6 RESULTS :
7 Of 10,365 incident CRCs , 725 occurred after colonoscopy examinations ( 70% ) .
8 These were more often located in the proximal colon ( odds ratio [OR] , 2.34 ; 95% confidence interval [CI] , 1.90-2.89 ) and were more likely to have dMMR ( OR , 126 ; 95% CI , 100-159 ) , but were less likely to be metastatic at presentation ( OR , 065 ; 95% CI , 048-089 ) compared with CRCs diagnosed in patients with no prior colonoscopy .
9 The highest proportions of proximal and/or dMMR tumors were observed in CRCs diagnosed 3-6 years after colonoscopy , but these features were still more frequent among cancers diagnosed up to 10 years after colonoscopy .
10 The relative excess of dMMR tumors was most pronounced in distal cancers .
11 Μ In an analysis of 85 cases detected after colonoscopy , we found BRAF mutations in 23% of tumors and that 7% of cases had features of Lynch syndrome .
12 Colonoscopy exams were incomplete in a higher proportion of cases diagnosed within <1 year ( in 38% ) than in those diagnosed within 1-10 years after colonoscopy ( 16% ) .
13 CONCLUSIONS :
14 In a study of incident CRC cases in Denmark , we observed that tumors found in patients who have undergone colonoscopy are more often proximal and have dMMR compared to CRCs detected in patients without previous colonoscopies .
15 The excess of right-sided tumors and the modest independent effects of dMMR reinforce the importance of proper colonoscopic examination of the proximal large bowel .



PMID: 27442239
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Treatment of Metastatic Colorectal Cancer Patients >/ = 75 Years Old in Clinical Practice : A Multicenter Analysis .
1 BACKGROUND :
2 Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials .
3 This large population contains patients unfit for treatment , those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear .
4 The aim of the study was to retrospectively analyse Overall Survival ( OS ) of elderly metastatic colorectal cancer ( mCRC ) patients treated with chemotherapy in daily practice .
5 METHODS :
6 Kaplan-Meir method was used for OS , the log-rank or Tarone-Ware test for differences between subgroups , Cox's proportional hazard model to assess the impact of known prognostic factors and treatment .
7 RESULTS :
8 751 patients with mCRC observed between January 2000 and January 2013 were collected .
9 Median age was 79 year ( 75-93 ) ; Male/Female 61/39% , ECOG-PS 0-1/2 85/15% ; colon/rectum 74/26% ; multiple metastatic sites 34% , only liver metastasis in 41% of patients .
10   Μ KRAS status was studied in 35% of patients : 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery .
11 Comorbidities observed : cardiovascular 34% , diabetes 14% , hypertension 50% .
12 Primary tumor was resected in 80.6% ; surgery of liver metastasis was done in 19% of patients ( 23% of patients >80years ) .
13   78% of patients underwent chemotherapy .
14 Median follow up was 12 months ( range 1-124 ) .
15   Median OS was 17 months ( CI 95%15-19 ) ; median OS in no-treated patients was 5 months ( 4-6 ) ; mOS of patients with atleast one treatment was 20 months ( 18-22 ) .
16 In KRAS mutated group median OS was 19months ( 15-23 ) while in KRAS wild type patients median OS was 25 months ( 20-30 ) .
17   At multivariate analysis sex ( Female ) , age ( <80y ) , performance status ( 0-1 ) , chemotherapy , Surgery of metastasis , Surgery of primary tumor and Site of metastasis ( liver ) were prognostic factors for OS .
18 CONCLUSION :
19   The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients , confirmed at multivariate analysis , included patients with age >80 years old or with a poor performance status ( respectively p<00001 and p<00001 ) .
20 KRAS analysis deserve further evaluation .



PMID: 27438067
(Patient)  
Terms: phase I study
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0 A phase I study of the combination of panitumumab and bevacizumab in KRAS wild-type colorectal cancer patients previously treated with fluoropyrimidine , oxaliplatin , irinotecan and bevacizumab .
1 PURPOSE :
2 The clinical benefit of combination treatment with panitumumab and bevacizumab ( PB ) based on bevacizumab beyond progression ( BBP ) after the failure of second - line chemotherapy remains unclear .
3 We assessed the tolerability and efficacy of PB as BBP in Japanese patients with metastatic colorectal cancer ( mCRC ) .
4 METHODS :
5 This phase I study comprised two parts : (1) PB part to estimate the recommended PB dose , (2) CPB part to investigate the safety of PB with irinotecan ( CPB ) .
6 Three panitumumab doses ( 4 , 5 , and 6 mg/kg at Levels -1 , 0 and 1 , respectively ) were set for the PB part , starting with Level 0 .
7 Bevacizumab was administered at a fixed dose of 5 mg/kg , regardless of panitumumab dose levels .
8 All drugs were administered on day 1 and repeated every 2 weeks .
9 RESULTS :
10 No dose-limiting toxicities were observed at Levels 0 ( n = 3 ) and 1 ( n = 3 ) for the PB part , determining the recommended dose as Level 1 .
11 During the whole treatment course at Level 1 , grade 3 acneiform rash was observed in two patients with a partial response .
12 For six patients ( irinotecan biweekly , 150 mg/m(2) n = 3 , 120 mg/m(2) n = 3 ) enrolled in the CPB part , grade 3 toxicities were leukopenia/neutropenia ( n = 1 ) , mucositis ( n = 1 ) , diarrhea ( n = 1 ) , rash acneiform ( n = 1 ) and thromboembolic event ( n = 1 ) , and two of six patients achieved partial responses .
13 CONCLUSION :
14 Recommended doses for the PB regimen in mCRC were panitumumab 6 mg/kg and bevacizumab 5 mg/kg .
15   PB and CPB showed manageable toxicities in KRAS wild-type patients previously managed with standard treatment , including bevacizumab .



PMID: 27435270
(Patient)  
Terms:
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0 CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin - and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer .
1 BACKGROUND :
2 The CpG island methylator phenotype ( CIMP ) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer ( CRC ) cases .
3 CIMP status , which is closely associated with specific clinicopathological and molecular characteristics , is considered a potential predictive biomarker for efficacy of cancer treatment .
4 However , the relationship between the effect of standard chemotherapy , including cytotoxic drugs and anti-epidermal growth factor receptor ( EGFR ) antibodies , and CIMP status has not been elucidated .
5 METHODS :
6 In 125 metastatic colorectal cancer ( mCRC ) patients , we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR ( MSP ) and to genetic status in five EGFR-related genes ( KRAS , BRAF , PIK3CA , NRAS , and AKT1 ) as detected by direct sequencing .
7 RESULTS :
8 CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis ( all P values <005 ) .
9   The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first - line treatment followed by irinotecan-based therapy as the second - line treatment ( median = 66 months ) was inferior to that of such patients receiving the reverse sequence ( median = 152 months ; P = 0043 ) .
10 Μ Furthermore , CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes ( 741 % ) than the CIMP-negative tumors did ( 500 % ) .
11 Among the KRAS wild-type tumors , CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy .
12 CONCLUSION :
13 Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors .
14 ✓ High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors . GM-REG-RO, RO-ASS-GM



PMID: 27433082
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Genomic diversity of colorectal cancer : Changing landscape and emerging targets .
1 Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers ( CRC ) where patients undergo treatment with a curative intent .
2 Despite these efforts , a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes , as CRC remains one of the leading causes of cancer-related deaths in the world .
3 The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC .
4 This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease .
5 ✓ Μ Additionally , the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes , largely due to better selection of personalized therapies based on an individual's tumor genomic makeup.The benefit of various treatments is often limited , where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance . GM-REG-RO
6   These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies , assessing the role of immunotherapy and prospective , dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC .



PMID: 27430658
(Patient)  
Terms: , rat
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0 Serrated polyposis associated with a family history of colorectal cancer and/or polyps : The preferential location of polyps in the colon and rectum defines two molecular entities .
1 Serrated polyposis ( SPP ) is characterized by the development of multiple serrated polyps and an increased predisposition to colorectal cancer ( CRC ) .
2 In the present study , we aimed to characterize , at a clinical and molecular level , a cohort of SPP patients with or without a family history of SPP and/or polyps/CRC ( SPP-FHP/CRC ) .
3 Sixty-two lesions from 12 patients with SPP-FHP/CRC and 6 patients with sporadic SPP were included .
4 The patients with SPP-FHP/CRC presented with an older mean age at diagnosis ( p = 0027 ) and a more heterogeneous histological pattern of lesions ( p = 0032 ) than the patients with sporadic SPP .
5 We identified two molecular forms of SPP-FHP/CRC , according to the preferential location of the lesions : proximal/whole-colon or distal colon .
6 Mismatch repair ( MMR ) gene methylation [mutS homolog 6 ( MSH6 ) /mutS homolog 3 ( MSH3 )] or loss of heterozygosity ( LOH ) of D2S123 ( flanking MSH6 ) were detected exclusively in the former ( p = 30x10-7 ) , in most early lesions .
7 ✓ Proximal/wholecolon SPP-FHP/CRC presented a higher frequency of O-6-methylguanine-DNA methyltransferase ( MGMT ) methylation/LOH , microsatellite instability ( MSI ) and Wnt mutations ( 19/29 vs. 7/17 ; 16/23 vs. 1/14 , p = 22x10-4 ; 15/26 vs. 2/15 , p = 0006 ; 14/26 vs. 4/20 , p = 002 ) but a lower frequency of B-raf proto-oncogene , serine/threonine kinase (BRAF) mutations ( 7/30 vs. 12/20 , p = 00089 ) than the distal form . GM-ASS-DS
8 CRC was more frequent in cases of rat Kirsten sarcoma viral oncogene homolog ( KRAS )- associated proximal/whole-colon SPP-FHP/CRC than in the remaining cases ( 4/4 vs. 1/8 , p = 001 ) .
9 Thus , SPP-FHP/CRC appears to be a specific entity , presenting two forms , proximal/whole-colon and distal , which differ in the underlying tumor initiation pathways .
10 Early MGMT and MMR gene deficiency in the former may underlie an inherited susceptibility to genotoxic stress .



PMID: 27423011
(None)  
Terms: , rat
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0 Determination of a novel B-Raf ( V600E ) and EGFR dual inhibitor in rat plasma by HPLC-MS/MS and its application in a pharmacokinetic study .
1 The EGFR and B-Raf ( V600E ) dual inhibition is a promising strategy in treatment of colorectal cancer patients with B-Raf ( V600E ) mutation .
2 Previously , compound 3 was designed and synthesized as a novel B-Raf ( V600E ) and EGFR dual inhibitor with highly potency in both kinase and cell based assay .
3 Herein , a sensitive and rapid HPLC-MS/MS quantitative method was developed and validated for the further pharmacokinetic evaluation of compound 3 in rats .



PMID: 27421843
(None)  
Terms:
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0 HIF-1alpha expression and high microvessel density are characteristic features in serrated colorectal cancer .
1 Serrated colorectal adenocarcinoma ( SAC ) is a morphologically distinct subtype of colorectal cancer ( CRC ) , in which increased HIF-1alpha mRNA expression and HIF-1alpha protein stabilization are typical features .
2 Here we aimed to further elucidate HIF-1alpha protein expression in serrated and non-serrated colorectal carcinomas ( CRCs ) and their precursor lesions and its association with vascular endothelial growth factor ( VEGF ) and microvascular density ( MVD ) .
3 HIF-1alpha and VEGF expressions were determined immunohistochemically in 134 serrated polyps ( SPs ) , 104 non-serrated adenomas ( NSAs ) , 81 SACs , and 74 matched conventional adenocarcinomas ( CCs ) and were correlated with morphology , clinicopathological features , and MVD .
4 In premalignant lesions , both HIF-1alpha and VEGF were expressed in the vast majority of SPs and NSAs .
5 In CRCs , HIF-1alpha protein was also present in 77.8 % of SACs , while only 20.3 % of CCs were HIF-1alpha proficient .
6 MVD was significantly higher in SACs , but the serrated morphology was the only significant predictor of MVD in CRC in multivariate analyses .
7 HIF-1alpha protein is often stabilized in well-vascularized SACs , suggesting hypoxia -independent stabilization of HIF-1alpha .
8 Moreover , HIF-1alpha stabilization did not associate with oncogenic activation of BRAF or KRAS or Von Hippel-Lindau ( VHL ) mutation .
9 Prevalent HIF-1alpha expression in SAC and its precursors support the importance of HIF-1alpha -mediated pathways for the serrated route of colorectal carcinogenesis .



PMID: 27411517
(Patient)  
Terms: in vitro, In vitro
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0 SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer .
1 BACKGROUND :
2 To improve current treatment strategies for patients with aggressive colorectal cancer ( CRC ) , the molecular understanding of subgroups of CRC with poor prognosis is of vast importance .
3 SOX2 positive tumors have been associated with a poor patient outcome , but the functional role of SOX2 in CRC patient prognosis is still unclear .
4 METHODS :
5 An in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC .
6 In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded ( FFPE ) tumor tissue from a cohort of 445 CRC patients .
7 RESULTS :
8 Using our in vitro model , we found that SOX2 expressing cells displayed several characteristics of cancer stem cells ; such as a decreased proliferative rate , a spheroid growth pattern , and increased expression of stem cell markers CD24 and CD44 .
9 Μ Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2 .
10 We next evaluated CDX2 expression in our patient cohort .
11 Μ CDX2 down-regulation was more often found in right sided tumors of high grade and high stage .
12 Furthermore , a decreased expression of CDX2 was closely linked to MSI , CIMP-high as well as BRAF mutated tumors .
13 A decreased expression of CDX2 was also , in a stepwise manner , strongly correlated to a poor patient prognosis .
14 Μ When looking at SOX2 expression in relation to CDX2 , we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2 .
15 ✓ In addition , SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression . GE-ASS-RO, RO-ASS-GE
16 CONCLUSIONS :
17 Our results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2 .
18 Furthermore , a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and atleast part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation .



PMID: 27405731
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Highly sensitive detection of the PIK3CA (H1047R) mutation in colorectal cancer using a novel PCR-RFLP method .
1 BACKGROUND :
2 The PIK3CA (H1047R) mutation is considered to be a potential predictive biomarker for EGFR-targeted therapies .
3 Μ In this study , we developed a novel PCR-PFLP approach to detect the PIK3CA (H1047R) mutation in high effectiveness .
4 METHODS :
5 A 126-bp fragment of PIK3CA exon-20 was amplified by PCR , digested with FspI restriction endonuclease and separated by 3 % agarose gel electrophoresis for the PCR-RFLP analysis .
6 The mutant sequence of the PIK3CA (H1047R) was spiked into the corresponding wild-type sequence in decreasing ratios for sensitivity analysis .
7 Eight-six cases of formalin-fixed paraffin-embedded colorectal cancer ( CRC ) specimens were subjected to PCR-RFLP to evaluate the applicability of the method .
8 RESULTS :
9 Μ The PCR-RFLP method had a capability to detect as litter as 0.4 % of mutation , and revealed 16.3 % of the PIK3CA (H1047R) mutation in 86 CRC tissues , which was significantly higher than that discovered by DNA sequencing ( 93 % ) .
10 Μ A positive association between the PIK3CA (H1047R) mutation and the patients' age was first found , except for the negative relationship with the degree of tumor differentiation .
11 In addition , the highly sensitive detection of a combinatorial mutation of PIK3CA , KRAS and BRAF was achieved using individual PCR-RFLP methods .
12 CONCLUSIONS :
13   Μ We developed a sensitive , simple and rapid approach to detect the low-abundance PIK3CA (H1047R) mutation in real CRC specimens , providing an effective tool for guiding cancer targeted therapy .



PMID: 27404452
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers .
1 BACKGROUND :
2 Μ The aim of this study was to reveal the clinicopathological and molecular characteristics of microsatellite instability-high ( MSI-H ) colorectal cancers ( CRCs ) showing programmed death ligand-1 ( PD-L1 ) positivity , which are good candidates for anti-PD-1/PD-L1 immunotherapy .
3 METHODS :
4 The PD-L1 expression status of 208 MSI-H CRCs was retrospectively analysed using immunohistochemistry .
5 PD-L1 positivity in tumour cells (PD-L1+(T)) and PD-L1 positivity in immune cells (PD-L1+(I)) were separately evaluated .
6 RESULTS :
7 Programmed death ligand -1 positivity in tumour cells and PD-L1+(I) were observed in 26 ( 125% ) and 62 ( 298% ) MSI-H CRCs , respectively , and occasionally overlapped ( n = 12 ; 58% ) .
8 Programmed death ligand -1 positivity tumours in MSI-H CRCs were significantly associated with older age , female sex , non-mucinous-type poor differentiation , infiltrating growth , tumour budding , advanced stage , CpG island methylator phenotype-high , MLH1 promoter methylation , and BRAF V600E mutations .
9 However , PD-L1+(I) MSI-H CRCs were characterised by high-density tumour-infiltrating immune cells , including T cells and macrophages , and intense peritumoural lymphoid reactions .
10 In patients with stage IV MSI-H CRCs who had undergone metastatectomy ( n = 4 ) , the PD-L1 status of primary tumours was maintained in corresponding distant metastatic lesions .
11 CONCLUSIONS :
12 In MSI-H CRCs , PD-L1+(T) and PD-L1+(I) are linked to a sporadic hypermethylated subtype and an immune cell -rich subtype , respectively .
13 Potential differential therapeutic implications of PD-L1+(T) and PD-L1+(I) in CRCs should be further investigated .



PMID: 27404270
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis . GM-ASS-RO
1 OBJECTIVE :
2 BRAF D594G mutations in colorectal cancer patients are not clearly understood .
3 We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations .
4 METHODS :
5 We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013 , and assessed BRAF , KRAS , microsatellite instability , and CpG island methylator phenotype ( CIMP ) .
6 RESULTS :
7 We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients .
8 The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type , but differed from those with BRAF V600E mutations .
9 Regarding microsatellite instability status , 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability , compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type .
10 There were no CIMP-positive tumors in cancers with BRAF D594G mutations , whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive .
11 In stage IV cancers , the survival rates of patients at 2 years were 8.5 , 50.0 , and 68.2% in the BRAF V600E mutation , BRAF D594G mutation , and BRAF wild-type groups , respectively .
12 CONCLUSION :
13 ✓ Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features , microsatellite instability status , and prognosis as those with BRAF wild-type . GM-ASS-RO



PMID: 27401719
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Challenging a dogma : co-mutations exist in MAPK pathway genes in colorectal cancer .
1 Sequencing of genes encoding mitogen -activated protein kinase ( MAPK ) pathway proteins in colorectal cancer ( CRC ) has established as dogma that of the genes in a pathway only a single one is ever mutated .
2 We searched for cases with a mutation in more than one MAPK pathway gene ( co-mutations ) .
3 Μ Tumor tissue samples of all patients presenting with CRC , and referred between 01/01/2008 and 01/06/2015 to three French cancer centers for determination of mutation status of RAS/RAF+/-PIK3CA , were retrospectively screened for co-mutations using Sanger sequencing or next-generation sequencing .
4 Μ We found that of 1791 colorectal patients with mutations in the MAPK pathway , 20 had a co-mutation , 8 of KRAS/NRAS , and some even with a third mutation .
5 More than half of the mutations were in codons 12 and 13 .
6 Μ We also found 3 cases with a co-mutation of NRAS/BRAF and 9 with a co-mutation of KRAS/BRAF .
7 In 2 patients with a co-mutation of KRAS/NRAS , the co-mutation existed in the primary as well as in a metastasis , which suggests that co-mutations occur early during carcinogenesis and are maintained when a tumor disseminates .
8 We conclude that co-mutations exist in the MAPK genes but with low frequency and as yet with unknown outcome implications .



PMID: 27401248
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer .
1 PURPOSE :
2 EphA2 receptor is involved in multiple cross-talks with other cellular networks , including EGFR , FAK , and VEGF pathways , with which it collaborates to stimulate cell migration , invasion , and metastasis .
3 Colorectal cancer ( CRC ) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy .
4 We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways .
5 We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC .
6 EXPERIMENTAL DESIGN :
7 Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures .
8 Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response .
9 RESULTS :
10 Μ We identified a gene expression pattern ( EphA2 , Efna1 , Egfr , Ptpn12 , and Atf2 ) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a .
11 Such a pattern showed prognostic significance in patients with stage I-III CRC , in both univariate and multivariate analysis .
12   In patients with stage IV and WT KRAS , EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment .
13 Μ Furthermore , EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance , independently from KRAS mutation status .
14 CONCLUSIONS :
15   These results suggest that EphA2/Efna1/Egfr genes , linked to a possible control by miR-200a and miR-26b , could be proposed as novel CRC prognostic biomarkers .
16 Moreover , EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations .
17 Clin Cancer Res ; 23(1) ; 159-70 .
18 (c) 2016 AACR .



PMID: 27399335
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 ✓ FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation .
1 Colorectal cancer ( CRC ) , the second leading cause of cancer-related deaths in the US , has been treated with targeted therapies .
2 However , the mechanisms of differential responses and resistance of CRCs to targeted therapies are not well understood .
3 Μ In this study , we found that genetic alterations of FBW7 , an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs , contribute to resistance to targeted therapies .
4 ✓ CRC cells containing FBW7-inactivating mutations are insensitive to clinically used multi - kinase inhibitors of RAS/RAF/MEK/ERK signaling , including regorafenib and sorafenib .
5 ✓ In contrast , sensitivity to these agents is not affected by oncogenic mutations in KRAS , BRAF , PIK3CA or p53 .
6 These cells are defective in apoptosis owing to blocked degradation of Mcl-1 , a pro-survival Bcl-2 family protein .
7 Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug -resistance phenotypes of FBW7-mutant cells .
8 ✓ CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations , and are cross-resistant to other targeted drugs that induce Mcl-1 degradation .
9 Furthermore , a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance .
10 Together , our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies , and Mcl-1 as an attractive therapeutic target .



PMID: 27399059
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Economic evaluation study ( CHEER-compliant ) : Cost-effectiveness analysis of RAS screening for treatment of metastatic colorectal cancer based on the CALGB 80405 trial .
1 Cetuximab ( Cetux ) /Bevacizumab ( Bev ) treatments have shown considerably survival benefits for patients with metastatic colorectal cancer ( mCRC ) in the last decade .
2 But they are costly .
3 Currently , no data is available on the health economic implications of testing for extended RAS wild-type ( wt ) prior to Cetux/Bev treatments of patients with mCRC .
4 This paper aimed to evaluate the cost-effectiveness of predictive testing for extended RAS-wt status in mCRC in the context of targeting the use of Cetux/Bev .
5 Markov model 1 was conducted to provide evidence evaluating the cost-effectiveness of predictive testing for KRAS-wt or extended RAS-wt status based on treatments of chemotherapy plus Cetux/Bev .
6 Markov model 2 assessed the cost-effectiveness of FOLFOX plus Cetux/Bev or FOLFIRI plus Cetux/Bev in extended RAS-wt population .
7 Primary base case data were identified from the CALGB 80405 trial and the literatures .
8 Costs were estimated from West China Hospital , Sichuan University , China .
9 Survival benefits were reported in quality-adjusted life-years ( QALYs ) .
10 The incremental cost-effectiveness ratio ( ICER ) was calculated .
11 In analysis 1 , the cost per QALY was $88,394.09 for KRAS-Cetux , $80,797.82 for KRAS-Bev , $82,590.72 for RAS-Cetux , and $75,358.42 for RAS-Bev .
12 The ICER for RAS-Cetux versus RAS-Bev was $420,700.50 per QALY gained .
13 In analysis 2 , the cost per QALY was $81,572.61 , $80,856.50 , $80,592.22 , and $66,794.96 for FOLFOX-Cetux , FOLFOX-Bev , FOLFIRI-Cetux , and FOLFIRI-Bev , respectively .
14 The analyses showed that the extended RAS-wt testing was less costly and more effective versus KRAS-wt testing before chemotherapy plus Cetux/Bev .
15 Furthermore , FOLFIRI plus Bev was the most cost-effective strategy compared with others in extended RAS-wt population .
16 It was economically favorable to identify patients with extended RAS-wt status .
17 Furthermore , FOLFIRI plus Bev was the preferred strategy in extended RAS-wt patients .



PMID: 27394063
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutation spectra of RAS gene family in colorectal cancer .
1 BACKGROUND :
2 The clinicopathologic features and frequency of KRAS mutations in colorectal cancer ( CRC ) patients have been reported ; however , the characteristics and impact of NRAS and HRAS mutations on the survival of CRC patients have seldom been addressed .
3 METHODS :
4 Under institutional review board approval , 1,519 CRC patients who underwent surgery were enrolled .
5 Mutation status of RAS was determined by polymerase chain reaction and mass spectrophotometry .
6 RESULTS :
7 The frequency of KRAS , NRAS , and HRAS mutations was 39.6% , 4.3% , and 1.7% , respectively .
8 The KRAS mutation was associated with fewer left-sided tumors , fewer poor differentiated tumors , more mucin component , and less lymphovascular invasion .
9 The NRAS or HRAS mutations were not associated with any of the clinicopathologic features examined .
10 ✓ After univariate analysis , only NRAS mutation was associated with patients' overall and disease-free survival . GM-ASS-RO
11 However , the association of NRAS with patients' overall and disease-free survival disappeared after stepwise elimination .
12 CONCLUSIONS :
13 This study demonstrates the clinicopathologic characteristics of CRC patients with RAS mutations .
14 Patients with NRAS mutation tended to have worse outcomes .



PMID: 27392434
(Patient)  
Terms: Retrospective
Sent# Symbols Sentence Mnemonics
0 In depth evaluation of the prognostic and predictive utility of PTEN immunohistochemistry in colorectal carcinomas : performance of three antibodies with emphasis on intracellular and intratumoral heterogeneity .
1 BACKGROUND :
2 Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer .
3 Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy .
4 Unfortunately , while immunohistochemical assessment of PTEN expression is widespread , it lacks standardization and the results are hardly comparable across the available publications .
5 METHODS :
6 Retrospectively collected , formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray ( TMA ) blocks .
7 We used three different PTEN antibodies to determine the frequency , intensity and intracellular pattern of PTEN immunohistochemical labeling : Neomarkers , Dako and CellSignaling .
8 We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity ( H1-H3-score ) .
9 We also evaluated intracellular localization .
10 RESULTS :
11 The Dako and CellSignaling antibodies stained predominantly cytoplasms , while the Neomarkers antibody specifically stained cell nuclei .
12 PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies .
13 Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies .
14 Μ Neither Dako , neither CellSignaling , nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT , Dukes/MAC and clinical stage .
15 KRAS status , histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody .
16 PTEN H-scores did not correlate with MMR status .
17 PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody .
18 CONCLUSIONS :
19 While PTEN expression decreased in colorectal cancer according to two antibodies , neither of the three applied PTEN antibodies could justify significant correlation with clinicopathological data , nor had prognostic value .
20 Thus , we might conclude that immunohistochemical PTEN investigation remains a challenge requiring more standardized evaluation on larger number of cases to clarify its utility as a prognostic and predictive tool in CRC .
21 The standardization of immunohistochemical method is key in the evaluation process , which is further discussed .



PMID: 27391152
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival .
1 Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells , immune cells , and microbiota that vary along the proximal to distal axis of colorectum .
2 Long interspersed nucleotide element-1 ( LINE-1 ) hypomethylation in colorectal cancer has been associated with worse clinical outcome .
3 Utilizing 1,317 colon and rectal carcinoma cases in two U .
4 S.-nationwide prospective cohort studies , we examined patient survival according to LINE-1 methylation level stratified by tumor location .
5 Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis , controlling for potential confounders including microsatellite instability , CpG island methylator phenotype , and KRAS , BRAF , and PIK3CA mutations .
6 A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis ( Pinteraction = 0011 ) .
7 The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers ( multivariable hazard ratio [HR] , 1.66 ; 95% confidence interval [CI] , 1.21 to 2.28 ) than in distal colon cancers ( multivariable HR , 118 ; 95% CI , 081 to 172 ) or rectal cancers ( multivariable HR , 087 ; 95% CI , 057 to 134 ) .
8 Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome .



PMID: 27391062
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Reactivation of ERK and Akt confers resistance of mutant BRAF colon cancer cells to the HSP90 inhibitor AUY922 .
1 Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients .
2 Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 ( HSP90 ) inhibitor AUY922 , and that this is caused by rebound activation of ERK and Akt .
3 Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells , activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922 -induced apoptosis .
4 Reactivation of ERK was associated with the persistent expression of mutant BRAF , which , despite being a client of HSP90 , was only partially degraded by AUY922 , whereas reactivation of Akt was related to the activity of the HSP90 co-chaperone , cell division cycle 37 ( CDC37 ) , in that knockdown of CDC37 inhibited Akt reactivation in mutant colon cancer cells treated with AUY922 .
5 In support , as a HSP90 client protein , Akt was only diminished by AUY922 in wild-type but not mutant BRAF colon cancer cells .
6   Collectively , these results reveal that reactivation of ERK and Akt associated respectively with the activity of mutant BRAF and CDC37 renders mutant BRAF colon cancer cells resistant to AUY922 , with implications of co-targeting mutant BRAF and /or CDC37 and HSP90 in the treatment of mutant BRAF colon cancers .



PMID: 27389564
(Patient)  
Terms: NCT02310477
Sent# Symbols Sentence Mnemonics
0 Survival , safety , and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies : results from a multicenter study ( REBACCA ) nested within a compassionate use program .
1 BACKGROUND :
2 Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer ( mCRC ) that progressed after standard therapies .
3 We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting .
4 METHODS :
5 REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival , safety , and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies .
6 Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models .
7 RESULTS :
8 Of 1178 patients in the compassionate use program , 654 were in the full analysis set .
9 Median follow-up was 16.5 months .
10 Median survival was 5.6 months .
11 The 12-month survival rate was 22 % .
12 Survival was independently and unfavourably affected by the following variables : poor performance status , short time from initial diagnosis of metastases to the start of regorafenib , low initial regorafenib dose , >3 metastatic sites , presence of liver metastases , and KRAS mutations .
13 Μ We identified prognostic groups of patients with low , intermediate , and high risk of death , with a median survival of 9.2 , 5.2 , and 2.5 months , respectively .
14 Five-hundred-twenty-four patients ( 80 % ) experienced atleast one regorafenib-related adverse event , most commonly , fatigue , hand-foot skin reaction , diarrhea , anorexia , arterial hypertension , and mucositis .
15 CONCLUSION :
16 The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials .
17   Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib .
18 TRIAL REGISTRATION :
19 Clinicaltrials .
20 gov NCT02310477 .



PMID: 27385211
(Cell)  
Terms: PDX
Sent# Symbols Sentence Mnemonics
0 Antitumor activity of the aurora a selective kinase inhibitor , alisertib , against preclinical models of colorectal cancer .
1 BACKGROUND :
2 The Aurora kinases are a family of serine/threonine kinases comprised of Aurora A , B , and C which execute critical steps in mitotic and meiotic progression .
3 Alisertib ( MLN8237 ) is an investigational Aurora A selective inhibitor that has demonstrated activity against a wide variety of tumor types in vitro and in vivo , including CRC .
4 RESULTS :
5 CRC cell lines demonstrated varying sensitivity to alisertib with IC50 values ranging from 0.06 to >5 umol/L .
6 Following exposure to alisertib we observed a decrease in pAurora A , B and C in four CRC cell lines .
7 We also observed an increase in p53 and p21 in a sensitive p53 wildtype cell line in contrast to the p53 mutant cell line or the resistant cell lines .
8 The addition of alisertib to standard CRC treatments demonstrated improvement over single agent arms ; however , the benefit was largely less than additive , but not antagonistic .
9 METHODS :
10 Forty-seven CRC cell lines were exposed to alisertib and IC50s were calculated .
11 Twenty-one PDX models were treated with alisertib and the Tumor Growth Inhibition Index was assessed .
12 Additionally , 5 KRAS wildtype and mutant PDX models were treated with alisertib as single agent or in combination with cetuximab or irinotecan , respectively .
13 CONCLUSION :
14 Alisertib demonstrated anti-proliferative effects against CRC cell lines and PDX models .
15   Our data suggest that the addition of alisertib to standard therapies in colorectal cancer if pursued clinically , will require further investigation of patient selection strategies and these combinations may facilitate future clinical studies .



PMID: 27384156
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Paired Primary and Metastatic Tumor Analysis of Somatic Mutations in Synchronous and Metachronous Colorectal Cancer .
1 PURPOSE :
2 Although the mutation status of KRAS is highly concordant in primary and metastatic lesions , it has not been generalized to other major pathway genes .
3 MATERIALS AND METHODS :
4 In this study , 41 genes were evaluated and the mutational profiles were compared in 46 colorectal cancer patients with paired surgical specimens of primary and metastatic lesions : synchronous ( n = 27 ) and metachronous ( n = 19 ) lesions .
5 A high-throughput mass spectrometry-based genotyping platform validated by orthogonal chemistry , OncoMap v.4.4 , was used to evaluate the formalin-fixed , paraffin-embedded surgical specimens .
6 The patients' demographics , tumor characteristics , and microsatellite instability status were analyzed by a retrospective chart review .
7 RESULTS :
8 In this study , with OncoMap , mutationswere identified in 80.4% of patientswith the following frequency : KRAS ( 391% ) , TP53 ( 283% ) , APC ( 283% ) , PIK3CA ( 65% ) , BRAF ( 65% ) , and NRAS ( 43% ) .
9 Μ Although 19.6% ( 9/46 ) of the patients showed no gene mutations , 43.5% ( 20/46 ) and 37.0% ( 17/46 ) had mutations in one and two or more genes , respectively .
10 The synchronous and metachronous lesions showed similar mutational profiles .
11 Paired samples between primary and metastatic tumors differed in 7.4% ( 2/27 ) and 10.5% ( 2/19 ) for synchronous and metachronous according to OncoMap .
12 CONCLUSION :
13 These findings indicate the major pathway genes , including KRAS , TP53 , APC , PIK3CA , BRAF , and NRAS , are often concordant between the primary and metastatic lesions regardless of the temporal relationship of metastasis .



PMID: 27383396
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Human Blood Autoantibodies in the Detection of Colorectal Cancer .
1 Colorectal cancer ( CRC ) is the second most common malignancy in the western world .
2 Early detection and diagnosis of all cancer types is vital to improved prognosis by enabling early treatment when tumours should be both resectable and curable .
3 Sera from 3 different cohorts ; 42 sera ( 21 CRC and 21 matched controls ) from New York , USA , 200 sera from Pittsburgh , USA ( 100 CRC and 100 controls ) and 20 sera from Dundee , UK ( 10 CRC and 10 controls ) were tested against a panel of multiple tumour-associated antigens ( TAAs ) using an optimised multiplex microarray system .
4 TAA specific IgG responses were interpolated against the internal IgG standard curve for each sample .
5 Individual TAA specific responses were examined in each cohort to determine cutoffs for a robust initial scoring method to establish sensitivity and specificity .
6 Sensitivity and specificity of combinations of TAAs provided good discrimination between cancer-positive and normal serum .
7 The overall sensitivity and specificity of the sample sets tested against a panel of 32 TAAs were 61.1% and 80.9% respectively for 6 antigens ; p53 , AFP , K RAS , Annexin , RAF1 and NY-CO16 .
8 Furthermore , the observed sensitivity in Pittsburgh sample set in different clinical stages of CRC ; stage I ( n = 19 ) , stage II ( n = 40 ) , stage III ( n = 34 ) and stage IV ( n = 6 ) was similar ( 736% , 750% , 735% and 833% , respectively ) , with similar levels of sensitivity for right and left sided CRC .
9 We identified an antigen panel of sufficient sensitivity and specificity for early detection of CRC , based upon serum profiling of autoantibody response using a robust multiplex antigen microarray technology .
10 This opens the possibility of a blood test for screening and detection of early colorectal cancer .
11 However this panel will require further validation studies before they can be proposed for clinical practice .



PMID: 27382031
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer .
1 INTRODUCTION :
2 Right - and left-sided colorectal cancers ( CRCs ) differ in clinical and molecular characteristics .
3 Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor ( EGFR ) antibodies ; however , molecular selection in those studies was not extensive .
4 PATIENTS AND METHODS :
5 Patients with RAS and BRAF wild-type metastatic CRC ( mCRC ) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan ( if refractory to previous irinotecan ) were included in the study .
6 Differences in outcome between patients with right - and left-sided tumors were investigated .
7 RESULTS :
8 Of 75 patients , 14 and 61 had right - and left-sided tumors , respectively .
9 None of the right-sided tumors responded according to RECIST , compared with 24 left-sided tumors ( overall response rate : 0% vs. 41% ; p = .0032 ) , and only 2 patients with right-sided tumors ( 15% ) versus 47 patients with left-sided tumors ( 80% ) achieved disease control ( p <0001 ) .
10 The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors , respectively ( hazard ratio : 3.97 ; 95% confidence interval : 2.09-7.53 ; p <.0001 ) .
11 CONCLUSION :
12   Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs .
13 IMPLICATIONS FOR PRACTICE :
14 Right - and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics , distinct gene expression profiles and genetic alterations , and different prognoses .
15   This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer .
16 The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type , right-sided tumors , thus suggesting a potential role for primary tumor location in driving treatment choices .



PMID: 27380142
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Caldoramide , a Modified Pentapeptide from the Marine Cyanobacterium Caldora penicillata .
1 The isolation , structure determination , and biological activities of a new linear pentapeptide , caldoramide (5) , from the marine cyanobacterium Caldora penicillata from Florida are described .
2 Caldoramide (5) has structural similarities to belamide A (4) , dolastatin 10 (1) , and dolastatin 15 (2) .
3 We profiled caldoramide against parental HCT116 colorectal cancer cells and isogenic cells lacking oncogenic KRAS or hypoxia-inducible factors 1alpha ( HIF-1alpha ) and 2alpha ( HIF-2alpha ) .
4 Caldoramide (5) showed differential cytotoxicity for cells containing both oncogenic KRAS and HIF over the corresponding knockout cells .
5 LCMS dereplication indicated the presence of caldoramide (5) in a subset of C .
6 penicillata samples .



PMID: 27376251
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer : Current status and management .
1 Serrated polyps have long been thought to lack malignant potential in the human colorectum .
2 However , identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers .
3 Accordingly , serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps ( SSA/P ) are now considered to be precursor lesions of the serrated pathway .
4 Recently , serrated polyps were classified into three subtypes , consisting of hyperplastic polyp , SSA/P , and traditional serrated adenoma , according to the World Health Organization classification .
5 It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability .
6 However , SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers , particularly in the proximal colon because it presents flat or sessile , isochroous appearance , and occasionally has a mucous cap.Furthermore , the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp.It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines .
7 In this review , we discuss the recent classification of serrated polyps ; the molecular characteristics of the serrated pathway ; appropriate diagnostic methods using endoscopy , including a new image-enhanced endoscopic technique ; and management of these lesions .



PMID: 27358379
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Outcome according to KRAS- , NRAS - and BRAF-mutation as well as KRAS mutation variants : pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group .
1 BACKGROUND :
2 To explore the impact of KRAS , NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer ( mCRC ) receiving first - line therapy .
3 PATIENTS AND METHODS :
4 A total of 1239 patients from five randomized trials ( FIRE-1 , FIRE-3 , AIOKRK0207 , AIOKRK0604 , RO91 ) were included into the analysis .
5 Outcome was evaluated by the Kaplan-Meier method , log-rank tests and Cox models .
6 RESULTS :
7 Μ In 664 tumors , no mutation was detected , 462 tumors were diagnosed with KRAS - , 39 patients with NRAS - and 74 patients with BRAF-mutation .
8 ✓ Mutations in KRAS were associated with inferior progression-free survival ( PFS ) and overall survival ( OS ) [multivariate hazard ratio ( HR ) for PFS : 1.20 ( 102-142 ) , P = 0.03 ; multivariate HR for OS : 1.41 ( 117-170 ) , P <0.001] . GM-ASS-RO
9 ✓ BRAF mutation was also associated with inferior PFS [multivariate HR : 2.19 ( 159-302 ) , P <0.001] and OS [multivariate HR : 2.99 ( 210-425 ) , P <0.001] . GM-ASS-RO
10 ✓ Among specific KRAS mutation variants , the KRAS G12C-variant ( n = 28 ) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 ( 125-41 ) , P = 0.001] . GM-ASS-RO
11 A similar trend for OS was seen in the KRAS G13D-variant [n = 71 , multivariate HR 1.46 ( 096-222 ) , P = 0.10] .
12 More frequent KRAS exon 2 variants like G12D [n = 152 , multivariate HR 1.17 ( 086-16 ) , P = 0.81] and G12V [n = 92 , multivariate HR 1.27 ( 087-186 ) , P = 0.57] did not have significant impact on OS .
13 CONCLUSION :
14 ✓ Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors . GM-ASS-RO
15 ✓ KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D ( trend ) being associated with rather poor survival . GM-ASS-RO



PMID: 27355330
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high , BRAF mutant metastatic colon cancer : a case report and review of literature .
1 IMPORTANCE :
2 Mismatch repair ( MMR ) and BRAF mutation status are established independent prognostic factors for colorectal cancer ( CRC ) .
3 MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis .
4 Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients .
5 Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients ; however little is known about combined MMR and BRAF mutation status in this context .
6 Therefore , it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients .
7 OBSERVATIONS :
8 We report the first case of MSI-high , BRAF mutant metastatic CRC that had an excellent response ( pathologic complete response ) to anti-PD-1 therapy .
9 We take this opportunity to review the similar cases in literature and discuss combined MMR and BRAF status as a potential biomarker for anti-PD-1 therapy .
10 CONCLUSION AND RELEVANCE :
11   The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors .
12   Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC .



PMID: 27354619
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of Panitumumab Plus Irinotecan and Cetuximab Plus Irinotecan for KRAS Wild-type Metastatic Colorectal Cancer .
1 BACKGROUND/AIM :
2 Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer ( mCRC ) .
3 However , it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine , oxaliplatin and irinotecan .
4 PATIENTS AND METHODS :
5 Data , from 139 patients who received panitumumab or cetuximab , in combination with irinotecan , for KRAS wild-type mCRC previously treated with fluoropyrimidine , oxaliplatin and irinotecan were analyzed .
6 The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan .
7 RESULTS :
8 Baseline characteristics of the panitumumab plus irinotecan ( n = 42 ) and cetuximab plus irinotecan ( n = 97 ) groups were similar .
9 Among patients with measurable lesions , the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group .
10 Median progression-free survival ( PFS ) was 4.3 and 5.7 months in the panitumumab and cetuximab groups , respectively .
11 Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab .
12 CONCLUSION :
13 Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan .



PMID: 27354468
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression .
1 PURPOSE :
2 Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers , a group with particularly poor prognosis .
3 The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts .
4 There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population .
5 EXPERIMENTAL DESIGN :
6 Μ In the biggest yet reported cohort of 218 BRAF V600E with gene expression data , we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation .
7 RESULTS :
8 We found strong support for a split into two distinct groups , called BM1 and BM2 .
9 These subtypes are independent of MSI status , PI3K mutation , gender , and sidedness .
10 Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation , mTOR/4EBP deregulation , and EMT whereas BM2 displays important deregulation of the cell cycle .
11 Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1 , and BM2 patients display high CDK1 and low cyclin D1 levels .
12 We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers .
13 CONCLUSIONS :
14 We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting .
15 Clin Cancer Res ; 23(1) ; 104-15 .
16 (c) 2016 AACR .



PMID: 27353028
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distinct Transcriptional Changes and Epithelial-Stromal Interactions Are Altered in Early-Stage Colon Cancer Development .
1 UNLABELLED :
2 Although the progression of mutated colonic cells is dependent upon interactions between the initiated epithelium and surrounding stroma , the nature of these interactions is poorly understood .
3 Here , the development of an ultrasensitive laser capture microdissection ( LCM ) /RNA-seq approach for studying the epithelial and stromal compartments of aberrant crypt foci ( ACF ) is described .
4 Μ ACF are the earliest identifiable preneoplastic lesion found within the human colon and are detected using high-definition endoscopy with contrast dye spray .
5 The current analysis focused on the epithelium of ACF with somatic mutations to either KRAS , BRAF , or APC , and expression patterns compared with normal mucosa from each patient .
6 THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
7 Immunofluorescence confirmed increased CD3(+) T cells within the stromal microenvironment of ACF and an abundance of activated fibroblasts .
8 Collectively , these results provide new insight into the cellular interplay that occurs at the earliest stages of colonic neoplasia , highlighting the important role of NF-kappaB , activated stromal fibroblasts , and lymphocyte infiltration .
9 IMPLICATIONS :
10 Fibroblasts and immune cells in the stromal microenvironment play an important role during the earliest stages of colon carcinogenesis .
11 Mol Cancer Res ; 14(9) ; 795-804 .
12 (c) 2016 AACR .



PMID: 27352204
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location .
1 BACKGROUND :
2 Right-sided and left-sided colorectal cancer ( CRC ) is known to differ in their molecular carcinogenic pathways .
3 We sought to investigate the variable prognostic implication of KRAS mutation after hepatectomy for colorectal liver metastases ( CRLM ) according to the site of primary CRC .
4 METHODS :
5 A total of 426 patients who underwent a curative-intent hepatic resection and whose KRAS status was available were identified .
6 Clinicopathologic characteristics and long-term outcomes were stratified by KRAS status ( wild type vs . mutant type ) and primary tumor location ( right-sided vs. left-sided ) .
7 Cecum , right and transverse colon were defined as right-sided , whereas left colon and rectum were defined as left-sided .
8 RESULTS :
9 ✓ Among patients with a right-sided CRC , 5-year recurrence-free survival ( RFS ) and overall survival ( OS ) were not correlated with KRAS status ( wild type : 30.8 and 47.2 % vs . mutant type : 38.5 and 49.1 % , respectively ) ( both P >005 ) . RO-ASS-GE
10 ✓ Specifically , mutant -type KRAS was not associated with either RFS or OS on multivariable analysis ( hazard ratio [HR] 1.51 , 95 % confidence interval [CI] 0.73-3.14 , P = 0.23 and HR 1.03 , 95 % CI 0.51-2.08 , P = 0.95 , respectively ) . GE-ASS-RO
11 In contrast , among patients who underwent resection of CRLM from a left-sided primary CRC , 5-year RFS and OS were worse among patients with mutant -type KRAS ( wild type : 23.7 and 57.2 % vs . mutant type : 19.6 and 38.2 % , respectively ) ( both P <005 ) .
12 ✓ On multivariable analysis , mutant -type KRAS remained independently associated with worse RFS and OS among patients with a left-sided primary CRC ( HR 157 , 95 % CI 101-244 , P = 004 and HR 181 , 95 % CI 111-296 , P = 002 , respectively ) . GE-ASS-RO
13 CONCLUSIONS :
14 KRAS status has a variable prognostic impact after hepatic resection for CRLM depending on the site of the primary CRC .
15 ✓ Future studies examining the impact of KRAS status on prognosis after hepatectomy should take into account the primary CRC tumor site . GE-ASS-RO



PMID: 27351224
(Cell)  
Terms: in vitro, xenograft
Sent# Symbols Sentence Mnemonics
0 BRAFV600E -dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells .
1 mTOR activation is commonly caused by oncogenic mutations in RAS/RAF/MAPK and PI3K/AKT pathways , and promotes cancer progression and therapeutic resistance .
2 However , mTOR inhibitors show limited single agent efficacy in patients .
3 mTOR inhibitors suppress tumor cell growth and angiogenesis , and have recently been shown to induce death receptor/FADD -dependent apoptosis in colon cancers .
4 Using a panel of BRAF V600E and WT colorectal cancer cell lines and in vitro selected resistant culture , and xenograft models , we demonstrate here that BRAFV600E confers resistance to mTOR inhibitors .
5   Everolimus treatment disrupts the S6K1-IRS-2/PI3K negative feedback loop , leading to BRAF V600E -dependent activation of ERK and Mcl-1 stabilization in colon cancer cells , which in turn blocks the crosstalk from the death receptor to mitochondria .
6 Co-treatment with inhibitors to Mcl-1 , PI3K , RAF or MEK restores mTOR inhibitor -induced apoptosis by antagonizing Mcl-1 or abrogating ERK activation in BRAFV600E cells .
7   Our findings provide a rationale for genotype-guided patient stratification and potential drug combinations to prevent or mitigate undesired activation of survival pathways induced by mTOR inhibitors .



PMID: 27347117
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 A comparison of four methods for detecting KRAS mutations in formalin-fixed specimens from metastatic colorectal cancer patients .
1 There is currently no standard method for the detection of Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation status in colorectal tumors .
2 In the present study , we compared the KRAS mutation detection ability of four methods : direct sequencing , Scorpion-ARMS assaying , pyrosequencing and multi-analyte profiling ( Luminex xMAP ) .
3 We evaluated 73 cases of metastatic colorectal cancer ( mCRC ) resistant to irinotecan , oxaliplatin and fluoropyrimidine that were enrolled in an all-case study of cetuximab .
4 The KRAS mutation detection capacity of the four analytical methods was compared using DNA samples extracted from tumor tissue , and the detection success rate and concordance of the detection results were evaluated .
5 Μ KRAS mutations were detected by direct sequencing , Scorpion-ARMS assays , pyrosequencing and Luminex xMAP at success rates of 93.2% , 97.3% , 95.9% and 94.5% , respectively .
6 The concordance rates of the detection results by Scorpion-ARMS , pyrosequencing and Luminex xMAP with those of direct sequencing were 0.897 , 0.923 and 0.900 ( kappa statistics ) , respectively .
7 The direct sequencing method could not determine KRAS mutation status in five DNA samples .
8 Μ Of these , Scorpion-ARMS , pyrosequencing and Luminex xMAP successfully detected three , two and one KRAS mutation statuses , respectively .
9 Μ Three cases demonstrated inconsistent results , whereby Luminex xMAP detected mutated KRAS in two samples while wild-type KRAS was detected by the other methods .
10 Μ In the remaining case , direct sequencing detected wild-type KRAS , which was identified as mutated KRAS by the other methods .
11 In conclusion , we confirmed that Scorpion-ARMS , pyrosequencing and Luminex xMAP were equally reliable in detecting KRAS mutation status in mCRC .
12 However , in rare cases , the KRAS status was differentially diagnosed using these methods .



PMID: 27347072
(None)  
Terms: in vivo, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 Effect of PLCepsilon gene silencing on inhibiting the cancerous transformation of ulcerative colitis .
1 The aim of the present study was to investigate the effect of phosphoinositide-specific phospholipase Cepsilon ( PLCepsilon ) gene silencing on the inhibition of cancer development in ulcerative colitis ( UC ) and to explore the pathogenesis and carcinogenic mechanism of UC , in order to facilitate the establishment of novel strategies for the treatment of UC , prevent the cancerous transformation of UC and discern the association between inflammation and cancer .
2 A pGenesil-PLCepsilon RNA interference vector was constructed and transfected into HEK293 cells ( pGenesil-PLCepsilon group ) .
3 HEK293 cells transfected with pGenesil empty plasmid were set as the negative control ( pGenesil-NC group ) .
4 Μ The expression of PLCepsilon was observed , and molecules associated with the PLC signaling pathway were detected using a reverse transcription-quantitative polymerase chain reaction and western blotting .
5 ELISA was used to determine the expression of serum interleukin-1 ( IL-1 ) and tumor necrosis factor -alpha ( TNF-alpha ) of mice in which the PLCepsilon gene had been silenced .
6 Compared with the pGenesil-NC group , the mRNA and protein levels of PLCepsilon were significantly decreased in the pGenesil-PLCepsilon group .
7 In addition , the mRNA levels of K-ras , NF-kappaB , Fas and Bcl-2 were markedly reduced , while P53 mRNA level was notably enhanced , in the pGenesil-PLCepsilon group , and these changes were accompanied by similar changes in the corresponding protein levels .
8 The serum IL-1 and TNF-alpha expression in the PLCepsilon gene -silenced mice was significantly reduced compared with that in the control mice .
9 In conclusion , PLCepsilon RNA silencing can effectively inhibit the cancerous transformation of UC by regulating the colorectal cancer-related cell proliferation and cell cycle in vivo .
10 In addition , PLCepsilon RNA silencing can suppress the expression of inflammatory factors in vitro .



PMID: 27346571
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 High frequency of KRAS mutation in early onset colorectal adenocarcinoma : implications for pathogenesis .
1 While the incidence of sporadic early onset ( defined here as colorectal cancer is increasing , its molecular pathogenesis remains unclear .
2 In particular , previous studies have suggested that the genetic initiating events in these patients may be distinct from those observed in older colorectal cancer patients .
3 We aimed to study clinical , histopathological , and molecular features of early onset colorectal cancer .
4 We identified 68 consecutive sporadic early onset colorectal cancer cases with available molecular data treated in our institution between 2007 and 2014 .
5 Consistent with previous reports , the majority of sporadic early onset colorectal cancer patients had left-sided tumors , which were predominantly of low histologic grade , but advanced clinical stage .
6 A subset of tumors ( <40% ) contained mucinous or signet ring cell features .
7 DNA mismatch repair pathway , commonly associated with Lynch syndrome , was abnormal only in a minor subset of cases .
8 Μ In contrast to the low prevalence ( <30% ) of KRAS mutations reported by previous studies , we found that a significantly higher proportion ( 54% ) of early onset colorectal cancer cases harbored KRAS mutations , a finding that was independent of tumor stage .
9 Μ The high prevalence of KRAS mutation in early onset colorectal cancer suggests that it shares common genetic initiating events with colorectal cancer in older patients .



PMID: 27345584
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting the serrated pathway of colorectal cancer with mutation in BRAF .
1 A recently acknowledged morphological pathway to colorectal cancer originates from precursor polyps with a serrated appearance due to branching and folding of the colon epithelium .
2 This serrated origin accounts for up to 30% of all colorectal tumors but these are heterogeneous regarding molecular characteristics and patient outcome .
3 Here we review the current knowledge about the classification of this tumor subtype and its association with five key features : mutation status of the BRAF or KRAS genes , the CpG island methylation phenotype , microsatellite instability , immune cell infiltration , and overexpression of GTPase RAC1b .
4 Subsequently , available therapeutic approaches for targeting these molecular characteristics are presented and critically discussed .



PMID: 27342247
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Panitumumab in combination with irinotecan plus S-1 ( IRIS ) as second - line therapy for metastatic colorectal cancer .
1 BACKGROUND :
2 Irinotecan plus S-1 ( IRIS ) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer ( mCRC ) patients .
3 However , the combination of IRIS plus an anti-EGFR agent has not been evaluated previously .
4 This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second - line therapy for wild-type KRAS mCRC .
5 METHODS :
6 Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC , ECOG PS 0-2 , and age >/ = 20 years .
7 Patients received panitumumab ( 6 mg/kg ) and irinotecan ( 100 mg/m(2) ) on days 1 and 15 and S-1 ( 40-60 mg according to body surface area ) twice daily for 2 weeks , repeated every 4 weeks .
8 The primary endpoint was the feasibility of the therapy .
9 The secondary endpoints were response rate ( RR ) , progression-free survival ( PFS ) , and overall survival ( OS ) .
10 RESULTS :
11   A total of 36 patients received protocol treatment in eight centers .
12   Of these , 23 patients ( 639 % ) completed protocol treatment , demonstrating achievement of the primary endpoint .
13 The most frequent grade 3/4 toxicities were diarrhea ( 167 % ) , acne-like rash ( 139 % ) , and neutropenia ( 111 % ) .
14 The overall RR was 33.3 % ( 12/36 ) .
15 Of these patients , five underwent conversion surgery .
16 Median PFS and OS were 9.5 months ( 95 % CI 35-154 months ) and 20.1 months ( 95 % CI 167-232 months ) , respectively .
17 CONCLUSION :
18   IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC .
19   Accordingly , this regimen can be an additional treatment option for second - line chemotherapy in wild-type KRAS mCRC .



PMID: 27341594
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 BRAF-Directed Therapy in Metastatic Colorectal Cancer .
1 Activating BRAF ( V-raf murine sarcoma viral oncogene homolog B ) mutations occur in approximately 5% to 10% of patients with metastatic colorectal cancer , mostly V600E mutation , and it is associated with distinct clinical and pathological features .
2 To date , there are no approved treatments to target this mutation .
3 BRAF inhibitor monotherapy has limited efficacy , in contrast to metastatic melanoma .
4 Μ Combination strategies that block not only BRAF mutated kinase but other alternative pathways are ongoing and have demonstrated improved activity .
5 This review aims to provide data about new strategies to target to BRAF gene mutation in metastatic colorectal cancer .



PMID: 27341592
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarker in Colorectal Cancer .
1 In the last 20 years , improvements in metastatic colorectal cancer treatment lead to a radical raise of outcomes with median survival reaching now more than 30 months .
2 Despite that , the identification of predictive and/or prognostic biomarker still represents a challenging issue , and until today , although clinician and researchers might face with a deeper knowledge of biological mechanisms related to colorectal cancer , many pieces of evidence underline the heterogeneity and the dynamism of such disease .
3 In the present review , we describe the road leading to the discovery of RAS mutations , BRAF V600E mutation , and microsatellite instability role in colorectal cancer ; second , we discuss some of the possible major pitfalls of biomarker research , and lastly , we give new suggestions for future research in this field .



PMID: 27341591
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Spectrum of Gene Mutations in Colorectal Cancer : Implications for Treatment .
1 Gene mutations acquired during colorectal carcinogenesis remain drivers of cancer progression in the metastatic setting .
2 KRAS and NRAS mutations define a population refractory to anti-epidermal growth factor receptor ( EGFR ) antibodies , either as single agents or in combination with standard chemotherapy .
3 High-sensitivity extended RAS testing is currently a requirement to select anti-EGFR therapy irrespective of treatment line , thus limiting unnecessary exposure and expense in patients unlikely to respond .
4 Multiple genetic alterations driving resistance to anti-EGFR monoclonal antibodies have been described , with significant overlap in primary and acquired resistance mechanisms , in line with a clonal selection process .
5 Some of them have been validated as targets for therapeutic intervention in clinical trials , such as ERBB2 amplifications .
6 With advances in drug development and better understanding of the dynamics of target inhibition , additional gene alterations are now promising positive predictive markers for matched targeted therapies in CRC , including BRAF V600E and RNF43 mutations .
7 Furthermore , the microsatellite instable hypermutated colorectal cancer population is particularly sensitive to immune checkpoint inhibitors .
8 In this article , we review the expanding landscape of druggable gene alterations in metastatic colorectal cancer .



PMID: 27340376
(Patient)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Molecular Subtypes and Personalized Therapy in Metastatic Colorectal Cancer .
1 Development of colorectal cancer occurs via a number of key pathways , with the clinicopathological features of specific subgroups being driven by underlying molecular changes .
2 Mutations in key genes within the network of signalling pathways have been identified ; however , therapeutic strategies to target these aberrations remain limited .
3 As understanding of the biology of colorectal cancer has improved , this has led to a move toward broader genomic testing , collaborative research and innovative , adaptive clinical trial design .
4 Recent developments in therapy include the routine adoption of wider mutational spectrum testing prior to use of targeted therapies and the first promise of effective immunotherapy for colorectal cancer patients .
5 This review details current biomarkers in colorectal cancer for molecular stratification and for treatment allocation purposes , including open and planned precision medicine trials .
6 Advances in our understanding , therapeutic strategy and technology will also be outlined .



PMID: 27340238
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer .
1 Metabolic reprogramming , in which altered utilization of glucose and glutamine supports rapid growth , is a hallmark of most cancers .
2 Mutations in the oncogenes KRAS and BRAF drive metabolic reprogramming through enhanced glucose uptake , but the broader impact of these mutations on pathways of carbon metabolism is unknown .
3 Global shotgun proteomic analysis of isogenic DLD-1 and RKO colon cancer cell lines expressing mutant and wild type KRAS or BRAF , respectively , failed to identify significant differences ( atleast 2-fold ) in metabolic protein abundance .
4 However , a multiplexed parallel reaction monitoring ( PRM ) strategy targeting 73 metabolic proteins identified significant protein abundance increases of 1.25-twofold in glycolysis , the nonoxidative pentose phosphate pathway , glutamine metabolism , and the phosphoserine biosynthetic pathway in cells with KRAS G13D mutations or BRAF V600E mutations .
5 These alterations corresponded to mutant KRAS and BRAF -dependent increases in glucose uptake and lactate production .
6 Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein .
7 In DLD-1 cells , these effects were independent of the ratio of KRAS G13D to KRAS wild type protein .
8 A study of 8 KRAS wild type and 8 KRAS mutant human colon tumors confirmed the association of increased expression of glycolytic and glutamine metabolic proteins with KRAS mutant status .
9 Μ Metabolic reprogramming is driven largely by modest ( <2-fold ) alterations in protein expression , which are not readily detected by the global profiling methods most commonly employed in proteomic studies .
10 The results indicate the superiority of more precise , multiplexed , pathway-targeted analyses to study functional proteome systems .
11 Data are available through MassIVE Accession MSV000079486 at ftp : //MSV000079486@massive .
12 ucsd .
13 edu .



PMID: 27338794
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 A combinatorial strategy for treating KRAS-mutant lung cancer .
1 Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology .
2 KRAS itself has proved difficult to inhibit , and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents .
3 Here we take a systematic approach towards identifying combination targets for trametinib , a MEK inhibitor approved by the US Food and Drug Administration , which acts downstream of KRAS to suppress signalling through the mitogen -activated protein kinase ( MAPK ) cascade .
4 Informed by a short-hairpin RNA screen , we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 ( FGFR1 ) that leads to signalling rebound and adaptive drug resistance .
5 As a consequence , genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo .
6 This compensatory response shows distinct specificities : it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells , but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells .
7   Importantly , KRAS-mutant lung cancer cells and patients' tumours treated with trametinib show an increase in FRS2 phosphorylation , a biomarker of FGFR activation ; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations .
8 These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer .



PMID: 27335808
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Diagnostic RAS mutation analysis by polymerase chain reaction ( PCR ) .
1 Μ RAS mutation analysis is an important companion diagnostic test .
2 Treatment of colorectal cancer with anti-Epidermal Growth Factor Receptor ( EGFR ) therapy requires demonstration of RAS mutation status ( both KRAS and NRAS ) , and it is good practice to include BRAF .
3 In Non-Small Cell Lung Cancer ( NSCLC ) and melanoma , assessment of RAS mutation status can be helpful in triaging patient samples for more extensive testing .
4 This mini-review will discuss the role of PCR methods in providing rapid diagnostic information for cancer patients .



PMID: 27332557
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Therapeutic Strategies in Diseases of the Digestive Tract - 2015 and Beyond Targeted Therapies in Colon Cancer Today and Tomorrow .
1   Treatment of EGFR-Mutant Lung Cancers After Progression in Patients Receiving First - Line EGFR Tyrosine Kinase Inhibitors : A Review .



PMID: 27331015
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Effect of RAS status on anti-EGFR monoclonal antibodies + 5-FU infusion-based chemotherapy in first - line treatment of metastatic colorectal cancer : A meta-analysis .
1 PURPOSE :
2 To investigate the effect of RAS on anti-EGFR moAb + 5-FU infusion based chemotherapy in first - line treatment of mCRC .
3 METHODS :
4 The MEDLINE , EMBASE , Cochrane Central Register of Controlled Trials , Cochrane databases and ClinicalTrials .
5 gov databases were independently reviewed .
6 Primary end points included overall response rate ( ORR ) , progression-free survival ( PFS ) , overall survival ( OS ) and toxicities .
7 Correlation between RAS status and PFS , OS , ORR or toxicities was expressed as a hazard ratio ( HR ) or relative risk ( RR ) .
8 RESULTS :
9 KRAS exon 2 wild-type ( -wt ) mCRC benefited from adding anti-EGFR moAb ( compared with chemotherapy alone : OS : HR 0.88 , P = 0.008 ; PFS : HR 0.74 , P <0.001 ; ORR : RR 1.34 , P = 0.003 .
10 Compared with Bevacizumab : OS : HR 0.83 , P = 0.003 ) .
11 KRAS exon 2-wt but other RAS mutations mCRC did not benefit from adding anti-EGFR moAb .
12 RAS-wt mCRC benefited from adding anti-EGFR moAb ( compared with chemotherapy alone : OS : HR : 0.75 , P <0.001 ; PFS : HR 0.65 , P <0.001 ; ORR : RR 1.51 , P = 0.020 .
13 Compared with Bevacizumab : OS : HR 0.79 , P = 0.002 ) .
14 KRAS exon 2-wt but BRAF mutation mCRC did not benefit from adding anti-EGFR moAb .
15 Subgroup analysis suggested that anti-EGFR moAb prolonged PFS for male , liver metastasis-only , ECOG 0-1 , and colon primary site groups .
16 Anti-EGFR moAb increased controllable grade 3-4 toxicities including rash , diarrhea , and anemia .
17 CONCLUSIONS :
18   Adding anti-EGFR moAb as first - line treatment in RAS-wt mCRC prolonged OS .
19 Whether BRAF mutation is a predictive marker to anti-EGFR moAb is not clear .



PMID: 27329244
(Patient)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation .
1 OBJECTIVE :
2 Serrated polyps ( hyperplastic polyps , sessile or traditional serrated adenomas ) , which can arise in a sporadic or polyposis setting , predispose to colorectal cancer ( CRC ) , especially those with microsatellite instability ( MSI ) due to MLH1 promoter methylation ( MLH1me+ ) .
3 We investigate genetic alterations in the serrated polyposis pathway .
4 DESIGN :
5 We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families , sporadic serrated polyps and CRCs , with validation by analysis of The Cancer Genome Atlas ( TCGA ) cohort , followed by organoid-based functional studies .
6 RESULTS :
7 Μ In one out of four serrated polyposis families , we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype , along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps ( 16 ) , adenomas (5) and cancer (1) examined , as well as coincidental BRAF mutation in 62.5% of the serrated polyps .
8 Μ Concurrently , somatic RNF43 mutations were identified in 34% of sporadic sessile/traditional serrated adenomas , but 0% of hyperplastic polyps ( p = 0013 ) .
9 Μ Lastly , in MSI CRCs , we found significantly more frequent RNF43 mutations in the MLH1me+ ( 85% ) versus MLH1me - ( 333% ) group ( p<0001 ) .
10 Μ These findings were validated in the TCGA MSI CRCs ( p = 0005 ) , which further delineated a significant differential involvement of three Wnt pathway genes between these two groups ( RNF43 in MLH1me+ ; APC and CTNNB1 in MLH1me - ) ; and identified significant co-occurrence of BRAF and RNF43 mutations in the MSI ( p<0001 ) , microsatellite stable ( MSS ) ( p = 0002 ) and MLH1me+ MSI CRCs ( p = 0042 ) .
11 Functionally , organoid culture of serrated adenoma or mouse colon with CRISPR -induced RNF43 mutations had reduced dependency on R-spondin1 .
12 CONCLUSIONS :
13 These results illustrate the importance of RNF43 , along with BRAF mutation in the serrated neoplasia pathway ( both the sporadic and familial forms ) , inform genetic diagnosis protocol and raise therapeutic opportunities through Wnt inhibition in different stages of evolution of serrated polyps .



PMID: 27328312
(Cell)  
Terms: in vivo, in vitro, xenograft, tumour models
Sent# Symbols Sentence Mnemonics
0 FAT1 : a potential target for monoclonal antibody therapy in colon cancer .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is one of the major causes of cancer-associated mortality worldwide .
3 The currently approved therapeutic agents have limited efficacy .
4 METHODS :
5 The atypical cadherin FAT1 was discovered as a novel CRC-associated protein by using a monoclonal antibody ( mAb1983 ) .
6 FAT1 expression was assessed in CRC cells by immunohistochemistry ( IHC ) , immunoblots , flow cytometry and confocal microscopy .
7 In addition , in vitro and in vivo tumour models were done to assess FAT1 potential value for therapeutic applications .
8 RESULTS :
9 Μ The study shows that FAT1 is broadly expressed in primary and metastatic CRC stages and detected by mAb198.3 , regardless of KRAS and BRAF mutations .
10 FAT1 mainly accumulates at the plasma membrane of cancer cells , whereas it is only marginally detected in normal human samples .
11 Moreover , the study shows that FAT1 has an important role in cell invasiveness while it does not significantly influence apoptosis .
12 mAb198.3 specifically recognises FAT1 on the surface of colon cancer cells and is efficiently internalised .
13 Furthermore , it reduces cancer growth in a colon cancer xenograft model .
14 CONCLUSIONS :
15 This study provides evidence that FAT1 and mAb198.3 may offer new therapeutic opportunities for CRC including the tumours resistant to current EGFR-targeted therapies .



PMID: 27325282
(Patient)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer .
1 UNLABELLED :
2 A patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib .
3 Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment , leading to the emergence of MET amplification in the rebiopsy taken at progression .
4 ✓ In BRAF-mutated colorectal cancer cells , ectopic expression of MET conferred resistance to panitumumab and vemurafenib , which was overcome by combining BRAF and MET inhibition .
5 Based on tumor genotyping and functional in vitro data , the patient was treated with the dual ALK-MET inhibitor crizotinib plus vemurafenib , thus switching to dual MET and BRAF blockade , with rapid and marked effectiveness of such strategy .
6 Although acquired resistance is a major limitation to the clinical efficacy of anticancer agents , the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies , maximizing patient benefit .
7 SIGNIFICANCE :
8 Μ MET amplification is here identified-clinically and preclinically-as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF-mutated colorectal cancer .
9 Switching from EGFR to MET inhibition , while maintaining BRAF inhibition , resulted in clinical benefit after the occurrence of MET-driven acquired resistance .
10 Cancer Discov ; 6(9) ; 963-71 .
11 (c) 2016 AACR .
12 This article is highlighted in the In This Issue feature , p. 932 .



PMID: 27325016
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Molecular pathological classification of colorectal cancer .
1 Colorectal cancer ( CRC ) shows variable underlying molecular changes with two major mechanisms of genetic instability : chromosomal instability and microsatellite instability .
2 This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer .
3 Two molecular pathological classification systems for CRC have recently been proposed .
4 Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies .
5 Μ This approach classified CRC into two major groups consistent with previous classification systems : (1) approximately 16 % hypermutated cancers with either microsatellite instability ( MSI ) due to defective mismatch repair ( approximately 13 % ) or ultramutated cancers with DNA polymerase epsilon proofreading mutations ( approximately 3 % ) ; and (2) approximately 84 % non-hypermutated , microsatellite stable ( MSS ) cancers with a high frequency of DNA somatic copy number alterations , which showed common mutations in APC , TP53 , KRAS , SMAD4 , and PIK3CA .
6 The recent Consensus Molecular Subtypes ( CMS ) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups : almost all hypermutated MSI cancers fell into the first category CMS1 ( MSI-immune , 14 % ) with the remaining MSS cancers subcategorised into three groups of CMS2 ( canonical , 37 % ) , CMS3 ( metabolic , 13 % ) and CMS4 ( mesenchymal , 23 % ) , with a residual unclassified group ( mixed features , 13 % ) .
7 Although further research is required to validate these two systems , they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions , particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade .



PMID: 27324368
(None)  
Terms: xenograft, ex vivo, In vivo, Mouse Model
Sent# Symbols Sentence Mnemonics
0 Evaluation of [18F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer .
1 PURPOSE :
2 In oncology , positron emission tomography imaging using dedicated tracers as biomarkers may assist in early evaluation of therapy efficacy .
3 Using 3'-deoxy-3'-[18F]fluorothymidine ( [18F]FLT ) , we investigated the early effects of chemotherapeutic treatment on cancer cell proliferation in a BRAF-mutated colorectal cancer xenograft model .
4 PROCEDURES :
5 Colo205 subcutaneously inoculated animals underwent 90-min dynamic imaging before and 24 h after treatment with vehicle ( control ) , cetuximab ( resistant ) or irinotecan ( sensitive ) .
6 Total distribution volume was quantified from dynamic data , and standardized uptake values as well as tumor-to-blood ratios were calculated from static images averaged over the last 20 min .
7 In vivo imaging data was correlated with ex vivo proliferation and thymidine metabolism proteins .
8 RESULTS :
9 All imaging parameters showed a significant post-treatment decrease from [18F] FLT baseline uptake for the irinotecan group ( p compared with the cetuximab and vehicle group and correlated strongly with each other ( p
10 In vivo data were in agreement with Ki67 staining , showing a significantly lower percentage of Ki67-positive cells in the irinotecan group as compared with other groups ( p
11 Tumor expression of thymidine kinase 1 phosphorylated on serine 13 , thymidylate synthase , and thymidine phosphorylase remained unaffected , while thymidine kinase 1 expression was , surprisingly , significantly higher in irinotecan-treated animals ( p
12 In contrast , tumor ATP levels were lowest in this group .
13 CONCLUSIONS :
14   [18F]FLT positron emission tomography was found to be a suitable biomarker of early tumor response to anti-proliferative treatment , with static imaging not being inferior to full compartmental analysis in our xenograft model .
15 The dynamics of thymidine kinase 1 protein expression and protein activity in low ATP environments merits further investigation .



PMID: 27323830
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer .
1 KRAS mutation is often present in many hard-to-treat tumors such as colon and pancreatic cancer and it is tightly linked to serious alterations in the normal cell metabolism and clinical resistance to chemotherapy .
2 In 1931 , the winner of the Nobel Prize in Medicine , Otto Warburg , stated that cancer was primarily caused by altered metabolism interfering with energy processing in the normal cell .
3 Increased cell glycolytic rates even in the presence of oxygen is fully recognized as a hallmark in cancer and known as the Warburg effect .
4 In the late 1970's , Linus Pauling and Ewan Cameron reported that vitamin C may have positive effects in cancer treatment , although deep mechanistic knowledge about this activity is still scarce .
5 We describe a novel antitumoral mechanism of vitamin C in KRAS mutant colorectal cancer that involves the Warburg metabolic disruption through downregulation of key metabolic checkpoints in KRAS mutant cancer cells and tumors without killing human immortalized colonocytes .
6 Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation .
7 Μ As a consequence of this activity , strong downregulation of the glucose transporter ( GLUT-1 ) and pyruvate kinase M2 ( PKM2 ) -PTB dependent protein expression are observed causing a major blockage of the Warburg effect and therefore energetic stress .
8 We propose a combination of conventional chemotherapy with metabolic strategies , including vitamin C and/or other molecules targeting pivotal key players involved in the Warburg effect which may constitute a new horizon in anti-cancer therapies .



PMID: 27323816
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Could gut microbiota serve as prognostic biomarker associated with colorectal cancer patients' survival? A pilot study on relevant mechanism .
1 Evidences have shown that dysbiosis could promote the progression of colorectal cancer ( CRC ) .
2 However , the association of dysbiosis and prognosis of CRC is barely investigated .
3 Therefore , we used 16S rRNA gene sequencing approach to determine differences in microbiota among tumor tissues of different prognosis and found that Fusobacterium nucleatum and Bacteroides fragilis were more abundant in worse prognosis groups , while Faecalibacterium prausnitzii displayed higher abundance in survival group .
4 To further explore the prognostic value of the found bacteria , Kaplan-Meier and Cox proportional regression analyses were used and the results exhibited that high abundance of F .
5 nucleatum and B .
6 fragilis were independent indicators of poor patient's survival .
7 Besides , the expression of major inflammatory mediator were analyzed using PCR and western blot methods , and it turned out that high abundance of F .
8 nucleatum was associated with increased expression of TNF-alpha , beta-catenin and NF-kappaB , while COX-2 , MMP-9 and NF-kappaB were positively related with high B .
9 fragilis level , and high level of F .
10 Μ prausnitzii showed lower expression of beta-catenin , MMP-9 and NF-kappaB .
11 Moreover , immunohistochemical analysis indicated that KRAS and BRAF expression were prominent in F .
12 nucleatum and B .
13 Μ fragilis high abundance group , while MLH1 showed lower expression .
14 In conclusion , F .
15 nucleatum , B .
16 fragilis and F .
17   prausnitzii can be identified as useful prognostic biomarkers for CRC , and dysbiosis might worsen the patients' prognosis by up-regulating gut inflammation level .



PMID: 27321184
(None)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Inhibition of the CRAF/prohibitin interaction reverses CRAF -dependent resistance to vemurafenib .
1 Activating BRAF mutations promote constitutive activation of the mitogen -activated protein kinase ( MAPK ) signaling pathway and are common in a variety of human malignancies , including melanoma and colon cancer .
2 Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy .
3 However , resistance typically emerges in most melanoma patients .
4 Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma .
5 Prohibitins ( PHBs ) are highly conserved proteins that are thought to control the cell cycle , senescence and tumor suppression .
6 PHB1 is essential for CRAF -mediated ERK1/2 activation through direct binding to CRAF .
7 We developed a CRAF -mediated model of vemurafenib resistance in melanoma cells to assess the importance of the interaction between CRAF and PHB1 in resistance to BRAF-targeting agents .
8 We demonstrate that CRAF overexpression renders melanoma cells resistant to BRAF-targeting agents .
9 Moreover , treatment with the natural compound rocaglamide A disrupts the interaction between PHB and CRAF in melanoma cells , thus reducing MEK1/2 and ERK1/2 signaling , inhibiting melanoma cell growth and inducing apoptosis .
10 The efficacy of these compounds was also demonstrated in a human melanoma xenograft model .
11 Taken together , these data suggest that PHB1 may serve as a novel , druggable target in CRAF -mediated vemurafenib resistance .



PMID: 27314237
(Cell)  
Terms: In vitro
Sent# Symbols Sentence Mnemonics
0 Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer .
1 The ability of Natural Killer ( NK ) cells to kill tumor targets has been extensively studied in various hematological malignancies .
2 However , NK cell therapy directed against solid tumors is still in early development .
3 Epidermal Growth Factor Receptor ( EGFR ) targeted therapies using monoclonal antibodies ( mAbs ) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer ( mCRC ) .
4 Still , the clinical efficacy of this treatment is hampered by mutations in RAS gene , allowing tumors to escape from anti-EGFR mAb therapy .
5 It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG1 mAbs through Fc receptors (CD16/FcgammaRIIIa) on their surface , thereby mediating antibody dependent cellular cytotoxicity ( ADCC ) .
6 In the current study , activated Peripheral Blood NK cells ( PBNK ) were combined with anti-EGFR mAbs to study their effect on the killing of EGFR+/- cancer cell lines , including those with RAS mutations .
7 In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320 , Caco-2 , SW620 , SW480 and HT-29 , demonstrated that PBNK cells are cytotoxic for a range of tumor cells , regardless of EGFR , RAS or BRAF status and at low E : T ratios .
8 Cetuximab enhanced the cytotoxic activity of NK cells on EGFR+ tumor cells ( either RASwt , RASmut or BRAFmut ) in a CD16 dependent manner , whereas it could not increase the killing of EGFR - COLO320 .
9   Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients .



PMID: 27313739
(Patient)  
Terms: Phase II trial, phase II trial
Sent# Symbols Sentence Mnemonics
0 Phase II trial of panitumumab with irinotecan as salvage therapy for patients with advanced or recurrent colorectal cancer ( TOPIC study ) .
1 Little is known about the clinical impact of salvage panitumumab with irinotecan for metastatic colorectal cancer ( mCRC ) patients .
2 The present study conducted a single-arm , multicenter phase II trial for mCRC with skin toxicity prevention program .
3 ✓ The subjects were mCRC patients with wild-type KRAS , who showed resistance to fluoropyrimidine , oxaliplatin and irinotecan . GM-ASS-SR
4 Panitumumab was administered at a dose of 6 mg/kg every 2 weeks by intravenous infusion over 60 min , and irinotecan was administered at a dose of 100-180 mg/m2 every 2 weeks by intravenous infusion over 90 min , depending on the preceding treatment dose .
5 To prevent skin toxicities , a moisturizer was applied and oral antibiotics ( 100 mg minocycline twice daily ) were initiated for 6 weeks .
6 The primary endpoint was the response rate ( RR ) determined by independent reviewers .
7 Secondary endpoints were the disease control rate ( DCR ) , progression-free survival ( PFS ) time , overall survival ( OS ) time and adverse events .
8 A total of 35 patients were enrolled between October 2010 and March 2012 .
9 The median age was 61 years ( range , 41-76 years ) , with 25 male and 10 female patients .
10 The initial irinotecan dose was 150 mg/m2 in 19 patients and 180 mg/m2 in 1 patient .
11 The remaining patients were treated with
12 A central review indicated a partial response in 8 patients ( 229% ) and stable disease in 6 patients ( 171% ) , with an RR of 22.9% ( 95% confidence interval , 121-390 ) and a DCR of 40% .
13 The RR of the patients with standard-dose irinotecan ( 150 or 180 mg/m2 ) was 30% , although that of low-dose irinotecan ( 100-120 mg/m2 ) was 13% .
14 The median PFS time was 2.7 months , and the median OS time was 6.3 months .
15 A grade 3 or above acne-like rash developed in 25.7% of patients .
16   In conclusion , panitumumab and irinotecan as salvage therapy for mCRC KRAS wild-type patients with skin toxicity prevention exhibits limited efficacy .
17 In particular , the effect of low-dose irinotecan with panitumumab appears to be clinically insignificant .
18 Routine use of skin toxicity prevention is currently under evaluation .



PMID: 27312529
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer .
1 Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer , emergence of acquired resistance limits clinical benefit .
2 Here , we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation .
3 We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations .
4 Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells , but not in their resistant counterparts , indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway .
5   Μ Genotyping of resistant cells identified gene amplification of EGFR , KRAS , and mutant BRAF , as well as acquired mutations in KRAS , EGFR , and MAP2K1 These mechanisms were clinically relevant , as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors .
6 To identify therapeutic combinations capable of overcoming drug resistance , we performed a systematic assessment of candidate therapies across the panel of resistant cell lines .
7 Independent of the molecular alteration acquired upon drug pressure , most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK , BRAF , and EGFR inhibitors were applied .
8 These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer .
9 Cancer Res ; 76 ( 15 ) ; 4504-15 .
10 (c) 2016 AACR .



PMID: 27312358
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy .
1 Mutation in K-RAS ( K-RAS-MT ) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor ( EGFR ) therapy in gastrointestinal tumors .
2 Insulin-like growth factor-1 receptor ( IGF-1R ) signaling is required for carcinogenicity and progression of many tumors as well .
3 Μ We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody .
4 In this study , we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants .
5 We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines , colorectal RKO and pancreatic BxPC-3 .
6 We assessed the effect of forced expression of K-RAS-MT on proliferation , apoptosis , migration , and invasion in gastrointestinal cancer cells .
7 Then we assessed anti-tumor effects of dominant negative IGF-1R ( IGF-1R/dn ) and an IGF-1R inhibitor , picropodophyllin , on the K-RAS-MT transfectants .
8 ✓ Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes , with increased proliferation , decreased apoptosis , and increased motility and invasion . GE-REG-RO
9 IGF-1R blockade suppressed cell growth , colony formation , migration , and invasion , and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells , even when K-RAS-MT was over-expressed .
10 IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase ( ERK ) pathway in the K-RAS-MT transfectants .
11 IGF-1R/dn , moreover , inhibited the growth of murine xenografts expressing K-RAS-MT .
12 Thus , K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers .
13 IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated .
14 (c) 2016 Wiley Periodicals , Inc .



PMID: 27311775
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Droplet digital PCR of circulating tumor cells from colorectal cancer patients can predict KRAS mutations before surgery . RO-REG-GM
1 In colorectal cancer ( CRC ) , KRAS mutations are a strong negative predictor for treatment with the EGFR-targeted antibodies cetuximab and panitumumab .
2 Since it can be difficult to obtain appropriate tumor tissues for KRAS genotyping , alternative methods are required .
3 Circulating tumor cells ( CTCs ) are believed to be representative of the tumor in real time .
4 In this study we explored the capacity of a size-based device for capturing CTCs coupled with a multiplex KRAS screening assay using droplet digital PCR ( ddPCR ) .
5 We showed that it is possible to detect a mutant ratio of 0.05% and less than one KRAS mutant cell per mL total blood with ddPCR compared to about 0.5% and 50-75 cells for TaqMeltPCR and HRM .
6 Next , CTCs were isolated from the blood of 35 patients with CRC at various stage of the disease .
7 KRAS genotyping was successful for 86% ( 30/35 ) of samples with a KRAS codon 12/13 mutant ratio of 57% ( 17/30 ) .
8 In contrast , only one patient was identified as KRAS mutant when size-based isolation was combined with HRM or TaqMeltPCR .
9 KRAS status was then determined for the 26 available formalin-fixed paraffin-embedded tumors using standard procedures .
10 The concordance between the CTCs and the corresponding tumor tissues was 77% with a sensitivity of 83% .
11 Μ Taken together , the data presented here suggest that is feasible to detect KRAS mutations in CTCs from blood samples of CRC patients which are predictive for those found in the tumor .
12   The minimal invasive nature of this procedure in combination with the high sensitivity of ddPCR might provide in the future an opportunity to monitor patients throughout the course of disease on multiple levels including early detection , prognosis , treatment and relapse as well as to obtain mechanistic insight with respect to tumor invasion and metastasis .



PMID: 27308590
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Endosomal acidification inhibitors for the treatment of BRAF mutant tumors .
1 Μ Mutations in KRAS and BRAF genes are commonly found in several types of cancer associated with poor prognosis and therapy resistance .
2 We have identified phosphorylated p45-IKKalpha as an essential mediator of BRAF -induced tumorigenesis .
3 Importantly , endosomal acidification inhibitors preclude phosphorylation of p45-IKKalpha and abolish the metastatic capacity of BRAF mutant cancer cells .



PMID: 27308562
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations .
1 Μ RAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer ( CRC ) but RAF inhibitor combinations have demonstrated improved efficacy , likely through superior suppression of MAPK signaling .
2 The first identified mechanisms of acquired resistance to these combinations all promote MAPK reactivation , underscoring the MAPK pathway as a critical target in BRAF-mutant CRC .



PMID: 27308494
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF inhibitors in colorectal cancer : Toward a differentiation therapy ?
1 BRAF inhibitor monotherapy appears to be ineffective in BRAF (V600E)- positive colorectal cancer ( CRC ) as a result of inherent EGFR -mediated resistance mechanisms .
2 This concept initiated combinatorial treatment approaches .
3 Nevertheless , BRAF inhibition in isogenic CRC cell lines induced enhanced cell - cell adhesion and differentiation , underlining a potential benefit of BRAF inhibitors in CRC .



PMID: 27306648
(Patient)  
Terms: phase II study, prospective
Sent# Symbols Sentence Mnemonics
0 Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05) .
1 BACKGROUND :
2 Retrospective studies have found that early tumor shrinkage ( ETS ) and depth of response ( DpR ) are associated with favorable outcomes in patients with metastatic colorectal cancer ( mCRC ) ; however , few prospective studies have evaluated ETS and DpR .
3 PATIENTS AND METHODS :
4 We performed a phase II study of FOLFOX plus cetuximab as first - line treatment in Japanese patients with KRAS wild-type mCRC .
5 The primary endpoint was response rate ( RR ) , and secondary endpoints included progression-free survival ( PFS ) , overall survival ( OS ) , chronological tumor shrinkage ( evaluated every 8 weeks ) , and safety .
6 The association of ETS and DpR with survival time was analyzed using Spearman's rank correlation coefficient .
7 RESULTS :
8 In 54 participants , the RR , median PFS , and OS were 66.7 % ( 95 % CI , 534-778 % ) , 11.1 months , and 33.9 months , respectively .
9 There was no unexpected toxicity .
10 Forty ( 80 % ) of 50 assessable patients had ETS , which was associated with prolonged PFS and OS ( 113 vs. 37 months , HR 026 , p = 00003 ; 428 vs. 90 months , HR 040 , p = 00279 , respectively ) .
11 Median DpR was 56.3 % .
12 The DpR correlated with OS ( r s = 0314 , p = 0027 ) as well as post-progression survival ( PPS ) ( r s = 0366 , p = 0017 ) .
13 Interestingly , DpR was moderately associated with OS and PPS ( r s = 0587 , r s = 0570 , respectively ) in patients harboring tumors with larger target lesions , but was not associated with OS or PPS in patients with smaller target lesions .
14   FOLFOX plus cetuximab was active as a first - line treatment for Japanese mCRC patients , with no unexpected toxicities .
15 CONCLUSIONS :
16   Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy ( UMIN000004197 ) .



PMID: 27302833
(Patient)  
Terms: prospective studies
Sent# Symbols Sentence Mnemonics
0 Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes .
1 BACKGROUND & ; AIMS : Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair ( MMR ) proteins .
2 We sought to define the molecular phenotype of this newly recognized tumor subtype .
3 METHODS :
4 From 2 prospective studies of the efficacy of screening for Lynch syndrome , we identified patients with colorectal and endometrial tumors who had 2 or more somatic ( but not germline ) mutations in genes encoding MMR proteins ( double somatic ) .
5 We determined the frequencies of tumor mutations in PIK3CA , BRAF , KRAS , NRAS , and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome , MLH1-hypermethylated , or microsatellite-stable tumors .
6 We validated our findings using independent data sets from The Cancer Genome Atlas .
7 RESULTS :
8 Among colorectal cancer cases , we found that 14 of 21 ( 67% ) patients with double somatic tumors also had PIK3CA mutations , compared with 4 of 18 ( 22% ) tumors from patients with Lynch syndrome , 2 of 10 ( 20% ) tumors with MLH1 hypermethylation , and 12 of 78 ( 15% ) tumors with microsatellite stability ( P <0001 for patients with double somatic tumors versus other subgroups ) .
9 Μ Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers ( P = 04 compared with other subgroups ) .
10 Μ We did not detect BRAF mutations in patients with double somatic colorectal tumors or Lynch syndrome .
11 We found highly similar results in a validation cohort from The Cancer Genome Atlas ( 113 patients with colorectal tumors , 178 endometrial tumors ) ; 100% of double somatic cases had a somatic mutation in PIK3CA ( P <0001 compared with other subgroups ) .
12 CONCLUSIONS :
13 Most patients with colorectal or endometrial tumors with 2 or more somatic ( but not germline ) mutations in MMR proteins also have mutations in PIK3CA ; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in other microsatellite-instability subgroups .
14   PIK3CA mutation status might be used to identify a specific group of colorectal tumors , and to select treatment or determine prognosis .



PMID: 27302369
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC .
1 Colorectal cancer ( CRC ) is a highly heterogeneous disease , for which prognosis has been relegated to clinicopathologic staging for decades .
2 There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies .
3 Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens , which identified a subset of 17 genes that best classify CRC , with APC playing a central role in predicting overall survival .
4 APC may assume 0 , 1 or 2 truncating mutations , each with a striking differential impact on survival .
5 ✓ Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours ; however , two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined . GM-ASS-RO, GM-REG-RO
6 Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC .



PMID: 27300552
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic and Molecular Features of Colorectal Adenocarcinoma with Signet-Ring Cell Component .
1 BACKGROUND :
2 We performed a retrospective study to assess the clinicopathological characters , molecular alterations and multigene mutation profiles in colorectal cancer patients with signet-ring cell component .
3 METHODS :
4 Between November 2008 and January 2015 , 61 consecutive primary colorectal carcinomas with signet-ring cell component were available for pathological confirmation .
5 RAS/BRAF status was performed by direct sequencing. 14 genes associated with hereditary cancer syndromes were analyzed by targeted gene sequencing .
6 RESULTS :
7 A slight male predominance was detected in these patients ( 590% ) .
8 Colorectal carcinomas with signet-ring cell component were well distributed along the large intestine .
9 A frequently higher TNM stage at the time of diagnosis was observed , compared with the conventional adenocarcinoma .
10 Family history of malignant tumor was remarkable with 49.2% in 61 cases .
11 The median OS time of stage IV patients in our study was 14 months .
12 Μ RAS mutations were detected in 22.2% ( 12/54 ) cases with KRAS mutations in 16.7% ( 9/54 ) cases and Nras mutations in 5.4% ( 3/54 ) cases .
13 Μ BRAF V600E mutation was detected in 3.7% ( 2/54 ) cases .
14 As an exploration , we analyzed 14 genes by targeted gene sequencing .
15 These genes were selected based on their biological role in association with hereditary cancer syndromes. 79.6% cases carried atleast one pathogenic mutation .
16 Finally , the patients were classified by the percentage of signet-ring cell. 39 ( 639% ) cases were composed of >/ = 50% signet-ring cells ; 22 ( 361% ) cases were composed of <50% signet-ring cells .
17 Μ We compared clinical parameters , molecular and genetic alterations between the two groups and found no significant differences .
18 CONCLUSIONS :
19 Colorectal adenocarcinoma with signet-ring cell component is characterized by advanced stage at diagnosis with remarkable family history of malignant tumor .
20 It is likely a negative prognostic factor and tends to affect male patients with low rates of RAS /BRAF mutation .
21 Colorectal patients with any component of signet-ring cells , regardless of the extent , shared similar clinicopathological characteristics , molecular alterations and genetic profiles .



PMID: 27296403
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Current Possibilities for Predicting Responses to EGFR Blockade in Metastatic Colorectal Cancer ] .
1 BACKGROUND :
2 The combination of modern systemic chemotherapy and anti-EGFR monoclonal antibodies improves overall survival and quality of life for patients with metastatic colorecal cancer .
3 By contrast , the addition of anti-EGFR therapy to the treatment regime of resistant patients may lead to worse progression-free survival and overall survival .
4 Therefore , identifying sensitive and resistant patients prior to targeted therapy of metastatic colorecal cancer is a key point during the initial decision making process .
5 Previous research shows that primary resistance to EGFR blockade is in most cases caused by constitutive activation of signaling pathways downstream of EGFR .
6 Of all relevant factors ( mutation of KRAS , NRAS , BRAF , and PIK3CA oncogenes , inactivation of tumor suppressors PTEN and TP53 , amplification of EGFR and HER2 , and expression of epiregulin and amphiregulin , mikroRNA miR-31-3p , and miR-31-5p ) , only evaluation of KRAS and NRAS mutations has entered routine clinical practice .
7 The role of the other markers still needs to be validated .
8 The ongoing benefit of anti-EGFR therapy could be indicated by specific clinical parameters measured after the initiation of targeted therapy , including early tumor shrinkage , the deepness of the response , or hypomagnesemia .
9 The accuracy of predictive dia-gnostic tools could be also increased by examining a combination of predictive markers using next generation sequencing methods .
10 However , unjustified investigation of many molecular markers should be resisted as this may complicate interpretation of the results , particularly in terms of their specific clinical relevance .
11 AIM :
12 The aim of this review is to describe current possibilities with respect to predicting responses to EGFR blockade in the context of the EGFR pathway , and the utilization of such results in routine clinical practice .



PMID: 27296402
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Lynch Syndrome - the Pathologist's Diagnosis ] .
1 Lynch syndrome ( formerly known as hereditary non-polyposis colorectal cancer ) is the most com-mon hereditary colorectal cancer syndrome .
2 The syndrome is caused by a germline mutation of one of the mismatch repair ( MMR ) genes responsible for DNA replication error repair .
3 Impaired function of the proteins encoded by these genes leads to microsatellite instability ( MSI ) , which is associated with increased incidence of neoplasms : mainly colorectal cancer .
4 According to recent estimates , up to 5% of all colorectal cancers are associated with Lynch syndrome .
5 Due to this relatively high frequency , familial occurence , absence of premorbid phenotype , and development of malignant tumors at a reproductive age , a correct diagnosis is important not only from an ethical but also from an economical point of view .
6 Unfortunately , clinical means of diagnosis , namely , the revised Bethesda guidelines designed to detect patients suitable for genetic testing for Lynch syndrome , lack sufficient sensitivity .
7 The methods associated with modern pathology are more sensitive than the clinical criteria used to detect patients suspected of having Lynch syndrome .
8 Pathological diagnostics are based on direct or indirect detection of MSI .
9 Indirect methods include analysis of morphological signs associated with MSI in histological samples from colorectal carcinoma patients and immunohistochemical investigation of MMR protein expression .
10 To rule out sporadic cases caused by epigenetic inactivation of an MMR gene , molecular genetic investigation of the BRAF gene and methylation analysis of the MLH1 promoter are performed during diagnostic workup.A suspicion of Lynch syndrome based on the results of the methods mentioned above should be proven by detection of a germline mutation in an MMR gene in peripheral blood leukocytes .



PMID: 27294323
(None)  
Terms: in vivo, in vitro, xenograft, mouse models, mouse, transgenic mouse
Sent# Symbols Sentence Mnemonics
0 Small-molecule binding of the axin RGS domain promotes beta-catenin and Ras degradation .
1 Both the Wnt/beta-catenin and Ras pathways are aberrantly activated in most human colorectal cancers ( CRCs ) and interact cooperatively in tumor promotion .
2 Inhibition of these signaling may therefore be an ideal strategy for treating CRC .
3 We identified KY1220 , a compound that destabilizes both beta-catenin and Ras , via targeting the Wnt/beta-catenin pathway , and synthesized its derivative KYA1797K .
4 KYA1797K bound directly to the regulators of G - protein signaling domain of axin , initiating beta-catenin and Ras degradation through enhancement of the beta-catenin destruction complex activating GSK3beta .
5 KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations , as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations .
6   Destabilization of both beta-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/beta-catenin and Ras pathways .



PMID: 27289420
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hybridization-Induced Aggregation Technology for Practical Clinical Testing : KRAS Mutation Detection in Lung and Colorectal Tumors .
1 KRAS mutations have emerged as powerful predictors of response to targeted therapies in the treatment of lung and colorectal cancers ; thus , prospective KRAS genotyping is essential for appropriate treatment stratification .
2 Μ Conventional mutation testing technologies are not ideal for routine clinical screening , as they often involve complex , time-consuming processes and/or costly instrumentation .
3 In response , we recently introduced a unique analytical strategy for revealing KRAS mutations , based on the allele -specific hybridization-induced aggregation ( HIA ) of oligonucleotide probe-conjugated microbeads .
4 Using simple , inexpensive instrumentation , this approach allows for the detection of any common KRAS mutation in <10 minutes after PCR .
5 Here , we evaluate the clinical utility of the HIA method for mutation detection ( HIAMD ) .
6 Μ In the analysis of 20 lung and colon tumor pathology specimens , we observed a 100% correlation between the KRAS mutation statuses determined by HIAMD and sequencing .
7 Μ In addition , we were able to detect KRAS mutations in a background of 75% wild-type DNA-a finding consistent with that reported for sequencing .
8 With this , we show that HIAMD allows for the rapid and cost-effective detection of KRAS mutations , without compromising analytical performance .
9 These results indicate the validity of HIAMD as a mutation-testing technology suitable for practical clinical testing .
10 Further expansion of this platform may involve the detection of mutations in other key oncogenic pathways .



PMID: 27284437
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Efficacy of cetuximab-based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups : A meta-analysis .
1 The epidermal growth factor receptor ( EGFR ) -targeting monoclonal antibody , cetuximab , has been added to standard chemotherapy regimens for treating metastatic colorectal cancer ( mCRC ) .
2 However , the efficacy of adding cetuximab to chemotherapy regimens for patients of differing genetic backgrounds remains controversial .
3 The present study aimed to investigate the efficacy of adding cetuximab to chemotherapeutic regimens in subgroups of patients defined according to the RAS and BRAF mutation status in the first - line treatment of patients with mCRC .
4 A systematic literature search was performed in databases ( including PubMed , Embase , the Cochrane library , the American Society of Clinical Oncology and the European Society For Medical Oncology ) up to August 2015 .
5 Μ Randomized controlled trials analyzing overall survival ( OS ) and progression-free survival ( PFS ) in mCRC treated with cetuximab , and grouped by RAS and BRAF mutation status , were identified .
6 The major outcome measures were hazard ratios ( HRs ) .
7 Pooled HRs were calculated using fixed - or random-effects models , according to the magnitude of the heterogeneity .
8 A total of nine studies met the inclusion criteria .
9 Use of cetuximab was significantly associated with longer OS in KRAS exon 2 wild-type tumors [HR = 0.87 , 95% confidence interval ( CI ) =0.79-0.96 , Z = 2.91 , P = 0.004] and wild-type KRAS/RAS ( in exons 2 , 3 and 4 of KRAS and exons 2 , 3 and 4 of an associated gene , NRAS ; HR = 072 , 95% CI = 060-085 , Z = 374 , P = 00002 ) .
10 ✓ Μ No significant differences in OS and PFS were identified between KRAS exon 2 mutations and tumors with the other RAS mutations ( in exons 3 and 4 of KRAS and exons 2 , 3 and 4 of an associated gene , NRAS ) . RO-ASS-GM
11   The meta-analysis demonstrated that cetuximab-based chemotherapeutic regimens led to a marked improvement in OS in patients with mCRC who lacked any RAS mutations ( either KRAS exon 2 or any other RAS mutation ) .
12 By contrast , the subgroup analyses revealed no evident PFS or OS benefit in using cetuximab for patients with any RAS mutation .
13 Taken together , the evidence indicates that cetuximab should only be used for mCRC patients with the wild-type RAS gene .
14   Some benefits were observed in patients with wild-type KRAS/BRAF who received cetuximab-based chemotherapy , even though there were insufficient data to perform meta-analysis with the BRAF mutation status .



PMID: 27280936
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Isolation of Bioactive Rotenoids and Isoflavonoids from the Fruits of Millettia caerulea .
1 Three new rotenoids ( 1-3 ) , two new isoflavonoids ( 4 and 5 ) , and six known analogues ( 6-11 ) were isolated from an n-hexane partition of a methanol extract of the fruits of Millettia caerulea , with the structures of the new compounds elucidated by analysis of their spectroscopic data .
2 The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data , and their absolute configurations were established using electronic circular dichroism spectra and specific rotation values .
3 All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line , and the known compounds , (-) -3-hydroxyrotenone (6) and (-)- rotenone (7) , were found to be potently active .
4 When tested in an NF-kappaB inhibition assay , compound 6 showed activity .
5 This compound , along with the new compound , (-)- caeruleanone D (1) , and the known compound , ichthynone (8) , exhibited K-Ras inhibitory potency .
6 Further bioactivity studies showed that the new compounds , (-) -3-deoxycaeruleanone D (2) and (-) -3-hydroxycaeruleanone A (3) , and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells .



PMID: 27275783
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Terpinen-4-ol : A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers .
1 BACKGROUND :
2 Terpinen-4-ol , a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities .
3 AIM :
4 To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies , alone and in combination with chemotherapeutic and biological agents .
5 METHODS :
6 Terpinen-4-ol was administrated alone or combined with standard chemotherapy ( Oxaliplatin , Fluorouracil , Gemcitabine , Tarceva ) and biological agent ( Cetuximab ) .
7 It was also combined with humanized anti-CD24 mAbs ( was developed by us ) .
8 Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis , following treatment of colorectal , pancreatic , gastric and prostate cancer cells .
9 Terpinen-4-ol effect on tumor development was evaluated in xenograft model .
10 RESULTS :
11 Terpinen-4-ol induces a significant growth inhibition of colorectal , pancreatic , prostate and gastric cancer cells in a dose -dependent manner ( 10-90% in 0005-01% ) .
12 Terpinen-4-ol and various anti-cancer agents ( 02muM oxaliplatin and 05muM fluorouracil ) demonstrated a synergistic inhibitory effect ( 83% and 91% , respectively ) on cancer cell proliferation .
13   In KRAS mutated colorectal cancer cells , which are resistant to anti-EGFR therapy , combining of terpinen-4-ol with cetuximab ( 1 muM ) resulted in impressive efficacy of 80-90% growth inhibition .
14 Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb ( 150mug/ml )- induced growth inhibition ( 90% ) .
15 Considerable reduction in tumor volume was seen following terpinen-4-ol ( 02% ) treatment alone and with cetuximab ( 10mg/kg ) ( 40% and 63% , respectively ) as compare to the control group .
16 CONCLUSION :
17 Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents .
18   The possible molecular mechanism for its activity involves induction of cell -death rendering this compound as a potential anti-cancer drug alone and in combination in the treatment of numerous malignancies .
19 Terpinen-4-ol restores the activity of cetuximab in cancers with mutated KRAS .



PMID: 27273229
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts .
1 BACKGROUND AND AIM :
2 Μ Tumor testing of colorectal cancers ( CRC ) for mismatch repair ( MMR ) deficiency is an effective approach to identify carriers of germline MMR gene mutation ( Lynch syndrome ) .
3 Μ The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches .
4 METHODS :
5 Colorectal cancers from 813 patients diagnosed with CRC <60 years of age from the Australasian Colorectal Cancer Family Registry ( ACCFR ) and from 826 patients from the Melbourne Collaborative Cohort Study ( MCCS ) were tested for MMR protein expression using immunohistochemistry , microsatellite instability ( MSI ) , BRAFV600E somatic mutation , and for MLH1 methylation .
6 MMR gene mutation testing ( Sanger sequencing and Multiplex Ligation Dependent Probe Amplification ) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs .
7 RESULTS :
8 Μ Of the 813 ACCFR probands , 90 probands demonstrated tumor MMR deficiency ( 111% ) , and 42 had a MMR gene germline mutation ( 52% ) .
9 Μ For the MCCS , MMR deficiency was identified in the tumors of 103 probands ( 125% ) and seven had a germline mutation ( 08% ) .
10 All the mutation carriers were diagnosed prior to 70 years of age .
11 Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS , respectively .
12 CONCLUSIONS :
13 Μ Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age .
14 A significant proportion of MMR-deficient CRCs will have unknown etiology ( Lynch-like ) proving problematic for clinical management .



PMID: 27272216
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 ✓ Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer . GE-ASS-DS
1 BACKGROUND :
2 High EREG and AREG expression , and left-sided primary tumours are associated with superior efficacy of anti-epidermal growth factor receptor ( EGFR ) therapy in metastatic colorectal cancer ( CRC ) , but a unifying explanation of these findings is lacking .
3 METHODS :
4 RNA-seq , gene expression arrays , and DNA methylation profiling were completed on 179 CRC tumours .
5 Results were validated using independent The Cancer Genome Atlas data sets .
6 An independent cohort of 198 KRAS wild-type metastatic CRC tumours was tested for CpG island methylator phenotype ( CIMP ) status , and progression-free survival ( PFS ) with the first anti-EGFR regimen was retrospectively determined .
7 RESULTS :
8 EREG and AREG expression was highly inversely correlated with methylation and was inversely associated with right-sided primary tumour , BRAF mutation , and CIMP-high status .
9 Treatment of CRC cell lines with hypomethylating agents decreased methylation and increased expression of EREG .
10 ✓ Μ Inferior PFS with anti-EGFR therapy was associated with CIMP-high status , BRAF mutation , NRAS mutation , and right-sided primary tumour on univariate analysis . RO-ASS-GM
11 Among known BRAF/NRAS wild-type tumours , inferior PFS remained associated with CIMP-high status ( median PFS 56 versus 90 mo , P = 0023 ) .
12 CONCLUSIONS :
13 EREG and AREG are strongly regulated by methylation , and their expression is associated with CIMP status and primary tumour site , which may explain the association of primary tumour site and EREG/AREG expression with anti-EGFR therapy efficacy .



PMID: 27270901
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients .
1 Detection of KRAS mutation status is a routine clinical procedure for predicting response to anti-EGFR therapy in colorectal cancer ( CRC ) patients .
2 Μ Previous studies showed high concordance of KRAS mutation status in primary lesion and corresponding metastatic sites in CRC .
3 However , the data were mostly from Caucasians .
4 The aim of this study is to compare KRAS mutation and other molecules mutation status between primary tumor and corresponding metastatic lesion in Chinese patients with CRC .
5 In this retrospective study , Chinese CRC patients with paired samples of primary tumor and metastatic site were detected for KRAS codon 12 and 13 with quantitative real-time PCR , or detected for OncoCarta panel of 19 genes with MassARRAY ( (R) ) technique , including KRAS , BRAF , NRAS and PIK3CA et al .
6 Forty-eight paired CRC samples were analyzed for KRAS codon 12 and 13 using quantitative real-time PCR .
7 Ten paired samples were analyzed by 19 genes OncoCarta Panel with MassARRAY ( (R) ) technique .
8 Μ KRAS mutation was found in 15 ( 259 % ) primary tumors and 18 ( 310 % ) metastases .
9 The discordance of KRAS was observed in 11 ( 190 % ) patients .
10 Alteration of mutation points in primary site with mutant KRAS was not observed .
11 Μ In the 10 patients with multiple gene detection , PIK3CA mutation showed concordant mutation status in primary tumor and metastatic site , whereas discordance in BRAF , NRAS and AKT1 was detected .
12 Μ A concordance rate of 81.0 % was detected in KRAS mutation between primary tumor and metastatic lesion in Chinese patients with CRC .
13 Μ Discordance of BRAF , NRAS and AKT1 mutation status in primary tumor and metastases was observed .



PMID: 27268964
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Isoledene from Mesua ferrea oleo-gum resin induces apoptosis in HCT 116 cells through ROS -mediated modulation of multiple proteins in the apoptotic pathways : A mechanistic study .
1 Colorectal cancer ( CRC ) is one of the most common human malignant tumors worldwide .
2 Arising from the transformation of epithelial cells in the colon and/or rectum into malignant cells , the foundation of CRC pathogenesis lies in the progressive accumulation of mutations in oncogenes and tumor-suppressor genes , such as KRAS and APC .
3 Resistance to apoptosis is one of the key mechanisms in the development of CRC as it is for any other kind of cancer .
4 Natural products have been shown to induce the expression of apoptosis regulators that are blocked in cancer cells .
5 In the present study , a series of in vitro assays were employed to study the apoptosis-inducing attributes of Isoledene rich sub-fraction ( IR-SF ) collected from the oleo-gum resin of M .
6 ferrea .
7 Data obtained , showed that IR-SF inhibited cell proliferation and induced typical apoptotic changes in the overall morphology of all the CRC cell lines tested .
8 Fluorescent staining assays revealed characteristic nuclear condensation , and marked decrease in mitochondrial outer membrane potential in the treated cells .
9 In addition , an increment in the levels of ROS , caspase-8 , -9 and -3 was observed .
10 Μ Proteomic analysis revealed that IR-SF up-regulated the expression of pro-apoptotic proteins , i.e. , Bid , Bim and cytochrome c .
11 Cytochrome c in turn activated caspases cascade resulting in the induction of apoptosis .
12 Moreover , IR-SF significantly down-regulated Bcl-2 , Bcl-w , survivin , xIAP and HSPs pro-survival proteins and induced DNA fragmentation and G0/G1-phase arrest in HCT 116 cells .
13 Chemical characterization of IR-SF by GC-MS and HPLC methods identified Isoledene as one of the major compounds .
14 Altogether , results of the present study demonstrate that IR-SF may induce apoptosis in human colorectal carcinoma cells through activation of ROS -mediated apoptotic pathways .



PMID: 27262159
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The prognostic yield of biomarkers harvested in chemotherapy-naive stage II colon cancer : can we separate the wheat from the chaff ?
1 The TNM-system fails to accurately predict disease recurrence in a considerate number of patients .
2 While node-negative ( stage II ) colon cancer is considered to have an overall good prognosis , the 5-year cancer-specific survival is reported at 81-83% in patients who did not have adjuvant chemotherapy .
3 Thus , reliance on node-status alone has lead to under-treatment in a subgroup of stage II patients with an unfavorable prognosis .
4 The search for new and better prognosticators in stage II colon cancer has suggested several proposed biomarkers of better prognostication and prediction .
5 However , few such biomarkers have reached widespread clinical utility .
6 For the clinician swimming in the sea of emerging biomarkers , it may be hard to recognize the true floating aid from the surrounding debris in the search for more precise decision-making .
7 Proposed markers include microsatellite instability ( MSI ) , KRAS mutations and BRAF mutations , but a number of gene panels and consensus molecular subtypes are proposed for clinical prediction and prognostication as well .
8 While several studies suggest such biomarkers or panels to have a prognostic role in subgroups of patients , a number of studies are reported in heterogeneous groups with in part discordant findings , which again distorts the predictive and prognostic ability of each marker .
9 Lack of homogeneous cohorts , underpowered studies in strict subgroups and challenges in analytical and clinical validity may hamper the progress towards widespread clinical utility .
10 The harvest of prognostic biomarkers in colon cancer has yielded a huge number of candidates for which it is now time to separate the wheat from the chaff .



PMID: 27261210
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF V600E mutation in metastatic colorectal cancer : Methods of detection and correlation with clinical and pathologic features .
1 Μ The screening for BRAF V600E mutation is employed in clinical practice for its prognostic and potentially predictive role in patients with metastatic colorectal carcinoma ( mCRC ) .
2 Μ Little information is available on the sensitivity and specificity of the testing methods to detect this mutation in CRC .
3 Μ By using serial dilution of BRAF mutant DNA with wild type DNA , we found that the sensitivity of allelic discrimination-Real Time PCR was higher than PCR-Sequencing ( 10% versus 20% ) .
4 In agreement , the Real Time PCR assay displayed increased analytical sensitivity in detecting the BRAF V600E mutation as compared with PCR-Sequencing in a cohort of 510 consecutive CRCs ( 21 versus 16 cases ) .
5 Μ Targeted resequencing demonstrated that all cases negative by PCR-Sequencing had an allelic frequency of the BRAF mutation <20% , thus suggesting tumor heterogeneity .
6 The association of BRAF mutations with clinical and pathological features was assessed next in a cohort of 840 KRAS exon 2 wild type CRC patients screened with the Real Time PCR assay .
7 The BRAF V600E mutation frequency in this cohort was 7.8% that increased to 33.4% in females over 70 y of age with right-sided tumor location .
8 Μ BRAF mutations were also detected in 4.4% of male patients with left-sided tumors and aged <70 y .
9 Fourteen of 61 ( 229% ) BRAF V600E mutation bearing patients exhibited microsatellite instability ( MSI ) as assessed by T17 mononucleotide sequence within intron 8 of HSP110 .
10 Μ Our study indicates that Real Time PCR-based assays are more sensitive than PCR-Sequencing to detect the BRAF V600E mutation in CRC and that BRAF mutations screening should not be restricted to selected patients on the basis of the clinical-pathological characteristics .



PMID: 27255180
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Design , synthesis , and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents .
1 A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed , synthesized , and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI .
2 Among them , compound 1d with p-chlorobenzenesulfonamido terminal moiety , ethylene spacer , and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 muM concentration .
3 It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types .
4 For instance , compound 1d inhibited the growth of HL-60 (TB) , SR leukemia , and T-47D and MCF-7 breast cancer cell line by 135.92% , 119.44% , 95.32% , and 82.03% at 10 muM , respectively .
5 And it inhibited the growth of COLO 205 colon , HT29 colon , BT-549 breast , and ACHN renal cancer cell lines by more than 80% at the same test concentration .
6 However , testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells) .
7 Compound 1d was further tested against 12 kinases of different kinase families , and the highest inhibitory effect was exerted against RAF1 , V600E-B-RAF , and V600K-B-RAF kinases .



PMID: 27246726
(None)  
Terms: phase II study, phase II, prospective, Clinical Trial
Sent# Symbols Sentence Mnemonics
0 ICECREAM : randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS , NRAS , BRAF and PI3KCA wild type , or G13D mutated tumours .
1 BACKGROUND :
2 Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin - and irinotecan-containing regimens may benefit from EGFR -inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene ( are "wild type" ) .
3 It is unknown whether these antibodies , such as cetuximab , are more efficacious in refractory metastatic colorectal cancer as monotherapy , or in combination with irinotecan .
4 Lack of mutation in KRAS , BRAF and PIK3CA predicts response to EFGR-inhibitors .
5 The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients : those with a "quadruple wild type" tumour genotype ( no mutations in KRAS , NRAS , PI3KCA or BRAF genes ) and those with the specific KRAS mutation in codon G13D , for whom possibly EGFR-inhibitor efficacy may be equivalent .
6 METHODS AND DESIGN :
7 ICECREAM is a randomised , phase II , open-label , controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer , whose disease has progressed on , or who are intolerant of oxaliplatin - and fluoropyrimidine-based chemotherapy .
8 The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen .
9 Secondary endpoints are response rate , overall survival , and quality of life .
10 The tertiary endpoint is prediction of outcome with further biological markers .
11 International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer .
12 DISCUSSION :
13 This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer : the "quadruple wild type" , which may 'superselect' for tumours sensitive to EGFR-inhibition , and the rare KRAS G13D mutated tumours , which are also postulated to be sensitive to the drug .
14 The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes , reduce toxicity and contain treatment costs .
15 Tissue and blood will yield a resource for molecular studies .
16 Recruitment , particularly of patients with the rare G13D mutation , will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups .
17 TRIAL REGISTRATION :
18 Australian and New Zealand Clinical Trials Registry : ACTRN12612000901808 , registered 16 August 2012 .



PMID: 27244218
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers .
1 BACKGROUND :
2 The incidence and outcomes of patients with colorectal cancer ( CRC ) varies by age .
3 Younger patients tend to have sporadic cancers that are not detected by screening and worse survival .
4 To understand whether genetic differences exist between age cohorts , the authors sought to characterize unique genetic alterations in patients with CRC .
5 METHODS :
6 In total , 283 patients who were diagnosed with sporadic CRC between 1998 and 2010 were identified and divided by age into 2 cohorts-ages / = 65 years ( the older cohort ) -and targeted exome sequencing was performed .
7 Μ The Fisher exact test was used to detect differences in mutation frequencies between the 2 groups .
8 Whole exome sequencing was performed on 21 additional younger patient samples for validation .
9 Findings were confirmed in The Cancer Genome Atlas CRC data set .
10 RESULTS :
11 In total , 246 samples were included for final analysis ( 195 from the older cohort and 51 from the younger cohort ) .
12 Mutations in the FBXW7 gene were more common in the younger cohort ( 275% versus 97% ; P = 0022 ) as were mutations in the proofreading domain of polymerase epsilon catalytic subunit ( POLE ) ( 98% versus 1% ; P = 0048 ) .
13 There were similar mutation rates between cohorts with regard to TP53 ( 647% versus 615% ) , KRAS ( 431% versus 462% ) , and APC ( 608% versus 738% ) .
14 BRAF mutations were numerically more common in the older cohort , although the difference did not reach statistical significance ( 2% versus 97% ; P = 082 ) .
15 CONCLUSIONS :
16 In this retrospective study , a unique genetic profile was identified for younger patients who have CRC compared with patients who are diagnosed at an older age .
17 These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger patients with CRC .
18 Cancer 2016 .
19 (c) 2016 American Cancer Society .
20 Cancer 2016 ; 122 : 2828-2835 .
21 (c) 2016 American Cancer Society .



PMID: 27239120
(Patient)  
Terms: prospective, Prospective
Sent# Symbols Sentence Mnemonics
0 Longitudinal molecular characterization of endoscopic specimens from colorectal lesions .
1 AIM :
2 To compare molecular profiles of proximal colon , distal colon and rectum in large adenomas , early and late carcinomas .
3 To assess feasibility of testing directed at molecular markers from this study in routine clinical practice .
4 METHODS :
5 A prospective 3-year study has resulted in the acquisition of samples from 159 large adenomas and 138 carcinomas along with associated clinical parameters including localization , grade and histological type for adenomas and localization and stage for carcinomas .
6 A complex molecular phenotyping has been performed using multiplex ligation -dependent probe amplification technique for the evaluation of CpG-island methylator phenotype ( CIMP ) , PCR fragment analysis for detection of microsatellite instability and denaturing capillary electrophoresis for sensitive detection of somatic mutations in KRAS , BRAF , TP53 and APC genes .
7 RESULTS :
8 Molecular types according to previously introduced Jass classification have been evaluated for large adenomas and early and late carcinomas .
9 An increase in CIMP+ type , eventually accompanied with KRAS mutations , was notable between large adenomas and early carcinomas .
10 As expected , the longitudinal observations revealed a correlation of the CIMP+/BRAF+ type with proximal location .
11 CONCLUSION :
12 Prospective molecular classification of tissue specimens is feasible in routine endoscopy practice .
13 Increased frequency of some molecular types corresponds to the developmental stages of colorectal tumors .
14 As expected , a clear distinction is notable for tumors located in proximal colon supposedly arising from the serrated ( methylation ) pathway .



PMID: 27234640
(Patient)  
Terms: CLINICAL TRIAL, NCT00433927
Sent# Symbols Sentence Mnemonics
0 CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first - line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) .
1 BACKGROUND :
2 To examine the relation of carcinoembryonic antigen ( CEA ) response with tumor response and survival in patients with (K) RAS wild-type metastatic colorectal cancer receiving first - line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab .
3 PATIENTS AND METHODS :
4 CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival .
5 Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders .
6 In addition , the time to CEA nadir was calculated .
7 RESULTS :
8 Of 592 patients in the intent-to-treat population , 472 were eligible for analysis of CEA ( cetuximab arm : 230 and bevacizumab arm : 242 ) .
9 Maximal relative CEA decrease ( % ) significantly ( P = 0003 ) differed between the cetuximab arm ( median 830% ; IQR 409%-947% ) and the bevacizumab arm ( median 723% ; IQR 263%-910% ) .
10 In a longitudinal analysis , the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start .
11 CEA nadir occurred after 3.3 months ( cetuximab arm ) and 3.5 months ( bevacizumab arm ) , ( P = 049 ) .
12 In the cetuximab arm , CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months ; hazard ratio ( HR ) 1.53 ; 95% Cl , 1.15-2.04 ; P = 0.004] and longer overall survival ( 366 versus 213 months ; HR 173 ; 95% Cl , 124-243 ; P = 0001 ) than CEA non-responders .
13 Analysis of extended RAS wild-type patients revealed similar results .
14 CONCLUSION :
15   In the FIRE-3 trial , CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab .
16 CLINICAL TRIALS NUMBER :
17 NCT00433927 (ClinicalTrialsgov) ; AIO KRK0306 FIRE-3 .



PMID: 27229742
(Patient)  
Terms: Phase II Study
Sent# Symbols Sentence Mnemonics
0 A Phase II Study of Third - Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study) .
1 OBJECTIVE :
2 No salvage treatment had been established for metastatic colorectal cancer ( mCRC ) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102 .
3 We performed a phase II study of third - line chemotherapy with combined bevacizumab and S-1 for mCRC .
4 METHODS :
5 Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan .
6 Bevacizumab was given intravenously every 2 weeks , and S-1 was administered orally on days 1-28 of a 42-day cycle .
7 The primary endpoint was disease control rate ( DCR ) .
8 RESULTS :
9 In total , 31 subjects were enrolled between August 2009 and June 2011 .
10 Three subjects in whom antitumor effects could not be evaluated were excluded .
11 The median follow-up period was 8.6 months .
12 The DCR was 67.9% , the response rate 0% , median progression-free survival 3.7 months , and overall survival 8.6 months .
13 In 30 subjects evaluated for safety , there was no treatment-related death .
14 The most common adverse events were anorexia ( grade >/ = 3 , 20% ) , diarrhea ( grade 3 , 10% ) , and decreased hemoglobin ( grade >/ = 3 , 17% ) .
15 CONCLUSIONS :
16 The results suggest that third - line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .



PMID: 27221876
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Screening for Lynch Syndrome in Young Colorectal Cancer Patients from Saudi Arabia Using Microsatellite Instability as the Initial Test .
1 BACKGROUND :
2 Lynch Syndrome ( LS ) is a familial cancer condition caused by germline mutations in DNA mismatch repair genes .
3 Μ Individuals with LS have a greatly increased risk of developing colorectal cancer ( CRC ) and it is therefore important to identify mutation carriers so they can undergo regular surveillance .
4 Tumor DNA from LS patients characteristically shows microsatellite instability ( MSI ) .
5 Our aim here was to screen young CRC patients for MSI as a first step in the identification of unrecognized cases of LS in the Saudi population .
6 MATERIALS AND METHODS :
7 Archival tumor tissue was obtained from 284 CRC patients treated at 4 institutes in Dammam and Riyadh between 2006 and 2015 and aged less than 60 years at diagnosis .
8 MSI screening was performed using the BAT-26 microsatellite marker and positive cases confirmed using the pentaplex MSI analysis system .
9 Μ Positive cases were screened for BRAF mutations to exclude sporadic CRC and were evaluated for loss of expression of 4 DNA mismatch repair proteins using immunohistochemistry .
10 RESULTS :
11 Μ MSI was found in 33/284 ( 116% ) cases , of which only one showed a BRAF mutation .
12 Saudi MSI cases showed similar instability in the BAT-26 and BAT-25 markers to Australian MSI cases , but significantly lower frequencies of instability in 3 other microsatellite markers .
13 CONCLUSIONS :
14 MSI screening of young Saudi CRC patients reveals that approximately 1 in 9 are candidates for LS .
15 Patients with MSI are strongly recommended to undergo genetic counselling and germline mutation testing for LS .
16 Other affected family members can then be identified and offered regular surveillance for early detection of LS-associated cancers .



PMID: 27221845
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Correlation between RAS Test Results and Prognosis of Metastatic Colorectal Cancer Patients : a Report from Western Iran .
1 In the patients with metastatic colorectal cancer ( mCRC ) , RAS testing is the first step to identify those that could benefit from anti-EGFR therapy .
2 This study examined associations between KRAS mutations and clinicopathological and survival data in Iranian patients with mCRC .
3 Between 2008 to2015 in a retrospective study , 83 cases of mCRC were referred to the Clinic of Medical Oncology .
4 The mean follow-up was 45 months that there were 27 deaths .
5 The 3 patients that did not complete follow-up were censored from the study .
6 KRAS and NRAS were analyzed using allele -specific PCR primers and pyrosequencing in exons 2 , 3 and 4 .
7 Multivariate survival analysis using Cox's regression model was used for affecting of variables on overall survival ( OS ) .
8 The mean age at diagnosis for patients was 57.7 ( range , 18 to 80 years ) and 61.4% were male .
9 There was no significant different between prognostic factors and KRAS mutation with wild-type .
10 ✓ Also , There was no significant different between KRAS mutation and KRAS wild-type for survival , but there was a significant different between KRAS 12 and 13 mutations for survival ( HR 013 , 95% CI 003-066 , P = 001 ) . GM-ASS-RO
11 Μ In conclusion , the prevalence of KRAS mutations in CRC patients was below 50% but higher than in other studies in Iran .
12 ✓ As in many studies , patients with KRAS 12 mutations had better OS thn those with KRAS 13 mutation . GM-ASS-RO, RO-ASS-GM
13   In addition to KRAS testing , other biomarkers are needed to determine the best treatment for patients with mCRC .



PMID: 27221731
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Primary tumor site is a useful predictor of cetuximab efficacy in the third - line or salvage treatment of KRAS wild-type ( exon 2 non-mutant ) metastatic colorectal cancer : a nationwide cohort study .
1 BACKGROUND :
2 Previous studies have shown left-sided colorectal cancer ( LCRC ) and right-sided colorectal cancer ( RCRC ) exhibit different molecular and clinicopathological features .
3 We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer ( CRC ) .
4 METHODS :
5 This study enrolled a cohort of patients , who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type ( exon 2 nonmutant ) metastatic CRC , from the databases of Taiwan Cancer Registry ( 2004-2010 ) and National Health Insurance ( 2004-2011 ) .
6 Survival data were obtained from the National Death Registry .
7 Time to treatment discontinuation ( TTD ) and overall survival ( OS ) after the start of cetuximab treatment were compared between patients with LCRC ( splenic flexure to rectum ) and RCRC ( cecum to hepatic flexure ) .
8 RESULTS :
9 A total of 969 CRC patients were enrolled .
10 Among them , 765 ( 789 % ) and 136 ( 140 % ) patients had LCRC and RCRC , respectively .
11   Patients with LCRC , compared to patients with RCRC , had longer TTD ( median , 459 vs. 275 months , P = 0005 ) and OS ( median , 1262 vs. 807 months , P <0001 ) after the start of cetuximab treatment .
12 ✓ Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD ( adjusted hazard ratio [HR] = 1.32 , using the LCRC group as a reference , 95 % confidence interval : 1.08-1.61 , P = .0072 ) and OS ( adjusted HR = 1.45 , 95 % CI : 1.18-1.78 , P = .0003 ) . GE-ASS-RO
13 CONCLUSION :
14   Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third - line or salvage treatment of KRAS wild-type ( exon 2 nonmutant ) metastatic CRC .



PMID: 27221540
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic Landscape of Colorectal Mucosa and Adenomas .
1 Μ The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis .
2 However , comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking .
3 Therefore , our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas .
4 Μ We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances ( AI ) in 37 adenomas using SNP arrays .
5 We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach .
6 Μ Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes ( APC , KRAS , FBXW7 , TCF7L2 ) and AIs in chromosomes 5 , 7 , and 13 .
7 Moreover , 80% of adenomas had somatic alterations in WNT pathway genes .
8 Adenomas displayed evidence of multiclonality similar to stage I carcinomas .
9 Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas .
10 Our data indicate that atleast 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation .
11 The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions .
12 Furthermore , substantial genomic variation exists in at-risk mucosa before adenoma formation , and deregulation of the WNT pathway is required to foster carcinogenesis .
13 Cancer Prev Res ; 9(6) ; 417-27 .
14 (c) 2016 AACR .



PMID: 27221051
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 TGFbeta signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype .
1 The heterogeneous nature of colorectal cancer ( CRC ) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients .
2 Based on gene expression profiling , CRC is currently classified into four consensus molecular subtypes ( CMSs ) , characterized by specific biological programs , thus suggesting the existence of unifying developmental drivers for each CMS Using human organoid cultures , we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFbeta plays an important role in the development of the mesenchymal CMS4 , which is of special interest due to its association with dismal prognosis .
3 We show that in tubular adenomas ( TAs ) , which progress to classical CRCs , the dominating response to TGFbeta is death by apoptosis .
4 Μ By contrast , induction of a mesenchymal phenotype upon TGFbeta treatment prevails in a genetically engineered organoid culture carrying a BRAF(V) (600E) mutation , constituting a model system for sessile serrated adenomas ( SSAs ) .
5 Our data indicate that TGFbeta signaling is already active in SSA precursor lesions and that TGFbeta is a critical cue for directing SSAs to the mesenchymal , poor-prognosis CMS4 of CRC .



PMID: 27220786
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 [ Current Progress and Feasibility of Using Molecular-Targeted Agent Combinations for Metastatic Colorectal Cancer ] .
1 The efficacy of molecular-targeted agent combinations for the treatment of metastatic colorectal cancer has become increasingly evident over recent years , although none of these combinations have been recognized yet as a standard therapy .
2 The intention here is to provide a synopsis of current progress in this developing area by reviewing existing publications and ongoing clinical trials .
3 While bevacizumab plus anti-EGFR agents exhibit detrimental effects in first - line setting , a combination of bevacizumab with erlotinib has been suggested as an effective maintenance therapy .
4 Dabrafenib plus panitumumab in combination with trametinib and encorafenib plus cetuximab in combination with alpelisib , are very promising combination treatments and are currently being developed in clinical trials for patients with BRAF mutant -type tumors .
5 An earlier nonclinical trial suggested that a combination of panitumumab plus trametinib was effective in patients who were resistant to anti - EGFR agents but developing KRAS - or NRAS-mutated tumors .
6   Μ The HERACLES trial further indicated that a combination of trastuzumab and lapatinib showed promising antitumor effects in patients with emerging HER2 amplification .
7 Other reports suggest that irinotecan and cetuximab in combination with tivantinib were more effective than a combination of irinotecan and cetuximab alone for patients with MET amplification , although further research is needed for this application , as results were based upon the analysis of subgroups .
8   It is clear that data arising from both primary research and clinical trials support the combined use of molecular-targeted drugs in the treatment of metastatic colorectal cancer .
9   As clinical trials progress , it is likely that such treatment combinations will become recognized as standard therapies .



PMID: 27220764
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Immunohistochemical staining for p16 and BRAFV600E is useful to distinguish between sporadic and hereditary ( Lynch syndrome-related ) microsatellite instable colorectal carcinomas .
1 DNA mismatch repair ( MMR ) protein analysis by immunohistochemistry ( IHC ) can identify colorectal cancer ( CRC ) with microsatellite instability ( MSI ) .
2 As MLH1-deficient CRC can be hereditary or sporadic , markers to distinguish between them are needed .
3 MLH1 promoter methylation assay is the reference method ; however , sometimes , it is challenging on formalin-fixed paraffin-embedded tissue samples .
4 We assessed by IHC the expression of BRAFV600E , p16 , MGMT , and CDX2 in 55 MLH1-deficient MSI CRC samples ( of which 8 had a germline MLH1 mutation ) to determine whether this panel differentiates between sporadic and hereditary CRCs .
5 We also analyzed MLH1 promoter methylation by methylation-specific PCR and pyrosequencing and BRAF status by genotyping .
6 Μ None of the hereditary CRCs showed MLH1 methylation , BRAF mutation , BRAFV600E-positive immunostaining , or loss of p16 expression .
7 Μ We detected MLH1 promoter methylation in 67 % and a BRAF mutation in 42 % of CRC , all showing MLH1 promoter methylation .
8 BRAFV600E IHC and BRAF genotyping gave concordant results in all but two samples .
9 Μ Loss of expression of p16 was found in 30 % of CRC with methylation of the MLH1 promoter , but its expression was retained in all non-methylated and part of MLH1-methylated tumors ( 100 % specificity , 30 % sensitivity ) .
10 CDX2 and MGMT expression was not associated with MLH1 status .
11 Thus , BRAFV600E and p16 IHC may help in differentiating sporadic from hereditary MLH1-deficient CRC with MSI .
12 Specifically , p16 IHC might be used as a surrogate marker for MLH1 promoter methylation , because all p16-negative CRCs displayed MLH1 methylation , whereas hereditary CRCs were all p16-positive .



PMID: 27218826
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Copy number changes of clinically actionable genes in melanoma , non-small cell lung cancer and colorectal cancer-A survey across 822 routine diagnostic cases .
1 Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded ( FFPE ) cancer samples .
2 Μ This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations ( CNV ) is limited .
3 Here , we retrospectively analyzed CNV in 822 cancer cases ( 135 melanoma , 468 non-small cell lung cancers ( NSCLC ) , 219 colorectal cancers ( CRC ) ) .
4 We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC .
5 The overall cohort displayed 168 ( 20% ) amplifications in 17 druggable targets .
6 The majority of BRAF mutant melanomas ( 54% ) showed co-occurring CNV in other genes , mainly affecting CDKN2A .
7 Μ Subsets showed clustered deletions in ABL1 , NOTCH1 , RET or STK11 , GNA11 , and JAK3 .
8 Μ Most NRAS mutant melanomas ( 49% ) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected .
9 Five BRAF/NRASwt tumors had co-amplifications of KDR , KIT , PDGFRA and another six mutated KIT .
10 Among all NSCLC , we identified 14 EGFRamp ( with ten EGFRmut ) and eight KRASamp ( with seven KRASmut ) .
11 KRASmut tumors displayed frequent amplifications of MYC ( n = 10 ) and MDM2 ( n = 5 ) .
12 Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications .
13 In CRC , amplified IGF2 was most prevalent ( n = 13 ) followed by MYC ( n = 9 ) .
14 Μ Two cases showed amplified KRAS wildtype alleles .
15 Μ Two of the KRASmut cases harbored amplifications of NRAS and three KRASwt cases amplification of EGFR .
16 In conclusion , we demonstrate that our approach i ) facilitates detection of CNV , ii ) enables detection of known CNV patterns , and iii ) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers .
17 (c) 2016 Wiley Periodicals , Inc .



PMID: 27215512
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Clinicopathological characteristics of colorectal carcinoma in the elderly ] .
1 Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients .
2 Colorectal cancers tend to localize in the proximal colon , from cecum to the splenic flexure in the elderly patients .
3 Changes in the stools , rectal bleeding or black stool , abdominal pain , fatigue , weight loss and anemia are the common symptoms .
4 Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy .
5 Therefore , the choice of diagnosis methods in elderly patients should be careful .
6 Achieving a clear diagnosis and avoiding complications should be considered at the same time .
7 Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced , and have less lymphatic and blood metastasis .
8 The proportion of poorly differentiated adenocarcinoma increases with the increase of age , which should be concerned .
9 Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients .
10 The common extra-colorectal tumors consist of gastric cancer , lung cancer , biliary carcinoma , pancreas cancer and malignancy from blood system .
11 Molecular events , such as mutations of KARS , BRAF , TP53 and deficiency of DNA mismatch repair , are more frequent in elderly colorectal cancer patients .
12 Many factors have impact on treatment decision in elderly patients with colorectal cancer , including age , comorbidities , physiological functions of organs and willingness of patients and their relatives .
13   Although surgery is still the main treatment , the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients .
14 With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management , laparoscopic surgery has become widespread in elderly patients with colorectal cancer .
15 In addition , more attention should be paid to adjuvant therapy .
16 Comprehensive individualized treatment plan should be taken to improve outcomes .



PMID: 27203373
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Linking Nucleoporins , Mitosis , and Colon Cancer .
1 Suppression of a nuclear pore protein Nup358/RanBP2 is linked to mitotic cell death , but the clinical relevance of this link is unknown .
2 In a recent issue of Cell , Vecchione et al. ( 2016 ) show that in approximately 10% of BRAF-like colorectal cancer ( CC ) patients , Nup358/RanBP2 is critical for survival .
3   Treatment with vinorelbine , a microtubule-depolymerizing drug that inhibits mitosis , might be a potential treatment for these CCs .



PMID: 27198570
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal tumor molecular phenotype and miRNA : expression profiles and prognosis .
1 MiRNAs regulate gene expression by post-transcriptionally suppressing mRNA translation or by causing mRNA degradation .
2 It has been proposed that unique miRNAs influence specific tumor molecular phenotype .
3 In this paper , we test the hypotheses that miRNA expression differs by tumor molecular phenotype and that those differences may influence prognosis .
4 Data come from population-based studies of colorectal cancer conducted in Utah and the Northern California Kaiser Permanente Medical Care Program .
5 A total of 1893 carcinoma samples were run on the Agilent Human miRNA Microarray V19.0 containing 2006 miRNAs .
6 We assessed differences in miRNA expression between TP53-mutated and non-mutated , KRAS-mutated and non-mutated , BRAF-mutated and non-mutated , CpG island methylator phenotype ( CIMP ) high and CIMP low , and microsatellite instability ( MSI ) and microsatellite stable ( MSS ) colon and rectal tumors .
7 Using a Cox proportional hazard model we evaluated if those miRNAs differentially expressed by tumor phenotype influenced survival after adjusting for age , sex , and AJCC stage .
8 Μ There were 22 differentially expressed miRNAs for TP53-mutated colon tumors and 5 for TP53-mutated rectal tumors with a fold change of >1.49 ( or <067 ) .
9 Μ Additionally , 13 miRNAS were differentially expressed for KRAS-mutated rectal tumors , 8 differentially expressed miRNAs for colon CIMP high tumors , and 2 differentially expressed miRNAs for BRAF-mutated colon tumors .
10 The majority of differentially expressed miRNAS were observed between MSI and MSS tumors ( 94 differentially expressed miRNAs for colon ; 41 differentially expressed miRNAs for rectal tumors ) .
11 Of these miRNAs differentially expressed between MSI and MSS tumors , the majority were downregulated .
12 Ten of the differentially expressed miRNAs were associated with survival ; after adjustment for MSI status , five miRNAS , miR-196b-5p , miR-31-5p , miR-99b-5p , miR-636 , and miR-192-3p , were significantly associated with survival .
13 In summary , it appears that the majority of miRNAs that are differentially expressed by tumor molecular phenotype are MSI tumors .
14 However , these miRNAs appear to have minimal effect on prognosis .



PMID: 27198569
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PD-L1 expression in colorectal cancer is associated with microsatellite instability , BRAF mutation , medullary morphology and cytotoxic tumor-infiltrating lymphocytes .
1 Programmed cell death 1 ( PD-1 ) and its ligand ( PD-L1 ) are key suppressors of the cytotoxic immune response .
2 PD-L1 expression on tumor cells may be induced by the immune microenvironment , resulting in immune escape ( adaptive immune resistance ) , and an adverse prognosis in many malignancies .
3 In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability .
4 However , little is known about the clinicopathologic , molecular , and prognostic characteristics of colorectal carcinoma with PD-L1 expression .
5 We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status , and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype , tumor mutational profile , and disease-specific survival .
6 PD-L1 was expressed in tumors from 16 patients ( 9% ) who were more often older ( P = 0006 ) and female ( P = 0035 ) , with tumors exhibiting a larger size ( P = 0013 ) , but lower stage ( P<0001 ) .
7 PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes , medullary phenotype , poor differentiation , microsatellite instability , BRAF mutation ( P<0001 for each ) , and a lower frequency of KRAS mutation ( P = 0012 ) .
8 On multivariate analysis , PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes , suggesting adaptive immune resistance .
9 PD-L1 positivity was not predictive of survival in the entire cohort , but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort .
10 PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis , and is associated with a worse outcome within microsatellite-unstable tumors .
11 These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology , provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade , and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma .



PMID: 27197524
(None)  
Terms: Meta-Analysis, meta-analysis
Sent# Symbols Sentence Mnemonics
0 Diagnostic Accuracy of BRAF Immunohistochemistry in Colorectal Cancer : a Meta-Analysis and Diagnostic Test Accuracy Review .
1 The aim of this study was to evaluate the concordance between the BRAF (V600E) mutation test and immunohistochemistry ( IHC ) and to evaluate the diagnostic accuracy of BRAF IHC for colorectal cancer ( CRC ) through a systematic review , meta-analysis , and diagnostic test accuracy review .
2 The current study included 1021 CRCs from eight eligible studies .
3 The concordance rates were investigated between BRAF IHC and the mutation test .
4 In addition , diagnostic test accuracy review was conducted and calculated using the value of area under curve ( AUC ) on the summary receiver operating characteristic ( SROC ) curve .
5 The positive rate of BRAF IHC was 30.5 % ( range ; 132-662 % ) , and the BRAF mutation was found in 30.2 % ( range ; 117-662 % ) .
6 The overall concordance rate between BRAF IHC and the mutation test was 0.944 ( 95 % confidence interval ( CI ) 0.873-0.977 ) .
7 In the BRAF IHC-positive and -negative groups , the concordance rates between BRAF IHC and the mutation test were 0.895 ( 95 % CI 0800-0945 ) and 0.956 ( 95 % CI 0878-0985 ) , respectively .
8 The pooled sensitivity and specificity were 0.94 ( 95 % CI 091-096 ) and 0.96 ( 95 % CI 095-098 ) , respectively .
9 The diagnostic odds ratio was 272.86 ( 95 % CI 4611-161488 ) , and the value of AUC on SROC curve was 0.9846 .
10 Μ Taken together , our results suggest that BRAF IHC is strongly concordant with the BRAF mutation test and has high diagnostic accuracy in BRAF mutation analysis of CRCs .
11 Further cumulative studies on detailed evaluation criteria are needed before application in daily practice .



PMID: 27196573
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumour CD274 (PD-L1) expression and T cells in colorectal cancer .
1 OBJECTIVE :
2 Evidence suggests that CD274 ( programmed death-ligand 1 , B7-H1 ) immune checkpoint ligand repress antitumour immunity through its interaction with the PDCD1 ( programmed cell death 1 , PD-1 ) receptor of T lymphocytes in various tumours .
3 We hypothesised that tumour CD274 expression levels might be inversely associated with T - cell densities in colorectal carcinoma tissue .
4 DESIGN :
5 We evaluated tumour CD274 expression by immunohistochemistry in 823 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study .
6 We conducted multivariable ordinal logistic regression analyses to examine the association of tumour CD274 expression with CD3+ , CD8+ , CD45RO (PTPRC) + or FOXP3+ cell density in tumour tissue , controlling for potential confounders including tumour status of microsatellite instability ( MSI ) , CpG island methylator phenotype , long interspersed nucleotide element -1 methylation level and KRAS , BRAF and PIK3CA mutations .
7 RESULTS :
8 Μ CD274 expression in tumour cells or stromal cells ( including immune cells ) was detected in 731 ( 89% ) or 44 ( 5% ) cases , respectively .
9 Tumour CD274 expression level correlated inversely with FOXP3+ cell density in colorectal cancer tissue ( outcome ) ( ptrend = 00002 ) .
10 For a unit increase in outcome quartile categories , multivariable OR in the highest ( vs lowest ) CD274 expression score was 0.22 ( 95% CI 010 to 047 ) .
11 Tumour CD274 expression was inversely associated with MSI-high status ( p = 0001 ) .
12 ✓ CD274 expression was not significantly associated with CD3+ , CD8+ or CD45RO+ cell density , pathological lymphocytic reactions or patient survival prognosis . GE-ASS-RO
13 CONCLUSIONS :
14 Tumour CD274 expression is inversely associated with FOXP3+ cell density in colorectal cancer tissue , suggesting a possible influence of CD274-expressing carcinoma cells on regulatory T cells in the tumour microenvironment .



PMID: 27196492
(Patient)  
Terms: Retrospective, retrospective
Sent# Symbols Sentence Mnemonics
0 Conversion Chemotherapy for Technically Unresectable Colorectal Liver Metastases : A Retrospective , STROBE-Compliant , Single-Center Study Comparing Chemotherapy Alone and Combination Chemotherapy With Cetuximab or Bevacizumab .
1 The response rate of patients with unresectable liver-limited metastases of colorectal cancer can be improved by converting inoperable disease to operable disease .
2 However , the benefits of conversion chemotherapy for survival are still controversial .
3 Patients considered to have technically inoperable disease by a multidisciplinary team were retrospectively analyzed .
4 Patients were stratified based on the treatment they received , into the chemotherapy only ( G1 ) , chemotherapy plus bevacizumab ( G2 ) , or chemotherapy plus cetuximab ( G3 ) groups .
5 The primary endpoint was the resection rate .
6 The secondary endpoint was the overall survival ( OS ) , according to both the treatment received and liver surgery status .
7 In total , 104 patients were included : 30 in the G1 , 39 in the G2 , and 35 in the G3 groups .
8 All G3 patients had the wild-type KRAS exon 2 .
9 The surgical resection rates for patients in the G1 , G2 , and G3 groups were 43.3% ( 13/30 ) , 30.7% ( 12/39 ) , and 51.4% ( 18/35 ) , respectively .
10 Disease-free survival did not show significant differences among the 3 groups .
11 The median OS was 35.2 months in the G1 , 28.8 months in the G2 , and 42.1 months in the G3 ( P = 025 ) groups .
12 The OS was significantly higher in patients who underwent surgical resection than those who did not .
13 The median OS was 28.4 months in patients who did not undergo resection , whereas it had not been reached after a median follow-up period of 37.5 months for patients who underwent surgical resection ( events : 21/43 ) .
14 Our data confirmed that the conversion of initially inoperable disease to operable disease conferred a survival benefit , even in patients who relapsed after surgery .
15   The addition of cetuximab to chemotherapy improved the objective response and resection rates , conferring a potential survival benefit even in patients whose diseases were not converted to operable disease , compared to chemotherapy alone or in combination with bevacizumab .



PMID: 27196139
(Patient)  
Terms: NCT01691391
Sent# Symbols Sentence Mnemonics
0 Early 18F-FDG PET/CT Evaluation Shows Heterogeneous Metabolic Responses to Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer .
1 OBJECTIVE :
2 The aim of this pilot study was to explore intrapatient mixed metabolic response and early 18F-FDG PET response evaluation using predefined quantification strategies in patients with advanced KRAS wild-type colorectal adenocarcinoma ( mCRC ) treated with cetuximab .
3 METHODS :
4 A 18F-FDG PET was performed at baseline and after 2 cycles of cetuximab .
5 Metabolic response was categorized using thresholds suggested in PERCIST .
6 Quantitative analysis was done for the sum of all target lesions ,
7 Quantitative data were correlated with clinical benefit , according to RECIST v1.1 , after two months of treatment .
8 RESULTS :
9 In nine evaluable patients the total number of target lesions was 34 ( 1-8 per patient ) .
10 Mixed metabolic response was observed in three out of seven patients with multiple target lesions , using TLG .
11 Dichotomised metabolic data of the sum of all or
12 Evaluating the metabolically most active lesion , concordance was 89% for all three units .
13 Additionally , the decrease in TLG was significantly correlated with PFS for all three quantification strategies .
14 CONCLUSION :
15   Mixed metabolic response was observed in nearly half of the patients with advanced KRAS wild-type mCRC treated with cetuximab .
16 If
17 Moreover , decrease in TLG is significantly correlated with the duration of PFS .
18 Validation of these promising preliminary results in a larger cohort is currently on-going .
19 TRIAL REGISTRATION : ClinicalTrials .
20 gov NCT01691391 .



PMID: 27195424
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical impact and network of determinants of tumour necrosis in colorectal cancer .
1 BACKGROUND :
2 The disease outcome in colorectal cancer ( CRC ) can vary in a wide range within the same tumour stage .
3 The aim of this study was to clarify the prognostic value and the determinants of tumour necrosis in CRC .
4 METHODS :
5 The areal proportion ( % ) of tumour tissue showing coagulative necrosis was evaluated in a cohort of 147 CRC patients and correlated with basic clinicopathological characteristics , microvascular density ( MVD ) , cell proliferation rate , KRAS and BRAF mutations , and survival .
6 To validate the prognostic significance of tumour necrosis , an independent cohort of 418 CRC patients was analysed .
7 RESULTS :
8 ✓ Tumour necrosis positively correlated with tumour stage ( P = 85E-4 ) -especially with T class ( 40E-6 ) -and inversely correlated with serrated histology ( P = 0014 ) , but did not significantly associate with cell proliferation rate , MVD , and KRAS or BRAF mutation . GM-ASS-RO
9 Abundant ( 10% or more ) tumour necrosis associated with worse disease-free survival independent of stage and other biological or clinicopathological characteristics in both cohorts , and the adverse effect was directly related to its extent .
10 High CD105 MVD was also a stage independent marker for worse disease-free survival .
11 CONCLUSIONS :
12 Tumour necrosis percentage is a relevant histomorphological prognostic indicator in CRC .
13 More studies are needed to disclose the mechanisms of tumour necrosis .



PMID: 27194209
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution .
1 Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma ( COAD ) .
2 We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data .
3 One hundred and twenty three cases of routinely collected mismatch repair proficient COAD were sequenced on the Illumina Truseq Amplicon assay .
4 Measures of intratumoral heterogeneity and the preferential timing of mutational events were assessed and compared to clinicopathologic data .
5 Survival subanalysis was performed on 55 patients .
6 Patient age ( p = 0013 ) and specimen percent tumor ( p = 0033 ) was associated with clonal diversity , and biopsy ( p = 0044 ) and metastasis ( p = 0044 ) returned fewer mutations per case .
7 Μ APC and TP53 mutations preferentially occurred early while alterations in FBXW7 , FLT3 , SMAD4 , GNAS and PTEN preferentially occurred as late events .
8 Temporal heterogeneity was evident in KRAS and PIK3CA mutations .
9 Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events .
10 Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype ( 8 months vs. 13 months ; univariate logrank p = 00380 , cox model p= 0018 ) .
11 Μ Neoadjuvant therapy associated mutations were found for ERBB2 ( p = 00481 ) and FBXW7 ( p = 0015 ) .
12 Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes .
13 Furthermore , we report treatment acquired and/or selected mutations in ERBB2 and FBXW7 .



PMID: 27188617
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Insights on colorectal carcinoma based on the biological differences between left-sided and right - sided colon cancers ] .
1 Previous studies have demonstrated that there are biological differences between colon and rectal cancers .
2 Recently , some authors have proposed that colorectal cancer could be classified into several categories according to the primary sites of the tumor , proximal or distal .
3 It is speculated that the differences are due to different embryologic origin and time to initial diagnosis .
4   Further evidence supports that the molecular differences in the status of K-ras , BRAF , and microsatellite instability ( MSI ) based on primary sites in the bowel are the basis that impacts the response to therapeutic agents and patient prognosis .



PMID: 27187477
(Cell)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth .
1 Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells , hyperthermia has had variable success as an anti-cancer therapy .
2 This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature .
3 We hypothesized that the varying sensitivity of colorectal cancer ( CRC ) cells to hyperthermia depends upon the differential induction of survival pathways .
4 Screening of such pathways revealed that Extracellular Signal-Regulated Kinase ( ERK ) signaling is augmented by hyperthermia , and the extent of this modulation correlates with the mutation status of rat V-Ki-ras2 Kirsten sarcoma viral oncogene homolog ( KRAS ) .
5 Through clonal growth assays , apoptotic analyses and transcription reporter assays of CRC cells that differ only in KRAS mutation status we established that mutant KRAS cells are more sensitive to hyperthermia , as they exhibit sustained ERK signaling hyperactivation and increased Wingless/Integrated (WNT) /beta-catenin signaling .
6 We propose that whereas increased levels of WNT and ERK signaling and a positive feedback between the two pathways is a major obstacle in anti-cancer therapy today , under hyperthermia the hyperinduction of the pathways and their positive crosstalk contribute to CRC cell death .
7 ✓ Ascertaining the causative association between types of mutations and hyperthermia sensitivity may allow for a mutation profile-guided application of hyperthermia as an anti-cancer therapy .
8   Since KRAS and WNT signaling mutations are prevalent in CRC , our results suggest that hyperthermia-based therapy might benefit a significant number , but not all , CRC patients .



PMID: 27186325
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 GNAS gene mutation may be present only transiently during colorectal tumorigenesis .
1 Mutations of the gene GNAS have been shown to activate the adenylate cyclase gene and lead to constitutive cAMP signaling .
2 Several preliminary reports have suggested a role for GNAS gene mutations during colorectal carcinogenesis , particularly mucinous carcinomas .
3 The aim of this study was to clarify the incidence of GNAS mutations in adenomas ( tubular , tubulovillous , and villous ) , carcinomas with residual adenoma , and carcinomas , and to relate these findings to mutations of the KRAS gene and to the mucinous status of the tumors .
4 We used standard PCR techniques and direct gene sequencing to evaluate tumors for gene mutations .
5 Μ No GNAS mutations were identified in 25 tubular adenomas , but were present in 6.4% of tubulovillous adenomas and 11.2% of villous adenomas .
6 Μ A GNAS mutation was found in 9.7% of the benign portion of carcinoma with residual adenoma , but in none of 86 carcinomas .
7 A similar trend was seen for KRAS mutation across the five groups of tumors .
8 GNAS mutations may function as an important driver mutation during certain phases of colorectal carcinogenesis , but may then be lost once the biological advantage gained by the mutated gene is no longer necessary to sustain or advance tumor development .



PMID: 27184911
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Locally advanced rectal cancers with simultaneous occurrence of KRAS mutation and high VEGF expression show invasive characteristics .
1 In this study , we investigated the mutation status of KRAS gene in pretherapeutic and preoperative biopsies in 63 specimens of locally advanced rectal cancers in order to evaluate its potential predictive and/or prognostic role .
2 Regions of interest of KRAS exon 2 were amplified and visualized on 2% agarose gel .
3 Obtained PCR products were subjected to direct sequencing .
4 Μ KRAS mutations were detected in 35% of patients , 91% of which were located in codon 12 and 9% in codon 13 .
5 ✓ In general , KRAS mutation status did not affect the response to neoadjuvant chemoradiotherapy ( CRT ) . GM-INV-RO
6 ✓ However , patients harboring mutated KRAS gene , simultaneously with high vascular endothelial growth factor ( VEGF ) expression , exhibited a worse response to CRT ( p = 0030 ) , a more frequent appearance of local recurrences and distant metastasis ( p = 0003 ) , and shorter overall survival ( p = 0001 ) compared to all others . GE-ASS-RO, RO-ASS-GE
7 ✓ On the contrary , patients with GGT>GCT KRAS mutation exhibited a significantly better response to CRT than those with any other type of KRAS mutation ( p = 0017 ) . GM-ASS-RO, RO-ASS-GM
8 Moreover , the presence of GGT>GCT mutation was associated with low VEGF and Ki67 expression ( p = 0012 in both cases ) , parameters related to less aggressiveness of the disease .
9 Our results suggest that KRAS mutation status could have some predictive and prognostic importance in rectal cancer when analyzed together with other parameters , such as VEGF and Ki67 expression .
10 In addition , it seems that not only the presence but the type of KRAS mutation is important for examining its impact on CRT response .



PMID: 27180965
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 [ BRAF mutation in progression and therapy of melanoma , papillary thyroid carcinoma and colorectal adenocarcinoma ] .
1 BRAF is mutated at a high frequency in various malignancies , including melanoma , papillary thyroid carcinoma and colorectal adenocarcinoma .
2 BRAF is an element of the RAS/RAF/MEK/ERK (MAPK) pathway , which when constitutively active can lead to increased proliferation rate , enhanced survival , invasion and metastasis .
3 The development of small molecule inhibitors of mutant BRAF kinase has changed the care of patients , especially with melanoma .
4 Despite the success in treating melanoma with inhibitors of mutant BRAF and other elements of RAS/RAF/MEK/ERK (MAPK) pathway , resistance limits the long-term responsiveness to these drugs .
5 The resistance mechanisms to MAPK pathway inhibition are complex , occur at genomic and phenotypic levels , and frequently the same patient can simultaneously develop diverse mechanisms of resistance in different progressive metastases or even in the same lesion .
6 In the current review , we summarize recent research on mutations in BRAF and their importance for the development of tumor .
7   This review will also give an overview on the current knowledge concerning therapies for patients harboring mutation in BRAF and discusses the diverse mechanisms of resistance developed in response to these targeted therapies .



PMID: 27179269
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Concordance of KRAS mutation status between luminal and peripheral regions of primary colorectal cancer . A laser-capture microdissection-based study .
1 The presence of KRAS mutation in colorectal cancer ( CRC ) is a marker of resistance to anti-EGFR therapy .
2 However , there are conflicting reports concerning intratumoral heterogeneity of KRAS mutations .
3 Μ The aim of this study was to determine whether within primary CRCs with KRAS mutations intratumoral KRAS mutation heterogeneity can be detected between two strictly defined areas , i.e.the luminal ( mucosa/submucosa ) and peripheral invasive front of the tumor .
4 Μ Using laser-capture microdissection , from every tumor about 400-500 nests of cancer cells were excised from each of the examined areas ( luminal and peripheral ) and PNAClamp , a high-sensitivity real-time PCR-based diagnostic assay for KRAS mutation testing , was used for molecular analysis .
5 Μ KRAS mutations were detected in codon 12 in both luminal and peripheral regions in all tumors examined .
6 We conclude that from the point of view of practical KRAS mutation testing for predictive purposes in patients with CRC ( i.e. testing mutations in codons 12 and 13 ) sampling errors are unlikely to occur if in CRCs with KRAS mutations only the luminal ( as in biopsy tissue ) or peripheral region is examined , provided a sensitive system of detection is applied and an appropriate number of tumor cells with minimal contamination by benign cells is analyzed .



PMID: 27179112
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Fc-gamma Receptor Polymorphisms , Cetuximab Therapy , and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer .
1 PURPOSE :
2 Two germline Fc-gamma receptor ( FCGR ) polymorphisms , rs1801274 [FCGR2A ; His(H) 131Arg(R) ] and rs396991 [FCGR3A ; Phe(F) 158Val(V) ] produce altered proteins through amino acid substitutions ; both are reported to be associated with cetuximab-related outcomes .
3 We performed a validation of these polymorphisms in NCIC CTG CO.17 , a randomized trial of cetuximab monotherapy in refractory , metastatic colorectal cancer expressing EGFR .
4 EXPERIMENTAL DESIGN :
5 DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped .
6 In addition to log-rank tests , Cox proportional hazard models assessed their relationships with overall ( OS ) and progression-free survival ( PFS ) , adjusting for clinically important prognostic factors , along with a polymorphism-treatment arm interaction term .
7 RESULTS :
8 Somatic KRAS status was wild-type for exon 2 in 153 ( 52% ) of 293 patients , from whom tumor DNA was available .
9 For FCGR2A H/H , a genotype-treatment interaction for KRAS wild-type patients was observed for OS ( P = 003 ) .
10 In KRAS wild-type patients carrying FCGR2A H/H , cetuximab ( vs. no cetuximab ) improved survival substantially , with adjusted HRs ( aHR ) of 0.36 ( OS ) and 0.19 ( PFS ) and absolute benefits of 5.5 months ( OS ; P = 0003 ) and 3.7 months ( PFS ; P = 002 ) .
11 Μ In contrast , patients carrying FCGR2A R alleles ( H/R or R/R ) had aHRs of only 0.78 ( OS ; 28-month benefit ) and 0.53 ( PFS ; 16-month benefit ) .
12 No relationships were found for rs396991 ( FCGR3A ) .
13 CONCLUSIONS :
14   In the CO.17 trial , cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes .
15 Μ Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles .
16 Clin Cancer Res ; 22 ( 10 ) ; 2435-44 .
17 (c) 2016 AACR .



PMID: 27178450
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Urachal Carcinoma Shares Genomic Alterations with Colorectal Carcinoma and May Respond to Epidermal Growth Factor Inhibition .
1 Metastatic urachal carcinoma is a rare , understudied , and aggressive malignancy with limited treatment options .
2 Histologically , urachal carcinomas resemble enteric adenocarcinomas and anecdotally respond to systemic therapies utilized in colorectal cancer .
3 Μ Targeted exome sequencing of archival primary tumor tissue from a patient with metastatic urachal cancer revealed EGFR amplification and wild-type KRAS .
4 The patient was treated with cetuximab , a monoclonal antibody directed against EGFR , as a single agent , and achieved a response lasting more than 8 mo .
5 Μ Subsequent whole-exome sequencing revealed no additional alterations likely to be associated with cetuximab sensitivity .
6 Formalin-fixed , paraffin-embedded tumor specimens from nine additional urachal cancers were subjected to targeted exome sequencing .
7 Μ Mitogen -activated protein kinase ( MAPK ) pathway mutations were found in four of the nine samples , but no EGFR amplification was detected .
8 Μ Importantly , APC mutations were detected in two of the nine patients .
9 To our knowledge , this is the first report of a response to single-agent cetuximab in a patient with metastatic urachal cancer and of molecular analysis to probe the basis for sensitivity .
10 On the basis of these findings and the histologic , and now genomic , similarities with colorectal cancer , monoclonal antibodies directed at EGFR could be used in the treatment of metastatic urachal cancer .
11 PATIENT SUMMARY :
12 Urachal cancers are morphologically and genomically similar to colon adenocarcinomas and may respond to drugs targeting the epidermal growth factor receptor .



PMID: 27167335
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer .
1 Telomeric dysfunction is linked to colorectal cancer ( CRC ) initiation .
2 However , the relationship of normal tissue and tumor telomere lengths with CRC progression , molecular features and prognosis is unclear .
3 Here , we measured relative telomere length ( RTL ) by real-time quantitative PCR in 90 adenomas ( aRTL ) , 419 stage I-IV CRCs ( cRTL ) and adjacent normal mucosa ( nRTL ) .
4 Μ Age-adjusted RTL was analyzed against germline variants in telomere biology genes , chromosome instability ( CIN ) , microsatellite instability ( MSI ) , CpG island methylator phenotype ( CIMP ) , TP53 , KRAS , BRAF mutations and clinical outcomes .
5 In 509 adenoma or CRC patients , nRTL decreased with advancing age .
6 Female gender , proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL .
7 Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases .
8 Age-adjusted nRTL and cRTL were independently associated with tumor stage , decreasing from adenoma to stage III and leveling out or increasing from stage III to IV , respectively .
9 Cancer MSI , CIMP , TP53 , KRAS and BRAF status were not related to nRTL or cRTL .
10 Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs , while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks .
11 Age-adjusted nRTL , cRTL or cRTL : nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC .
12 Taken together , our data show that both normal mucosa and tumor RTL are independently associated with CRC progression , and highlight divergent associations of CRC telomere length with tumor CIN profiles .



PMID: 27165728
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal Cancer Yields to Dual HER2 Blockade .
1 According to data from a phase II study , the anti-HER2 combination of trastuzumab and lapatinib is active in patients with KRAS-wild-type , HER2-positive metastatic colorectal cancer .
2 None of the study participants responded to previous , standard treatment with the EGFR inhibitors cetuximab or panitumumab , but 30% achieved an objective response to dual HER2 blockade .



PMID: 27160084
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer .
1 BACKGROUND :
2 Podocalyxin-like 1 ( PODXL ) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer ( CRC ) .
3 The gene encoding PODXL is located to chromosome 7 , which also harbours the gene for the epidermal growth factor receptor ( EGFR ) .
4 The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo .
5 METHODS :
6 EGFR expression was analysed in tumours from three independent patient cohorts ; cohort 1 ( n = 533 ) , cohort 2 ( n = 259 ) and cohort 3 ( n = 310 ) , previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations ( cohort 1 and 3 ) .
7 Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines .
8 RESULTS :
9 High expression of PODXL was significantly associated with high EGFR expression ( p <0001 ) in all three cohorts , and with BRAF mutation ( p <0001 ) in cohort 1 and 3 .
10 High EGFR expression correlated with BRAF mutation ( p <0001 ) in cohort 1 .
11 High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival ( OS ) in cohort 1 ( HR 177 ; 95 % CI 127-246 ) , cohort 2 ( HR 158 ; 95 % CI 105-238 ) and cohort 3 ( HR 183 ; 95 % CI 119-281 ) .
12 Μ The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 ( HR 197 ; 95 % CI 118-328 and HR 356 ; 95 % CI 175-722 , respectively ) .
13 Μ Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines .
14 CONCLUSIONS :
15 The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC .
16 Moreover , strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro , and with BRAF mutation in vivo .
17 High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival .
18 These findings suggest a potential functional link in CRC between PODXL , EGFR and BRAF , all originating from chromosome 7 , which may be highly relevant in the clinical setting and therefore merit future in-depth study .



PMID: 27155924
(Patient)  
Terms: retrospective, retrospective study
Sent# Symbols Sentence Mnemonics
0 ✓ [ KRAS mutation does not influence oxaliplatin or irinotecan efficacy , in association with bevacizumab , in first line treatment of metastatic colorectal cancer ] . GM-REG-RO
1 INTRODUCTION :
2 The identification of RAS status ( KRAS and NRAS ) has changed the management of metastatic colorectal cancer ( mCRC ) .
3 The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined .
4 Nevertheless , several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation .
5 METHODS :
6 We analyzed retrospectively the progression free survival ( PFS ) and overall survival ( OS ) in 216 patients with mCRC receiving first line treatment between 2008 and 2010 according to KRAS status and chemotherapy regimen used ( oxaliplatin - or irinotecan-based , in association with fluoropyrimidine and bevacizumab ) .
7 RESULTS :
8 In KRAS mutated tumors , median OS was 23.4 months with oxaliplatin-based regimen , and 23.6 months with irinotecan-based regimen , with no significant difference ( HR 130 ; 95 % CI 081-209 ; P = 027 ) .
9 In KRAS wild-type tumors , median OS was 30.3 months with oxaliplatin-based regimen , and 25.4 months with irinotecan-based regimen , with no significant difference ( HR 081 ; 95 % CI 052-124 ; P = 033 ) .
10 ✓ Similarly , KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS . GE-ASS-RO
11 ✓ DISCUSSION : In this retrospective study , KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab . GE-REG-RO



PMID: 27155048
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Driver Gene Mutations in Stools of Colorectal Carcinoma Patients Detected by Targeted Next-Generation Sequencing .
1 Μ Detection of driver gene mutations in stool DNA represents a promising noninvasive approach for screening colorectal cancer ( CRC ) .
2 Amplicon-based next-generation sequencing ( NGS ) is a good option to study mutations in many cancer genes simultaneously and from a low amount of DNA .
3 Our aim was to assess the feasibility of identifying mutations in 22 cancer driver genes with Ion Torrent technology in stool DNA from a series of 65 CRC patients .
4 The assay was successful in 80% of stool DNA samples .
5 Μ NGS results showed 83 mutations in cancer driver genes , 29 hotspot and 54 novel mutations .
6 One to five genes were mutated in 75% of cases .
7 TP53 , KRAS , FBXW7 , and SMAD4 were the top mutated genes , consistent with previous studies .
8 Of samples with mutations , 54% presented concomitant mutations in different genes .
9 Phosphatidylinositol 3-kinase/mitogen -activated protein kinase pathway genes were mutated in 70% of samples , with 58% having alterations in KRAS , NRAS , or BRAF .
10 ✓ Because mutations in these genes can compromise the efficacy of epidermal growth factor receptor blockade in CRC patients , identifying mutations that confer resistance to some targeted treatments may be useful to guide therapeutic decisions .
11 Μ In conclusion , the data presented herein show that NGS procedures on stool DNA represent a promising tool to detect genetic mutations that could be used in the future for diagnosis , monitoring , or treating CRC .



PMID: 27154421
(None)  
Terms: phase III trial
Sent# Symbols Sentence Mnemonics
0 Challenging chemoresistant metastatic colorectal cancer : therapeutic strategies from the clinic and from the laboratory .
1 As survival has improved for patients with metastatic colorectal cancer ( mCRC ) , there is an increasing need for effective and well-tolerated third - line and subsequent - lines of treatment .
2 Despite recent advances with the development of new-targeted therapies in this setting , there remains an unmet need to exploit oncogenic drivers of colorectal cancer and overcome acquired resistance .
3   Potential treatment strategies include revisiting old targets such as human epidermal growth factor receptor 2 , RAS , and BRAF and investigating new targets such as c-MET , the PI3 kinase , and Wnt pathways , and also the use of immune-checkpoint inhibitors .
4   Here , we review recent phase III trials exploring approved agents , early trials investigating new drugs for chemorefractory mCRC , and the potential of capturing tumour dynamics during its evolution by liquid biopsy analysis .



PMID: 27154293
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 GNAS mutations as prognostic biomarker in patients with relapsed peritoneal pseudomyxoma receiving metronomic capecitabine and bevacizumab : a clinical and translational study .
1 BACKGROUND :
2 There is lack of evidence about systemic treatment of pseudomyxoma peritonei ( PMP ) relapsing after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy .
3 There is also lack of biomarkers able to predict outcomes beyond known clinical and pathological prognostic features .
4 METHODS :
5 Fifteen patients with relapsed PMP and progressive disease within the last 6 months were included and received metronomic capecitabine ( 625 mg/mq/day bid ) and bevacizumab ( 75 mg/Kg three-weekly ) until progressive disease/unacceptable toxicity .
6 The primary endpoint was progression-free survival ( PFS ) .
7 Ion Torrent ( (R) ) next generation sequencing technology ( Hot-spot Cancer Panel ) was used to characterize molecular features .
8 RESULTS :
9 At a median follow up of 12 months , median PFS was 8.2 months and 1-year overall survival was 91 % .
10 Partial responses were observed in 20 % of cases , but a significant reduction of tumor markers in up to 79 % .
11 Treatment was very well tolerated without no new safety signals .
12 All tumor samples except one had KRAS mutations .
13 ✓ Patients with GNAS mutations had a significantly shorter median PFS as compared to GNAS wild-type ones ( 53 months vs. not reached ; p <0007 ) . GM-ASS-RO, RO-ASS-GM
14 The results were externally validated on our previous series of PMP patients .
15 GNAS mutations were rare in a parallel cohort of 121 advanced colorectal cancers ( 25 % ) , but were associated with peculiar clinical-pathological features and aggressive course .
16 CONCLUSIONS :
17 Metronomic capecitabine and bevacizumab is an active and well tolerated option in patients with relapsed PMP .
18 The negative prognostic effect of GNAS mutations in gastrointestinal cancers warrants further confirmatory studies and may prompt the development of effective targeted strategies .



PMID: 27153478
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Associations between markers of colorectal cancer stem cells , mutation , microRNA and the clinical features of ulcerative colitis .
1 AIM :
2 Several factors have been implicated in the pathogenesis of colorectal cancer ( CRC ) associated with ulcerative colitis ( UC ) .
3 We investigated markers of cancer cell pluripotency , including CD44 and CD166 , microRNA-21 ( miR-21 ) and microRNA-215 ( miR-215 ) , and APC , K-ras and DCC mutations in biopsy specimens from patients with UC to evaluate any correlations with clinical risk factors .
4 METHOD :
5 We observed 18 patients with UC and collected two biopsy specimens from each patient at diagnosis and at a follow-up end-point .
6 We examined the expression of CD44 , CD166 , miR-21 and miR-215 , and APC , K-ras and DCC mutations .
7 We compared these markers at the two time points and assessed their associations with clinical characteristics , including the duration of colitis , histological alterations and the age of the patient at the onset of UC .
8 RESULTS :
9 Μ Most ( 16/18 ) patients had alleviation of mucosal inflammation or remained stable during follow-up ; one patient developed dysplasia and one had severe aggravation of the lesion during follow-up.Enhanced expression of CD44 , CD166 and miR-21 with miR-215 was found in the specimens obtained at follow-up , despite alleviation of mucosal lesions .
10 Coherence of cancer stem cell markers and miRNAs was seen in patients who had significant worsening of inflammation , dysplasia and a long duration of colitis .
11 Μ APC mutation occurred in only one patient ; this patient had the longest duration of UC ( 23 years ) .
12 CONCLUSION :
13 Enhanced markers of CRC in follow-up colonic mucosal samples support the conclusion that the duration of UC plays the most important role in UC-related carcinogenesis .



PMID: 27152634
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer : a single centre experience of 486 patients .
1 BACKGROUND :
2 Germline mutations in DNA mismatch repair ( MMR ) genes MLH1 , MSH2 , MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome .
3 Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance .
4 Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome .
5 OBJECTIVE :
6 The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015 .
7 DESIGN :
8 Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1 , PMS2 , MSH2 and MSH6 , independent of clinical criteria .
9 In the case of loss of MLH1 , the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry .
10 Clinical follow-up of potential Lynch syndrome carriers ( patients with tumours showing loss of MLH1 expression with absence of BRAFV600E , loss of PMS2 , MSH2 or MSH6 ) was evaluated .
11 RESULTS :
12 Μ Of all patients ( n = 486 ) , loss of MMR protein expression was found in 73 ( 150% ) tumours .
13 Twenty-eight ( 60% ) were classified as potential Lynch syndrome carriers .
14 Of the genetically tested potential Lynch syndrome carriers ( 10 out of 28 patients ) , 40% were first diagnosed with Lynch syndrome .
15 CONCLUSIONS :
16 Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related .
17 Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and , in MMR deficient cases , include clear recommendations for genetic counselling for all potential Lynch syndrome patients .



PMID: 27146902
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical significance of frequent somatic mutations detected by high-throughput targeted sequencing in archived colorectal cancer samples .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is a heterogeneous disease with different molecular characteristics associated with many variables such as the sites from which the tumors originate or the presence or absence of chromosomal instability .
3 Identification of such variables , particularly mutational hotspots , often carries a significant diagnostic and/or prognostic value that could ultimately affect the therapeutic outcome .
4 METHODS :
5 Μ High-throughput mutational analysis of 99 CRC formalin-fixed and paraffin-embedded ( FFPE ) cases was performed using the Cancer Hotspots Panel ( CHP ) v2 on the Ion Torrent platform .
6 Correlation with survival and other Clinicopathological parameters was performed using Fisher's exact test and Kaplan-Meier curve analysis .
7 RESULTS :
8 Targeted sequencing lead to the identification of frequent mutations in TP53 ( 65 % ) , APC ( 36 % ) , KRAS ( 35 % ) , PIK3CA ( 19 % ) , PTEN ( 13 % ) , EGFR ( 11 % ) , SMAD4 ( 11 % ) , and FBXW7 ( 7 % ) .
9 Μ Other genes harbored mutations at lower frequency .
10 EGFR mutations were relatively frequent and significantly associated with young age of onset ( p = 0028 ) .
11 ✓ Additionally , EGFR or PIK3CA mutations were a marker for poor disease-specific survival in our cohort ( p = 0009 and p = 0032 , respectively ) . GM-MRK-RO, GM-ASS-RO
12 ✓ Interestingly , KRAS or PIK3CA mutations were significantly associated with poor disease-specific survival in cases with wild-type TP53 ( p = 0001 and p = 002 , respectively ) . GE-ASS-RO, GM-ASS-RO
13 CONCLUSIONS :
14 Frequent EGFR mutations in this cohort as well as the differential prognostic potential of KRAS and PIK3CA in the presence or absence of detectable TP53 mutations may serve as novel prognostic tools for CRC in patients from the Kingdom of Saudi Arabia .
15   Such findings could help in the clinical decision-making regarding therapeutic intervention for individual patients and provide better diagnosis or prognosis in this locality .



PMID: 27146067
(Patient)  
Terms: retrospective study, retrospective
Sent# Symbols Sentence Mnemonics
0 ( 18 ) F-FDG PET/CT imaging in rectal cancer : relationship with the RAS mutational status .
1 OBJECTIVE :
2 Treating metastatic colorectal cancer with anti-EGFR monoclonal antibodies is recommended only for patients whose tumour does not harbour mutations of KRAS or NRAS .
3 The aim of this study was to investigate the biology of rectal cancers and specifically to evaluate the relationship between fluorine-18 fludeoxyglucose ( ( 18 ) F-FDG ) positron emission tomography ( PET ) intensity and heterogeneity parameters and their mutational status .
4 METHODS :
5 151 patients with newly diagnosed rectal cancer were included in this retrospective study .
6 All patients underwent a baseline ( 18 ) F-FDG PET/CT within a median time interval of 27 days of tumour tissue sampling , which was performed before any treatment .
7 Standardized uptake values ( SUVs ) , volume-based parameters and texture analysis were studied .
8 We retrospectively performed KRAS genotyping on codons 12 , 13 , 61 , 117 and 146 , NRAS genotyping on codons 12 , 13 and 61 and BRAF on codon 600 .
9 Μ Associations between PET/CT parameters and the mutational status were assessed using univariate and multivariate analysis .
10 RESULTS :
11 83 ( 55% ) patients had an RAS mutation : 74 KRAS and 9 NRAS , while 68 patients had no mutation ( wild-type tumours ) .
12 No patient had BRAF mutation .
13 First-order features based on intensity histogram analysis were significantly associated with RAS mutations : maximum SUV ( SUVmax ) ( p-value = 0002 ) , mean SUV ( p-value = 0006 ) , skewness ( p-value = 0049 ) , SUV standard deviation ( p-value = 0001 ) and SUV coefficient of variation ( SUVcov ) ( p-value = 0001 ) .
14 Both SUVcov and SUVmax showed an area under the curve of 0.65 with sensitivity of 56% and 69% , respectively , and specificity of 64% and 52% , respectively .
15 None of the volume-based ( metabolic tumour volume and total lesion glycolysis ) , nor local or regional textural features were associated with the presence of RAS mutations .
16 CONCLUSION :
17 Although rectal cancers with KRAS or NRAS mutations display a significantly higher glucose metabolism than wild-type cancers , the accuracy of the currently proposed quantitative metrics extracted from ( 18 ) F-FDG PET/CT is not sufficiently high for playing a meaningful clinical role .
18 ADVANCES IN KNOWLEDGE :
19 RAS-mutated rectal cancers have a significantly higher glucose metabolism .
20 However , the accuracy of ( 18 ) F-FDG PET/CT quantitative metrics is not as such as the technique could play a clinical role .



PMID: 27144545
(Patient)  
Terms: retrospective, clinical trial, Prospective
Sent# Symbols Sentence Mnemonics
0 A Novel Computational Tool for Mining Real-Life Data : Application in the Metastatic Colorectal Cancer Care Setting .
1 BACKGROUND :
2 Randomized clinical trials constitute the gold-standard for evaluating new anti-cancer therapies ; however , real-life data are key in complementing clinically useful information .
3 We developed a computational tool for real-life data analysis and applied it to the metastatic colorectal cancer ( mCRC ) setting .
4 This tool addressed the impact of oncology/non-oncology parameters on treatment patterns and clinical outcomes .
5 METHODS :
6 The developed tool enables extraction of any computerized information including comorbidities and use of drugs ( oncological/non-oncological ) per individual HMO member .
7 The study in which we evaluated this tool was a retrospective cohort study that included Maccabi Healthcare Services members with mCRC receiving bevacizumab with fluoropyrimidines ( FP ) , FP plus oxaliplatin ( FP-O ) , or FP plus irinotecan ( FP-I ) in the first - line between 9/2006 and 12/2013 .
8 RESULTS :
9 The analysis included 753 patients of whom 15.4% underwent subsequent metastasectomy ( the Surgery group ) .
10 For the entire cohort , median overall survival ( OS ) was 20.5 months ; in the Surgery group , median duration of bevacizumab-containing therapy ( DOT ) pre-surgery was 6.1 months ; median OS was not reached .
11 In the Non-surgery group , median OS and DOT were 18.7 and 11.4 months , respectively ; no significant OS differences were noted between FP-O and FP-I , whereas FP use was associated with shorter OS ( 123 month ; p <0002 ; notably , these patients were older ) .
12 Patients who received both FP-O - and FP-I-based regimens achieved numerically longer OS vs.those who received only one of these regimens ( 22.1 [199-240] vs. 18.9 [155-219] months ) .
13   Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent , OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients ( non-significant ) .
14 Cox analysis ( controlling for age and gender ) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton-pump inhibitors .
15 CONCLUSIONS :
16 Our tool provided insights that confirmed/complemented information gained from randomized-clinical trials .
17 Prospective tool implementation is warranted .



PMID: 27145369
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations .
1 To clarify the molecular and clinicopathological characteristics of colorectal serrated lesions , we assessed the DNA methylation of cancer-associated genes in a cohort of BRAF-mutant precancerous lesions from 94 individuals .
2 We then compared those results with the lesions' clinicopathological features , especially colorectal subsites .
3 The lesions included hyperplastic polyps ( n = 16 ) , traditional serrated adenomas ( TSAs ) ( n = 15 ) , TSAs with sessile serrated adenomas ( SSAs ) ( n = 6 ) , SSAs ( n = 49 ) and SSAs with dysplasia ( n = 16 ) .
4 The prevalence of lesions exhibiting the CpG island methylator phenotype ( CIMP ) was lower in the sigmoid colon and rectum than in other bowel subsites , including the cecum , ascending , transverse and descending colon .
5 In addition , several cancer-associated genes showed higher methylation levels within lesions in the proximal to sigmoid colon than in the sigmoid colon and rectum .
6 These results indicate that the methylation status of lesions with BRAF mutation is strongly associated with their location , histological findings and neoplastic pathways .
7 By contrast , no difference in aberrant DNA methylation was observed in normal-appearing background colonic mucosa along the bowel subsites , which may indicate the absence of an epigenetic field defect .



PMID: 27144434
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 MEK5/ERK5 signaling inhibition increases colon cancer cell sensitivity to 5-fluorouracil through a p53 -dependent mechanism .
1 The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset , progression and metastasis ; however , its relevance to chemotherapy resistance remains unknown .
2 Here , we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil ( 5-FU ) .
3 Increased ERK5 expression was correlated with poor overall survival in colon cancer patients .
4 In colon cancer cells , 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation .
5 In turn , MEK5 constitutive activation reduced 5-FU-induced cytotoxicity .
6 Using genetic and pharmacological approaches , we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure .
7 Mechanistically , this was further associated with increased p53 transcriptional activation of p21 and PUMA .
8 In addition , ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU , but failed to sensitize HCT116 p53-/- cells to the cytotoxic effects of this chemotherapeutic agent , suggesting a p53 -dependent axis mediating 5-FU sensitization .
9 Finally , ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model , enhancing apoptosis while markedly reducing tumor growth .
10   Collectively , our results suggest that ERK5-targeted inhibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment .



PMID: 27144068
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Second - line panitumumab as a triweekly dose for patients with wild-type KRAS exon 2 metastatic colorectal cancer : a single-institution experience .
1 OBJECTIVE :
2 Panitumumab administered as monotherapy in colorectal cancer ( CRC ) has shown response and disease stabilization rates of approximately 30% .
3 The current study aimed to evaluate the progression-free survival ( PFS ) and overall survival ( OS ) of patients with metastatic colorectal cancer ( mCRC ) treated with panitumumab every 3 weeks as a second line treatment .
4 METHODS :
5 This study is a retrospective analysis of 18 patients , aged more than 18 years , with wild-type KRAS exon 2 mCRC treated with panitumumab as a second - line single agent after progression on first - line chemotherapy .
6 RESULTS :
7 The median number of courses received was 10 ( range , 4-29 ) , and the median duration of treatment was 30 weeks ( range , 12-96 weeks ) .
8 After a median follow-up period of 13 months , the median PFS was 6 months ( range , 43-77 months ) and the median OS was 11 months ( range , 74-145 months ) .
9 The median PFS was 4 months for patients with / = grade 2 skin rash ( P = 005 ) .
10 The median OS was 9 months ( range , 64-115 months ) and 14 months ( range , 116-163 months ) for the two groups of patients ( P = 0002 ) .
11 CONCLUSIONS :
12   Panitumumab given every 3 weeks is effective and well tolerated in patients with advanced CRC that progressed after standard chemotherapy .



PMID: 27143928
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Comparison of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer .
1 PURPOSE :
2 In metastatic or recurrent colorectal cancer ( MRCRC ) , the concordance of rat Kirsten sarcoma viral oncogene homolog ( KRAS ) and LONGTOKEN mutation status between the primary tumors and metastases is still controversial .
3 The purpose of this study was to evaluate the association between KRAS and PIK3CA mutational status and various clinicopathologic features , and compare their genotype in primary tumors with that of the paired metastatic tumors .
4 METHOD :
5 We compared the mutation status of KRAS and PIK3CA between the primary tumors and the paired metastases of 59 MRCRC patients with available tissues ( resection or biopsy ) .
6 Μ The presence of KRAS and PIK3CA mutations were determined by direct sequencing analysis .
7 RESULTS :
8 Seventeen patients ( 288% ) had the KRAS mutation and 46 patients ( 800% ) had the PIK3CA mutation when considering both the primary and metastatic sites .
9 Μ KRAS mutation was observed in ten primary tumors and eleven related metastases ( 169% versus 186% ) , while PIK3CA mutation was found in 26 primary tumors and 32 related metastases ( 441% versus 542% ) .
10 KRAS status was concordant between primary and metastatic sites in 45 patients ( 763% , kappa =0157 ) , while the concordance of PIK3CA status was only found in 25 patients ( 424% , kappa =-0141 ) .
11 The PIK3CA status discordance rate was significantly higher in 40 patients undergoing metachronous resection of primary tumor or metastasis , compared with that in 19 patients with synchronous resection of primary tumor or metastasis ( 67.5% [27/40] versus 36.8% [7/19] ; P = 0.026 ) .
12 CONCLUSION :
13 Our results demonstrate that low concordance of KRAS and high discordance of PIK3CA mutational status exist between the primary tumors and paired metastasis , and these findings remind us to have second thoughts about the need to evaluate metastatic tumors separately rather than only based on the primary tumor data when targeted therapy is considered .



PMID: 27143691
(Cell)  
Terms: ex vivo, in vitro, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer .
1 PURPOSE :
2 KRAS mutations confer adverse prognosis to colorectal cancer , and no targeted therapies have shown efficacy in this patient subset .
3 Paracrine , nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment ( TME ) proteins , which in principle can be exploited as alternative therapeutic targets .
4 EXPERIMENTAL DESIGN :
5 A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer .
6 Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens ( n = 71 ) .
7 The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models .
8 The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhesion assays .
9 RESULTS :
10 BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS-mutant hepatic metastasis from colorectal cancer , where they were specifically overexpressed .
11 Two BCAM-mimic peptides inhibited KRAS-mutant hepatic metastasis in preclinical models .
12 Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells , whereas adhesion to pericytes and hepatocytes was unaffected .
13 CONCLUSIONS :
14 These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS-mutant colorectal cancer by mediating tumor-TME interactions and as such represents a valuable therapeutic candidate for this large , currently untreatable patient group .
15 Clin Cancer Res ; 22 ( 19 ) ; 4923-33 .
16 (c) 2016 AACR .



PMID: 27143148
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cost-Effectiveness Analysis of Different Sequences of the Use of Epidermal Growth Factor Receptor Inhibitors for Wild-Type KRAS Unresectable Metastatic Colorectal Cancer .
1 PURPOSE :
2 Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines ( FP ) , oxaliplatin (O) , irinotecan (I) , bevacizumab ( Bev ) , and epithelial growth factor receptor inhibitors ( EGFRI ) .
3 The most cost-effective regimen remains unclear .
4 METHODS :
5 A Markov model was constructed to examine the costs and outcomes of three treatment strategies : strategy A ( reference strategy ) : EGFRI monotherapy in third line ( [3L] ; ie , first - line [1L] : Bev + FOLFIRI [FP + I] or FOLFOX [FP + O] ; second line [2L] : FOLFIRI/FOLFOX ; 3L : EGFRI ) ; strategy B : EGFRI and I in 3L ( ie , 1L : Bev + FOLFIRI/FOLFOX ; 2L : FOLFIRI/FOLFOX ; 3L : EGFRI + I ) ; and strategy C : EGFRI in 1L ( ie , 1L : EGFRI + FOLFIRI/FOLFOX ; 2L : Bev + FOLFIRI/FOLFOX ; 3L : best supportive care ) .
6 Efficacy data of the treatments were obtained from the literature .
7 Health system resource use information was derived from chart review and the literature .
8 Using Euro-QOL 5 Dimensions , utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature .
9 The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars .
10 RESULTS :
11 All three strategies had similar efficacy , but strategy C was most expensive .
12 The incremental cost-effectiveness ratios ( ICERs ) for strategies B and C compared with A were 119,623 and 3,176,591 , respectively .
13 The model was primarily driven by the acquisition cost of the drugs .
14 Strategy B was most cost effective when the willingness-to-pay threshold was >$130,000 per quality-adjusted life-year .
15 Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio <0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year .
16 CONCLUSION :
17   First - line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev .



PMID: 27138801
(Patient)  
Terms: Meta-Analysis, Clinical Trial, meta-analysis, clinical trial, phase III
Sent# Symbols Sentence Mnemonics
0 Prognostic Role of BRAF Mutation in Stage II/III Colorectal Cancer Receiving Curative Resection and Adjuvant Chemotherapy : A Meta-Analysis Based on Randomized Clinical Trials .
1 BACKGROUND AND OBJECTIVE :
2 Studies examining the prognostic value of the BRAF mutation on relapse-free survival ( RFS ) , disease-free survival ( DFS ) and overall survival ( OS ) in stage II/III colorectal cancer ( CRC ) patients receiving curative resection and adjuvant chemotherapy so far showed discrepant results .
3 Therefore , a meta-analysis of relevant studies was performed for clarification .
4 METHODS :
5 Randomized trials of stage II/III colorectal cancer treated with curative resection followed by adjuvant chemotherapy were selected to conduct a meta-analysis .
6 The necessary descriptive and statistical information such as hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) were derived from published survival data .
7 RESULTS :
8   Seven phase III randomized clinical trials ( RCTs ) including 1,035 BRAF mutation stage II/III CRC patients receiving curative resection and adjuvant chemotherapy were analyzed .
9 ✓ Overall , BRAF mutation resulted in poorer OS ( HR = 1.42 , 95% CI : 1.25-1.60 ; P <0.00001 ) , and poorer DFS ( HR = 1.26 , 95% CI : 1.07-1.48 , P = 0.006 ) compared with BRAF wild-type CRC . GM-REG-RO
10 The prognostic role on RFS could not be elucidated in the meta-analysis because of limited data .
11 CONCLUSIONS :
12 ✓ BRAF mutation was significantly related with shorter DFS and OS among stage II/III CRC patients receiving adjuvant chemotherapy after curative resection . GM-ASS-RO
13 Its prognostic role for RFS needs to be further analyzed when more data is available .



PMID: 27131021
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability and B-type Raf proto - oncogene mutation in colorectal cancer : Clinicopathological characteristics and effects on survival .
1 Prognostic significance of microsatellite instability ( MSI ) status and B-type Raf proto-oncogene ( BRAF ) mutation in colorectal cancer is controversial .
2 The aim of this study was to examine the clinical and pathological characteristics associated with microsatellite stability and the effect of MSI and BRAF mutation on the survival of patients with colorectal cancer .
3 The study included 145 colorectal cancer cases .
4 All the patients were examined for DNA mismatch repair ( MMR ) proteins with an immunohistochemical method .
5 Molecular assessment of MSI was available in a subset of 41 patients .
6 Μ In addition , BRAF mutation analysis was performed in 30 cases .
7 Immunohistochemically , MMR deficiency was present in 28 ( 193% ) patients .
8 Female gender ( p = 0001 ) , lesion size >/ = 5 cm ( p = 0013 ) , Crohn-like response ( p = 0035 ) , and right-sided localization ( p <0001 ) were significantly more frequent among MMR-deficient patients .
9 The overall survival was 44.1 +/- 5.1 months ( 95% confidence interval [CI] , 33.7-54.4 ) .
10 Μ Multivariate analyses identified only high tumor grade as an independent predictor of poor overall survival : odd ratio , 6.7 ( 95% CI 21-217 ) , p = 0.002 .
11 ✓ In the subset of patients with available BRAF assessment ( n = 30 ) , a negative BRAF status was associated with better survival when compared to a positive BRAF status ( 367 +/- 21 vs. 341 +/- 72 months , p = 0048 ) . GE-ASS-RO
12 The sensitivity and specificity of the immunohistochemical method in predicting positive MSI status , with the molecular method as a reference , were 85.7% ( 95% CI : 56.2%-97.5% ) and 88.9% ( 95% CI : 69.7%-97.1% ) , respectively .
13 BRAF appears to be a significant predictor of a worse outcome in patients with colorectal cancer .
14 Further studies with a large spectrum of clinical and biological variables are warranted .



PMID: 27130653
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Interaction of KRAS G-quadruplex with natural polyphenols : A spectroscopic analysis with molecular modeling .
1 Researchers are endeavoring to find out new therapeutics for curing cancer and G-quadruplex DNA has already been identified as a prospective one in this venture .
2 Stabilizing G-quadruplex structures of telomere has emerged to be an important strategy in this context .
3 Mutation in KRAS is mostly responsible for pancreatic , lung and colon cancer .
4 In this present study we explored binding and conformational behaviour of G-quadruplex with different ligands by utilizing several biophysical techniques .
5 Natural polyphenols like Curcumin and Ellagic acid were observed to bind with the G-quadruplex and enhance the melting temperature significantly indicating higher stability .
6 UV-vis spectroscopy confirms formation of G quadruplex-ligand complex for both the compounds with specific binding affinity .
7 Fluorimetric studies revealed that Ellagic acid had stronger binding affinity , 1.10x10(5) M ( -1 ) compared to Curcumin , 1.6x10(4) M ( -1 ) towards G-quadruplex .
8 Interestingly , Curcumin provides greater stability by stacking on the top of the quadruplex structure with the help of the loops compared to Ellagic acid as is evident by docking studies .
9 The keto form of curcumin showed stronger affinity than the enol form .
10 We have developed a general model to estimate the influence of the ligands towards stabilizing the G-quadruplex subsequently characterizing the binding profile to enlighten prospective therapeutics .



PMID: 27127165
(Patient)  
Terms: Phase II Study, prospective study
Sent# Symbols Sentence Mnemonics
0 Initial Report of Phase II Study on Bi-weekly SOX plus Cetuximab Treatment for Wild-type K-RAS Advanced and Recurrent Colorectal Cancer .
1 AIM :
2 This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX ( S-1 and oxaliplatin ) +cetuximab as first - line chemotherapy for wild-type K-RAS metastatic colorectal cancer .
3 PATIENTS AND METHODS :
4 We studied patients with previously untreated , unresectable , advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013 .
5 Their performance status ( PS ) was 0 to 1 .
6 Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab) .
7 S-1 was given orally at a dose of 40 mg/m(2) ( 40-60 mg , calculated according to body surface area ) twice daily after meals for 2 weeks , followed by a 2-week rest ( course 1 ) .
8 Oxaliplatin ( 85 mg/m(2) ) was given on days 1 and 15 of each course .
9 Cetuximab was administered on days 1 ( 400 mg/m(2) ) , 8 ( 250 mg/m(2) ) and 15 ( 500 mg/m(2) ) of course 1 , followed by every 2 weeks ( 500 mg/m(2) ) thereafter .
10 RESULTS :
11 The study group comprised of 18 patients .
12 The mean age was 61 ( range = 32-72 ) years , the male : female ratio was 10 : 8 and the PS was 0 in 12 patients and 1 in 6 patients .
13 The median number of administered courses was 6 ( range = 2-12 ) .
14   The treatment response was complete response ( CR ) in 2 and partial response ( PR ) in 10 ( response rate = 67% ( 12/18 patients ) ) .
15 The minimum number of treatment courses until a PR was 2 , indicating an early response .
16 Liver resection was performed in 4 patients ( 222% ) .
17 The incidence of any adverse events ( Grade 3/4 ) was 28% ( 5/18 ) , including skin disorder ( 167% ) as dry skin , cutaneous pruritus , contusion and paronychia , as well as peripheral sensory neuropathy ( 111% ) .
18 The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients .
19 These events were controllable by preventive skin care and by withdrawal and dose reduction , respectively .
20 Death due to adverse events was not observed .
21 Adverse events did not require the withdrawal of this regimen .
22 CONCLUSION :
23   Based on the 18 patients studied , combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment , as required .
24   These regimens seem to be promising for conversion therapy ( 4 out of 18 patients ) because of good outcomes and an early response .



PMID: 27126591
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Benefit of Bevacizumab-Based Frontline Therapy in Patients with Metastatic Colorectal Cancer ( mCRC ) : a Turkish Oncology Group Study .
1 BACKGROUND :
2 Several chemotherapy regimens using bevacizumab have been developed .
3 Our goal was to investigate regimens that have demonstrated significant clinical activity in patients with metastatic colorectal cancer ( mCRC ) .
4 MATERIALS AND METHODS :
5 Six hundred and sixty six patients with mCRC who received first - line chemotherapy combination with bevacizumab were studied .
6 Fluoropyrimidine (F) plus irinotecan (I)- based ( FI-bev ) , F plus oxaliplatin (O)- based ( FO-bev ) , and F-based ( F-bev ) treatment regimens were compared with respect to progression-free survival ( PFS ) and overall survival ( OS ) .
7 RESULTS :
8 ✓ The median PFS of FI-bev ( n = 414 ) was 10.9 months ( 95 % CI 10-118 ) , of FO-bev ( n = 211 ) was 9.4 months ( 95 % CI 83-104 ) , and of F-bev ( n = 41 ) was 9.5 months ( 95 % CI 59-131 ) ( p = 0089 ) . GE-ASS-RO
9 The median OS of FI-bev was 26.3 months ( 95 % CI 217-309 ) , of FO-bev was 27 months ( 95 % CI 243-297 ) , and of F-bev was 23.3 months ( 95 % CI 127-339 ) ( p = 0102 ) .
10 In KRAS wild-type patients , the median PFS of FI-bev group was significantly longer than FO-bev group ( 105 vs. 91 months , p = 0006 ) .
11 The FI-bev group had better OS than FO-bev group with borderline significance ( p = 0058 ) .
12 The FI-bev group had significantly longer OS than F-bev group .
13   Patients who underwent metastasectomy or those with Eastern Cooperative Oncology Group performance status ( ECOG-PS ) had longer PFS and OS independent of the type of chemotherapy regimen .
14 CONCLUSION :
15 FI-bev may be the preferred frontline regimen for patients with KRAS wild-type mCRC .
16 Metastasectomy and performance score were the strongest positive predictors of OS and PFS regardless of backbone chemotherapy regimen .



PMID: 27124490
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biobanking of Fresh-Frozen Human Adenocarcinomatous and Normal Colon Tissues : Which Parameters Influence RNA Quality ?
1 Medical research projects become increasingly dependent on biobanked tissue of high quality because the reliability of gene expression is affected by the quality of extracted RNA .
2 Hence , the present study aimed to determine if clinical , surgical , histological , and molecular parameters influence RNA quality of normal and tumoral frozen colonic tissues .
3 RNA Quality Index ( RQI ) was evaluated on 241 adenocarcinomas and 115 matched normal frozen colon tissues collected between October 2006 and December 2012 .
4 RQI results were compared to patients' age and sex , tumor site , kind of surgery , anastomosis failure , adenocarcinoma type and grade , tumor cell percentage , necrosis extent , HIF-1alpha and cleaved caspase-3 immunohistochemistry , and BRAF , KRAS and microsatellites status .
5 The RQI was significantly higher in colon cancer tissue than in matched normal tissue .
6 RQI from left-sided colonic cancers was significantly higher than RQI from right-sided cancers .
7 The RNA quality was not affected by ischemia and storage duration .
8 According to histological control , 7.9% of the samples were unsatisfactory because of inadequate sampling .
9 Biobanked tumoral tissues with RQI >/ = 5 had lower malignant cells to stromal cells ratio than samples with RQI <5 ( p <005 ) .
10 Cellularity , necrosis extent and mucinous component did not influence RQI results .
11 Cleaved caspase-3 and HIF-1alpha immunolabelling were not correlated to RQI .
12 BRAF , KRAS and microsatellites molecular status did not influence RNA quality .
13 Multivariate analysis revealed that the tumor location , the surgical approach ( laparoscopy versus open colectomy ) and the occurrence of anastomotic leakage were the only parameters influencing significantly RQI results of tumor samples .
14 We failed to identify parameter influencing RQI of normal colon samples .
15 These data suggest that RNA quality of colonic adenocarcinoma biospecimens is determined by clinical and surgical parameters .
16 More attention should be paid during the biobanking procedure of right-sided colon cancer or laparoscopic colectomy specimen .
17 Histological quality control remains essential to control sampling accuracy .



PMID: 27121720
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Use of a High-Throughput Genotyping Platform ( OncoMap ) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer .
1 PURPOSE :
2 Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer ( mCRC ) harboring wild-type KRAS exon 2 .
3 Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2 .
4 Μ We performed extended RAS Mutational analysis using a high-throughput genotyping platform ( OncoMap ) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing .
5 MATERIALS AND METHODS :
6 Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0 .
7 Targeted genes included exon 2 , exon 3 , and exon 4 , both in KRAS and NRAS , and included BRAF exon 15 .
8 We assessed efficacy by the new RAS mutation status .
9 RESULTS :
10 Μ The OncoMap detected 57 additional mutations ( 251% ) : 25 ( 11% ) in KRAS exon 2 and 32 ( 141% ) beyond KRAS exon 2 .
11 Survival differences were observed after dividing patients into the wild-type RAS group ( n = 170 ) and mutant RAS group ( n = 57 ) using OncoMap .
12 Progression-free survival was 4.8 months versus 1.8 months ( hazard ratio [HR] , 0.44 ; 95% confidence interval [CI] , 0.32 to 0.61 ) , and overall survival was 11.9 months versus 8.4 months ( HR , 065 ; 95% CI , 047 to 088 ) .
13 CONCLUSION :
14 Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment .
15   High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment .



PMID: 27119498
(None)  
Terms: , transgenic mice, mice
Sent# Symbols Sentence Mnemonics
0 Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype .
1 Development of cribriform morphology ( CM ) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy .
2 This study investigated CM pathobiology in three-dimensional ( 3D ) Caco-2 culture models of colorectal glandular architecture , assessed translational relevance and tested effects of 1,25 ( OH ) 2D3 , theactive form of vitamin D .
3 CM evolution was driven by oncogenic perturbation of the apical polarity ( AP ) complex comprising PTEN , CDC42 and PRKCZ ( phosphatase and tensin homolog , cell division cycle 42 and protein kinase C zeta ) .
4 Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation , apical membrane misalignment and aberrant epithelial configuration .
5 Collectively , these events promoted "Swiss cheese-like" cribriform morphology ( CM ) comprising multiple abnormal "back to back" lumens surrounded by atypical stratified epithelium , in 3D colorectal gland models .
6 Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC , CM associated with PTEN and PRKCZ readouts .
7 Treatment of PTEN-deficient 3D cultures with 1,25 ( OH ) 2D3 upregulated PTEN , rapidly activated CDC42 and PRKCZ , corrected mitotic spindle alignment and suppressed CM development .
8 Conversely , mutationally-activated KRAS blocked1,25 (OH) 2D3 rescue of glandular architecture .
9 We conclude that 1,25 ( OH ) 2D3 upregulates AP signalling to reverse CM in a KRAS wild type ( wt ) , clinically predictive CRC model system .
10 Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors .



PMID: 27118441
(Patient)  
Terms: Phase II Trial
Sent# Symbols Sentence Mnemonics
0 A Randomized , Phase II Trial of Cetuximab With or Without PX-866 , an Irreversible Oral Phosphatidylinositol 3 - Kinase Inhibitor , in Patients With Metastatic Colorectal Carcinoma .
1 BACKGROUND :
2 Μ The phosphotidylinositol-3 kinase ( PI3K ) /serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer ( CRC ) .
3 PX-866 is an oral , irreversible , pan-isoform inhibitor of PI3K .
4 This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic , anti-epidermal growth factor receptor -naive , KRAS codon 12 and 13 wild-type CRC .
5 PATIENTS AND METHODS :
6 Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized ( 1 : 1 ) to cetuximab ( 400 mg/m2 loading then 250 mg/m2 weekly ) with or without PX-866 ( 8 mg orally daily ; arms A and B , respectively ) .
7 The primary endpoint was progression-free survival ( PFS ) .
8 Secondary endpoints included objective response rate , overall survival ( OS ) , toxicity , and correlation of relevant biomarkers with efficacy outcomes .
9 RESULTS :
10 A total of 85 patients were enrolled .
11 The median PFS was 59 days versus 104 days for arms A ( cetuximab + PX-866 ) and B ( cetuximab alone ) , respectively ( P = 77 ) .
12 OS between the 2 arms ( 266 vs. 333 days for arm A vs. B ) were similar ( P = 83 ) .
13 Overall toxicity , including treatment-related toxicity , was higher in arm A compared with arm B , especially in terms of all-grade nausea ( 66% vs. 37% ) , vomiting ( 50% vs. 29% ) , diarrhea ( 64% vs. 18% ) , and rash ( 66% vs. 37% ) .
14 Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B .
15 PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen .
16 CONCLUSION :
17 The addition of PX-866 to cetuximab did not improve PFS , objective response rate , or OS in patients with metastatic CRC .
18 The combination arm had greater toxicity and may have been harmful in this study .



PMID: 27117408
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes .
1 Secretion of RNAs in extracellular vesicles is a newly recognized form of intercellular communication .
2 A potential regulatory protein for microRNA ( miRNA ) secretion is the critical RNA-induced silencing complex ( RISC ) component Argonaute 2 ( Ago2 ) .
3 Here , we use isogenic colon cancer cell lines to show that overactivity of KRAS due to mutation inhibits localization of Ago2 to multivesicular endosomes ( MVEs ) and decreases Ago2 secretion in exosomes .
4 Mechanistically , inhibition of mitogen -activated protein kinase kinases ( MEKs ) I and II , but not Akt , reverses the effect of the activating KRAS mutation and leads to increased Ago2-MVE association and increased exosomal secretion of Ago2 .
5 Μ Analysis of cells expressing mutant Ago2 constructs revealed that phosphorylation of Ago2 on serine 387 prevents Ago2-MVE interactions and reduces Ago2 secretion into exosomes .
6 Furthermore , regulation of Ago2 exosomal sorting controls the levels of three candidate miRNAs in exosomes .
7 These data identify a key regulatory signaling event that controls Ago2 secretion in exosomes .



PMID: 27116474
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Utility of KRAS mutation detection using circulating cell -free DNA from patients with colorectal cancer .
1 In this study , we evaluated the clinical utility of detecting KRAS mutations in circulating cell -free ( ccf ) DNA of metastatic colorectal cancer patients .
2 We prospectively recruited 94 metastatic colorectal cancer patients .
3 Μ Circulating cell -free DNA was extracted from plasma samples and analyzed for the presence of seven KRAS point mutations .
4 Μ Using the Invader Plus assay with peptide nucleic acid clamping method and digital PCR , KRAS mutations were detected in the ccfDNA in 35 of 39 patients previously determined to have primary tumors containing KRAS mutations using the Luminex method , and in 5 of 55 patients with tumors containing wild-type KRAS .
5 Curative resection was undertaken in 7 of 34 patients with primary and ccfDNA KRAS mutations , resulting in the disappearance of the mutation from the cell -free DNA in five of seven patients .
6 Three of these patients had tumor recurrence and KRAS mutations in their ccfDNA reappeared .
7 Epidermal growth factor receptor blockade was administered to 24 of the KRAS tumor wild-type patients .
8   Of the 24 patients with wild-type KRAS in their primary tumors , three patients had KRAS mutations in their ccfDNA and did not respond to treatment with epidermal growth factor receptor ( EGFR ) blockade .
9   Μ We also detected a new KRAS mutation in five patients during chemotherapy with EGFR blockade , before disease progression was detectable with imaging .
10 The detection of KRAS mutations in ccfDNA is an attractive approach for predicting both treatment response and acquired resistance to EGFR blockade , and for detecting disease recurrence .



PMID: 27114605
(Patient)  
Terms: phase II trial, prospective, retrospective
Sent# Symbols Sentence Mnemonics
0 Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation : Australasian Gastro-Intestinal Trials Group ICECREAM Study .
1 PURPOSE :
2 RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer ( mCRC ) , but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab .
3 We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected ( G13D mutation ) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype .
4 PATIENTS AND METHODS :
5 Patients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks .
6 The primary end point was 6-month progression-free survival ; secondary end points were response rate , overall survival , quality of life , and toxicity .
7 RESULTS :
8 Fifty-one of 53 patients recruited over 2 years were eligible .
9 The 6-month progression-free survival rate was 10% ( 95% CI , 2% to 26% ) for cetuximab versus 23% ( 95% CI , 9% to 40% ) for cetuximab plus irinotecan with a hazard ratio of 0.74 ( 95% CI , 042 to 132 ) .
10   Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment , respectively .
11 Overall survival and quality of life were similar ; toxicities were higher with combination therapy .
12 CONCLUSION :
13   In patients with G13D-mutated chemotherapy-refractory mCRC , there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan .
14 No responses were seen with single-agent cetuximab .
15 The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity .
16 The LONGTOKEN study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes .



PMID: 27108243
(Patient)  
Terms: , tumour growth in patient-derived xenografts
Sent# Symbols Sentence Mnemonics
0 Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory , KRAS codon 12/13 wild-type , HER2-positive metastatic colorectal cancer ( HERACLES ) : a proof-of-concept , multicentre , open-label , phase 2 trial .
1 BACKGROUND :
2 We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer .
3 In this study , we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer .
4 METHODS :
5 HERACLES was a proof-of-concept , multicentre , open-label , phase 2 trial done at four Italian academic cancer centres .
6 We enrolled adult patients with KRAS exon 2 ( codons 12 and 13 ) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care ( including cetuximab or panitumumab ) , an Eastern Cooperative Oncology Group performance status of 0 or 1 , and atleast one measurable lesion .
7 We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria .
8 Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week , and oral lapatinib at 1000 mg per day until evidence of disease progression .
9 The primary endpoint was the proportion of patients achieving an objective response ( defined as complete response or partial response ) , which was assessed by independent central review in the intention-to-treat population .
10 This trial is registered with EudraCT , number 2012-002128-33 .
11 FINDINGS :
12 Μ Between Aug 27 , 2012 , and May 15 , 2015 , we screened 914 patients with KRAS exon 2 ( codons 12 and 13 ) wild-type metastatic colorectal cancer and identified 48 ( 5% ) patients with HER2-positive tumours , although two died before enrolment .
13 Of these patients , 27 were eligible for the trial .
14 All were evaluable for response .
15 At the time of data cutoff on Oct 15 , 2015 , with a median follow-up of 94 weeks ( IQR 51-127 ) , eight ( 30% , 95% CI 14-50 ) of 27 patients had achieved an objective response , with one patient ( 4% , 95% CI -3 to 11 ) achieving a complete response , and seven ( 26% , 95% CI 9-43 ) achieving partial responses ; 12 ( 44% , 95% CI 25-63 ) patients had stable disease .
16 Six ( 22% ) of 27 patients had grade 3 adverse events , which consisted of fatigue in four patients , skin rash in one patient , and increased bilirubin concentration in one patient .
17 No grade 4 or 5 adverse events were reported .
18 We detected no drug -related serious adverse events .
19 INTERPRETATION :
20   The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer .
21 FUNDING :
22 Associazione Italiana Ricerca Cancro ( AIRC ) , Fondazione Oncologia Niguarda Onlus , and Roche .



PMID: 27106835
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hypomagnesemia is a reliable predictor for efficacy of anti-EGFR monoclonal antibody used in combination with first - line chemotherapy for metastatic colorectal cancer .
1 PURPOSE :
2 Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer ( mCRC ) , but frequently causes several adverse reactions , including hypomagnesemia and skin disorders .
3 The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first - line chemotherapy .
4 METHODS :
5 Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study .
6 All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash .
7 Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events , version 3.0 .
8 Overall response rate ( ORR ) and time to treatment failure ( TTF ) were compared between patients with and without these adverse events .
9 RESULTS :
10 The incidence rates of hypomagnesemia and acneiform rash were 32.6 % ( grade 1 : 20.9 % , grade 2 : 11.6 % ) and 93.0 % ( grade 1 : 41.9 % , grade 2 : 41.9 % , grade 3 : 9.3 % ) , respectively .
11 ORR was significantly higher in patients with hypomagnesemia than in those without it ( 714 versus 345 % , P = 0048 ) .
12 Median TTF tended to be longer , though not significantly , in patients with hypomagnesemia than in those without it .
13 However , no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash .
14 CONCLUSION :
15 Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients .



PMID: 27104867
(Patient)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Combined assessment of EGFR-related molecules to predict outcome of 1st - line cetuximab-containing chemotherapy for metastatic colorectal cancer .
1 Several studies have reported that epidermal growth factor receptor ( EGFR )- related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer ( mCRC ) , such as EGFR gene copy number ( GCN ) , expression of 2 ligands of EGFR , amphiregulin (AREG) and epiregulin (EREG) , and EGFR CA simple sequence repeat 1 ( CA-SSR1 ) polymorphism ; however , these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy .
2 Μ We therefore analyzed associations of mRNA expression of AREG and EREG , EGFR GCN , and CA-SSR1 polymorphism [short ( S ; /= 20 ) ] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX ( n = 28/57 , UMIN000004197 ) or SOX ( n = 49/67 , UMIN000007022 ) plus cetuximab as first - line therapy .
3 ✓ High AREG expression correlated with significantly better progression-free survival ( median 116 vs. 66 months , HR 052 , P = 0037 ) ; moreover , it remained statistically significant in multivariate analysis ( HR : 0.48 , P = 0.027 ) . GE-ASS-RO
4 S/S genotype of CA-SSR1 predicted severe skin toxicity ( P = 0040 ) .
5 Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others ( median 222 vs. 428 months , HR 234 , P = 0042 ) .
6 Μ The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival ( P = 0006 ) .
7 ✓ In conclusion , AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity , respectively , of initial chemotherapy with cetuximab . GM-REG-RO, GE-REG-RO
8   Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first - line cetuximab treatment .



PMID: 27104828
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 DNA Methylation and Mutation of Small Colonic Neoplasms in Ulcerative Colitis and Crohn's Colitis : Implications for Surveillance .
1 BACKGROUND :
2 Μ Stool DNA testing in patients with inflammatory bowel disease ( IBD ) may detect colorectal cancer and advanced precancers with high sensitivity ; less is known about the presence of DNA markers in small IBD lesions , their association with metachronous neoplasia , or contribution to stool test positivity .
3 METHODS :
4 At a single center in 2 blinded phases , we assayed methylated bone morphogenic protein 3 , methylated N-Myc downstream-regulated gene 4 , and mutant KRAS in DNA extracted from paraffin-embedded benign lesions , and matched control tissues of patients with IBD , who were followed for subsequent colorectal dysplasia .
5 Stool samples from independent cases and controls with lesions <1 cm or advanced neoplasms were assayed for the same markers .
6 RESULTS :
7 Among IBD lesions ( 29 low-grade dysplasia , 19 serrated epithelial change , and 10 sessile serrated adenoma/polyps ) , the prevalence of methylation was significantly higher than in mucosae from 44 matched IBD controls ( P <00001 for methylated bone morphogenic protein 3 or methylated N-Myc downstream-regulated gene 4 ) .
8 KRAS mutations were more abundant in serrated epithelial change than all other groups ( P <0001 ) .
9 Subsequent dysplasia was not associated with DNA marker levels .
10 In stools , the sensitivity of methylated bone morphogenic protein 3 as a single marker was 60% for all lesions <1 cm , 63% for low-grade dysplasia >/ = 1 cm and 81% for high-grade dysplasia/colorectal cancer , all at 91% specificity ( P <00001 ) .
11 CONCLUSIONS :
12 Selected DNA markers known to be present in advanced IBD neoplasia can also be detected in both tissues and stools from IBD patients with small adenomas and serrated lesions .
13 Mutant KRAS exfoliated from serrated epithelial change lesions might raise false-positive rates .
14 These findings have relevance to potential future applications of stool DNA testing for IBD surveillance .



PMID: 27102293
(None)  
Terms: in vivo, This review
Sent# Symbols Sentence Mnemonics
0 Kirsten Ras* oncogene : significance of its discovery in human cancer research .
1 The KRAS/ K-RAS oncogene is crucially involved in human cancer .
2 The term "oncogene" - - i.e. , a gene able to transform a normal cell into a tumor cell - was introduced in 1969 , but the word was not used in the human carcinogenesis literature until much later .
3 Transforming Kras and Hras oncogenes from the Kirsten and Harvey sarcoma viruses were not identified until the early 1980s due to the complicated structures of the viral genomes .
4 Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes .
5 Thus , RAS genes were the first human oncogenes to be identified .
6   Μ Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver , as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers .
7 This review addresses the historical background and experimental studies that led to the discovery of Kirsten Ras as an oncogene , the role of mutated KRAS in human carcinogenesis , and recent therapeutic studies of cancer cells with KRAS mutations .



PMID: 27102074
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF-Like Colorectal Cancer Cells Are Selectively Dependent on RANBP2 .
1 In BRAF-like colorectal cancer cells , RANBP2 loss induces mitotic abnormalities and cell death .



PMID: 27099668
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lack of BRAFV600E mutation in stage I and II of colorectal cancer .
1 AIM :
2 We aimed to explore the frequency of BRAFV600E mutation in Iranian patients with colorectal cancer ( CRC ) as well as its association with clinic pathological characteristic of patients .
3 BACKGROUND :
4 CRC is the third leading cause of cancer related death .
5 There is a growing body of data showing the association of BRAFV600E mutation with malignant transformation and clinical outcome of different tumors , including CRC .
6 These findings suggest that BRAFV600E mutation can be used as diagnostic and/or prognostic biomarker for management of cancer patients .
7 PATIENTS AND METHODS :
8 A total of 85 patients with sporadic tumor were recruited .
9 BRAFV600E mutation was investigated using sequencing of extracted DNAs from formalin-fixed paraffin-embedded ( FFPE ) tumor tissues .
10 Electropherograms were analyzed using Laser - gene 6 software .
11 RESULTS :
12 More than 95% of patients were in stage I and II and none of them were in stage IV .
13 Patients were mostly below 55 years old and tumors were dominantly located in the distal colon .
14 Μ Of note , no BRAFV600E mutations were detected in our population .
15 CONCLUSION :
16 Μ Our results showed no V600E mutation in the BRAF gene in stage I and II of CRC patients .
17 Further studies in multi-center settings are warranted to examine the prognostic and/or predictive value of this marker in different stages of colorectal cancer patients .



PMID: 27096769
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ K-ras gene mutation as an early prognostic marker of colon cancer . GM-MRK-DS
1 UNLABELLED :
2 Due to increased colorectal cancer incidence there is a necessity of seeking new both prognostic and prediction factors that will allow to evolve new diagnostic tests .
3 K-ras gene seems to be such a factor and its mutations are considered to be an early marker of progression of colorectal cancer .
4 Μ The aim of the study was to find a correlation between K-ras gene mutation in patients with diagnosed colorectal cancer and selected clinical parameters .
5 MATERIAL AND METHODS :
6 A total of 104 patients ( 41 women and 63 men ) with diagnosed colorectal cancer were included in this study .
7 The average age of male group was 68.3 and in female group - 65.9 .
8 Μ Samples were taken from paraffine blocks with tissue from diagnosed patients and K-ras gene mutation were identified .
9 Afterwards the statistical analysis was made seeking the correlation between K-ras gene mutation incidence and clinical TNM staging system , tumour localisation , histological type , sex , age .
10 RESULTS :
11 Μ K-ras gene mutations were detected in 20.1% of all colorectal cancers .
12 Significantly higher rate of K-ras gene mutations were diagnosed among patients classified at stage I ( 40% ) , stage IIC ( 50% ) and stage IV ( 50% ) according to the TNM classification .
13 CONCLUSIONS :
14 The results of our study are compatible with other studies and indicate the correlation between K-ras gene mutation and colorectal cancer incidence .
15 Identification of K-ras gene mutation may complement other diagnostic methods at early stage of colorectal cancer .



PMID: 27089049
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer .
1 Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors : implications for therapy .



PMID: 27087961
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Type 1 serrated polyposis represents a predominantly female disease with a high prevalence of dysplastic serrated adenomas , without germline mutation in MUTYH , APC , and PTEN genes .
1 PURPOSE :
2 Small molecule inhibitors of the mitogen -activated protein kinase ( MAPK ) pathway , such as sorafenib , represent novel treatment options for advanced hepatocellular carcinoma .
3 The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors .
4 EXPERIMENTAL DESIGN :
5 Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation , proliferation , induction of apoptosis , and chemokine secretion .
6 RESULTS :
7 Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dose -dependent manner , even those targeting the same kinase .
8 Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations .
9 Similarly , PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas .
10 MEK inhibitors decreased ERK1/2 phosphorylation in a dose -dependent manner .
11 These signaling characteristics correlated with inhibition of proliferation , induction of apoptosis , and chemokine secretion .
12 Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells .
13 CONCLUSIONS :
14 Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas .
15 MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling .
16   Therefore , novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors .



PMID: 27087959
(Patient)  
Terms: prospective study
Sent# Symbols Sentence Mnemonics
0 Sporadic colorectal cancer : Studying ways to an end .
1 INTRODUCTION :
2 Although colorectal cancer ( CRC ) has often been regarded as a single entity , different pathways may lead to macroscopically similar cancers .
3 These pathways may evolve into a patchy colonic field defect that we aimed to study in consecutive CRC patients .
4 METHODS :
5 In a single-center , observational , prospective study , consecutive CRC patients were included if surgery and a perioperative colonoscopy were planned .
6 Personal and familial history data were collected .
7 Tumors were studied for microsatellite instability ( MSI ) status , DNA repair protein expression ( DRPE ) and presence of BRAF and/or APC mutations .
8 Macroscopically normal mucosa samples were tested for APC mutations .
9 Presence and location of synchronous and metachronous adenomas and patient follow-up were analyzed .
10 The association of two categorical variables was tested through the Fisher's exact test ( SPSS 19 ) .
11 RESULTS :
12 Twenty-four patients ( 12 male , mean age 69 years ) were studied .
13 Μ High-grade MSI ( MSI-H ) was found in eight tumors-these were significantly more common in the right colon ( p = 0047 ) and more likely to have an altered DRPE ( p = 0007 ) .
14 Μ BRAF mutation was found in two of six tested MSI-H tumors .
15 Μ APC gene mutations were found in nine of 16 non-MSI-H tumors and absent in normal mucosa samples .
16 There was a nonsignificant co-localization of CRC and synchronous adenomas and a significant co-localization ( p = 005 ) of synchronous and metachronous adenomas .
17 DISCUSSION :
18 Sporadic CRCs evolve through distinct pathways , evidenced only by pathological and molecular analysis , but clinically relevant both for patients and their families .
19 Μ In non-MSI-H tumors , the expected APC gene mutations were not detected by the most commonly used techniques in a high number of cases .
20 More studies are needed to fully characterize these tumors and to search for common early events in normal mucosa patches , which might explain the indirect evidence found here for a field defect in the colon .



PMID: 27085587
(None)  
Terms: NCT01001377
Sent# Symbols Sentence Mnemonics
0 Economic Analysis of Panitumumab Compared With Cetuximab in Patients With Wild-type KRAS Metastatic Colorectal Cancer That Progressed After Standard Chemotherapy .
1 PURPOSE :
2 In this analysis , we compared costs and explored the cost-effectiveness of subsequent - line treatment with cetuximab or panitumumab in patients with wild-type KRAS ( exon 2 ) metastatic colorectal cancer ( mCRC ) after previous chemotherapy treatment failure .
3 Data were used from LONGTOKEN , a Phase III , head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population .
4 METHODS :
5 A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS ( exon 2 ) mCRC .
6 The cost-minimization model assumed equivalent efficacy ( progression-free survival ) based on data from ASPECCT .
7 The cost-effectiveness analysis was conducted with the full information ( uncertainty ) from ASPECCT .
8 Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT .
9 Costs associated with drug acquisition , treatment administration ( every 2 weeks for panitumumab , weekly for cetuximab ) , and incidence of infusion reactions were estimated in both models .
10 The cost-effectiveness model also included physician visits , disease progression monitoring , best supportive care , and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT .
11 FINDINGS :
12 The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab , with a projected cost savings of $9468 ( 165% ) per panitumumab-treated patient .
13 In the cost-effectiveness model , the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly , with marginally better outcomes than cetuximab .
14 IMPLICATIONS :
15 These economic analyses comparing panitumumab and cetuximab in chemorefractory wild-type KRAS ( exon 2 ) mCRC suggest benefits in favor of panitumumab .
16 ClinicalTrials .
17 gov identifier : NCT01001377 .



PMID: 27083443
(None)  
Terms: clinical trial, This review, genetically engineered mouse, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Skin toxicity and quality of life during treatment with panitumumab for RAS wild-type metastatic colorectal carcinoma : results from three randomised clinical trials .
1 Over the past decade , there have been substantial improvements in our knowledge of pancreatic neoplasms and their precursor lesions .
2 Extensive genetic analyses , recently using high-throughput molecular techniques and next-generation sequencing methodologies , and the development of sophisticated genetically engineered mouse models closely recapitulating human disease , have improved our understanding of the genetic basis of pancreatic neoplasms .
3 These advances are paving the way for refined , molecular-based classifications of pancreatic neoplasms with the potential to better predict prognosis and , possibly , response to therapy .
4 Another major development resides in the identification of subsets of pancreatic exocrine and endocrine neoplasms which occur in the context of hereditary syndromes and whose genetic basis and tumor development have been atleast partially defined .
5 However , despite all molecular progress , correct and careful morphological characterization of tissue specimens both in the context of experimental and routine diagnostic pathology represents the basis for any further genetic investigation or clinical decision .
6 This review focuses on the current and new concepts of classification and on the current models of tumor development , both in the field of exocrine and endocrine neoplasms , and underscores the importance of applying standardized terminology to allow adequate data interpretation and promote scientific exchange in the field of pancreas research .



PMID: 27082577
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers .
1 BRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis .
2 However , BRAF-mutated colorectal cancers ( CRCs ) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF-mutated CRCs are associated with a much worse prognosis for the afflicted patients .
3 This study aimed to determine the different miRNA expression signatures associated with BRAF-mutated CRCs in comparison to KRAS-mutated ones , and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF-mutated CRCs .
4 We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation , and selected 7 BRAF-mutated and 7 KRAS-mutated CRCs that were tumor size , stage , and microsatellite status-matched .
5 Affymetrix GeneChip(R) miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples .
6 We validated the array results by quantitative reverse transcription polymerase chain reaction ( qRT-PCR ) for selected miRNAs .
7 Μ A total of 10 differentially expressed ( DE ) miRNAs associated with BRAF-mutated CRCs were obtained , including miR-31-5p , miR-877-5p , miR-362-5p , and miR-425-3p .
8 miR-31-5p showed the highest fold change ( 83-fold ) among all of the miRNAs analyzed .
9 From the analyses of GO biological processes , the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression ( P = 1.26 x 10 ( -10 ) ) , transcription ( P = 9.70 x 10 ( -10 ) ) , and RNA metabolic process ( P = 1.97 x 10 ( -9 ) ) .
10 Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling ( P = 6.84 x 10 ( -5 ) ) , pathways in cancer ( P = 00016 ) , Wnt signaling ( P = 00027 ) , and MAPK signaling pathway ( P = 00036 ) .
11 Our results suggest that the DE-miRNAs in BRAF-mutated CRCs in comparison to KRAS-mutated CRCs are implicated in the aggressive phenotype of the BRAF-mutated CRCs .
12 Further experimental validation is required to confirm these results .



PMID: 27074743
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Prognostic impact of mutation profiling in patients with stage II and III colon cancer .
1 Development of colorectal cancer ( CRC ) associates with accumulation of genetic mutations include the epidermal growth factor receptor ( EGFR ) signaling pathway .
2 However , whether mutations in KRAS together with downstream factors BRAF , PIK3CA and NRAS impact prognosis is still unclear for stage II-III colon cancer .
3 Μ In the present study a total of 228 stage II-III colon cancer samples were retrospectively collected , KRAS ( codons 12 , 13 and 61 ) , BRAF ( exon 11 and exon 15 ) , PIK3CA ( exon 9 and exon 20 ) and NRAS ( codons 12 , 13 and 61 ) status was detected by Sanger sequencing , 37.89% ( 86/227 ) tumors harbored a KRAS mutation , 7.02% ( 16/228 ) harbored a BRAF mutation , 13.18% ( 29/220 ) harbored a PIK3CA mutation and 0.89% ( 2/224 ) harbored a NRAS mutation .
4 NRAS mutations existed only in stage II colon cancer .
5 Μ Older groups harbored a higher KRAS and BRAF mutation ( P <005 ) , PIK3CA ( exon9 ) mutations appeared more common in worse differentiation tumors ( P = 0032 ) .
6 Moreover , PIK3CA (E545K) mutation was significantly associated with tumor recurrence ( P = 0031 ) and acted independently prognostic for poor OS ( P = 0044 ) , while only in stage III colon cancer .
7 KRAS , BRAF and NRAS mutations do not have major prognostic value in stage II and III colon cancer , subtypes of gene mutations should be further investigated for a better understanding in CRC .



PMID: 27072236
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic significance of KRAS gene mutations in colorectal cancer--preliminary study .
1 BACKGROUND :
2 Μ The aim of our study was to analyze the possible relationships between treatment efficacy , and germinal gene polymorphisms linked to the irinotecan in combination with bevasizumab or panitumumab and capecitabine or 5-FU that has been routinely used in our practice , in the management of metastatic colorectal cancer ( CRC ) .
3 MATERIALS AND METHODS :
4 Ninety-four Greek with histologically proven metastatic CRC were included in the study .
5 Treatment was administered until disease progression or unacceptable toxicity , for a maximum of eight cycles .
6 Patients were stratified into stable disease. ( SD ) and progressive disease. ( PD ) .
7 Μ Associations between clinical data , KRAS , UGT1A1. ( UGT1A1*28 ) and DPD ( IVS14+1 G >A ) polymorphisms , and toxicity were analyzed .
8 RESULTS :
9 Fifty-eight ( 6170% ) patients were characterized with SD disease and 36 ( 3830% ) with PD .
10 There were not statistical significant differences between carriers of KRAS mutated alleles between SD and PD groups .
11 No significant difference was found between response rates and toxicity and DPD or UGT1A1 genotypes .
12 Our results suggested that determination of DPD or UGT1A1 genotypes could not be useful for predicting severe toxicity of irinotecan in our population .
13 CONCLUSIONS :
14 The clinical significance of the findings requires replication in larger populations .
15 Furthermore , as 5 .
16 FU and irinotecan metabolism is complex , numerous genes in addition to DPD and UGT1A1 should be investigated .



PMID: 27072218
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ The association of clinicopathological features and survival in colorectal cancer patients with kras mutation status . RO-ASS-GM
1 BACKGROUND :
2 KRAS mutations have a significant role in the consecutive activation of RAS .
3 RAF .
4 MEK .
5 ERK pathway in colorectal cancer .
6 Approximately 30.35% of sporadic colorectal cancers have KRAS mutation .
7 While the predictive role of KRAS is commonly accepted at the present time , its prognostic role and association with different clinical and histopathological properties are currently unclear and inconsistent .
8 The intent of this study , has been to evaluate the associations between KRAS gene mutations and clinicopathological features and survival times in Turkish colorectal cancer patients .
9 MATERIALS AND METHODS : In this study , the file records of 115 metastatic colorectal cancer patients who applied to the Department of Medical Oncology between 2000 and 2011 were monitored ; data on clinicopathological features and survival times were collected .
10 DNA .
11 Μ sequencing method with PCR amplification from archival paraffin blocks were used for KRAS mutation status analysis .
12 The associations between KRAS mutation status and clinicopathological features and survival times were compared statistically .
13 RESULTS :
14 While a significant association hadbeen determined between KRAS mutation status and tumor localization , there was no determined significant association with other clinicopathological properties .
15 ✓ Similarly , there was no association between KRAS mutation status and survival parameters . GM-ASS-RO
16 CONCLUSIONS :
17 ✓ As a result , the effect of KRAS mutation status on clinicopathological features , survival time and prognosis is unclear . GM-INV-RO



PMID: 27070934
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 The Lymphocyte-to-Monocyte Ratio is a Superior Predictor of Overall Survival in Comparison to Established Biomarkers of Resectable Colorectal Cancer .
1 OBJECTIVE :
2 The study aims to investigate the prognostic value of the lymphocyte-to-monocyte ratio ( LMR ) in patients with colorectal cancer ( CRC ) undergoing curative resection and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio ( NLR ) , platelet-to-lymphocyte ratio ( PLR ) , modified Glasgow prognostic score ( mGPS ) , and combined BRAF-mismatch repair ( MMR ) status .
3 BACKGROUND :
4 The prognostic significance of systemic inflammatory markers in CRC such as the NLR , PLR , and mGPS has been well defined .
5 Commonly used genetic markers such as combined BRAF-MMR status have also been found to be prognostic .
6 Recent evidence , although limited , suggests that the preoperative LMR may be prognostic in CRC .
7 METHODS :
8 Data from the Northern Sydney Local Health District from January 1998 to December 2012 were retrospectively collected .
9 Of 3281 consecutive patients identified , 1623 patients who underwent curative resection were deemed eligible for inclusion .
10 The relation between the LMR , clinicopathologic variables , and other biomarkers were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models looking for association with overall survival ( OS ) .
11 RESULTS :
12 In multivariate analysis of all patients , elevated LMR was associated with better OS ( hazard ratio 0.569 , 95% confidence interval : 0.478-0.677 , P <0.001 ) independent of age ( P <0001 ) , T stage ( P <0001 ) , N stage ( P <0001 ) , and grade ( P = 0049 ) .
13 The NLR , PLR , and combined BRAF-MMR status were not independently significant .
14 In multivariate subgroup analysis of 389 patients with mGPS , LMR remained the only independently significant biomarker ( hazard ratio 0.620 , 95% confidence interval : 0.437-0.880 , P = 0.007 ) .
15 CONCLUSIONS :
16 The LMR is an independent predictor of OS in patients with CRC undergoing curative resection and appears to be superior to pre-existing biomarkers .



PMID: 27069437
(None)  
Terms: phase III
Sent# Symbols Sentence Mnemonics
0 Aspirin and Colorectal Cancer Prevention and Treatment : Is It for Everyone ?
1 There is now a considerable body of data supporting the hypothesis that aspirin could be effective in the prevention and treatment of colorectal cancer , and a number of phase III randomised controlled trials designed to evaluate the role of aspirin in the treatment of colorectal cancer are ongoing .
2 Although generally well tolerated , aspirin can have adverse effects , including dyspepsia and , infrequently , bleeding .
3 To ensure a favourable balance of benefits and risks from aspirin , a more personalised assessment of the advantages and disadvantages is required .
4 Emerging data suggest that tumour PIK3CA mutation status , expression of cyclo-oxygenase-2 and human leukocyte antigen class I , along with certain germline polymorphisms , might all help to identify individuals who stand to gain most .
5   We review both the underpinning evidence and current data , on clinical , molecular and genetic biomarkers for aspirin use in the prevention and treatment of colorectal cancer , and discuss the opportunities for further biomarker research provided by ongoing trials .



PMID: 27069133
(Patient)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer .
1 RAS belongs to the guanosine 5'-triphosphate ( GTP )- binding proteins' family , and oncogenic mutations in codons 12 , 13 , or 61 of RAS family occur in approximately one third of all human cancers with N-RAS mutations found in about 15-20% of melanomas .
2 Μ The importance of RAS signaling as a potential target in cancer is emphasized not only by the prevalence of RAS mutations , but also by the high number of RAS activators and effectors identified in mammalian cells that places the RAS proteins at the crossroads of several , important signaling networks .
3 Ras proteins are crucial crossroads of signaling pathways that link the activation of cell surface receptors with a wide variety of cellular processes leading to the control of proliferation , apoptosis and differentiation .
4 Furthermore , oncogenic ras proteins interfere with metabolism of tumor cells , microenvironment's remodeling , evasion of the immune response , and finally contributes to the metastatic process .
5 After 40 years of basic , translational and clinical research , much is now known about the molecular mechanisms by which these monomeric guanosine triphosphatase-binding proteins promote cellular malignancy , and it is clear that they regulate signaling pathways involved in the control of cell proliferation , survival , and invasiveness .
6 In this review we summarize the biological role of RAS in cancer by focusing our attention on the biological rational and strategies to target RAS in melanoma .



PMID: 27067860
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of an Unresectable Locally Advanced Rectal Cancer with Surrounding Organ Invasion Successfully Resected after Chemotherapy with mFOLFOX6 plus Cetuximab ] .
1 Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels .



PMID: 27067845
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 [ Pathological Diagnosis and Its Molecular Basis in Colorectal Cancer ] .
1 The genomic instability in colon cancer can be divided into atleast 2 major types : chromosomal instability ( CIN ) and microsatellite instability ( MSI ) .
2 Although there are some overlaps between the 2 types , these are thought to be mutually exclusive .
3 Colorectal tumors progress through a series of histopathologic grades , ranging from dysplastic crypts through small benign tumors to malignant cancers .
4 This progression is the result of a series of genetic changes that involve activation of oncogenes and inactivation of tumor suppressor genes , ie , the CIN pathway .
5 Μ In contrast , MSI develops as a result of epigenetic silencing of MLH1 in sporadic tumors-in a background of methylation of CpG islands in gene promoters -and in tumors that frequently show BRAF mutation .
6 Several tumor prognostic factors have been identified for colorectal cancer , including , tumor budding and molecular factors .
7   In this review , we discuss the genetic mechanisms of colorectal cancer and the relationship of these alterations with emerging biomarkers for pathological diagnosis , patient prognosis , and the prediction of treatment responses .



PMID: 27067688
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Relationship between the Incidence of Hypomagnesemia and Acneiform Rash and the Therapeutic Effect of Anti-EGFR Monoclonal Antibody in Patients with Metastatic Colorectal Cancer ] .
1 SEOM guidelines for the management of Malignant Melanoma 2015 .



PMID: 27064574
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Fibroblast growth factor receptor splice variants are stable markers of oncogenic transforming growth factor beta1 signaling in metastatic breast cancers .
1 INTRODUCTION :
2 Anti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy .
3 However , at which occasions this should be performed is still under debate .
4 We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy ( CRT ) , and if there are any changes in KRAS mutation status due to this intervention .
5 MATERIALS AND METHODS :
6 Μ KRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer .
7 To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT , 114 biopsies from 34 patients ( mean 3 biopsies per patient ) were analyzed ( pre-therapeutic intratumoral heterogeneity ) .
8 For the assessment of heterogeneity after CRT residual tumor tissue ( 85 samples ) from 12 patients ( mean 42 tissue samples per patient ) were analyzed ( post-therapeutic intratumoral heterogeneity ) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples ( interventional heterogeneity ) .
9 Primer extension method ( SNaPshot ) was used for initial KRAS mutation status testing for Codon 12 , 13 , 61 , and 146 .
10 Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24 , V1 and the RAS Extension Pyro Kit 24 , V1 Kit ( therascreen(R) KRAS test ) .
11 RESULTS :
12 Μ For 20 ( 43% ) out of the 47 patients , a KRAS mutation was detected .
13 With 12 out of 20 , the majority of these mutations affected codon 35 .
14 We did not obtained evidence that CRT results in changes of the KRAS mutation pattern .
15 In addition , no intratumoral heterogeneity in the KRAS mutational status could be proven .
16 This was true for both the biopsies prior to CRT and the resection specimens thereafter .
17 The discrepancy observed in some samples when using the SNaPshot assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen(R) KRAS test revealed concordant results .
18 CONCLUSION :
19 Our results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous .
20 Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens .
21 The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method .



PMID: 27063727
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease .
1 BACKGROUND & ; AIMS : Patients with inflammatory bowel diseases , such as Crohn's disease ( CD ) and ulcerative colitis ( UC ) , are at increased risk for small bowel or colorectal cancers ( colitis-associated cancers [CACs] ) .
2 We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers ( CRCs ) and investigated differences between CACs from patients with CD versus UC .
3 METHODS :
4 We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015 .
5 We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations .
6 RESULTS :
7 We performed genomic analyses of 47 CACs ( from 29 patients with UC and 18 with CD ; 43 primary tumors and 4 metastases ) .
8 Primary tumors developed in the ileum ( n = 2 ) , right colon ( n = 18 ) , left colon ( n = 6 ) , and rectosigmoid or rectum ( n = 21 ) .
9 Μ We found genomic alterations in TP53 , IDH1 , and MYC to be significantly more frequent , and mutations in APC to be significantly less frequent , than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine .
10 Μ We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 ( 36% ) CACs .
11 These included the mutation encoding IDH1 R132 ; amplification of FGFR1 , FGFR2 , and ERBB2 ; and mutations encoding BRAF V600E and an EML4-ALK fusion protein .
12 Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC .
13 CONCLUSIONS :
14 ✓ Μ In an analysis of CACs from 47 patients , we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs . GM-ASS-DS
15 Μ We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC , as well as a high frequency of MYC amplification in CACs .
16 Μ Many genetic alterations observed in CACs could serve as therapeutic targets .



PMID: 27062566
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS mutation associated with CD44/CD166 immunoexpression as predictors of worse outcome in metastatic colon cancer .
1 INTRODUCTION :
2 Multiple stages of carcinogenesis in colon cancer encompass subpopulations of cancer stem cells ( CSC ) , responsible for tumor cell transformation , growth and proliferation .
3 CD44 and CD166 proteins are CSC markers associated with cell signaling , adhesion , migration , metastasis and lymphocytic response .
4 The expression of CSC may be modulated by some factors , such as the KRAS gene mutation .
5 OBJECTIVE :
6 Correlate the expression of CD44 and CD166 markers in metastatic colon adenocarcinoma and KRAS mutation status ( wild-type/mutated ) with clinical pathological features and patients' outcome .
7 MATERIAL AND METHODS :
8 Fifty-eight samples of tumor tissue samples of metastatic colon adenocarcinoma were collected from patients treated with CapeOx at the HCFMRP-USP Clinical Oncology Service .
9 Clinical and survival data were collected from medical records .
10 KRAS status was determined by the polymerase chain reaction ( PCR ) technique , and analysis of immunohistochemical expression of CD44 and CD166 proteins was performed by tissue microarray .
11 RESULTS :
12 The expression of CD44 and CD166 were positive in 41% and 43% of patients , respectively , and mutated KRAS was detected in 48% of patients .
13 Μ A significant association was found between CD166 and CD44 expression ( p= 0016 ) , mainly in the wild-type KRAS group ( p= 0042 ) and patients over 65 years ( p= 0001 ) .
14 CD44-positive patients had 3.7-fold and 5.3-fold greater risk of liver metastasis and lung metastasis , respectively ( p<001 ) , compared with CD44-negative patients .
15 CD166-negative patients had 2.7 greater risk of lymph node involvement ( 003 ) , compared with CD166-positive patients .
16 KRAS mutation increased the risk of liver metastasis by 8 times ( p<001 ) , and the risk of lung metastasis by 5 times ( p= 004 ) in CD44-positive patients .
17 KRAS mutation increased the risk of lymph node involvement by 8 times in CD166-negative patients ( p= 00007 ) .
18 CONCLUSION :
19 Μ An association between CD44 and CD166 expression was demonstrated in this study .
20 Μ Analysis of KRAS mutation combined with immunohistochemical expression of CD44 and CD166 identified subgroups of patients with colon adenocarcinoma at higher risk of lymph node involvement by the tumor and development of liver and lung metastasis .



PMID: 27061533
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cetuximab in third - line therapy of patients with metastatic colorectal cancer : A single institution experience .
1 Detection of EGFR mutational profile by direct dideoxy sequencing in cytology and non-cytology biopsy samples .



PMID: 27058664
(None)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility .
1 Μ BRAF (V600E) mutant colon cancers ( CCs ) have a characteristic gene expression signature that is also found in some tumors lacking this mutation .
2 Collectively , they are referred to as "BRAF-like" tumors and represent some 20% of CCs .
3 We used a shRNA-based genetic screen focused on genes upregulated in BRAF (V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically .
4 Here , we identify RANBP2 ( also known as NUP358 ) as essential for survival of BRAF-like , but not for non-BRAF-like , CC cells .
5 Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells , leading to cell death .
6 Mechanistically , RANBP2 silencing reduces microtubule outgrowth from the kinetochores , thereby inducing spindle perturbations , providing an explanation for the observed mitotic defects .
7   We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo , suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs .



PMID: 27057691
(Patient)  
Terms: Xenograft
Sent# Symbols Sentence Mnemonics
0 Surgical and Oncological Factors Affecting the Successful Engraftment of Patient-derived Xenografts in Pancreatic Ductal Adenocarcinoma .
1 Birt-Hogg-Dube syndrome ( BHD ) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene .
2 Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas ( RCCs ) .
3 Currently , little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms .
4 Herein , we describe 14 pulmonary neoplastic lesions in 7 patients with BHD .
5 All patients were confirmed to have germline FLCN mutations .
6 Neoplasm histologies included adenocarcinoma in situ ( n = 2 ) , minimally invasive adenocarcinoma ( n = 1 ) , papillary adenocarcinoma ( n = 1 ) , micropapillary adenocarcinoma ( n = 1 ) , atypical adenomatous hyperplasia ( n = 8 ) , and micronodular pneumocyte hyperplasia ( MPH )- like lesion ( n = 1 ) .
7 Five of the six adenocarcinoma/MPH-like lesions ( 833% ) demonstrated a loss of heterozygosity ( LOH ) of FLCN .
8 All of these lesions lacked mutant alleles and preserved wild-type alleles .
9 Three invasive adenocarcinomas possessed additional somatic events : 2 had a somatic mutation in the epidermal growth factor receptor gene ( EGFR ) and another had a somatic mutation in KRAS .
10 Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin ( p-mTOR ) and phospho-S6 .
11 Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling .
12 Μ Additional driver gene mutations were detected only in invasive cases , suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients .



PMID: 27053844
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Serrated colorectal cancer : Molecular classification , prognosis , and response to chemotherapy .
1 Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes .
2 This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis .
3 New classifications for colorectal cancer ( CRC ) were proposed recently based on genetic profiles that show four types of molecular alterations : BRAF gene mutations , KRAS gene mutations , microsatellite instability , and hypermethylation of CpG islands .
4   This review summarizes what is known about the serrated pathway of CRC , including CRC molecular and clinical features , prognosis , and response to chemotherapy .



PMID: 27050078
(Patient)  
Terms: observational study, retrospective
Sent# Symbols Sentence Mnemonics
0 Mutation profiling in chinese patients with metastatic colorectal cancer and its correlation with clinicopathological features and anti-EGFR treatment response .
1 An increasing number of studies reveal the significance of genetic markers in guiding target treatment and refining prognosis .
2   This retrospective observational study aims to assess the mutation profile of metastatic colorectal cancer ( mCRC ) in Chinese population with the help of MassARRAY(R) technique platform and OncoCarta Panel.322 Chinese patients with mCRC who received clinical molecular testing as part of their standard care were investigated. 80 patients received cetuximab palliative treatment. 238 common hot-spot mutations of 19 cancer related genes in the OncoCarta Panel were tested.44 mutations in 11 genes were detected in 156 cases ( 484% ) .
3 Μ At least one mutation was identified in 38.5% ( 124/322 ) of all tested cases , two concomitant mutations in 9.0% ( 29/322 ) and three mutations in 3 cases ( <1% ) .
4 Μ KRAS was the most frequently mutated gene ( 348% ) , followed by PIK3CA ( 96% ) , NRAS ( 43% ) , BRAF ( 34% ) , EGFR ( 25% ) and HRAS ( 12% ) .
5 Μ Less frequent mutations were detected in PDGFRA , RET , AKT1 , FGFR1 , and ERBB2 .
6 Μ Co-mutation of RAS family subtypes was observed in 5 patients , and KRAS and BRAF concurrent mutation in 1 patient .
7 KRAS , NRAS , BRAF and PIK3CA mutations had association with some clinicopathological features statistically .
8 Patients identified as wild-type in all 19 genes had better objective response rate when treated with cetuximab .
9 The clinical molecular testing with OncoCarta Panel supplemented the limited data of mCRC in Chinese population , and offered a clearer landscape of multiple gene mutational profile in not only clinically prognostic KRAS , NRAS , BRAF and PIK3CA genes , but also less frequent mutated genes .
10   Knowledge of these multiple gene mutation patterns may give clues in exploring interesting accompanying co-occurrence relationship or mutually exclusive relationship between mutated genes , as well as in predicting benefit of all-wild-type patients from anti-EGFR treatment .



PMID: 27048246
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy .
1 UNLABELLED :
2 Neuroendocrine tumors comprise a heterogeneous group of malignancies with a broad spectrum of clinical behavior .
3 Poorly differentiated tumors follow an aggressive course with limited treatment options , and new approaches are needed .
4 Μ Oncogenic BRAF V600E ( BRAF ( V600E ) ) substitutions are observed primarily in melanoma , colon cancer , and non-small cell lung cancer , but have been identified in multiple tumor types .
5 Μ Here , we describe the first reported recurrent BRAF (V600E) mutations in advanced high-grade colorectal neuroendocrine tumors and identify a BRAF alteration frequency of 9% in 108 cases .
6 Μ Among these BRAF alterations , 80% were BRAF (V600E) Dramatic response to BRAF-MEK combination therapy occurred in two cases of metastatic high-grade rectal neuroendocrine carcinoma refractory to standard therapy .
7 Urinary BRAF (V600E) circulating tumor DNA monitoring paralleled disease response .
8 Our series represents the largest study of genomic profiling in colorectal neuroendocrine tumors and provides strong evidence that BRAF (V600E) is an oncogenic driver responsive to BRAF-MEK combination therapy in this molecular subset .
9 SIGNIFICANCE :
10 BRAF (V600E) is an established oncogenic driver , but significant disparities in response exist among tumor types .
11 ✓ Two patients with treatment-refractory high-grade colorectal neuroendocrine tumors harboring BRAF (V600E) exhibited rapid and durable response to combined BRAF-MEK inhibition , providing the first clinical evidence of efficacy in this aggressive tumor type . GM-ASS-RO
12 Cancer Discov ; 6(6) ; 594-600 .
13 (c) 2016 AACR .
14 This article is highlighted in the In This Issue feature , p. 561 .



PMID: 27047802
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genotoxicity of Cytolethal Distending Toxin ( CDT ) on Isogenic Human Colorectal Cell Lines : Potential Promoting Effects for Colorectal Carcinogenesis .
1 The composition of the human microbiota influences tumorigenesis , notably in colorectal cancer ( CRC ) .
2 Pathogenic Escherichia coli possesses a variety of virulent factors , among them the Cytolethal Distending Toxin ( CDT ) .
3 CDT displays dual DNase and phosphatase activities and induces DNA double strand breaks , cell cycle arrest and apoptosis in a broad range of mammalian cells .
4 As CDT could promote malignant transformation , we investigated the cellular outcomes induced by acute and chronic exposures to E .
5 coli CDT in normal human colon epithelial cells ( HCECs ) .
6 Μ Moreover , we conducted a comparative study between isogenic derivatives cell lines of the normal HCECs in order to mimic the mutation of three major genes found in CRC genetic models : APC , KRAS , and TP53 .
7 Our results demonstrate that APC and p53 deficient cells showed impaired DNA damage response after CDT exposure , whereas HCECs expressing oncogenic KRAS (V12) were more resistant to CDT .
8 Compared to normal HCECs , the precancerous derivatives exhibit hallmarks of malignant transformation after a chronic exposure to CDT .
9 HCECs defective in APC and p53 showed enhanced anchorage independent growth and genetic instability , assessed by the micronucleus formation assay .
10 In contrast , the ability to grow independently of anchorage was not impacted by CDT chronic exposure in KRAS (V12) HCECs , but micronucleus formation is dramatically increased .
11 Thus , CDT does not initiate CRC by itself , but may have promoting effects in premalignant HCECs , involving different mechanisms in function of the genetic alterations associated to CRC .



PMID: 27043547
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell -Free DNA of Colorectal Cancer Patients .
1 Epithelial-mesenchymal transition ( EMT ) is associated with reduced sensitivity to many chemotherapeutic drugs , including EGFR tyrosine kinase inhibitors .
2 Here , we investigated if this reduced sensitivity also contributes to resistance to crizotinib , an ALK inhibitor of lung cancer that exhibits the EML4-ALK translocation .
3 We established a crizotinib-resistant subline ( H2228/CR ) , which was derived from the parental H2228 cell line by long-term exposure to increasing concentrations of crizotinib .
4 Characteristics associated with EMT , including morphology , EMT marker proteins , and cellular mobility , were analyzed .
5 Compared with H2228 cells , the growth of H2228/CR cells was independent of EML4-ALK , and H2228/CR cells showed cross-resistance to TAE-684 ( a second-generation ALK inhibitor ) .
6 Phenotypic changes to the spindle - cell shape were noted in H2228/CR cells , which were accompanied by a decrease in E-cadherin and increase in vimentin and AXL .
7 Μ In addition , H2228/CR cells showed increased secretion and expression of TGF-beta1 .
8 Invasion and migration capabilities were dramatically increased in H2228/CR cells .
9 Applying TGF-beta1 treatment to parental H2228 cells for 72 h induced reversible EMT , leading to crizotinib resistance , but this was reversed by the removal of TGF-beta1 .
10 Suppression of vimentin in H2228/CR cells by siRNA treatment restored sensitivity to crizotinib .
11 Furthermore , these resistant cells remained highly sensitive to the Hsp90 inhibitors , similar to the parental H2228 cells .
12 In conclusion , we suggest EMT is possibly involved in acquired resistance to crizotinib , and that HSP90 inhibitors could be a promising option for the treatment of EMT .



PMID: 27039744
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer .
1 The results of this study demonstrate the potential prognostic and predictive values of KRAS and BRAF gene mutations in patients with colorectal cancer ( CRC ) .
2 ✓ It has been proven that KRAS and BRAF mutations are predictive biomarkers for resistance to anti-EGFR monoclonal antibody treatment in patients with metastatic CRC ( mCRC ) .
3 We demonstrated the distribution of KRAS ( codons 12 , 13 and 61 ) and BRAF ( codon 600 ) gene mutations in 50 mCRCs using direct sequencing and compared the results with clinicopathological data .
4 Μ KRAS and BRAF mutations were identified in 15 ( 30% ) and 1 ( 2% ) patients , respectively .
5 Μ We identified KRAS mutations in codon 12 , 13 and 61 in 73.3% ( 11/15 ) , 20% ( 3/15 ) and 6.67% ( 1/15 ) of the positive patients , respectively .
6 The KRAS mutation frequency was significantly higher in tumors located in the ascending colon ( p = 0043 ) .
7 Thus , we found that approximately 1/3 of the patients with mCRC had KRAS mutations and the only clinicopathological factor related to this mutation was tumor location .
8 Future studies with larger patient groups should yield more accurate data regarding the molecular mechanism of CRC and the association between KRAS and BRAF mutations and clinicopathological features .



PMID: 27037411
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies .
1 The clinical significance of low-frequent RAS pathway-mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer ( mCRC ) patients remains controversial .
2 We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR ( dPCR ) approach .
3 A panel of 34 hotspots , including RAS ( KRAS and NRAS exons 2/3/4 ) and BRAF (V600E) , was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy .
4 dPCR was compared with conventional quantitative PCR ( qPCR ) .
5 Response rates , progression-free survival ( PFS ) , and overall survival ( OS ) were correlated to the mutational status and the mutated allele fraction .
6 Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis .
7 Twenty-two percent of patients were positive for one mutation with qPCR ( mutated alleles ranged from 21% to 666% ) .
8 Analysis by dPCR increased the number of positive patients to 47% .
9 Μ Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8% .
10 ✓ Μ An inverse correlation between the fraction of mutated alleles and radiologic response was observed . GM-ASS-RO
11 Μ ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis .
12 In addition , this threshold also optimized prediction both PFS and OS .
13 We conclude that mutation testing using an extended gene panel , including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy .
14 Mol Cancer Ther ; 15(5) ; 1106-12 .
15 (c) 2016 AACR .



PMID: 27037031
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Systematic review : brain metastases from colorectal cancer--Incidence and patient characteristics .
1 STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma .



PMID: 27036313
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS and YAP1 converge to regulate EMT and tumor survival . GE-REG-RO
1 Colorectal cancers ( CRC ) often show activating mutations of the KRAS or BRAF genes , which stimulate the extracellular signal-regulated kinase ( ERK ) pathway , thus increasing cell proliferation and inhibiting apoptosis .
2 However , immunohistochemical results on ERK activation in such tumors differ greatly .
3 Recently , using a highly optimized immunohistochemical method , we obtained evidence that high levels of ERK activation in rectal adenocarcinomas were associated with resistance to radiochemotherapy .
4 In order to determine whether KRAS and/or BRAF mutations correlate to immunohistochemically detectable increases in phosphorylation of ERK ( pERK ) , we stained biopsies from 36 CRC patients with activating mutations in the BRAF gene ( BRAFV600E : BRAF(m) ) , the KRAS gene (KRAS(m)) or in neither ( BRAF/KRAS(n) ) with this optimized method .
5 Staining was scored in blind-coded specimens by two observers .
6 Staining of stromal cells was used as a positive control .
7 BRAF(m) or KRAS(m) tumors did not show higher staining scores than BRAF/KRAS(n) tumors .
8 Although BRAFV600E staining occurred in over 90% of cancer cells in all 9 BRAF(m) tumors , 3 only showed staining for pERK in less than 10% of cancer cell nuclei .
9 The same applied to 4 of the 14 KRAS(m) tumors .
10 Μ A phophorylation-insensitive antibody demonstrated that lack of pERK staining did not reflect defect expression of ERK1/2 protein .
11 Thus , increased staining for pERK does not correlate to BRAF or KRAS mutations even with a highly optimized procedure .
12 Further studies are required to determine whether this reflects differences in expression of counterregulatory molecules , including ERK phosphatases .



PMID: 27034809
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Molecular testing to optimize therapeutic decision making in advanced colorectal cancer .
1 Colorectal cancer ( CRC ) is a leading cause of cancer death in the United States .
2 In recent years , therapeutic advances have prolonged the survival of patients with advanced disease .
3 Along with the addition of new treatments , an increasing body of literature explores the potential benefit of using molecular testing to define tumor , circulating , or host biomarkers of benefit to specific treatment strategies .
4 At present , testing for specific mutations in exons 2 , 3 , and 4 of KRAS and NRAS has become accepted practice to select patients for treatment with epidermal growth factor receptor ( EGFR )- targeted agents .
5 Additionally , testing for the BRAF V600E mutation is used to refine decisions based on patient prognosis .
6 The presence of the uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) *28 polymorphism is associated with toxicity from irinotecan , although it has not been universally applied .
7 Nonetheless , molecular markers to predict response and toxicity of cytotoxic therapy are evolving .
8   While the development of selection biomarkers for anti-angiogenic treatments has not proved fruitful to date , improved development strategies and novel targeted agents are anticipated to revolutionize the approach to treatment of advanced CRC in the near future .
9   This review summarizes currently available data to select treatment strategies in patients with advanced CRC .



PMID: 27034803
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic profiling of high-grade large - cell neuroendocrine carcinoma of the colon .
1 High-grade neuroendocrine carcinoma ( HGNEC ) of the colon is a rare and aggressive cancer that has a poor prognosis .
2 Currently no standard treatment exists , and published case series report an overall survival of approximately one year with treatment .
3   Typically patients receive treatment similar to that recommended for small - cell lung cancer , extrapolating from the similarity in cancer biology .
4 Μ Here we report a case of HGNEC of the colon with genomic profiling that identified a KRAS G12D mutation and a PI3K mutation that has not yet been reported in the literature for this tumor type .



PMID: 27034263
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF mutation may have different prognostic implications in early - and late-stage colorectal cancer .
1 The prognostic implication of BRAF mutant colorectal cancer remains paradoxical .
2 Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed .
3 Clinicopathologic features , including microsatellite instability , CpG islands methylator phenotype , and overall survival , of these patients were analyzed .
4 Between 2005 and 2013 , 428 colorectal cancer patients were enrolled in this study .
5 The overall survival between BRAF mutant and wild-type patients with early-stage ( stages I and II ) colorectal cancer differed nonsignificantly ( P = 099 ) .
6 By contrast , in late-stage ( stages III and IV ) patients , the median overall survival of BRAF mutant patients ( N = 25 ) was significantly poorer than that of BRAF wild-type ( N = 207 ) patients ( BRAF mutant : 21.3 months ( 95% confidence interval [CI] 7.1-35.5 ) ; BRAF wild-type : 53.5 months ( 95% CI 375-695 ) , P <0.0001 ) .
7 Μ In early-stage patients , we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive ( P <0001 ) , and microsatellite instability-high status ( P = 00013 ) .
8 Conversely , in late-stage patients , BRAF mutation was significantly associated with CpG island methylator phenotype-positive ( P = 00015 ) and the right-side colon ( P = 0014 ) .
9 BRAF mutation may have different prognostic implications in early - and late-stage colorectal cancer .



PMID: 27033063
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Prognostic Influence of BRAF Mutation and other Molecular , Clinical and Laboratory Parameters in Stage IV Colorectal Cancer .
1   Crizotinib administered via nasogastric and percutaneous endoscopic gastrostomy tubes for the successful treatment of ALK-rearranged lung cancer in a patient with poor performance status .



PMID: 27026680
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype .
1 Sessile serrated colon adenoma/polyps ( SSA/P ) are found during routine screening colonoscopy and may account for 20% to 30% of colon cancers .
2 However , differentiating SSA/Ps from hyperplastic polyps ( HP ) with little risk of cancer is challenging and complementary molecular markers are needed .
3 In addition , the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood .
4 RNA sequencing ( RNA-Seq ) was performed on 21 SSA/Ps , 10 HPs , 10 adenomas , 21 uninvolved colon , and 20 control colon specimens .
5 Differential expression and leave-one-out cross-validation methods were used to define a unique gene signature of SSA/Ps .
6 Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas ( TCGA ) to identify a subtype of colon cancers that may develop from SSA/Ps .
7 A total of 1,422 differentially expressed genes were found in SSA/Ps relative to controls .
8 Μ Serrated polyposis syndrome ( n = 12 ) and sporadic SSA/Ps ( n = 9 ) exhibited almost complete ( 96% ) gene overlap.A 51 - gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability .
9 Μ A smaller 7 - gene panel showed high sensitivity and specificity in identifying BRAF-mutant , CpG island methylator phenotype high , and MLH1-silenced colon cancers .
10 We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway .
11 These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway .
12 Cancer Prev Res ; 9(6) ; 456-65 .
13 (c) 2016 AACR .



PMID: 27026089
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer in Crohn's colitis is comparable to sporadic colorectal cancer .
1 Glypican-1 identifies cancer exosomes and detects early pancreatic cancer .



PMID: 27022117
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels .
1 PURPOSE :
2 Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer ( CRC ) .
3 In metastatic CRC , sequencing of RAS/BRAF is necessary to guide clinical management .
4 Μ We hypothesized that a next-generation sequencing ( NGS ) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency ( MMR-D ) on the basis of increased mutational load .
5 METHODS :
6 Μ We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015 .
7 Tumor mutational load , with exclusion of copy number changes , was determined for each case and compared with MMR status as determined by routine immunohistochemistry .
8 RESULTS :
9 Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT .
10 Thirteen percent ( n = 28 ) exhibited MMR-D by immunohistochemistry .
11 Using the 341 - gene assay , 100% of the 193 tumors with <20 mutations were MMR-proficient .
12 Of 31 tumors with >/= 20 mutations , 28 ( 90% ) were MMR-D .
13 Μ The three remaining tumors were easily identified as being distinct from the MMR-D tumors with >150 mutations each .
14 Μ Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype .
15 Among MMR-D tumors , the median number of mutations was 50 ( range , 20 to 90 ) compared with six ( range , 0 to 17 ) in MMR-proficient/POLE wild-type tumors ( P <001 ) .
16 With a mutational load cutoff of >/= 20 and <150 for MMR-D detection , sensitivity and specificity were both 1.0 ( 95% CI , 093 to 10 ) .
17 CONCLUSION :
18 A cutoff for mutational load can be identified via multigene NGS tumor profiling , which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping .



PMID: 27020587
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy . GE-ASS-RO, GM-ASS-RO
1 BACKGROUND :
2 HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors ( GIST ) .
3 BIIB021 is an oral non-ansamycin HSP90 inhibitor .
4 We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib .
5 PATIENTS AND METHODS :
6 The primary end-point was metabolic partial response ( mPR ) as assessed by fluorodeoxyglucose positron emission tomography ( FDG-PET ) .
7 The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70 .
8 Twenty-three patients were treated on two schedules : 12 pts received 600 mg twice a week ( BIW ) and 11 patients received 400 mg three times a week ( TIW ) .
9 All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021 .
10 RESULTS :
11 The median age was 59 years ( 33-88 years ) , 61% male , 44% Eastern Cooperative Oncology Group 1 ( ECOG1 ) .
12 The best response was PR by FDG-PET for five patients ( 3/12 at 600 mg BIW and 2/9 at 400 TIW ) for an overall response rate of 22% .
13 The response duration was 25-138 days .
14 Adverse events ( AEs ) were mild to moderate .
15 The mean Cmax was 1.5 micromol and the mean AUC was 2.9 micromol h .
16 Cmax>1.5 micromol was associated with a decrease in standardized uptake value ( SUVmax ) .
17 HSP70 increased substantially following treatment .
18 CONCLUSIONS :
19 This study met its primary end-point .
20 BIIB021 leads to objective responses in refractory GIST patients .
21 Pharmacodynamic studies confirmed HSP90 inhibition .
22 Further evaluation of BIIB021 in GIST is warranted .



PMID: 27020206
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Serrated lesions of the appendix in serrated polyposis patients .
1 Get the GIST? An overview of gastrointestinal stromal tumours .



PMID: 27017409
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Dual targeting of HER3 and EGFR in colorectal tumors might overcome anti-EGFR resistance .
1 Multiple genetic alterations have been associated with resistance to anti-EGFR therapy in metastatic colorectal cancer ( CRC ) patients .
2 Research has been mainly focused on driver mutations in KRAS , NRAS , BRAF and PI3K .
3 However , recent evidence suggests a crucial role for non-genetic mechanisms in conferring resistance to anti-EGFR therapy .
4 Specifically , the HER3 receptor is capable of heterodimerizing with multiple EGFR family members resulting in downstream activation of the PI3K and MAPK pathways .
5 Monoclonal antibodies targeted against the HER3 receptor are being investigated in clinical trials ; however , preliminary data has shown limited clinical activity .
6 Thus , given the relevance of the HER3 receptor in activating downstream effector pathways and in conferring resistance to anti-EGFR therapy , the therapeutic targeting of HER3 in combination with primary drivers of the tumor is also being investigated .
7   Here , we review the role of HER3 as a promoter of clinical resistance to EGFR therapy and discuss therapeutic approaches that could potentially overcome this resistance .



PMID: 27012422
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ L-Ascorbic acid can abrogate SVCT-2 -dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells .
1 Numerous proteins have been identified as constituents of the adhesome , the totality of molecular components in the supramolecular assemblies known as focal adhesions , fibrillar adhesions and other kinds of adhesive contact .
2 The transmembrane receptor proteins called integrins are pivotal adhesome members , providing a physical link between the extracellular matrix ( ECM ) and the actin cytoskeleton .
3 Tensins are ever more widely investigated intracellular adhesome constituents .
4 Involved in cell attachment and migration , cytoskeleton reorganization , signal transduction and other processes relevant to cancer research , tensins have recently been linked to functional properties of deleted in liver cancer 1 ( DLC1 ) and a mitogen -activated protein kinases ( MAPK ) , to cell migration in breast cancer , and to metastasis suppression in the kidney .
5 Tensins are close relatives of phosphatase homolog/tensin homolog ( PTEN ) , an extensively studied tumor suppressor .
6 Such findings are recasting the earlier vision of tensin ( TNS ) as an actin-filament ( F-actin ) capping protein in a different light .
7 This critical review aims to summarize current knowledge on tensins and thus to highlight key points concerning the expression , structure , function , and evolution of the various members of the TNS brotherhood .
8 Insight is sought by comparisons with homologous proteins .
9 Some historical points are added for perspective .



PMID: 27010906
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Update on optimal treatment for metastatic colorectal cancer from the ACTG/AGITG expert meeting : ECCO 2015 .
1 The treatment of metastatic CRC ( mCRC ) has evolved over the last 20 years , from fluoropyrimidines alone to combination chemotherapy and new biologic agents .
2 Median overall survival is now over 24 months for RAS mutated ( MT ) patients and over 30 months for RAS wild-type ( WT ) patients .
3 However , there are subgroups of patients with BRAF V600E MT CRC who have a significantly poorer outlook .
4 Newer treatment options are also being explored in select subgroups of patients ( anti-HER 2 in HER2 positive mCRC and immunotherapy in patients with defective mismatch repair ( dMMR ) ) .
5   The best use of these systemic treatment options , as well as surgery in well-selected patients requires careful consideration of predictive biomarkers and importantly , the optimal sequence in which therapies should be given to derive maximal benefit .
6 A group of colorectal subspecialty medical oncologists from Australia , USA , The Netherlands and Germany met during ECCO 2015 in Vienna to review current practice .



PMID: 27009213
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomically Driven Tumors and Actionability across Histologies : BRAF-Mutant Cancers as a Paradigm .
1 The diagnosis , classification , and management of cancer are traditionally dictated by the site of tumor origin , for example , breast or lung , and by specific histologic subtypes of site-of-origin cancers ( e.g. , non-small cell versus small cell lung cancer ) .
2 However , with the advent of sequencing technologies allowing for rapid , low cost , and accurate sequencing of clinical samples , new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor .
3 We discuss a genomically driven strategy for cancer treatment using BRAF as an example .
4 Several key points are highlighted : (i) molecular aberrations can be shared across cancers ; ( ii ) approximately 15% of all cancers harbor BRAF mutations ; and ( iii ) BRAF inhibitors , while approved only for melanoma , have reported activity across numerous cancers and related disease types bearing BRAF aberrations .
5 However , BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy , striking a cautionary note .
6 Yet , even in this case , emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors , albeit when administered in combination with other agents that impact resistance pathways .
7 Taken together , these data suggest that molecular aberrations may be the basis for a new nosology for cancer .
8 Mol Cancer Ther ; 15(4) ; 533-47 .
9 (c) 2016 AACR .



PMID: 27007150
(Patient)  
Terms: prospective, observational study
Sent# Symbols Sentence Mnemonics
0 A prospective observational study to examine the relationship between quality of life and adverse events of first - line chemotherapy plus cetuximab in patients with KRAS wild-type unresectable metastatic colorectal cancer : QUACK Trial .
1 Triple-negative breast cancer ( TNBC ) is an aggressive cancer with a poor prognosis due to its epithelialto-mesenchymal transition ( EMT ) phenotype .
2 Cancer patients often experience several detrimental effects of cancer treatment , such as chemoresistance , radioresistance and the maintenance of cancer stem cells due to EMT .
3 Thus , EMT signaling is considered to be a valuable therapeutic target for cancer treatment , and its inhibition is being attempted as a new treatment option for TNBC patients .
4 Previously , we showed that 3 - ( 2-chlorobenzyl ) -1,7-dimethyl-1H-imidazo[2,1-f]purine2,4 (3H,8H)- dione (IM-412) inhibits transforming growth factor -beta ( TGF-beta )- induced differentiation of human lung fibroblasts through both Smad -dependent and -independent pathways .
5 In the present study , we examined the inhibitory effect of IM-412 on EMT pathways and invasiveness in TNBC cells since the TGF-beta signaling pathway is a typical signaling pathway that functions in EMT .
6 IM-412 not only potently suppressed the migration and invasion of MDA-MB-231 cells , but also lowered the expression of mesenchymal markers and EMT -activating transcription factors in these cells .
7 IM-412 inhibited the activation of several signaling proteins , including Smad2/Smad3 , p38MAPK , Akt and JNK , and it also attenuated the phosphorylation of FGFR1 and FGFR3 .
8 Collectively , our findings suggest that the synthetic compound IM-412 suppressed the EMT process in MDA-MB-231 cells and thereby effectively inhibited the migration and invasion of these cancer cells .
9 Thus , IM-412 could serve as a novel therapeutic agent for malignant cancers .



PMID: 27004837
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hepatocellular carcinoma and liver metastases : clinical data on a new dual-lumen catheter kit for surgical sealant infusion to prevent perihepatic bleeding and dissemination of cancer cells following biopsy and loco-regional treatments .
1 Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer ( CRC ) and gene mutations of the EGFR pathway ; however , no studies have examined metastatic CRC ( mCRC ) patients with metastasectomy .
2 The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients .
3 A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013 .
4 Detailed information was obtained through review of medical records .
5 Μ Gene mutations of EGFR pathway were analyzed by Luminex assay .
6 Overall survival ( OS ) and recurrence free survival were estimated by the Kaplan-Meier method and the log-rank test was used to compare the survival outcomes by gene mutation status .
7 A total of 132 patients received metastasectomy .
8 The frequencies of KRAS exon 2 , KRAS exon 3.4 , NRAS , BRAF , and PIK3CA mutations were 38.6% ( 51/132 ) , 3.6% ( 5/132 ) , 5.1% ( 7/132 ) , 5.1% ( 7/132 ) , and 8.7% ( 12/132 ) , respectively .
9 With a median follow-up of 84.1 months ( 572-NA ) for a survivor , the 4-year OS rate was 65.6% for mCRC with RAS mutation , and 81.3% for mCRC with wild-type RAS ( p <005 ) .
10 Μ We observed a statistically significant correlation for only the RAS mutation and OS .
11 ✓ In multivariate analysis , RAS mutation and liver metastasis were independent factors for shorter OS . GM-MRK-RO
12 There were no significant differences between gene mutations of EGFR pathway and recurrence free survival .
13 ✓ RAS mutation in mCRC metastasectomy patients was associated with shorter overall survival . GM-ASS-RO



PMID: 27004155
(Patient)  
Terms: Phase III trial, rat
Sent# Symbols Sentence Mnemonics
0 ✓ KDR Mutation as a Novel Predictive Biomarker of Exceptional Response to Regorafenib in Metastatic Colorectal Cancer . GM-MRK-RO
1 This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma ( CRC ) metastatic to the liver , retroperitoneum , anastomotic site , and distal rectal sigmoid colon .
2 She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab , as well as disease progression .
3 Next generation sequencing of her tumor was ordered , and further discussion of her malignancy's genomic information took place at a multidisciplinary molecular tumor board .
4 The patient had mutations in rat KRAS ( Kirsten sarcoma viral oncogene homolog ) which made her ineligible for epidermal growth factor receptor ( EGFR ) inhibitors ; however , a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance ( VUS ) .
5 KDR ( kinase insert domain receptor ) is the human gene encoding for vascular endothelial growth factor receptor 2 ( VEGFR-2 ) .
6 She was then considered a suitable candidate for regorafenib , which she could only tolerate at a low dose of 40 mg daily , with the intent of prolonging her survival and to optimize her quality of life .
7 We report her excellent tolerance and exceptional response to low dose regorafenib , including symptomatic , tumor marker , and sustained partial metabolic radiological improvement .
8 In the largest Phase III trial of regorafenib in CRC , only five patients ( 1% ) of 760 experienced a partial response ( versus one patient , 04% , receiving placebo ) .
9 KDR R961W mutation has been described but no functional data has been reported .
10 This mutation occurs in the tyrosine kinase domain of the VEGFR-2 .
11 Regorafenib targets VEGFR-2 (KDR) .
12 ✓ Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer . GM-MRK-RO
13   To our knowledge , this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC , leading to what is considered an exceptional response .
14 Further studies based on this preliminary data are warranted .



PMID: 27002945
(Patient)  
Terms: , genetically engineered mouse, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 RAS signaling and anti-RAS therapy : lessons learned from genetically engineered mouse models , human cancer cells , and patient-related studies .
1 Colorectal cancer is one of the most frequent solid tumors in the western world , with low survival rates in patients with metastatic disease .
2 Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first - line chemotherapy in the metastatic setting .
3 The conventional treatment as a first - line approach is continuous application until progression or intolerable toxicities .
4 However , only one third of patients are treated until progression mainly due to the side effects of chemotherapy .
5 Notably , oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy , which is the main reason for treatment discontinuation or treatment de-escalation .
6 On this basis , recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting , together with various strategies to optimize maintenance therapy including regimens with targeted therapies , such as cetuximab , ziv-aflibercept and regorafenib .
7   Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient , tumor and treatment characteristics , as well as molecular biomarkers .
8   This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer , and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies .



PMID: 27002940
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic role of ERBB2 , MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies .
1 BACKGROUND :
2 High amplification of epiregulin ( EREG ) and amphireglin ( AREG ) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer ( mCRC ) patients who were treated with anti-EGFR antibodies .
3 Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment .
4 METHODS :
5 The relative mRNA levels of seven genes including ERBB2 , MET , VEGFA , EREG , AREG , PTEN and ERCC1 between tumour (T) and non-tumour ( NT ) tissue sections were analysed by quantitative real-time PCR .
6 Relative mRNA values , that is , T/NT ratios , of target genes were calculated and hazard ratios ( HRs ) for each gene of interest were adjusted for age , gender , performance status , minor RAS mutations and other clinicopathological variables which exhibited P-values<0.1 on the basis of univariate analysis .
7 RESULTS :
8 Among 108 cases who received anti-EGFR antibodies , there were 96 cases of KRAS exon2 wild-type patients enroled in this study .
9 When the cutoff values for relative mRNA levels were set to the upper 25th percentile of all patients , there were statistically significant differences in overall survival ( OS ) between the patients with high and low levels of EREG ( HR : 0.326 , 95% CI : 0.136-0.772 , P = 0.011 ) , ERBB2 ( HR : 1.31 , 95% CI : 1.084-1.652 , P = 0.040 ) , MET ( HR : 2.48 , 95% CI : 1.356-5.463 , P = 0.026 ) , and VEGF-A ( HR : 1.29 , 95% CI : 1.036-1.606 , P = 0.046 ) .
10 In addition , patients with high ERBB2 had shorter progression-free survival ( PFS ) compared with low ERBB2 ( HR : 1.98 , 95% CI : 1.062-3.850 ) .
11 There were no significant differences in PFS and OS with respect to relative expression levels of PTEN and ERCC1 .
12 The prognostic role of AREG was evaluated in only T sections , as the mRNA expression level of this gene was mostly ( 91% cases ) undetectable in NT sections .
13 Patients with high AREG had longer OS compared with low AREG ( HR : 0.227 , 95% CI : 0.095-0.808 ) .
14 CONCLUSIONS :
15 Our study has shown that higher T/NT ratios of ERBB2 , MET and VEGFA mRNA were associated with worse OS in mCRC patients treated with anti-EGFR antibodies , with higher EREG and AREG were associated with better prognosis in the same setting .
16   These findings will contribute the further understanding and management of anti-EGFR antibody treatment in mCRC patients .



PMID: 27002107
(None)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Cetuximab continuation after first progression in metastatic colorectal cancer ( CAPRI-GOIM ) : a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX .
1 Extragastrointestinal stromal tumor in a kidney transplant recipient .



PMID: 26998897
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/beta-catenin signaling pathway mutations .
1 Caveolin-1 is an essential component of membrane caveolae .
2 It is an important regulator of cellular processes such as signal transduction and endocytosis .
3 We report here , for the first time , that caveolin-1 is a target of the K-RAS oncogene in colon carcinogenesis .
4 Caveolin-1 is induced in colon cancer cells and in human colon tumor samples , in response to K-RAS activating mutations .
5 An activated K-RAS oncogene transcriptionally induces caveolin-1 expression in human colon cancer cells and this effect is not restricted to the type of activating K-RAS mutation .
6 Inhibition of the P-I3 Kinase -AKT pathway , but not the ERK MAPK pathway , both important K-RAS effectors , leads to a decrease in caveolin-1 expression indicating that the AKT pathway is involved in caveolin-1 expression in response to an activated K-RAS .
7 Increased AKT signaling induces caveolin-1 expression by increasing the activity of the transcription factor , Sp1 .
8 Interestingly ; caveolin-1 depletion alters K-RAS -dependent signaling by decreasing Grb2-SOS activity .
9 Consistent with these finding , caveolin-1-depleted cells shows decreased migration in vitro .
10 However , caveolin-1 overexpression by itself does not increase migration whereas an activated Src can increase migration in a caveolin-1 -dependent manner .
11 This increased migration is highly dependent on the RhoA GTPase , indicating that an activated K-RAS modulates migration in part via caveolin-1 induction , and increasing RhoA activity via phospho-caveolin-1 .
12 Our findings indicate that K-RAS regulates both caveolin-1 expression and other factors affecting caveolin-1 functions in colon cancer-derived cell migration .



PMID: 26997454
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Early signet ring cell carcinoma arising from colonic adenoma : the molecular profiling supports the adenoma-carcinoma sequence .
1 Among colorectal cancers , the prevalence of signet ring cell carcinoma ( SRCC ) is lower than 1% ; to date , only 6 cases of early SRCCs arising in colonic adenoma have been reported .
2 In spite of the well-established understanding of the phenotypic and genetic changes occurring in conventional colonic carcinogenesis , the molecular landscape of colon SRCC is still far to be elucidated .
3 We describe the histologic and immunohistochemical phenotype and the molecular profile of a case of intramucosal SRCC developed within a 4.5-cm large sigmoid adenoma .
4 Μ The DNA sequencing of the 2 microdissected neoplastic components ( adenomatous and SRCC ) showed the same G12V KRAS mutation .
5 Interestingly , although the adenomatous epithelium showed unequivocal p53 overexpression , no signet ring cancer cells featured p53 nuclear immunostain .
6 This molecular pattern supports the unique histogenesis of the 2 coexisting neoplastic oncotypes , also suggesting that the signet ring cell component is derived from the molecular de-differentiation ( p53 loss ) of the preexisting adenomatous lesion .



PMID: 26995877
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Companion Diagnostics for Solid Tumors ] .
1 Companion diagnostics ( CoDx ) will likely continue to rapidly increase in number and application to disease areas including solid tumors , for example EGFR for gefitinib and ALK fusion gene for crizotinib in non-small - cell lung cancer ; KRAS against the use of cetuximab and panitumumab in colorectal cancer ; HER2 for trastuzumab in breast cancer .
2 CoDx are an indispensable part of personalized medicine and pharmacogenomics .
3 In CoDx development , there are still many challenges , such as the business model promoting cooperation between diagnostics and pharmaceutical companies , and also the regulations related to CoDx .
4 The FDA notice on the development of CoDx in 2011 recommended the co-development of a new drug and CoDx as the best practice , and the Ministry of Health , Labour and Welfare in Japan also issued a statement in 2013 .
5 In addition , the recent discovery of many novel variants in the DNA sequence , advances in sequencing and genomic technology , and improved analytic methods have enabled the impact of germline and somatic mutations to be determined using multiplex diagnosis .
6 The complex challenges to develop CoDx necessitate a close collaboration among academic institutions , regulatory authorities , and pharmaceutical companies. [Review] .



PMID: 26991699
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors .
1 Although most sporadic colorectal cancers ( CRC ) are thought to develop from protruded adenomas through the adenoma-carcinoma sequence , some CRC develop through flat lesions , so-called laterally spreading tumors ( LST ) .
2 We previously analyzed epigenetic aberrations in LST and found that LST are clearly classified into two molecular subtypes : intermediate-methylation with KRAS mutation and low-methylation with absence of oncogene mutation .
3 Intermediate-methylation LST were mostly granular type LST ( LST-G ) and low-methylation LST were mostly non-granular LST ( LST-NG ) .
4 In the present study , we conducted a targeted exon sequencing study including 38 candidate CRC driver genes to gain insight into how these genes modulate the development of LST .
5 Μ We identified a mean of 11.5 suspected nonpolymorphic variants per sample , including indels and non-synonymous mutations , although there was no significant difference in the frequency of total mutations between LST-G and LST-NG .
6 Μ Genes associated with RTK/RAS signaling pathway were mutated more frequently in LST-G than LST-NG ( P = 0004 ) , especially KRAS mutation occurring at 70% ( 30/43 ) of LST-G but 26% ( 13/50 ) of LST-NG ( P <00001 ) .
7 Μ Both LST showed high frequency of APC mutation , even at adenoma stage , suggesting its involvement in the initiation stage of LST , as it is involved at early stage of colorectal carcinogenesis via adenoma-carcinoma sequence .
8 Μ TP53 mutation was never observed in adenomas , but was specifically detected in cancer samples .
9 Μ TP53 mutation occurred during development of intramucosal cancer in LST-NG , but during development of cancer with submucosal invasion in LST-G .
10 It is suggested that TP53 mutation occurs in the early stages of cancer development from adenoma in both LST-G and LST-NG , but is involved at an earlier stage in LST-NG .



PMID: 26991344
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Integrated genomic characterization of adrenocortical carcinoma .
1 We determined prognostic impact of KRAS , BRAF , PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer ( CRC ) patients undergoing liver resections for metastatic disease .
2 Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits .
3 In univariate analysis , KRAS ( 335% ) , BRAF ( 61% ) and PIK3CA ( 134% ) mutations each predicted reduced median time to relapse ( TTR ) ( 7 vs. 22 , 3 vs. 16 and 4 vs. 17 months ; p <0001 , 0002 and 0023 , respectively ) .
4 KRAS and BRAF mutations also predicted a reduced median disease-specific survival ( DSS ) ( 29 vs. 51 and 16 vs. 49 months ; p <0001 and 0008 , respectively ) .
5 Μ No effect of TP53 ( 604% ) mutation status was observed .
6 Postoperative , but not preoperative chemotherapy improved both TTR and DSS ( p <0001 for both ) with no interaction with gene mutation status .
7 Μ Among 94 patients harboring two or more metastatic deposits , 13 revealed mutation heterogeneity across metastatic deposits for atleast one gene .
8 Μ Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations ( 18 vs. 37 months ; p = 0011 for all genes ; 16 vs. 26 months ; p <0001 analyzing BRAF or KRAS mutations separately ) .
9 Μ In multivariate analyses , KRAS or BRAF mutations consistently predicted poor TRR and DSS .
10 Mutation heterogeneity robustly predicted DSS but not TTR , while postoperative chemotherapy improved both TTR and DSS .
11 ✓ Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions . GE-REG-RO



PMID: 26991109
(Patient)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Clinical Validation of a Multiplex Kit for RAS Mutations in Colorectal Cancer : Results of the RASKET ( RAS KEy Testing ) Prospective , Multicenter Study .
1 BACKGROUND :
2 Emerging targeted lung cancer therapies require the accurate morphologic subclassification of non-small cell lung cancer ( NSCLC ) , even in scant and distorted specimens obtained by transthoracic needle aspiration ( TTNA ) .
3 MicroRNAs ( miRNAs ) are small noncoding genes recently reported as useful in differentiating squamous cell carcinoma ( SCC ) from adenocarcinoma ( AD ) in resected tumor specimens .
4 We investigated their ability to do so in TTNA specimens .
5 METHODS :
6 Smears , immunocytochemistry slides , and corresponding cell blocks of 31 NSCLC TTNA specimens were retrieved and classified as AD or SCC based on their cytologic features and immunocytochemical profiles .
7 Data on EGFR and K-RAS mutational status were available for all cases of AD .
8 We quantified the hsa-let-7 family and hsa-miR-205 by quantitative reverse transcription-polymerase chain reaction and compared the miRNA expression levels in AD and SCC using Student t test .
9 RESULTS :
10 Eighteen cases were classified as AD and 13 as SCC by light microscopy and immunocytochemistry .
11 Μ miRNA expression profiles demonstrated considerable , statistically significant differences between AD and SCC , showing an upregulation of hsa-let-7a , hsa-let-7b , hsa-let-7c , hsa-let-7f , hsa-let-7g , hsa-let-7i , and hsa-miR-98 and a downregulation of hsa-miR-205 in AD specimens ( all P <05 ; t test ) .
12 CONCLUSIONS :
13 Profiling the hsa-let-7 family and hsa-miR-205 is a promising method for differentiating AD from SCC , even in such small specimens as transthoracic aspirates .
14 Subject to the validation of these findings in further , larger studies , this could prove to be a reliable , standardizable tool for the subclassification of NSCLC .



PMID: 26989027
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients .
1 Approximately 45% of metastatic colorectal cancer ( mCRC ) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment .
2 We set out to identify additional genetic markers that might predict the response to cetuximab treatment .
3 Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first - or third - line therapy .
4 Μ The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing .
5 Μ BRAF , PIK3CA , KRAS ( exons 3 and 4 ) , NRAS , PTEN , and AKT1 mutations were detected in 6 , 6 , 5 , 4 , 1 , and 1 patient , respectively .
6 Four of the BRAF mutations were non-V600 variants .
7 Μ Four tumors harbored multiple co-existing ( complex ) mutations .
8 ✓ All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders . GM-MRK-RO
9 ✓ All patients but one harboring KRAS , NRAS , or BRAF mutations were non-responders . GM-MRK-RO
10 ✓ Mutations in any one of these three genes were associated with a poor response rate ( 71% ) and reduced survival ( PFS = 80 months ) compared to wild-type patients ( 744% and 116 months ) . GM-ASS-RO
11 ✓ Our data suggest that KRAS , NRAS , and BRAF mutations predict response to cetuximab treatment in mCRC patients . GM-REG-RO



PMID: 26985396
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposure .
1 Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries , they are increasing in several developed countries because of an unhealthy western lifestyles including smoking , physical inactivity and consumption of calorie-dense food .
2 The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries .
3 Among them , lung cancer is the main cause of cancer death in worldwide .
4 The cumulative survival rate at five years differs between 13 and 21 % in several countries .
5 Although the most important risk factors are smoking for lung cancer , however , the increased incidence of lung cancer in never smokers ( LCINS ) is necessary to improve knowledge concerning other risk factors .
6 Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk .
7 Μ Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor ( EGFR ) gene .
8 Also , K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors .
9 Recently , radon ( Rn ) , natural and noble gas , has been recognized as second common reason of lung cancer .
10 In this review , we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms .



PMID: 26984642
(Patient)  
Terms: NCT00113763
Sent# Symbols Sentence Mnemonics
0 Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer .
1 AIM :
2 Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti-epidermal growth factor receptor ( EGFR ) therapy in patients with metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas ( (R) ) KRAS mutation test ( cobas test ) , the therascreen ( (R) ) KRAS RGQ PCR kit test ( therascreen test ) , and Sanger sequencing as the reference method for detecting mutations in codons 12/13 .
5 RESULTS :
6 For 461 eligible samples , the cobas test , therascreen test , and sequencing had invalid results for 5.2 , 10.8 , and 2.6 % of specimens , respectively .
7 Valid cobas and therascreen test results had similar KRAS mutation-positive rates ( 373 vs. 363 % , respectively ) ; sequencing was 28.5 % .
8 Positive and negative percent agreement ( PPA/NPA ) between the cobas test and sequencing was 96.9 % ( 95 % confidence interval [CI] 92.2-98.8 ) , and 88.7 % ( 95 % CI 847-918 ) , respectively .
9 PPA/NPA between the cobas and therascreen tests was 93.3 % ( 95 % CI 881-963 ) and 96.5 % ( 95 % CI 935-981 ) , respectively .
10 Bridging analysis from NCIC-CO.17 and NCT00113763 using the cobas test yielded modeled hazard ratios for overall survival and progression-free survival ( PFS ) of 0.558 ( 95 % CI 0422-0752 ) and 0.413 ( 95 % CI 0304-0550 ) , respectively , for cetuximab and 0.989 ( 95 % CI 0778-1299 ) and 0.471 ( 95 % CI 0360-0626 ) , respectively , for panitumumab , demonstrating significant efficacy in the KRAS-negative population for PFS .
11 CONCLUSION :
12   Μ The cobas test showed similar accuracy to the therascreen test for detecting KRAS mutations and could appropriately identify mCRC patients ineligible for anti-EGFR therapy as demonstrated by bridging analysis results .



PMID: 26984550
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Carcinoma of the colon and rectum with deregulation of insulin-like growth factor 2 signaling : clinical and molecular implications .
1 BACKGROUND :
2 Loss of imprinting ( LOI ) of the insulin-like growth factor 2 ( IGF2 ) is an early event in the development of colorectal cancer ( CRC ) .
3 Whether LOI of IGF2 denotes a molecular or clinical cancer subgroup is currently unknown .
4 METHODS :
5 Tumor biopsies and paired normal mucosa from 399 patients with extensive clinical annotations were analyzed for LOI and IGF2 expression .
6 LOI status in 140 informative cases was correlated with clinicopathologic parameters and outcome .
7 RESULTS :
8 LOI was frequent in normal mucosa and tumors and occurred throughout the large intestine .
9 LOI was unrelated to microsatellite instability , KRAS mutation status , stage , and survival .
10 However , CRC with LOI showed increased IGF2 protein levels and activation of AKT1 .
11 Gene expression analysis of tumors with and without LOI and knockdown of IGF2 in cell lines revealed that IGF2 induced distinct sets of activated and repressed genes , including Wnt5a , CEACAM6 , IGF2BP3 , KPN2A , BRCA2 , and CDK1 .
12 Inhibition of AKT1 in IGF2 -stimulated cells showed that the downstream effects of IGF2 on cell proliferation and gene expression were strictly AKT1 -dependent .
13 CONCLUSIONS :
14 LOI of IGF2 is a frequent and early event in CRC that occurs both in the adenomatous polyposis coli ( APC ) gene -mutated and serrated route of carcinogenesis .
15 LOI leads to overexpression of IGF2 , activates IGF1R and AKT1 , and is a powerful driver of cell proliferation .
16 Moreover , our results suggest that IGF2 via AKT1 also contributes to non-canonical wnt signaling .
17 Although LOI had no significant impact on major clinical parameters and outcome , its potential as a target for preventive and therapeutic interventions merits further investigation .



PMID: 26983878
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Characterization of principal predictive biomarkers of targeted therapies in thoracic cancer ] .
1 BACKGROUND :
2 Gastrointestinal stromal tumor ( GIST ) is the most common mesenchymal neoplasm of the gastrointestinal tract .
3 They are believed to originate from the interstitial cells of Cajal .
4 Most of these tumors contain activating mutations in the KIT receptor tyrosine kinase .
5 This is the first study in Iran to evaluate GISTs at the molecular level .
6 METHODS :
7 In the present study , during 5 years ( 2007-2012 ) , we found 50 cases of GISTs ( recurrent or treated cases have been omitted ) from the affiliated hospitals of Shiraz University of Medical Sciences .
8 Demographic findings and gross characteristics have been extracted from the clinical charts and pathology reports , respectively .
9 In addition , immunohistochemistry for c-KIT and DOG-1 were performed and reviewed by two pathologists .
10 Molecular study for two common exons of KIT ( 9,11 ) were performed by PCR and bidirectional DNA sequencing .
11 RESULTS :
12 Μ Among 50 cases of GIST , 17 cases showed wild type KIT and 33 cases ( 66% ) with mutation either in exon 9 or in exon 11 .
13 Μ The mutation of exon 9 was detected in 11 ( 22% ) cases , while 29 ( 58% ) cases had mutation of exon 11 .
14 Μ In seven cases , both exon 11 and exon 9 mutations were detected at the same time ( 14% ) .
15 CONCLUSION :
16 There is significant variation in the frequency of KIT mutation in exon 9 and 11 from the previous reports .
17 Part of this variation in the previous and current studies is due to methodological differences ; however , it seems that ethnic differences should not be underestimated .
18 There are very few studies from the geographic region of Iran ; however , the reported cases from the countries such as Turkey are very similar to our findings .



PMID: 26980732
(Patient)  
Terms: phase II study, prospective study, prospective
Sent# Symbols Sentence Mnemonics
0 Genomic markers of panitumumab resistance including ERBB2/ HER2 in a phase II study of KRAS wild-type ( wt ) metastatic colorectal cancer ( mCRC ) .
1 A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer ( mCRC ) .
2 Patients with previously treated , codon 12/13 KRAS wt , mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks .
3 Of 34 panitumumab-treated patients , 11 ( 32% ) had progressive disease at 8 weeks and were classified as non-responders .
4 Μ A Nanostring nCounter-based assay identified a 5 - gene expression signature ( ERBB2 , MLPH , IRX3 , MYRF , and KLK6 ) associated with panitumumab resistance ( P = 0001 ) .
5 Immunohistochemistry and in situ hybridization determined that the HER2 ( ERBB2 ) protein was overexpressed in 4/11 non-responding and 0/21 responding cases ( P = 0035 ) .
6 Μ Two non-responding tumors had ERBB2 gene amplification only , and one demonstrated both ERBB2 amplification and mutation .
7 Μ A non - codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities .
8 This study identifies a 5 - gene signature associated with non-response to single agent panitumumab , including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling .
9 KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis , and the HER2 pathway plays an important role in resistance to therapy .



PMID: 26980146
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer .
1 UNLABELLED :
2 Urothelial carcinoma of the bladder ( UCB ) is genomically heterogeneous , with frequent alterations in genes regulating chromatin state , cell cycle control , and receptor kinase signaling .
3 Μ To identify prognostic genomic markers in high-grade UCB , we used capture-based massively parallel sequencing to analyze 109 tumors .
4 Μ Mutations were detected in 240 genes , with 23 genes mutated in >/ = 5% of cases .
5 ✓ The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3 - kinase , catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival ( RFS ) ( hazard ratio [HR] : 0.35 ; p = 0.014 ) and improved cancer-specific survival ( CSS ) ( HR : 0.35 ; p = 0.040 ) in patients treated with radical cystectomy ( RC ) . GM-ASS-RO
6 ✓ Μ In multivariable analyses controlling for pT and pN stages , PIK3CA mutation remained associated with RFS ( HR : 0.39 ; p = 0.032 ) . GM-ASS-RO
7 The most frequent alteration , TP53 mutation ( 57% ) , was more common in extravesical disease ( 69% versus 32% , p = 0005 ) and lymph node-positive disease ( 77% versus 56% , p = 0025 ) .
8 Patients with cyclin-dependent kinase inhibitor 2A ( CDKN2A )- altered tumors experienced worse RFS ( HR : 5.76 ; p<0.001 ) and worse CSS ( HR : 2.94 ; p = 0.029 ) in multivariable analyses .
9 ✓ Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes . GM-ASS-RO
10 ✓ In UCB patients treated with RC , PIK3CA mutations are associated with favorable outcomes , whereas TP53 and CDKN2A alterations are associated with poor outcomes . GM-ASS-RO
11 Genomic profiling may aid in the identification of UCB patients at highest risk following RC .
12 PATIENT SUMMARY :
13 Μ Using next-generation sequencing , we identified genomic subsets of high-grade urothelial bladder cancer associated with favorable and unfavorable outcomes .
14   These findings may aid in the selection of patients most likely to benefit from novel combined modality approaches .



PMID: 26975418
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation .
1 Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression .



PMID: 26970738
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene .
1 INTRODUCTION :
2 Μ Population-wide screening for epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) gene rearrangements to inform cancer therapy in non-small-cell lung cancer ( NSCLC ) is recommended by guidelines .
3 We estimated cost-effectiveness of multiplexed predictive biomarker screening in metastatic NSCLC from a societal perspective in the United States .
4 METHODS :
5 We constructed a microsimulation model to compare the life expectancy and costs of multiplexed testing and molecularly guided therapy versus treatment with cisplatin-pemetrexed ( CisPem ) .
6 All testing interventions included a two-step algorithm of concurrent EGFR mutation and ALK overexpression testing with immunohistochemistry followed by ALK rearrangement confirmation with a fluorescence in situ hybridization assay for immunohistochemistry-positive results .
7 Three strategies were included : "Test-treat" approach , where molecularly guided therapy was initiated after obtainment of test results ; "Empiric switch therapy , " with concurrent initiation of CisPem and testing and immediate switch to test-result conditional treatment after one cycle of CisPem ; and "Empiric therapy" approach in which CisPem was continued for four cycles before start of a tyrosine kinase inhibitor .
8 RESULTS :
9 The incremental cost-effectiveness ratio for "Test-treat" compared with treatment with CisPem was $136,000 per quality-adjusted life year gained .
10   Both empiric treatment approaches had less favorable incremental cost-effectiveness ratios . "Test-treat" and "Empiric switch therapy" yielded higher expected outcomes in terms of quality-adjusted life years and life-years than "Empiric therapy." These results were robust across plausible ranges of model inputs .
11 CONCLUSION :
12   From a societal perspective , our cost-effectiveness results support the value of multiplexed genetic screening and molecularly guided therapy in metastatic NSCLC .



PMID: 26968814
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Determination of somatic oncogenic mutations linked to target-based therapies using MassARRAY technology .
1 Μ Somatic mutation analysis represents a useful tool in selecting personalized therapy .
2 The aim of our study was to determine the presence of common genetic events affecting actionable oncogenes using a MassARRAY technology in patients with advanced solid tumors who were potential candidates for target-based therapies .
3 The analysis of 238 mutations across 19 oncogenes was performed in 197 formalin-fixed paraffin-embedded samples of different tumors using the OncoCarta Panel v1.0 ( Sequenom Hamburg , Germany ) .
4 Of the 197 specimens , 97 ( 492% ) presented atleast one mutation .
5 Μ Forty-nine different oncogenic mutations in 16 genes were detected .
6 Μ Mutations in KRAS and PIK3CA were detected in 40/97 ( 412% ) and 30/97 ( 309% ) patients respectively .
7 Thirty-one patients ( 320% ) had mutations in two genes , 20 of them ( 645% ) initially diagnosed with colorectal cancer .
8 The co-occurrence of mutation involved mainly KRAS , PIK3CA , KIT and RET .
9 Mutation profiles were validated using a customized panel and the Junior Next-Generation Sequencing technology ( GS-Junior 454 , Roche ) .
10   Twenty-eight patients participated in early clinical trials or received specific treatments according to the molecular characterization ( 280% ) .
11   MassARRAY technology is a rapid and effective method for identifying key cancer-driving mutations across a large number of samples , which allows for a more appropriate selection for personalized therapies .



PMID: 26968810
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Quantification of a Pharmacodynamic ERK End Point in Melanoma Cell Lysates : Toward Personalized Precision Medicine .
1 Non-small cell lung cancer ( NSCLC ) is one of the most deadly cancers worldwide , with poor prognosis once the disease has progressed past the point at which surgery is a viable option .
2 Whilst chemotherapy has improved survival over recent decades , there is still great need for improvements in treatments for patients with advanced disease .
3 Over the last decade , a variety of such drugs have received market approval for treating NSCLC , with a variety of others in the pipeline .
4 Here , we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC , including those already in clinical practice and those in early trials .
5 The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC .
6 Moreover , the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug .
7 The recent approval of the immune checkpoint inhibitor nivolumab , along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA , demonstrates how rapidly this area of research is expanding .
8   Over the last decade there has been significant progress made in the treatment of advanced NSCLC , and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer .



PMID: 26963001
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Frequency and clinicopathologic profile of PIK3CA mutant GISTs : molecular genetic study of 529 cases .
1 Large-cell neuroendocrine carcinoma ( LCNEC ) of the lung is a high-grade carcinoma belonging to the neuroendocrine tumors of the lung and is different from typical lung large - cell carcinoma .
2 It represents about 3% of all pulmonary malignancies and is characterized by neuroendocrine cytologic features .
3 The treatment usually is platinum-based chemotherapy , however the outcome remains poor .
4 Therefore new therapeutic options are needed .
5 Tyrosine kinase inhibitors have demonstrated greater efficacy and better tolerability than standard chemotherapy in non-small - cell lung cancer harboring epidermal growth factor receptor ( EGFR ) mutations .
6 Μ EGFR gene mutations were also rarely identified in LCNEC .
7 ✓ We report a patient with lung LCNEC activating EGFR mutations who showed an impressive response to gefitinib . GM-ASS-RO



PMID: 26962170
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncologists' Selection of Genetic and Molecular Testing in the Evolving Landscape of Stage II Colorectal Cancer .
1 Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers .
2 We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase ( PI3K ) inhibition caused synergistic cell death .
3 Additional combinations that enhanced ERK inhibitor action were also identified .
4 Unexpectedly , long-term treatment of sensitive cell lines caused senescence , mediated in part by MYC degradation and p16 reactivation .
5 Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor , as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen .
6 Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK .



PMID: 26959890
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Suppression of B-Raf ( V600E ) cancers by MAPK hyper-activation .
1 B-Raf ( V600E ) activates MEK/MAPK signalling and acts as oncogenic driver of a variety of cancers , including melanoma , colorectal and papillary thyroid carcinoma .
2 Specific B-Raf ( V600E ) kinase inhibitors ( e.g. , Vemurafenib ) prove initial efficacy in melanoma followed shortly by acquired resistance , while failing in most other B-Raf ( V600E ) cancers due to primary resistance .
3 Resistance is due to acquired mutations in the Ras/Raf/MEK/MAPK pathway and/or other oncogenic drivers that bypass B-Raf ( V600E ) .
4 Surprisingly , hyper-activation of MAPK by inhibiting its protein phosphatase 2A by a synthetic long - chain fatty acid analogue (MEDICA) , results in oncogene -induced growth arrest and apoptosis of B-Raf ( V600E ) cancer cells .
5 Growth arrest is accompanied by MAPK -mediated serine/threonine phosphorylation and suppression of a variety of oncogenic drivers that resist treatment by B-Raf ( V600E ) kinase inhibitors , including ErbB members , c-Met , IGFR , IRS , STAT3 and Akt .
6 The combined activities of mutated B-Raf and MEDICA are required for generating hyper-activated MAPK , growth arrest and apoptosis , implying strict specificity for mutated B-Raf cancer cells .



PMID: 26959608
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Outcomes of chemotherapy in patients with EGFR mutation-negative non-small cell lung cancer ] .
1 ERK5 , encoded by MAPK7 , has been proposed to play a role in cell proliferation , thus attracting interest as a cancer therapeutic target .
2 While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway , ERK5 is directly activated by MEK5 .
3 It has been proposed that RAS and RAF proteins can also promote ERK5 activation .
4 Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models .
5 We demonstrate that although an inducible form of CRAF ( CRAF : ER* ) can activate ERK5 in fibroblasts , the response is delayed and reflects feed-forward signaling .
6 Additionally , oncogenic KRAS and BRAF do not activate ERK5 in epithelial cells .
7 Although KRAS and BRAF do not couple directly to MEK5-ERK5 , ERK5 signaling might still be permissive for proliferation .
8 However , neither the selective MEK5 inhibitor BIX02189 or ERK5 siRNA inhibited proliferation of colorectal cancer cells harbouring KRAS (G12C/G13D) or BRAF (V600E) .
9 Furthermore , there was no additive or synergistic effect observed when BIX02189 was combined with the MEK1/2 inhibitor Selumetinib (AZD6244) , suggesting that ERK5 was neither required for proliferation nor a driver of innate resistance to MEK1/2 inhibitors .
10 Finally , even cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA , showing that ERK5 amplification does not confer addiction to ERK5 for cell proliferation .
11 Thus ERK5 signaling is unlikely to play a role in tumor cell proliferation downstream of KRAS or BRAF or in tumor cells with ERK5 amplification .
12 These results have important implications for the role of ERK5 as an anti-cancer drug target .



PMID: 26957558
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA MIR21 ( miR-21 ) and PTGS2 Expression in Colorectal Cancer and Patient Survival .
1 PURPOSE :
2 Prostaglandin-endoperoxide synthase 2 ( PTGS2 , cyclooxygenase-2 ; a target of aspirin ) produces inflammatory mediator prostaglandin E2 ( PGE2 ) , and contributes to colorectal neoplasia development .
3 PTGS2-driven inflammatory responses can induce tumor expression of microRNA MIR21 ( miR-21 ) that can increase local PGE2 level by downregulating PGE2-metabolizing enzymes .
4 We hypothesized that the prognostic association of tumor MIR21 expression level in colorectal carcinoma might depend on inflammatory tumor microenvironment and be stronger in tumors expressing high-level PTGS2 .
5 EXPERIMENTAL DESIGN :
6 Utilizing 765 rectal and colon cancer specimens in the Nurses' Health Study and the Health Professionals Follow-up Study , we measured MIR21 expression by quantitative reverse transcription PCR , and PTGS2 expression by immunohistochemistry .
7 Cox proportional hazards regression model was used to assess statistical interaction between MIR21 and PTGS2 in colorectal cancer-specific survival analysis , controlling for potential confounders including microsatellite instability , CpG island methylator phenotype , LINE-1 methylation level , and KRAS , BRAF , and PIK3CA mutations .
8 RESULTS :
9 Tumor MIR21 expression level was associated with higher colorectal cancer-specific mortality ( Ptrend = 0029 ) , and there was a statistically significant interaction between MIR21 and PTGS2 ( Pinteraction = 00004 ) .
10 The association between MIR21 expression and colorectal cancer-specific mortality was statistically significant in PTGS2-high cancers ( multivariable hazard ratio of the highest vs. lowest quartile of MIR21 , 228 ; 95% confidence interval , 142-367 ; Ptrend = 00004 ) but not in PTGS2-absent/low cancers ( Ptrend = 022 ) .
11 CONCLUSIONS :
12 MIR21 expression level in colorectal carcinoma is associated with worse clinical outcome , and this association is stronger in carcinomas expressing high-level PTGS2 , suggesting complex roles of immunity and inflammation in tumor progression .
13 Clin Cancer Res ; 22 ( 15 ) ; 3841-8 .
14 (c) 2016 AACR .



PMID: 26955660
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel treatment approach prolonging survival in an uncommon metastatic primary bladder adenocarcinoma .
1 Transforming growth factor beta signaling overcomes dasatinib resistance in lung cancer .



PMID: 26952655
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer .
1 BACKGROUND :
2 An increase in thyroid cancers , predominantly papillary thyroid carcinoma ( PTC ) , has been recently reported in children .
3 METHODS :
4 The histopathology of 28 consecutive PTCs from the northeast United States was reviewed .
5 None of the patients ( ages 6-18 years ; 20 females , 8 males ) had significant exposure to radiation .
6 Nucleic acid from tumors was tested for genetic abnormalities ( n = 27 ) .
7 Negative results were reevaluated by targeted next-generation sequencing .
8 RESULTS :
9 Seven of 27 PTCs ( 26% ) had neurotrophic tyrosine kinase receptor ( NTRK ) fusion oncogenes ( NTRK type 3/ets variant 6 [NTRK3/ETV6] , n =5 ; NTRK3/unknown , n = 1 ; and NTRK type 1/translocated promoter region , nuclear basket protein [NTRK1/TPR] , n = 1 ) , including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe .
10 All 7 tumors had lymphatic invasion , and 5 had vascular invasion .
11 Six of 27 PTCs ( 22% ) had ret proto-oncogene ( RET ) fusions ( RET/PTC1 , n = 5 ; RET/PTC3 , n = 1 ) ; 2 tumors measured >2 cm and diffusely involved the thyroid , and 5 had lymphatic invasion , with vascular invasion in 2 .
12 Thirteen PTCs had the B-Raf proto-oncogene , serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 ( BRAF(V) ( 600E ) ) ( 13 of 27 tumors ; 48% ) , 11 measured <2 cm , and 6 had lymphatic invasion ( 46% ) , with vascular invasion in 3 .
13 Fusion oncogene tumors , compared with BRAF(V) (600E) PTCs , were associated with large size ( mean , 22 cm versus 15 cm , respectively ; P = 05 ) , solid and diffuse variants ( 11 of 13 versus 0 of 13 tumors , respectively ; P <001 ) , and lymphovascular invasion ( 12 of 13 versus 6 of 13 tumors , respectively ; P = 02 ) ; BRAF(V) (600E) PTCs were predominantly the classic variant ( 12 of 13 versus 1 of 13 tumors ) .
14 Two tumors metastasized to the lung , and both had fusion oncogenes ( NTRK1/TPR , n = 1 ; RET/PTC1 , n = 1 ) .
15 CONCLUSIONS :
16 Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population .
17 Μ The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation .



PMID: 26945839
(Cell)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 A Crosstalk Between K ras ( Kirsten Rat Sarcoma Viral Oncogene Homologue ) and Adherence Molecular Complex Leads to Disassociation of Cells -A Possible Contribution Towards Metastasis in Colorectal Cancer .
1 Constitutive activation of mutant K ras ( Kirsten rat sarcoma viral oncogene homologue ) and disassembly of E-cadherin-catenin complex ( E-cadherin , alpha-catenin , beta-catenin , and gamma-catenin ) play an important role in apoptosis , differentiation , and cell proliferation .
2 In this study , the expression pattern of K ras and E-cadherin-catenin complex has been evaluated in normal and mutant colorectal cancer cell lines with an object to determine its impact on disassociation of cells from one another .
3 We addressed the expression analysis of K ras with reference to its association with adherence molecules in two colorectal cancer cell lines , that is , Caco-2 ( wild type K ras served as a control ) and DLD1 ( heterozygous mutation at codon 13 ) at message level by qRT-PCR and translational level by western blotting .
4 Μ Compared to the control Caco-2 cell lines , the K ras in DLD1 cell lines showed slightly higher values while alpha-catenin showed a slight lower ( 13-folds ) , beta-catenin and E-cadherin showed significantly lower expression ( 42-fold decrease ) .
5 It can be inferred that a possible cross talk exists between K ras and adherent junction mediated signalling .
6 Mutation at codon 13 ( G to D ) leads to the overexpression of K ras and reduced expression of adherent junction complex resulting in metastasis .
7 J .
8 Cell .
9 Biochem. 117 : 2340-2345 , 2016 .
10 (c) 2016 Wiley Periodicals , Inc .



PMID: 26938486
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer .
1 High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer .



PMID: 26935861
(Patient)  
Terms: Phase I/II study
Sent# Symbols Sentence Mnemonics
0 Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate .
1 BACKGROUND :
2 Patients with neurofibromatosis type 1 ( NF1 ) suffer from cutaneous , neurological and intestinal complications due to the mutation of the neurofibromin gene and abnormal protein product .
3 Gastrointestinal stromal tumors ( GISTs ) are relatively rare primary tumors of the stomach and small intestine .
4 Patients with NF1 are prone to developing GISTs .
5 We present a case of recurrent gastrointestinal ( GI ) bleeding from multiple GISTs in a patient with NF1 .
6 CASE :
7 A 42 year-old male with NF1 presented with significant GI bleeding ; endoscopies failed to identify the source .
8 Multiple lesions involving the small bowel were seen on laparotomy ; he underwent reparative small bowel resection .
9 Pathology showed a well circumscribed spindle cell proliferation with minimal atypia and rare mitoses ; immunostaining was positive for CD117 (KIT) and CD34 ; KIT mutations in exons 9 , 11 , 13 and 17 were negative .
10 DISCUSSION :
11 Up to 25% of patients with NF1 develop GISTs with non-specific presentations ; however they may be a source of significant GI bleeding .
12 The pathology , course and molecular composition of these tumors are different from sporadic GISTs .
13 In NF1 , GISTs are usually multiple , located in the small bowel ( as opposed to the stomach as in sporadic cases ) and occur at a younger age .
14 Their clinical scenario is not unlike other hereditary tumor syndromes-multiple tumors with a 10-20% malignant potential .
15 NF1-associated GISTs almost uniformly do not exhibit gain-of-function activation of KIT or PDGFA ( pathogenesis is suggested to be from the loss of heterozygosity of the NF1 gene ) and are not likely to respond to imatinib .
16 Multiple means of localizing GISTs exist and capsule endoscopy should be recommended to all NF1 patients as it provides a non-invasive approach to localizing the tumors for further surgical management .



PMID: 26935130
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Primary tumor location is an important predictive factor for wild-type KRAS metastatic colon cancer treated with cetuximab as front - line bio-therapy .
1 INTRODUCTION :
2 Left - and right-sided colon cancers were significantly different in epidemiologic , clinical and histological parameters .
3 However , the impact of primary tumor location in metastatic colon cancer treated with front - line targeted triplet regimens is unclear , particularly in Asian populations .
4 METHODS :
5 A total of 121 patients with KRAS exon 2 codon 12/13 wild-type metastatic colon cancer were enrolled between January 2007 and December 2013 .
6 All patients received one target agent , such as cetuximab or bevacizumab , as a front - line targeted triplet regimen .
7 The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed , respectively .
8 RESULTS :
9 In cetuximab group , left-sided metastatic colon cancer was superior to right-sided metastatic colon cancer in objective response rate ( 701% versus 333% , P = 0024 ) , progression-free survival ( 150 versus 53 months , P <0001 ) and overall survival ( 358 versus 144 months , P = 0031 ) .
10 Primary tumor location was an independent prognostic factor for progression-free survival ( hazard ratio 0240 , 95% confidence interval 0114-0508 , P <0001 ) .
11 However , in the bevacizumab group , there were no differences in outcomes for either side .
12 Primary tumor location was insignificant for progression-free survival and overall survival in univariate analysis .
13 CONCLUSION :
14 Left-sided primary tumors were favored in cetuximab-based front - line targeted triplet regimen for metastatic colon cancer .



PMID: 26933125
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target .
1 PURPOSE :
2 Chromosomal translocations in the anaplastic lymphoma kinase ( ALK ) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors , recently including rare cases of colorectal carcinoma .
3 We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib .
4 Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort .
5 EXPERIMENTAL DESIGN :
6 Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling ( CGP ) or by ALK immunohistochemistry ( IHC ) were reviewed retrospectively .
7 FISH and microsatellite instability ( MSI ) analyses were performed .
8 RESULTS :
9 Nine colorectal carcinoma cases harbored ALK gene fusions .
10 Six cases were identified by CGP of 3,157 colorectal carcinoma ( 02% ) and three by IHC of 2,980 colorectal carcinoma ( 01% ) .
11 The ALK fusions involved known ALK partners EML4 , C2orf44 , CAD , and the novel STRN , PPP1R21 , SENPF , MAPRE3 , and PRKAP1B partners .
12 These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers , predominantly involved the proximal colon , and often exhibited MSI and mucinous phenotype .
13 The index patient was treated with the ALK inhibitor ceritinib , resulting in a marked decrease in size of a skin metastasis , and resolution by computerized tomography of all contrast enhancing tumor .
14 ✓ Μ After 9 months of treatment , biopsy of progressive disease demonstrated a KRAS mutation , consistent with acquired resistance to ceritinib . RO-ASS-GM
15 CONCLUSIONS :
16 Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features .
17   This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors .
18 Clin Cancer Res ; 22 ( 15 ) ; 3831-40 .
19 (c) 2016 AACR .



PMID: 26927802
(None)  
Terms: this review, rat
Sent# Symbols Sentence Mnemonics
0 Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis .
1 Colorectal cancer ( CRC ) is one of the leading causes of cancer-related mortality worldwide .
2 In the past 2 decades , advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC .
3 The advent of targeted therapy , coupled with more efficient chemotherapy regimens , was the pillar achievement that contributed to the success of CRC therapy .
4 Cetuximab and panitumumab , monoclonal antibodies targeting the epidermal growth factor receptor pathway , are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker , the rat Kristen Sarcoma viral oncogene ( KRAS ) .
5   More recently , another biomarker , the rat neuroblastoma sarcoma viral oncogene ( NRAS ) , was found to be as valuable for the refinement of this targeted therapy .
6   The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy .



PMID: 26925673
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Impact of Cellular Genetic Make-up on Colorectal Cancer Cell Lines Response to Ellagic Acid : Implications of Small Interfering RNA .
1 BACKGROUND :
2 K-Ras activation is an early event in colorectal carcinogenesis and associated mutations have been reported in about 40% of colorectal cancer patients .
3 These mutations have always been responsible for enhancing malignancy and silencing them is associated with attenuation of tumorigenicity .
4 Among downstream effectors are the RAF/MEK/ERK and the PI3K/Akt signaling pathways .
5 PI3K/Akt signaling leads to reduction of apoptosis , stimulated cell growth and enhanced proliferation .
6 Ellagic acid ( EA ) , a naturally occurring antioxidant , has recently emerged as a promising anti-cancer agent .
7 PURPOSE :
8 To evaluate the impact of cellular genetic make - up of two colon cancer cell lines with different genetic backgrounds , HCT-116 ( K-Ras-/p53+ ) and Caco-2 ( K-Ras+/ p53 - ) , on response to potential anti-tumour effects of EA .
9 In addition , the influence of K-Ras silencing in HCT - 116 cells was investigated .
10 MATERIALS AND METHODS :
11 Cellular proliferation , morphology and cell cycle analysis were carried out in addition to Western blotting for detecting total Akt and p-Akt ( at Thr308 and Ser473 ) in the presence and absence of different concentrations of EA .
12 Cell proliferation was also assessed in cells transfected with different concentrations of K-Ras siRNA or incubated with ellagic acid following transfection .
13 RESULTS :
14 The results of the present study revealed that EA exerts anti-proliferative and dose -dependent pro-apoptotic effects .
15 Cytostatic and cytotoxic effects were also observed .
16 p-Akt ( at Thr308 and Ser473 ) was downregulated .
17 Μ Moreover , EA treatment was found to (i) reduce K-Ras protein expression ; ( ii ) in cells transfected with siRNA and co-treated with EA , pronounced anti-proliferative effects as well as depletion of p-Akt ( at Thr308 ) were detected .
18 CONCLUSIONS :
19   Cellular genetic makeup ( K-Ras-/p53 - ) was not likely to impose limitations on targeting EA in treatment of colon cancer .
20 EA had a multi-disciplinary pro-apoptotic anti-proliferative approach , having inhibited Akt phosphorylation , induced cell cycle arrest and showed an anti-proliferative potential in HCT-116 cells ( expressing mutant K-Ras ) .



PMID: 26925650
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutation Analysis of KRAS and BRAF Genes in Metastatic Colorectal Cancer : a First Large Scale Study from Iran .
1 BACKGROUND :
2 The investigation of mutation patterns in oncogenes potentially can make available a reliable mechanism for management and treatment decisions for patients with colorectal cancer ( CRC ) .
3 This study concerns the rate of KRAS and BRAF genes mutations in Iranian metastatic colorectal cancer ( mCRC ) patients , as well as associations of genotypes with clinicopathological features .
4 MATERIALS AND METHODS :
5 A total of 1,000 mCRC specimens collected from 2008 to 2012 that referred to the Mehr Hospital and Partolab center , Tehran , Iran enrolled in this cross sectional study .
6 Using HRM , Dxs Therascreen and Pyrosequencing methods , we analyzed the mutational status of KRAS and BRAF genes in these .
7 RESULTS :
8 KRAS mutations were present in 33.6% cases ( n = 336 ) .
9 Of KRAS mutation positive cases , 85.1% were in codon 12 and 14.9% were in codon 13 .
10 The most frequent mutation at KRAS codon 12 was Gly12Asp ; BRAF mutations were not found in any mCRC patients ( n = 242 ) .
11 Μ In addition , we observed a strong correlation of KRAS mutations with some clinicopathological characteristics .
12 CONCLUSIONS :
13 KRAS mutations are frequent in mCRCs while presence of BRAF mutations in these patients is rare .
14 Moreover , associations of KRAS genotypes with non-mucinous adenocarcinoma and depth of invasion ( pT3 ) were remarkable .



PMID: 26925640
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Value of KRAS , BRAF , and PIK3CA Mutations and Survival Benefit from Systemic Chemotherapy in Colorectal Peritoneal Carcinomatosis .
1 BACKGROUND :
2 It is well known that peritoneal carcinomatosis ( PC ) from colorectal cancer ( CRC ) is associated with a poor prognosis .
3 However , data on the prognostic significance of modern chemotherapy containing bevacizumab , cetuximab or panitumumab are not available .
4 MATERIALS AND METHODS :
5 This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC , and were treated with systemic chemotherapy , with or without bevacizumab or anti-EGFR antibodies .
6 The genetic background , in particular KRAS , BRAF , and PIK3CA gene mutations , and overall survival ( OS ) were compared between the two groups .
7 RESULTS :
8 ✓ The median OS values were 23.3 and 29.1 months for PC and non-PC patients , respectively ( hazard ratio [HR] =1.20 ; p = 0.17 ) . GE-ASS-RO
9 ✓ Among all patients , tumor location , number of metastatic sites and BRAF mutation status were significant prognostic factors , whereas the presence of PC was not . GM-MRK-RO
10 In the PC group , chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab ( HR = 038 , p<001 ) , but this was not the case in the non-PC group ( HR = 080 , p = 010 ) .
11 Furthermore , the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients ( 277% versus 73% , p<001 ) .
12 ✓ BRAF mutations displayed a strong correlation with shorter OS in non-PC ( HR = 226 ) , but not PC patients ( HR = 104 ) . GM-ASS-RO
13 CONCLUSIONS :
14   Systemic chemotherapy , especially when combined with bevacizumab , improved survival in patients with PC from CRC as well as non-PC patients .
15 Μ While BRAF mutation demonstrated a high frequency in PC patients , but it was not associated with prognosis .



PMID: 26922358
(None)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Stool Investigations for Colorectal Cancer Screening : From Occult Blood Test to DNA Analysis .
1 PURPOSE :
2 We report an update of current methods for colorectal cancer ( CRC ) screening based on fecal sample analysis .
3 METHODS :
4 A systematic review of the literature was performed in MEDLINE , EMBASE , and Science Direct electronic databases .
5 RESULTS :
6 Blood in the stools is the first and most used strategy .
7 Fecal occult blood test ( FOBT ) and fecal immunochemical test ( FIT ) are the main methods .
8 Both are economic , easy to perform with high specificity , and low sensitivity .
9 Μ Based on CRC multi-step process with genetic and epigenetic alterations in large bowel cell DNA , single mutations or panels of alterations have been detected .
10 These tests have the advantage of a marked improvement of the sensitivity when compared to fecal blood .
11 However , high costs , poor availability , and correct choice of marker panel represent the major limits .
12 A specific sDNA panel including aberrantly methylated BMP3 and NDRG4 promoter regions , mutant k-ras and beta-actin ( a reference gene for human DNA quantity ) , and an immunochemical assay for human hemoglobin has been recently approved by Food and Drug Administration .
13 Μ Novel promising biomarkers for CRC screening are represented by microRNAs ( miRNAs ) , a group of 18-25 nucleotide non-coding RNA molecules that regulate gene expression .
14 Reports on these fecal biomarkers are case-control studies , and each of them evaluates single miRNAs or multi-target panels .
15 On the other hand , some fecal proteins have been studied as possible CRC screening markers , even though they demonstrated poor results .
16 Finally , alterations of estrogen receptor -beta ( i.e. , dramatic reduction in the early stage of CRC ) have been demonstrated in tissue samples .
17 CONCLUSIONS :
18 Specific investigations are warranted in order to add further noninvasive markers to the panel of CRC screening tools .



PMID: 26917275
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Genotyping of colorectal cancer for cancer precision medicine : Results from the IPH Center for Molecular Pathology .
1 Cancer precision medicine has opened up new avenues for the treatment of colorectal cancer ( CRC ) .
2 To fully realize its potential , high-throughput sequencing platforms that allow genotyping beyond KRAS need to be implemented and require performance assessment .
3 We comprehensively analyzed first-year data of 202 consecutive formalin-fixed paraffin embedded ( FFPE ) CRC samples for which prospective genotyping at our institution was requested .
4 Deep targeted genotyping was done using a semiconductor-based sequencing platform and a self-designed panel of 30 CRC-related genes .
5 Additionally , microsatellite status ( MS ) was determined .
6 Ninety-seven percent of tumor samples were suitable for sequencing and in 88% MS could be assessed .
7 The minimal drop-out rates of 6 and 25 cases , respectively were due to too low amounts or heavy degradation of DNA .
8 Of 557 nonsynonymous mutations , 90 ( 16% ) have not been described in COSMIC at the time of data query .
9 Forty-three cases ( 22% ) had double - or triple mutations affecting a single gene .
10 Sixty-four percent had genetic alterations influencing oncological therapy .
11 Eight percent of patients ( MSI phenotype : 6% ; mutated POLE : 2% ) were potentially eligible for treatment with immune checkpoint inhibitors .
12 Of 56% of KRASwt CRC that potentially qualified for anti-EGFR treatment , 30% presented with mutations in BRAF/NRAS .
13 Μ Mutated PIK3CA was detected in 21% .
14 In conclusion , we here present real-life routine diagnostics data that not only demonstrate the robustness and feasibility of deep targeted sequencing and MS-analysis of FFPE CRC samples but also contribute to the understanding of CRC genetics .
15   Most importantly , in more than half of the patients our approach enabled the selection of the best treatment currently available .
16 (c) 2016 Wiley Periodicals , Inc .



PMID: 26916220
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer : A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies .
1 Although fibroblast growth factor ( FGF ) signals are strongly associated with malignancy , limited information is available regarding the role of the FGF9 signal in colorectal cancer ( CRC ) .
2 In this study , we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies .
3 In clinical samples , an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 ( 55% ) and tended to be related to wild-type KRAS ( 7/96 , 73% ) .
4 Μ Furthermore , FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS , and two samples from non-responders also had high FGF9 mRNA expression levels .
5 FGF9 amplification was validated using a fluorescence in situ hybridization ( FISH ) analysis , and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry .
6 In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines , FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal , and this resistance was cancelled by the application of an FGFR inhibitor .
7   Considering these results , the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC , and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor .
8   These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation .
9 (c) 2016 Wiley Periodicals , Inc .



PMID: 26915040
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin .
1 A review of the literature finds that women diagnosed with breast cancer , who were on an aspirin regimen , experienced a decreased risk of distant metastases and death .
2 Μ Several recent studies have reported an improvement in overall survival in colorectal cancer patients who harbored mutations in the oncogene PIK3CA and received a daily aspirin regimen .
3 Breast cancer patients on a daily aspirin regimen experienced decreased risk of distant metastases and death .
4 Μ PIK3CA is the most frequently mutated oncogene in breast cancer , occurring in up to 45 % of all breast cancers .
5 ✓ Μ In order to determine if mutations in PIK3CA sensitized breast cancers to aspirin treatment , we employed the use of isogenic cellular clones of the non-tumorigenic , breast epithelial cell line MCF-10A that harbored mutations in either PIK3CA or KRAS or both .
6 ✓ We report that mutations in both PIK3CA and KRAS are required for the greatest aspirin sensitivity in breast cancer , and that the GSK3beta protein was hyperphosphorylated in aspirin-treated double knockin cells , but not in other clones/treatments .
7 A more modest effect was observed with single mutant PIK3CA , but not KRAS alone .
8 These observations were further confirmed in a panel of breast cancer cell lines .
9 Our findings provide the first evidence that mutations in PIK3CA sensitize breast cancer cells to aspirin .



PMID: 26912804
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 GeneGazer : A Toolkit Integrating Two Pipelines for Personalized Profiling and Biosignature Identification .
1 BACKGROUND :
2 Next-generation sequencing provides useful information about gene mutations , gene expression , epigenetic modification , microRNA expression , and copy number variations .
3 More and more computing tools have been developed to analyze this large quantity of information .
4 However , to test and find suitable analytical tools and integrate their results is tedious and challenging for users with little bioinformatics training .
5 In the present study , we assembled the computing tools into a convenient toolkit to simplify the analysis and integration of data between bioinformatics tools .
6 MATERIALS AND METHODS :
7 The toolkit , GeneGazer , comprises of two parts : the first , named Gaze Profiler , was designed for personalized molecular profiling from next-generation sequencing data of paired samples ; the other , named Gaze BioSigner , was designed for the discovery of disease-associated biosignatures from expressional and mutational profiles of a cohort study .
8 RESULTS :
9 To demonstrate the capabilities of Gaze Profiler , we analyzed a pair ( colon cancer and adjacent normal tissues ) of RNA-sequencing data from one patient downloaded from the Sequencing Read Archive database and used them to profile somatic mutations and digital gene expression .
10 Μ In this case , alterations in the RAS/RAF/MEK/ERK signaling pathway ( activated by KRAS G13D mutation ) and canonical WNT signaling pathway ( activated by truncated APC ) were identified ; no EGFR mutation or overexpression was found .
11 These data suggested a limited efficacy of cetuximab in the patient .
12 To demonstrate the ability of Gazer BioSigner , we analyzed gene -expression data from 192 cancer tissues downloaded from The Cancer Genome Atlas and found that the activation of cAMP/PKA signaling , OCT-3/4 and SRF were associated with colon cancer progression and could be potential therapeutic targets .
13 CONCLUSION :
14 GeneGazer is a reliable and robust toolkit for the analysis of data from high-throughput platforms and has potential for clinical application and biomedical research .



PMID: 26911408
(None)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 TEMHEAD : a single-arm multicentre phase II study of temsirolimus in platin - and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck ( SCCHN ) of the German SCCHN Group (AIO) .
1 BACKGROUND :
2 Pancreatic cancer remains one of the most difficult cancers to treat with the poorest prognosis .
3 The key to improving survival rates in this disease is early detection and monitoring of disseminated and residual disease .
4 However , this is hindered due to lack reliable diagnostic and predictive markers which mean that the majority of patients succumb to their condition within a few months .
5 METHODS :
6 We present a pilot study of the detection circulating free DNA ( cfDNA ) combined with tumor specific mutation detection by digital PCR as a novel minimally invasive biomarker in pancreatic ductal adenocarcinoma ( PDAC ) .
7 This was compared to the detection of CTC by the CellSearch(R) system and a novel CTC enrichment strategy based on CD45 positive cell depletion .
8 The aim of the study was to assess tumor specific DNA detection in plasma and CTC detection as prognostic markers in PDAC .
9 RESULTS :
10 We detected KRAS mutant cfDNA in 26% of patients of all stages and this correlated strongly with Overall Survival ( OS ) , 60 days ( 95% CI : 19-317 ) for KRAS mutation positive versus 772 days for KRAS mutation negative ( 95% CI : 416-1127 ) .
11 Μ Although , the presence of CTC detected by the CellSearch(R) system did correlate significantly with OS , 88 days ( 95% CI : 27-206 ) CTC positive versus 393 days CTC negative ( 95% CI : 284-501 ) , CTC were detected in only 20% of patients , the majority of which had metastatic disease , whereas KRAS mutant cfDNA was detected in patients with both resectable and advanced disease .
12 CONCLUSIONS :
13 Tumor specific cfDNA detection and CTC detection are promising markers for the management of patients with PDAC , although there is a need to validate these results in a larger patient cohort and optimize the detection of CTC in PDAC by applying the appropriate markers for their detection .



PMID: 26910894
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic distribution of KRAS and BRAF mutations in a Chinese population with colorectal cancer precursor lesions .
1 Investigating the clinical features and corresponding histomorphologic and molecular profiles of precursor lesions of colorectal cancer in a natural population provides new insights into the nature of colorectal cancer , uncovers new screening markers and establishes new prevention strategies for colorectal cancer .
2 Μ In this study , 4302 patients with atleast one colorectal polyp from a large colorectal cancer screening program were evaluated and genetic mutations in either KRAS or BRAF were detected in 495 patients .
3 The population-based mutation rates of KRAS and BRAF genes in colorectal polyps within this Chinese patient population were 21.8% and 12.1% respectively .
4 Μ Interestingly , considerable variability in the KRAS and BRAF mutations rates were found among different types of polyps .
5 In a multivariate analysis , presence of villous histology and high-grade dysplasia was associated with KRAS mutations ( OR , 30 ; 95% CI , 17-54 and OR , 35 ; 95% CI 19-65 , respectively ) , while serrated adenomas and hyperplastic polyps were associated with BRAF V600E mutations ( OR , 206 ; 95% CI , 82-518 and OR , 119 ; 95% CI 49-290 , respectively ) .
6 KRAS mutations may , in part , drive the histologic progression of adenomas toward a villous histology and higher grades of dysplasia .
7 Mutant BRAF may , in part , drive the histologic progression of adenomas toward serrated histology .
8 Dysplasia may arise from hyperplastic polyps , resulting in the formation of serrated adenomas and potentially the development of colorectal carcinoma .



PMID: 26909603
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Molecular characterization of colorectal cancer patients and concomitant patient-derived tumor cell establishment .
1 BACKGROUND :
2 We aimed to establish a prospectively enrolled colorectal cancer ( CRC ) cohort for targeted sequencing of primary tumors from CRC patients .
3 In parallel , we established collateral PDC models from the matched primary tumor tissues , which may be later used as preclinical models for genome -directed targeted therapy experiments .
4 RESULTS :
5 In all , we identified 27 SNVs in the 6 genes such as PIK3CA ( N = 16 ) , BRAF ( N = 6 ) , NRAS ( N = 2 ) , and CTNNB1 ( N = 1 ) , PTEN ( N = 1 ) , and ERBB2 ( N = 1 ) .
6 RET-NCOA4 translocation was observed in one out of 105 patients ( 09% ) .
7 PDC models were successfully established from 62 ( 554% ) of the 112 samples .
8 To confirm the genomic features of various tumor cells , we compared variant allele frequency results of the primary tumor and progeny PDCs .
9 The Pearson correlation coefficient between the variants from primary tumor cells and PDCs was 0.881 .
10 METHODS :
11 Between April 2014 and June 2015 , 112 patients with CRC who underwent resection of the primary tumor were enrolled in the SMC Oncology Biomarker study .
12 The PDC culture protocol was performed for all eligible patients .
13 All of the primary tumors from the 112 patients who provided written informed consent were genomically sequenced with targeted sequencing .
14 In parallel , PDC establishment was attempted for all sequenced tumors .
15 CONCLUSIONS :
16 We have prospectively sequenced a CRC cohort of 105 patients and successfully established 62 PDC in parallel .
17 Each genomically characterized PDCs can be used as a preclinical model especially in rare genomic alteration event .



PMID: 26909137
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of antibody -dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients .
1 The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma ( PDAC ) and other cancers .
2 However , the control of Nrf2 expression and activity in cancer is not fully understood .
3 We previously reported the absence of Keap1 , a pivotal regulator of Nrf2 , in approximately 70% of PDAC cases .
4 Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels .
5 Μ UHRF1 expression was observed in 20% ( 5 of 25 ) of benign pancreatic ducts compared to 86% ( 114 of 132 ) of pancreatic tumours , and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours ( n = 124 ) was apparent ( p = 0002 ) .
6 We also provide evidence that UHRF1 -mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC .
7 Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest .
8 UHRF1 depletion also led to reduced levels of Nrf2 -regulated downstream proteins and was accompanied by heightened oxidative stress , in the form of lower glutathione levels and increased reactive oxygen species .
9 Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species .
10 Mechanistically , depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines , and KEAP1 gene promoter methylation was reduced in one of three cell lines examined .
11 Thus , methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1 , although our data suggest that additional mechanisms need to be explored .
12 Finally , we demonstrate that K-Ras drives UHRF1 expression , establishing a novel link between this oncogene and Nrf2 -mediated cellular protection .
13 Since UHRF1 over-expression occurs in other cancers , its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers .



PMID: 26902020
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Primary Tumor Resection Offers Higher Survival Advantage in KRAS Mutant Metastatic Colorectal Cancer Patients .
1 Racial diversity of actionable mutations in non-small cell lung cancer .



PMID: 26898652
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sessile Serrated Polyps are Precursors of Colon Carcinomas With Deficient DNA Mismatch Repair .
1 We investigated whether sessile serrated adenomas/polyps ( SSA/Ps ) are direct precursors of colorectal carcinomas .
2 We identified colon carcinomas that arose from SSA/Ps among 2646 colorectal cancers included in the surgical pathology database at the Mayo Clinic ( 2006-2012 ) .
3 Molecular features of the serrated neoplasia pathway were analyzed in these tumors by immunohistochemical analyses of mutant BRAF (V600E) and MLH1 proteins .
4 Among the 33 identified SSA/P-associated colonic adenocarcinomas ( median patient age , 75 y ) , 24 developed in women ( 73% ) , 31 were located in the proximal colon ( 94% ) , and 23 ( 69% ) were TNM stage I or II .
5 Thirty-one of the tumors ( 94% ) expressed mutant BRAF ; of these , 26 also had loss of MLH1 ( 79% ) , indicating deficient DNA mismatch repair of sporadic origin .
6 Twenty-two of the tumors ( 67% ) were interval cancers that were more common in women and did not differ significantly in TNM stage , BRAF mutation , or loss of MLH1 .
7 By histopathology , SSA/Ps that were associated with colon carcinomas contained frequent dysplasia ( 48% ) .
8 Most cancers that arose from SSA/Ps were located on the right side of the colon and had mutant BRAF and loss of MLH1 .
9 These findings indicate that SSA/Ps are precursors of most sporadic colon carcinomas with deficient DNA mismatch repair .



PMID: 26897942
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Significance of Combined Measurement of p53 Antibody and other Tumor Markers for Colorectal Cancer after Curative Resection .
1 BACKGROUND/AIMS :
2 Though serum p53 antibody has been widely used , it is mentioned that it is not related to clinical parameters of colorectal cancer ( CRC ) and has no prognostic significance in long-term follow-up.The aim of this study was to explore the possibility to increase the value of p53 antibody in combination with carcinoembryonic antigen ( CEA ) and CA19-9 for post operation follow up .
3 METHODOLOGY :
4 One hundred twenty-eight patients with primary CRC who underwent surgery were enrolled in this study .
5 Serum p53 antibodies , CEA and CA19-9 were measured before and after the surgery and their impact on CRC staging patient survival .
6 Μ DNA was extracted from colorectal cancer tissue and KRAS mutation analysis was determined by direct sequencing .
7 RESULTS :
8 Thirty seven point five patients were positive for serum p53 antibodies before the operation .
9 Total 67.2% patients were positive with any tumor markers , but it was only 3.9% that were positive with all markers .
10 There was no association between KRAS mutation and p53 antibody level .
11 CONCLUSIONS :
12 The combined use of tumor markers can be an effective screening method for detection of colorectal cancer .



PMID: 26893723
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Association between the expression levels of TAZ , AXL and CTGF and clinicopathological parameters in patients with colon cancer .
1 Colon cancer accounts for a large proportion of all the cancer-associated morbidities worldwide .
2 Genetic analysis and stratification of patients based on survival may identify genetic signatures potentially useful for prognostic or treatment planning purposes .
3 Previous studies have reported that the messenger (m) RNA expression levels of tafazzin ( TAZ ) , AXL receptor tyrosine kinase ( AXL ) and connective tissue growth factor ( CTGF ) were able to predict the survival of patients with colon cancer in two independent colon cancer datasets .
4 However , limited clinicopathological data were available from these two datasets .
5 By contrast , a large colon cancer dataset comprising 566 patients has been recently published in the Gene Expression Omnibus database , which contains data regarding tumor stage and location , and genetic status of mismatch repair ( MMR ) , rat Kirsten sarcoma viral oncogene homolog ( KRAS ) , B-Raf proto - oncogene serine/threonine kinase (BRAF) and tumor protein p53 ( TP53 ) .
6 In the present study , the mRNA expression levels of TAZ , AXL and CTGF were evaluated , and the TAZ-AXL-CTGF signature was correlated with the available pathological parameters and survival data .
7 Overexpression of TAZ , AXL and CTGF was observed to be associated with severe pathological stage , deficiency in MMR , colon cancer subtype C4 and mutations in the BRAF gene .
8 In addition , overexpression of TAZ-AXL-CTGF was associated with short overall survival in patients with mutations in the TP53 gene , colon cancer subtype C6 , proficient MMR and wild-type status of the KRAS and BRAF genes .
9 Μ Furthermore , the prognostic value of TAZ-AXL-CTGF overexpression was observed to be independent of all the clinicopathological parameters and mutational statuses analyzed .
10 The results of the present study confirm the previously reported findings , and suggest that the TAZ-AXL-CTGF mRNA signature is a potential prognostic indicator in colon cancer .



PMID: 26893603
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Early onset of colorectal cancer in a 13-year-old girl with Lynch syndrome .
1 Lynch syndrome is the most common inherited colon cancer syndrome .
2 Patients with Lynch syndrome develop a range of cancers including colorectal cancer ( CRC ) and carry a mutation on one of the mismatched repair ( MMR ) genes .
3 Although CRC usually occurs after the fourth decade in patients with Lynch syndrome harboring a heterozygous MMR gene mutation , it can occur in children with Lynch syndrome who have a compound heterozygous or homozygous MMR gene mutation .
4 We report a case of CRC in a 13-year-old patient with Lynch syndrome and congenital heart disease .
5 This patient had a heterozygous mutation in MLH1 ( an MMR gene ) , but no compound MMR gene defects , and a K-RAS somatic mutation in the cancer cells .



PMID: 26892442
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma .
1 Μ Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor ( EGFR ) chemotherapy in colorectal cancer .
2 But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas .
3 In this work , the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables , including survival of the patients , was analyzed .
4 Μ KRAS or BRAF mutations were observed in 63 ( 33% ) cases .
5 Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive .
6 The majority of KRAS mutations were G>A transition ( 43/61 cases , 71% ) or p.G12D ( 31/61 cases , 51% ) .
7 ✓ The patients with mutant KRAS tended to have higher pT classifications ( P = 0034 ) and more frequent pancreatic invasion ( P = 0020 ) than those with wild-type KRAS . RO-ASS-GM
8 Μ Multivariate logistic regression analysis showed that certain mutated KRAS subtypes ( G>A transitions and G12D mutations ) were significantly correlated with higher pT classification ( P = 0015 and 0004 , respectively ) than wild-type KRAS and other KRAS mutations .
9 ✓ Μ The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF ( P = 0148 ) , but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival ( median , 460 months ; P = 0046 ) than those with wild-type KRAS ( 854 months ) in lower pT classification ( pT1-pT3 ) group . GM-ASS-RO, RO-ASS-GM
10 ✓ Μ In summary , KRAS and , infrequently , BRAF mutations are observed in a subset of small intestinal adenocarcinomas , and are associated with higher pT classification and more frequent pancreatic invasion . GM-ASS-RO
11 KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors .
12   Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients , namely those with wild-type KRAS and BRAF if they have metastatic disease , similar to colorectal cancer patients .



PMID: 26891420
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A randomized , placebo-controlled , phase 1/2 study of tivantinib ( ARQ 197 ) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first - line systemic therapy .
1 In an era of personalized medicine , an increased effort is being made to identify patients likely to benefit from targeted therapy .
2 By limiting treatment to selected patients , both unnecessary cost and toxicity may be avoided .
3 Restricting the use of anti-epidermal growth factor receptor ( anti-EGFR )- targeted agents in metastatic colorectal cancer to only patients with KRAS exon 2 wild-type tumors has become well-established in clinical practice .
4 However , lack of KRAS exon 2 mutations does not necessarily predict response , and a significant proportion of patients with KRAS wild-type tumors do not benefit from therapy with cetuximab or panitumumab .
5 Further characterization is needed of the subset of patients with KRAS exon 2 wild-type tumors who are likely to benefit from anti-EGFR therapy .
6   Recent data suggest that patients with KRAS mutations at loci other than exon 2 , and those with other RAS mutations , might not benefit from EGFR -directed therapy .
7 This article briefly reviews established work on KRAS exon 2 mutations , but focuses primarily on emerging data on non-exon 2 KRAS mutations and additional RAS and BRAF mutations and how this information may impact clinical decision-making .



PMID: 26887348
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 ✓ The impact of KRAS mutations on prognosis in surgically resected colorectal cancer patients with liver and lung metastases : a retrospective analysis . GM-ASS-RO
1 BACKGROUND :
2 KRAS mutations are common in colorectal cancer ( CRC ) .
3 The role of KRAS mutation status as a prognostic factor remains controversial , and most large population-based cohorts usually consist of patients with non-metastatic CRC .
4 We evaluated the impact of KRAS mutations on the time to recurrence ( TTR ) and overall survival ( OS ) in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy .
5 METHODS :
6 Patients who underwent curative resection for primary and synchronous metastases were retrospectively collected in a single institution during a 6 year period between January 2008 and June 2014 .
7 Patients with positive surgical margins , those with known BRAF mutation , or those with an unknown KRAS mutation status were excluded , and a total of 82 cases were identified .
8 The pathological and clinical features were evaluated .
9 Patients' outcome with KRAS mutation status for TTR and OS were investigated by univariate and multivariate analysis .
10 RESULTS :
11 Μ KRAS mutations were identified in 37.8% of the patients and not associated with TTR or OS between KRAS wild type and KRAS mutation cohorts ( log-rank p = 0425 for TTR ; log-rank p = 0137 for OS ) .
12 When patients were further subdivided into three groups according to mutation subtype ( wild-type vs . KRAS codon 12 mutation vs . KRAS codon 13 mutation ) or amino acid missense mutation type ( G >A vs. G >T vs. G >C ) , there were no significant differences in TTR or OS .
13 Mutational frequencies were significantly higher in patients with lung metastases compared with those with liver and ovary/bladder metastases ( p = 0039 ) , however , KRAS mutation status was not associated with an increased risk of relapsed in the lung .
14 CONCLUSIONS :
15 ✓ KRAS mutation was not associated with TTR or OS in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy . GM-ASS-RO



PMID: 26883113
(None)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 Clinical trials for lung cancer in China .
1 The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma ( CRC ) with the CpG island methylator phenotype ( CIMP ) .
2 Here , we investigated the differential characteristics of CIMP-high ( CIMP-H ) CRCs according to MLH1 methylation status .
3 To further confirm the MLH1 -dependent features in CIMP-H CRC , an independent analysis was performed using data from The Cancer Genome Atlas ( TCGA ) .
4 In our CIMP-H CRC samples , MLH1-methylated tumors were characterized by older patient age , proximal colonic location , mucinous histology , intense lymphoid reactions , RUNX3/SOCS1 promoter methylation , BRAF mutations , and microsatellite instability-high ( MSI-H ) status .
5 By contrast , MLH1-unmethylated tumors were associated with earlier age of onset , increased distal colorectal localization , adverse pathologic features , and KRAS mutations .
6 Μ In the TCGA dataset , the MLH1-silenced CIMP-H CRC demonstrated proximal location , MSI-H status , hypermutated phenotype , and frequent BRAF mutations , but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations .
7 In conclusion , the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status .
8 Based on the current knowledge , the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs , whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps .



PMID: 26880400
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors .
1 Μ In this report , point mutations of the K-ras gene at codon 146 were analyzed in 25 cases of colon cancer , 4 cases of lung cancer , and 41 cases of lymphoid malignancy .
2 Μ A codon 146 mutation substituting threonine (ACA) for alanine (GCA) was detected in the tumor tissue of a patient with colon cancer and was not detected in the normal tissue of the same patient .
3 Μ Any additional mutations of the ras gene family were not detected in this patient .
4 These results suggest that the codon 146 mutation of the K-ras gene could be involved in the development of naturally occurring human malignancies .



PMID: 26873344
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 K-Ras4B/calmodulin/PI3Kalpha : A promising new adenocarcinoma-specific drug target ?
1 INTRODUCTION :
2 Decades of efforts have yet to yield a safe and effective drug to target KRAS-driven pancreatic , colorectal and lung cancers ; particularly those driven by the highly oncogenic splice variant KRAS4B .
3 K-Ras4B 's fairly smooth surface , cancer tissue/cell heterogeneity , tolerated lipid post-translational modification exchange , as well as drug -elicited toxicity present a daunting challenge .
4 AREAS COVERED :
5 Within this framework , hee we focus on a new adenocarcinoma-specific drug concept .
6 Calmodulin ( CaM ) binds to K-Ras4B but not to the H-Ras or N-Ras isoforms .
7 Physiologically , in calcium - and calmodulin-rich environments such as ductal tissues , calmodulin can sequester K-Ras4B from the membrane ; in cancer , CaM/Ca(2+) can replace the missing receptor tyrosine kinase ( RTK ) signal , acting to fully activate PI3Kalpha .
8 EXPERT OPINION :
9 An oncogenic GTP-bound K-Ras4B/CaM/PI3Kalpha complex is supported by available experimental and clinical data ; therefore , targeting it may address a pressing therapeutic need .
10 High resolution electron microscopy ( EM ) or crystal structure of the tripartite complex would allow orthosteric or allosteric drug discovery to disrupt the CaM/PI3Kalpha interface and thus Akt/mTOR signaling .
11 However , since drug resistance is expected to develop , combining it with compensatory pathways , particularly those involved in cell -cycle control , appears a reasonable strategy .



PMID: 26872400
(None)  
Terms: Meta-analysis
Sent# Symbols Sentence Mnemonics
0 Meta-analysis of intentional sublobar resections versus lobectomy for early stage non-small cell lung cancer .
1 Colorectal cancer ( CRC ) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression .
2 Large variation exists in individual patient prognosis and response to chemotherapy , caused by molecular heterogeneity .
3 Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging , and inform treatment selection .
4 Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy , and is advocated for prognostic stratification .
5 Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up.Classifiers of CRC have been developed that integrate genetic and/or epigenetic features .
6 Μ The mutational status of KRAS and BRAF (V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype ( CIMP ) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses .
7 Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing .
8 A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes .
9 Efforts to validate and refine these subtypes to include additional genomic features are ongoing .
10 The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC .



PMID: 26871294
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway .
1 Polycomb group protein enhancer of zeste homolog 2 ( EZH2 ) is a methyltransferase that correlates with the regulation of invasion and metastasis and is overexpressed in human cancers such as colorectal cancer .
2 MicroRNA-31 ( miR-31 ) plays an oncogenic role and is associated with BRAF mutation and poor prognosis in colorectal cancer .
3 EZH2 is functionally considered to suppress miR-31 expression in human cancers ; however , no study has reported its relationship with colon cancer .
4 We therefore evaluated EZH2 expression using immunohistochemistry and assessed miR-31 and epigenetic alterations using 301 colorectal carcinomas and 207 premalignant lesions .
5 Functional analysis was performed to identify the association between EZH2 and miR-31 using cancer cell lines .
6 Μ In the current study , negative , weak , moderate , and strong EZH2 expressions were observed in 15% , 19% , 25% , and 41% of colorectal cancers , respectively .
7 EZH2 was inversely associated with miR-31 ( P <00001 ) , independent of clinicopathological and molecular features .
8 ✓ In a multivariate stage-stratified analysis , high EZH2 expression was related to favorable prognosis ( P = 00022 ) . GE-ASS-RO
9 Μ Regarding premalignant lesions , negative EZH2 expression was frequently detected in sessile serrated adenomas/polyps ( SSA/Ps ) ( 76% ; P <00001 ) compared with hyperplastic polyps , traditional serrated adenomas , and non-serrated adenomas ( 25-36% ) .
10 Μ Functional analysis demonstrated that the knockdown of EZH2 increased miR-31 expression .
11 In conclusion , an inverse association was identified between EZH2 and miR-31 in colorectal cancers .
12 Μ Our data also showed that upregulation of EZH2 expression may be rare in SSA/Ps .
13 These results suggest that EZH2 suppresses miR-31 in colorectal cancer and may correlate with differentiation and evolution of serrated pathway .



PMID: 26870292
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Management of patients with melanoma ] .
1   Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies .



PMID: 26870275
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Expression of hepatocyte growth factor and c-Met is characteristic of alpha-fetoprotein -producing colorectal adenocarcinoma : A report of three cases .
1 alpha-fetoprotein ( AFP )- producing colorectal adenocarcinoma is rare and typically not well recognized .
2 In the present study , 3 cases of AFP-producing colorectal cancer are described .
3 All 3 of these cases demonstrated increased levels of blood AFP associated with disease progression .
4 Only case 2 exhibited classical histological hepatoid features .
5 Μ Following immunohistochemical tissue staining , all 3 cases were observed to be positive for AFP expression .
6 Μ In addition , the expression of hepatocyte growth factor ( HGF ) , c-Met receptor and the transcription factor c-Myc were identified to be associated with the expression of AFP .
7 The 3 cases demonstrated resistance to multiple drugs , including epidermal growth factor receptor inhibitors , despite the presence of wild-type Kirsten rat sarcoma viral oncogene homolog ( K-RAS ; codons 12 and 13 ) , neuroblastoma-RAS ( codons 12 and 13 ) and B-Raf proto-oncogene , serine/threonine kinase (V600E) .
8 We propose that hepatoid histological features or a positive AFP finding by immunohistochemistry are sufficient for a diagnosis of AFP-producing colorectal adenocarcinoma .
9 Furthermore , we speculates that autocrine HGF/c-Met activation may be capable of inducing the dedifferentiation of common adenocarcinoma cells , reverting them to a cancer stem cell state and producing AFP or hepatoid differentiation .
10   Consequently , therapy targeted to the HGF/c-Met signaling pathway may potentially be effective for the treatment of AFP-producing colorectal adenocarcinoma .



PMID: 26870147
(None)  
Terms: PDX
Sent# Symbols Sentence Mnemonics
0 The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells .
1 Overall benefits of EGFR-TKIs are limited because these treatments are largely only for adenocarcinoma ( ADC ) with EGFR activating mutation .
2 The treatments also usually lead to development of resistances .
3 We have established a panel of patient-derived xenografts ( PDXs ) from treatment naive Asian NSCLC patients , including those containing "classic" EGFR activating mutations .
4 Some of these EGFR-mutated PDXs do not respond to erlotinib : LU1868 containing L858R/T790M mutations , and LU0858 having L858R mutation as well as c-MET gene amplification , both squamous cell carcinoma ( SCC ) .
5 Treatment of LU0858 with crizotinib , a small molecule inhibitor for ALK and c-MET , inhibited tumor growth and c-MET activity .
6 Combination of erlotinib and crizotinib caused complete response , indicating the activation of both EGFR and c-MET promote its growth/survival .
7 ✓ Μ LU2503 and LU1901 , both with wild-type EGFR and c-MET gene amplification , showed complete response to crizotinib alone , suggesting that c-MET gene amplification , not EGFR signaling , is the main oncogenic driver . GM-ASS-RO
8 ✓ Interestingly , LU1868 with the EGFR L858R/T790M , but without c-met amplification , had a complete response to cetuximab . GM-ASS-RO
9 Our data offer novel practical approaches to overcome the two most common resistances to EGFR-TKIs seen in the clinic using marketed target therapies .



PMID: 26869800
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prediagnostic Physical Activity and Colorectal Cancer Survival : Overall and Stratified by Tumor Characteristics .
1 Comparing BRAF mutation status in matched primary and metastatic cutaneous melanomas : implications on optimized targeted therapy .



PMID: 26867820
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 From genotype to phenotype : Are there imaging characteristics associated with lung adenocarcinomas harboring RET and ROS1 rearrangements .
1 Epidermal growth factor receptor ( EGFR ) is one of the targeted molecular markers in many cancers including lung malignancies .
2 Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase ( TK ) domains .
3 We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks ( FFPE ) from tissue biopsies of 167 non-small cell lung carcinoma ( NSCLC ) patients and 167 healthy controls .
4 The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene .
5 This study was performed using PCR followed by DNA sequencing .
6 Μ We identified 63 mutations in 33 men and 30 women .
7 Μ Mutations were detected in exon 19 ( delE746-A750 , delE746-T751 , delL747-E749 , delL747-P753 , delL747-T751 ) in 32 patients , exon 20 ( S786I , T790M ) in 16 , and exon 21 ( L858R ) in 15 .
8 Μ No mutations were observed in exon 18 .
9   The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor ( TKI ) drugs and have responded well to therapy over the last 15 months .
10 The control patients had no mutations in any of the exons studied .
11   The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC .
12 The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population .



PMID: 26866578
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses .
1 PURPOSE :
2 Mismatch repair-deficient ( dMMR ) colorectal cancer ( CRC ) is caused by Lynch syndrome ( LS ) in 3% and sporadic inactivation of MLH1 by hypermethylation ( MLH1-hm ) in 12% of cases .
3 It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ .
4 The objective of this study was to explore differences in clinical factors and outcomes in these two groups .
5 METHODS :
6 Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included .
7 Μ MLH1-hm was established with BRAF mutational analysis or hypermethylation testing .
8 Patients' charts were accessed for information on pathology , germ - line MMR mutation testing , and clinical course .
9 RESULTS :
10 A total of 143 patients had CRC associated with LS ( 37 patients , 26% ) or MLH1-hm ( 106 patients , 74% ) .
11 Patients with LS were younger , more often male , presented more often with stage III disease , and had more metachronous disease than patients with MLH1-hm tumors .
12 There was no difference in cancer-specific survival ( CSS ) between the groups ; overall survival was longer in patients with LS , but this difference was minimal after adjusting for age and stage at diagnosis .
13 CONCLUSION :
14 CSS did not differ in LS-associated CRC compared with MLH1-hm CRC , suggesting that they carry a similar prognosis .
15 Genet Med 18 9 , 863-868 .



PMID: 26865419
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition : design , synthesis , and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives .
1 Cetuximab plus FOLFOX-4 in untreated patients with advanced colorectal cancer : a Gruppo Oncologico dell'Italia Meridionale Multicenter phase II study .



PMID: 26864072
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Integrative modeling of multi-omics data to identify cancer drivers and infer patient-specific gene activity .
1 BACKGROUND :
2 High throughput technologies have been used to profile genes in multiple different dimensions , such as genetic variation , copy number , gene and protein expression , epigenetics , metabolomics .
3 Computational analyses often treat these different data types as independent , leading to an explosion in the number of features making studies under-powered and more importantly do not provide a comprehensive view of the gene's state .
4 We sought to infer gene activity by integrating different dimensions using biological knowledge of oncogenes and tumor suppressors .
5 RESULTS :
6 This paper proposes an integrative model of oncogene and tumor suppressor activity in cells which is used to identify cancer drivers and compute patient-specific gene activity scores .
7 We have developed a Fuzzy Logic Modeling ( FLM ) framework to incorporate biological knowledge with multi-omics data such as somatic mutation , gene expression and copy number measurements .
8 The advantage of using a fuzzy logic approach is to abstract meaningful biological rules from low-level numerical data .
9 Biological knowledge is often qualitative , thus combining it with quantitative numerical measurements may leverage new biological insights about a gene's state .
10 We show that the oncogenic and altered tumor suppressing state of a gene can be better characterized by integrating different molecular measurements with biological knowledge than by each data type alone .
11 We validate the gene activity score using data from the Cancer Cell Line Encyclopedia and drug sensitivity data for five compounds : BYL719 (PIK3CA inhibitor) , PLX4720 (BRAF inhibitor) , AZD6244 (MEK inhibitor) , Erlotinib ( EGFR inhibitor ) , and Nutlin-3 (MDM2 inhibitor) .
12 The integrative score improves prediction of drug sensitivity for the known drug targets of these compounds compared to each data type alone .
13 The gene activity scores are also used to cluster colorectal cancer cell lines .
14 Two subtypes of CRCs were found and potential cancer drivers and therapeutic targets for each of the subtypes were identified .
15 CONCLUSIONS :
16 We propose a fuzzy logic based approach to infer gene activity in cancer by integrating numerical data with descriptive biological knowledge .
17 We compute general patient-specific gene -level scores useful to determine the oncogenic or tumor suppressor status of cancer gene drivers and to cluster or classify patients .



PMID: 26863631
(Patient)  
Terms: , mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 Dietary n-3 polyunsaturated fatty acids fail to reduce prostate tumorigenesis in the PB-ErbB-2 x Pten(+/-) preclinical mouse model .
1 In primary melanoma , ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF (V600E) .
2 Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases .
3 We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene ( located at chromosome 7p21 ) and centromere chromosome 7 and immunohistochemistry for ETV1 , BRAF (V600E) , and ETV1/BRAF associated proteins pMSK1 , pRSK1 , pp38 , pMEK1/2 , MAPKAP kinase 2 , CIC , HIF-1alpha and Ki-67 .
4 We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH .
5 The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF (V600E) conditions were determined in melanoma cell lines using qRT-PCR and Western Blot .
6 Μ No ETV1 high grade amplifications were observed in tissue samples , but low grade ETV1 gene amplifications were found in 7 ( 103 % ) melanoma brain metastases .
7 ETV1 protein expression in tissue samples ( 15 % ) correlated with BRAF (V600E) status ( p = 0007 ) and HIF-1alpha expression ( p = 0049 ) , but not with ETV1 gene dose .
8 Application of the BRAF (V600E)- specific inhibitor vemurafenib and the BRAF (V6ooE/V600K)- inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway .
9 ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals , by BRAF (V600E) mutation , than on ETV1 gene amplification .
10 Consequently , therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression .



PMID: 26861657
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 New Therapeutic Opportunities Based on DNA Mismatch Repair and BRAF Status in Metastatic Colorectal Cancer .
1 Recently , colorectal cancer ( CRC ) subtyping consortium identified four consensus molecular subtypes ( CMS1-4 ) .
2 CMS1 is enriched for deficient mismatch repair ( dMMR ) and BRAF (V600E) tumors .
3 Intriguingly , this subtype has better relapse-free survival but worse overall survival after relapse compared with the other subtypes .
4 Growing evidence is accumulating on the benefit of specific therapeutic strategies such as immune checkpoint inhibition therapy in dMMR tumors and mitogen -activated protein kinase ( MAPK ) pathway targeted therapy in tumors harboring BRAF (V600E) mutation .
5 After reviewing dMMR prognostic value , immune checkpoints as major targets for dMMR carcinomas will be highlighted .
6   Following , BRAF (V600E) prognostic impact will be reviewed and therapeutic strategies with the combination of cytotoxic agents and especially the combinations of BRAF and MAPK inhibitors will be discussed .



PMID: 26860615
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway emanating from ELK1 .
1 Splicing aberrations are prominent drivers of cancer , yet the regulatory pathways controlling them are mostly unknown .
2 Here we develop a method that integrates physical interaction , gene expression , and alternative splicing data to construct the largest map of transcriptomic and proteomic interactions leading to cancerous splicing aberrations defined to date , and identify driver pathways therein .
3 We apply our method to colon adenocarcinoma and non-small - cell lung carcinoma .
4 By focusing on colon cancer , we reveal a novel tumor-favoring regulatory pathway involving the induction of the transcription factor MYC by the transcription factor ELK1 , as well as the subsequent induction of the alternative splicing factor PTBP1 by both .
5 We show that PTBP1 promotes specific RAC1 , NUMB , and PKM splicing isoforms that are major triggers of colon tumorigenesis .
6 Μ By testing the pathway's activity in patient tumor samples , we find ELK1 , MYC , and PTBP1 to be overexpressed in conjunction with oncogenic KRAS mutations , and show that these mutations increase ELK1 levels via the RAS-MAPK pathway .
7 We thus illuminate , for the first time , a full regulatory pathway connecting prevalent cancerous mutations to functional tumor-inducing splicing aberrations .
8 Our results demonstrate our method is applicable to different cancers to reveal regulatory pathways promoting splicing aberrations .



PMID: 26855534
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer tumour markers and biomarkers : Recent therapeutic advances .
1 Colorectal cancer ( CRC ) is the second most commonly diagnosed cancer among females and third among males worldwide .
2 It also contributes significantly to cancer-related deaths , despite the continuous progress in diagnostic and therapeutic methods .
3 Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer .
4 Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease .
5 Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients .
6   There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers .
7   In this review , we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening , diagnosis , treatment and follow-up.Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis , as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments .



PMID: 26854029
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS insertion mutations are oncogenic and exhibit distinct functional properties .
1 Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins ( GAPs ) .
2 Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60 A66dup in a child with an atypical myeloproliferative neoplasm .
3 Μ K-Ras proteins containing this tandem duplication or a similar five amino acid E62 A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells .
4 Recombinant K-Ras ( G60 A66dup ) and K-Ras ( E62 A66dup ) proteins display reduced intrinsic GTP hydrolysis rates , accumulate in the GTP-bound conformation and are resistant to GAP -mediated GTP hydrolysis .
5 Remarkably , K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation , and are hypersensitive to MEK inhibition .
6 These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications .



PMID: 26852686
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MET FISH-positive status predicts short progression-free survival and overall survival after gefitinib treatment in lung adenocarcinoma with EGFR mutation .
1 Management of Dermatologic Complications of Lung Cancer Therapies .



PMID: 26851024
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 High PTPRQ Expression and Its Relationship to Expression of PTPRZ1 and the Presence of KRAS Mutations in Colorectal Cancer Tissues .
1 BACKGROUND :
2 The risk of sporadic colorectal cancer ( CRC ) is strongly influenced by Iifestyle , environmental and genetic factors .
3 Protein tyrosine phosphatases belong to a group of enzymes whose role in CRC has not yet been intensively studied .
4 They play an important role in activation/de-activation of many enzymes , influencing cell biology by catalyzing reactions opposing those catalyzed by kinases .
5 Protein tyrosine phosphatase receptor-like type Q ( PTPRQ ) and protein tyrosine phosphatase receptor-like type Z polypeptide 1 ( PTPRZ1 ) have both been shown to be important in development of many cancer types including CRC .
6 MATERIALS AND METHODS :
7 The expression level of PTPRQ and PTPRZ1 was determined by real-time polymerase chain reaction in 16 CRC tissues obtained from patients diagnosed with adenocarcinoma coli .
8 RESULTS :
9 Μ We revealed a high level of PTPRQ expression ( p = 00080 ) , as well as an association between expression levels of PTPRQ and PTPRZ1 ( p<00001 ) .
10 Moreover PTPRQ expression was higher in tissues presenting with rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutation ( p = 00293 ) .
11 CONCLUSION :
12 We confirmed the contribution of PTPRZ1 and especially PTPRQ in CRC development , supporting the hypothesis that PTPRQ is a candidate oncogene , playing a crucial role in phosphorylation/dephosphorylation signaling pathways .



PMID: 26849815
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 The State of the Art in Colorectal Cancer Molecular Biomarker Testing .
1 The number of molecular biomarkers to inform treatment decisions in patients with metastatic colorectal cancer ( mCRC ) continues to expand and with it the methodologies that can be employed to evaluate these biomarkers .
2 Beyond standard diagnostic and prognostic biomarkers , such as those used for Lynch syndrome , mutations in KRAS exon 2 are well established as predictive for lack of response to the antiepidermal growth factor receptor therapies panitumumab and cetuximab .
3 Recent studies have extended these findings by demonstrating that mutations in KRAS exons 3 and 4 and in NRAS exons 2 , 3 , and 4 ( with all KRAS and NRAS mutations collectively referred to as RAS ) are also predictive for treatment outcomes among patients with mCRC receiving panitumumab and cetuximab in combination with chemotherapy or as monotherapy .
4 Consequently , evaluation of these additional loci has been incorporated into current clinical guidelines , and pathologists will need to develop testing procedures and algorithms to reliably and rapidly evaluate RAS status .
5 With the increased number of mutations that must be examined to evaluate the status of RAS and other emerging biomarkers , next-generation sequencing technologies are likely to become increasingly important in mCRC testing .
6 This review describes new considerations for pathologists that have arisen as a consequence of the incorporation of additional biomarker testing into clinical practice for mCRC .



PMID: 26849813
(None)  
Terms: in vivo, in vitro, mouse models, mouse, mice
Sent# Symbols Sentence Mnemonics
0 Updates in the Pathologic Diagnosis and Classification of Epithelial Neoplasms of Urachal Origin .
1 OBJECTIVE :
2 The impact of glia cells during GI carcinogenesis and in cancer pain is unknown .
3 Here , we demonstrate a novel mechanism how Schwann cells ( SCs ) become activated in the pancreatic cancer ( PCa ) microenvironment and influence spinal activity and pain sensation .
4 DESIGN :
5 Human SCs were exposed to hypoxia , to pancreatic cancer cells ( PCCs ) and/or to T-lymphocytes .
6 Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression , proliferation and for transcriptional alterations of pain-related targets .
7 In conditional PCa mouse models with selective in vivo blockade of interleukin ( IL ) -6 signalling ( Ptf1a-Cre ; LSL-Kras ( G12D )/KC interbred with IL6(-/-) or sgp130 ( tg ) mice ) , SC reactivity , abdominal mechanosensitivity and spinal glial/neuronal activity were quantified .
8 RESULTS :
9 Tumour hypoxia , PCC and/or T-lymphocytes activated SC via IL-6 -signalling in vitro .
10 Blockade of the IL-6 -signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia ( PanIN )) in KC ; IL6(-/-) ( 3206%+/-525% of PanINs ) and KC ; sgp130 ( tg ) ( 5584%+/-551% ) mouse models compared with KC mice ( 7827%+/-391% ) .
11 Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice ( von Frey score of KC : 3.9+/-0.5 versus KC ; IL6(-/-) mice : 5.9+/-0.9 ; and KC ; sgp130 ( tg ) : 10.21+/-1.4 ) parallel to attenuation of spinal astroglial and/or microglial activity .
12 Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features .
13 CONCLUSIONS :
14 Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia .
15 Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression .



PMID: 26848526
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression .
1 Histone deacetylase inhibitors ( HDIs ) represent a new class of anticancer drugs .
2 Suberoylanilide hydroxamic acid ( SAHA ) , the first HDI approved for the treatment of cutaneous T cell lymphoma ( CTCL ) , is currently being tested in clinical trials for other cancers .
3 However , SAHA has been ineffective against solid tumors in many clinical trials .
4 A better understanding of molecular mechanisms of SAHA resistance may provide the basis for improved patient selection and the enhancement of clinical efficacy .
5 Here we demonstrate that oncogenic K-ras contributes to SAHA resistance by upregulating HDAC6 and c-myc expression .
6 Μ We find that the high levels of HDAC6 expression are associated with activated K-ras mutant in colon cancer patients .
7 And expressions of HDAC6 and c-myc are increased in fibroblasts transformed with activated K-ras .
8 Surprisingly , we find that activated K-ras transformed cells are more resistant to SAHA inhibition on cell growth and anchorage -independent colony formation .
9 We show that a K-ras inhibitor sensitizes K-ras mutated lung cancer cells to SAHA induced growth inhibition .
10 Μ We also find that mutant K-ras induces HDAC6 expression by a MAP kinase dependent pathway .
11 Our study suggests that combined treatment with SAHA and K-ras inhibitors may represent an effective strategy to overcome SAHA resistance .



PMID: 26847055
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care .
1 Μ We describe the landscape of genomic alterations in cutaneous melanomas through DNA , RNA , and protein -based analysis of 333 primary and/or metastatic melanomas from 331 patients .
2 We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes : mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT ( wild-type ) .
3 Μ Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype .
4 We found no significant outcome correlation with genomic classification , but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression , a T cell marker , were associated with improved patient survival .
5   This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology , offering insights to further personalize therapeutic decision-making .



PMID: 26842924
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Segmental distribution of some common molecular markers for colorectal cancer ( CRC ) : influencing factors and potential implications .
1 Proximal and distal colorectal cancers ( CRCs ) are regarded as distinct disease entities , evolving through different genetic pathways and showing multiple clinicopathological and molecular differences .
2 Segmental distribution of some common markers ( e.g. , KRAS , EGFR , Ki-67 , Bcl-2 , COX-2 ) is clinically important , potentially affecting their prognostic or predictive value .
3 However , this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events , associations of some markers with other clinicopathological features ( stage and/or grade ) , and wide methodological variability in markers' assessment .
4   All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers , whereas the role of other potential influences ( e.g. , pre-adjuvant treatment , interaction between markers ) remains rather unclear .
5   Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC , potentially allowing the application of a novel patient stratification for treatment , based on particular molecular profiles in combination with tumor location .



PMID: 26836283
(None)  
Terms: prospective, retrospective
Sent# Symbols Sentence Mnemonics
0 TNMF versus TNM in staging of colorectal cancer .
1 AIM :
2 TNM staging and histological grading of rectal cancer has undergone no or minimal changes during the past 20 years despite their major impact on planning , reporting and outcome of the disease .
3 The addition of category 'F' to the 'TNM' staging of colorectal cancer , which becomes TNMF will accommodate the expanding list of risk factors that may affect the management and thus avoid squeezing them into the TNM categories .
4 METHODS :
5 Reporting of the following risk factors was traced in 730 ( 664 retrospective and 66 prospective ) cases of colorectal cancer : age , Tumor location , preoperative CEA , intraoperative tumor perforation and blood transfusion , quality of TME , tumor grade , non nodal T .
6 Ds , Lymphovascular invasion , lymph node ratio , circumferential tumor margins , apical lymph nodes , infiltrating or pushing and K-ras gene mutation .
7 RESULTS :
8 The reporting of most risk factors was inadequate ; also there is marked improvement in reporting in the prospective cases in preoperative CEA , intra operative blood transfusion and tumor perforation , quality of TME , tumor grade and non-nodal T .
9 Ds ( P-value <00001 ) .
10 CONCLUSION :
11 The addition of category 'F' to the TNM staging system to become TNMF may avoid ignoring already established risk factors due to our inability to accommodate them in the inhospitable TNM categories .



PMID: 26832792
(None)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress .
1 Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer .
2 Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS .
3 Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses , those with mutant KRAS were markedly more sensitive to AUY922 -induced apoptosis .
4 This was associated with upregulation of the BH3-only proteins Bim , Bik , and PUMA .
5 However , only Bim appeared essential , in that knockdown of Bim abolished , whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922 .
6 Mechanistic investigations revealed that endoplasmic reticulum ( ER ) stress was responsible for AUY922 -induced upregulation of Bim , which was inhibited by a chemical chaperone or overexpression of GRP78 .
7 Conversely , siRNA knockdown of GRP78 or XBP-1 enhanced AUY922 -induced apoptosis .
8 Remarkably , AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress .
9   Taken together , these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers , and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy .



PMID: 26832730
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarkers for the identification of precursor polyps of colorectal serrated adenocarcinomas .
1 BACKGROUND :
2 In contrast to conventional colorectal carcinomas ( CCs ) , which develop through a so-called chromosome instability or suppressor phenotype pathway , the sequence of events leading from precursor polyps/adenomas to serrated adenocarcinomas ( SACs ) , which are more aggressive and exhibit a poorer survival than CCs , is as yet not clearly defined .
3 Here , we aimed at detecting protein and DNA biomarkers for SAC in a series of primary colorectal polyps .
4 METHODS :
5 In total 303 colorectal polyps were included : 121 serrated polyps ( 33 hyperplastic polyps , 37 sessile serrated adenomas ( SSA ) , 51 traditional serrated adenomas ( TSA ) ) , 143 conventional polyps ( 72 tubular polyps , 34 tubulovillous polyps , 37 villious adenomas ) , and 39 bi-phenotypic serrated-conventional polyps .
6 The protein biomarkers tested were deduced from previously published SAC and CC expression profiling studies .
7 Μ A representative subset of 106 polyps was selected for DNA biomarker analyses , i.e. , proto - oncogene mutation and microsatellite instability ( MSI ) status .
8 In order to confer proper weight to each biomarker , a multivariate logistic regression model was employed .
9 RESULTS :
10 We found that serrated and conventional polyps differed in most of the SAC biomarkers tested .
11 Μ Of these biomarkers , FSCN1 showed the largest difference in expression ( p = 00001 ) .
12 Μ Despite sharing a serrated morphology , we found that SSAs and TSAs differed considerably with respect to anatomical location , expression of EPHB2 and PTCH1 , presence of the V600E BRAF mutation and MSI status .
13 Logistic regression analysis revealed that SSA was the polyp type that shared most biomarkers with SAC .
14 CONCLUSION :
15 Based on the shared presence of protein and molecular biomarkers , especially FSCN1 expression , SSA may serve as a precursor lesion of SAC .
16 Biomarker assessment may help in discerning colorectal carcinogenic routes with distinct prognostic implications .



PMID: 26831663
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical significance of fibroblast growth factor receptor 2 expression in patients with residual rectal cancer after preoperative chemoradiotherapy : relationship with KRAS or BRAF mutations and MSI status .
1 This study was designed to determine the prognostic impact and clinical significance of FGFR2 in residual disease after preoperative chemoradiotherapy ( CRT ) in patients with rectal cancer .
2 The surgical specimens of 145 patients with residual rectal cancer after preoperative CRT were analyzed .
3 To evaluate FGFR2 expression , immunohistochemistry was performed on whole section tissues .
4 KRAS exon 2 ( codon 12 and 13 ) , BRAF V600E mutational status , and microsatellite instability ( MSI ) were determined using polymerase chain reactions .
5 ✓ Μ Of the eligible 141 patients , FGFR2 over-expression was observed in 75.9 % ( n = 107 ) and was correlated with perineural invasion ( P = 0005 ) and inferior tumor regression grading ( TRG ) ( P = 0009 ) . GE-ASS-RO
6 However , FGFR2 expression had no relationship with KRAS and BRAF mutation results or with MSI results .
7 ✓ On univariate analysis , FGFR2 over-expression was significantly associated with worse rectal cancer-specific survival ( RCSS ) ( P = 0005 ) and disease-free survival ( DFS ) ( P = 0035 ) . GE-ASS-RO
8 ✓ Μ However , multivariate analysis revealed that FGFR2 over-expression was not independently associated with RCSS and DFS ( all P >005 ) . GE-ASS-RO
9 ✓ Although FGFR2 over-expression did not independently influence patient outcome , FGFR2 over-expression was associated with worse prognosis and inferior TRG . GE-ASS-RO, GE-REG-RO
10 Our data may aid in understanding the therapeutic approaches targeting FGFR2 in patients with residual rectal cancer after preoperative CRT .



PMID: 26824772
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogenic Ras/Src cooperativity in pancreatic neoplasia .
1 Μ A network model for the determination of tumor metabolic fluxes from ( 13 ) C NMR kinetic isotopomer data has been developed and validated with perfused human DB-1 melanoma cells carrying the BRAF V600E mutation , which promotes oxidative metabolism .
2 The model generated in the bonded cumomer formalism describes key pathways of tumor intermediary metabolism and yields dynamic curves for positional isotopic enrichment and spin-spin multiplets .
3 Cells attached to microcarrier beads were perfused with 26 mm [1,6 - ( 13 ) C2] glucose under normoxic conditions at 37 degrees C and monitored by ( 13 ) C NMR spectroscopy .
4 Excellent agreement between model -predicted and experimentally measured values of the rates of oxygen and glucose consumption , lactate production , and glutamate pool size validated the model .
5 ATP production by glycolytic and oxidative metabolism were compared under hyperglycemic normoxic conditions ; 51% of the energy came from oxidative phosphorylation and 49% came from glycolysis .
6 Even though the rate of glutamine uptake was approximately 50% of the tricarboxylic acid cycle flux , the rate of ATP production from glutamine was essentially zero ( no glutaminolysis ) .
7 De novo fatty acid production was approximately 6% of the tricarboxylic acid cycle flux .
8 The oxidative pentose phosphate pathway flux was 3.6% of glycolysis , and three non-oxidative pentose phosphate pathway exchange fluxes were calculated .
9 Mass spectrometry was then used to compare fluxes through various pathways under hyperglycemic ( 26 mm ) and euglycemic ( 5 mm ) conditions .
10 Under euglycemic conditions glutamine uptake doubled , but ATP production from glutamine did not significantly change .
11 A new parameter measuring the Warburg effect ( the ratio of lactate production flux to pyruvate influx through the mitochondrial pyruvate carrier ) was calculated to be 21 , close to upper limit of oxidative metabolism .



PMID: 26824186
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 miR-143 or miR-145 overexpression increases cetuximab-mediated antibody -dependent cellular cytotoxicity in human colon cancer cells .
1 miR-143 and miR-145 are downregulated in colon cancer .
2 Here , we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS ( HCT116 and SW480 ) and wild-type KRAS ( SW48 ) colon cancer cells .
3 We evaluated cetuximab-mediated antibody -dependent cellular cytotoxicity ( ADCC ) and the modulation of signaling pathways involved in immune effector cell -mediated elimination of cancer cells .
4 Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab , resulting in a significant increase of cetuximab-mediated ADCC independently of KRAS status .
5 Importantly , HCT116 cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated ADCC , effected by peripheral blood mononuclear cells ( p <001 ) .
6 This was associated with increased apoptosis and caspase-3/7 activity , and reduced Bcl-2 protein expression ( p <001 ) .
7 In addition , caspase inhibition abrogated cetuximab-mediated ADCC in HCT116 cells overexpressing either miR-143 or miR-145 ( p <001 ) .
8 Furthermore , Bcl-2 silencing led to high level of cetuximab-mediated ADCC , compared to control siRNA ( p <005 ) .
9 Importantly , granzyme B inhibition , abrogated cetuximab-mediated ADCC , reducing caspase-3/7 activity ( p <001 ) .
10 Collectively , our data suggests that re-introduction of miR-143 or miR-145 may provide a new approach for development of therapeutic strategies to re-sensitize colon cancer cells to cetuximab by stimulating cetuximab -dependent ADCC to induce cell death .



PMID: 26824184
(Cell)  
Terms: In vitro, in vitro
Sent# Symbols Sentence Mnemonics
0 Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer ?
1 Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer .
2 However , it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy .
3 We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor .
4 These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third - line .
5 Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy .
6 In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death .
7 The median progression free survival ( PFS ) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group ( 28 and 4 months respectively ; p = 0003 ) .
8 The median overall survival from the beginning of the metastatic disease was similar in the two groups ( 413 and 42 months respectively ; p = 07 ) .
9 In vitro , VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3 -dependent manner .
10 All in all , our clinical data , supported by in vitro procedures , suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy .
11 Although these results are observed in a limited cohort , they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer .



PMID: 26820797
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Pre-clinical use of isogenic cell lines and tumours in vitro and in vivo for predictive biomarker discovery ; impact of KRAS and PI3KCA mutation status on MEK inhibitor activity is model dependent .
1 [ KRAS gene somatic mutations in Chilean patients with colorectal cancer ] .



PMID: 26820161
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HistoMosaic Detecting KRAS G12V Mutation Across Colorectal Cancer Tissue Slices through in Situ PCR .
1 We report on HistoMosaic , a novel technique for genetic analysis of formalin-fixed , paraffin-embedded tissue slices .
2 It combines microfluidic compartmentalization , in situ allele -specific PCR , and fluorescence microscopy .
3 The experimental proof of principle was achieved by in situ detection of KRAS G12V mutation in colorectal cancer tissues and is presented herein .
4 Μ HistoMosaic offers the ability to detect mutations over the entire tissue slide simultaneously , rapidly , economically , and without selection bias , while coregistering the genetic information with the preserved morphological information .
5 Thus , HistoMosaic has wide applicability in basic science as a tool to map genetic heterogeneity .
6   It is also a platform to build companion diagnostics for targeted therapies in oncology , to help ensure that the right drug is given to the right patient , thereby saving healthcare resources and improving patient outcomes .



PMID: 26819545
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Correlation between Gene Variants , Signaling Pathways , and Efficacy of Chemotherapy Drugs against Colon Cancers .
1 Efficacies , toxicities , and resistance mechanisms of chemotherapy drugs , such as oxaliplatin and 5-fluorouracil ( 5-FU ) , vary widely among various categories and subcategories of colon cancers .
2 By understanding the differences in the drug efficacy and resistance at the level of protein - protein networks , we identified the correlation between the drug activity of oxaliplatin/5-FU and gene variations from the US National Cancer Institute-60 human cancer cell lines .
3 The activity of either of these drugs is correlated with specific amino acid variants of KRAS and other genes from the signaling pathways of colon cancer progression .
4 We also discovered that the activity of a non-DNA-binding novel platinum drug , phosphaplatin , is comparable with oxaliplatin and 5-FU when it was tested against colon cancer cell lines .
5   Our strategy that combines the knowledge from pharmacogenomics across cell lines with the molecular information from specific cancer cells is beneficial for predicting the outcome of a possible combination therapy for personalized treatment .



PMID: 26817995
(Patient)  
Terms: Prospective, in vitro
Sent# Symbols Sentence Mnemonics
0 Prospective Evaluation of Cetuximab-Mediated Antibody -Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy .
1 Cetuximab is a monoclonal antibody to the EGFR that induces antibody -dependent cell cytotoxicity ( ADCC ) through Fcgamma receptors on immune cells .
2 Although SNPs in genes encoding Fcgamma receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer , a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined .
3 We therefore enrolled 96 consecutive metastatic colorectal cancer ( mCRC ) patients at diagnosis in a study that assessed FcgammaR status and cetuximab-mediated ADCC .
4 Μ Patients carrying the FcgammaRIIa H alleles 131H/Hand 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles ( P= 0013 ) .
5 Μ Patients carrying FcgammaRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype ( P= 0001 ) .
6 ✓ Progression-free survival of patients with an FcgammaRIIIa 158V allele was significantly longer compared with patients carrying 158F/F ( P= 005 ) , whereas no significant difference was observed for overall survival . RO-ASS-GM
7 Twenty-eight of 50 mCRC patients with wild-type KRAS received cetuximab .
8 The average ADCC -mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response , 21% in patients with stable disease and 9% in patients with progressive disease .
9 To characterize basal natural killer ( NK ) activity , cytotoxicity was evaluated in 39 of 96 mCRC patients .
10   Patients who responded to first - line treatment had higher NK-cell cytotoxicity .
11 Thus , although limited to this cohort of patients , in vitro cetuximab-mediated ADCC correlated with FcgammaR polymorphisms and predicted cetuximab responsiveness .



PMID: 26812617
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Validation of a Multiplex Allele -Specific Polymerase Chain Reaction Assay for Detection of KRAS Gene Mutations in Formalin-Fixed , Paraffin-Embedded Tissues from Colorectal Cancer Patients .
1 Detection of colorectal serrated polyps by stool DNA testing : comparison with fecal immunochemical testing for occult blood ( FIT ) .



PMID: 26812186
(None)  
Terms: Meta-analysis, meta-analysis
Sent# Symbols Sentence Mnemonics
0 Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours .
1 BACKGROUND :
2 Metastatic colorectal cancer ( mCRC ) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies ( mAbs ) .
3 However , observational evidence has led to speculation that mCRC patients with KRAS G13D mutant ( MT ) tumours may derive a benefit from treatment with anti-EGFR mAbs .
4 METHODS :
5 We conducted a systematic review and meta-analysis of randomized controlled trials ( RCTs ) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation ( KRAS G13D ) and KRAS mutations other than G13D ( other KRAS MT ) .
6 RESULTS :
7 Eight RCTs ( n = 5967 ) met the inclusion criteria for assessment of both overall survival ( OS ) and progression-free survival ( PFS ) .
8 ✓ For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 ( 95% confidence interval [CI] ; 0.96 , 1.17 ) , compared to 1.08 ( 95% CI ; 073 , 160 ) for KRAS G13D [test for interaction p = 099] . GM-ASS-RO
9 In contrast , the hazard ratio for KRAS wild-type ( WT ) tumours was 0.85 ( 95% CI ; 076 , 095 ) .
10 ✓ Regarding PFS benefit with anti-EGFR mAbs , the hazard ratio was 1.07 ( 95% CI ; 092 , 126 ) for other KRAS MT , 0.96 ( 95% CI ; 073 , 127 ) for KRAS G13D , and 0.68 ( 95% CI ; 054 , 085 ) for KRAS WT . GM-ASS-RO
11 ✓ Again , the test for interaction ( p = 046 ) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT . RO-ASS-GM
12 CONCLUSION :
13   This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC .



PMID: 26811634
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Enhancing the Effects of Low Dose Doxorubicin Treatment by the Radiation in T47D and SKBR3 Breast Cancer Cells .
1 Concordant BRAFV600E mutation status in primary melanomas and associated naevi : implications for mutation testing of primary melanomas .



PMID: 26811627
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 The KRAS mutation detection within the initial management of patients with metastatic colorectal cancer : a status report in France in 2011 .
1 Metastatic melanoma remains a mostly incurable disease .
2 Although newly approved targeted therapies are efficacious in a subset of patients , resistance and relapse rapidly ensue .
3 Alternative therapeutic strategies to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell identity are emerging .
4 Bromodomain and extraterminal domain ( BET ) proteins are epigenome readers known to exert key roles at the interface between chromatin remodeling and transcriptional regulation .
5 Here , we report that BRD4 , a BET family member , is significantly upregulated in primary and metastatic melanoma tissues compared with melanocytes and nevi .
6 Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo , effects that were mostly recapitulated by individual silencing of BRD4 .
7 RNA sequencing of BET inhibitor -treated cells followed by Gene Ontology analysis showed a striking impact on transcriptional programs controlling cell growth , proliferation , cell -cycle regulation , and differentiation .
8 In particular , we found that , rapidly after BET displacement , key cell -cycle genes ( SKP2 , ERK1 , and c-MYC ) were downregulated concomitantly with the accumulation of cyclin-dependent kinase ( CDK ) inhibitors ( p21 and p27 ) , followed by cell -cycle arrest .
9 ✓ Importantly , BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status , opening the possibility of using these small-molecule compounds to treat patients for whom no effective targeted therapy exists . GE-REG-RO
10 Collectively , our study reveals a critical role for BRD4 in melanoma tumor maintenance and renders it a legitimate and novel target for epigenetic therapy directed against the core transcriptional program of melanoma .



PMID: 26811607
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer .
1 High frequency of BRAF proto - oncogene hot spot mutation V600E in cohort of colorectal cancer patients from Ahvaz City , southwest Iran .



PMID: 26810733
(Cell)  
Terms: in vivo, in vitro, xenograft, tumor xenograft, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 EBI-907 , a novel BRAF (V600E) inhibitor , has potent oral anti-tumor activity and a broad kinase selectivity profile .
1 Μ The oncogenic mutation of BRAF (V600E) has been found in approximately 8% of all human cancers , including more than 60% of melanoma and 10% of colorectal cancers .
2 The clinical proof of concept in treating BRAF (V600E) -driving melanoma patients with the BRAF inhibitors has been well established .
3 We have sought to identify and develop novel BRAF (V600E) inhibitors with more favorable profiles .
4 Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF (V600E) inhibitor with potent anti-tumor activity in vitro and in vivo .
5 In a LanthaScreen BRAF (V600E) kinase assay , EBI-907 showed an IC50 of 4.8 nM , which is >10 -fold more potent than Vemurafenib ( IC50 = 585 nM ) .
6 In addition , EBI-907 showed a broader kinase selectivity profile , with potent activity against a number of important oncogenic kinases including FGFR1-3 , RET , c-Kit , and PDGFRb .
7 Concomitant with such properties , EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAF (V600E) -dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib .
8 In BRAF (V600E) human -dependent Colo-205 and A375 tumor xenograft mouse models , EBI-907 caused a marked tumor regression in a dose -dependent manner , with superior efficacy to Vemurafenib .
9 Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone .
10 Our findings present EBI-907 as a potent and promising BRAF inhibitor , which might be useful in broader indications .



PMID: 26805315
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Serrated Polyposis Syndrome with Early Colon Cancer ] .
1 The patient was a 65-year-old man without any noteworthy medical history .
2 Μ A colonoscopy conducted after a positive fecal occult blood test revealed approximately 100 polyps in the large intestine .
3 A biopsy of some these polyps revealed serrated and hyperplastic polyps , which were histologically determined to be well-differentiated adenocarcinoma .
4 Based on these findings , a diagnosis of serrated polyposis syndrome ( SPS ) was made , and the patient underwent laparoscopic pancolectomy/ileoproctostomy .
5 Histopathological analysis revealed a total of 91 lesions , out of which 15 were >/ = 10 mm .
6 A 30 mm lesion in the ascending colon was a well-differentiated adenocarcinoma , stage colon cancer ( T1a [sm] , ly0 , v0 , N0 , and M0 ) .
7 Μ No germline mutations were found on genetic testing of the adenomatous polyposis coli ( APC ) , mutY homolog ( MUTYH ) , mutL homolog 1 ( MLH1 ) , mutS homolog 2 ( MSH2 ) , mutS homolog 6 ( MSH6 ) , and postmeiotic segregation increased 2 ( PMS2 ) genes .
8 Μ No loss of MLH1 protein expression or expression of mutated B-Raf ( BRAF ) V600E protein was observed in the cancer regions after immunostaining .
9 This case is important because not only is the condition rare but also because it showed that the serrated pathway may not necessarily be the mechanism by which serrated lesions become cancerous in patients with SPS .



PMID: 26802026
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF associated autophagy exploitation : BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells .
1 Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components .
2 Autophagy has a controversial role in cancer--both in protecting against tumor progression by isolation of damaged organelles , or by potentially contributing to cancer growth .
3 The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context .
4 In the present study , the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 ( SQSTM1 ) , Beclin-1 ( BECN1 ) and MAP1LC3 (LC3) in colon cancer cells was investigated .
5 This study provides evidence that BRAF oncogene induces the expression of key autophagic markers , like LC3 and BECN1 in colorectal tumor cells .
6 Herein , PI3K/AKT/MTOR inhibitors induce autophagic tumor properties , whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers .
7 Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors , the BRAF related autophagic properties in colorectal cancer cells are further exploited , by novel combinatorial anti-cancer protocols .
8 Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors .
9 Notably , colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor , Bafilomycin A1 .
10 The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E , by exploiting the autophagic properties induced by BRAF oncogene .



PMID: 26799289
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis .
1 Targeted therapies within the RAS/RAF/MEK/ERK signalling axis become increasingly popular , yet cross-talk and feedbacks in the signalling network lead to unexpected effects .
2 Here we look systematically into how inhibiting RAF and MEK with clinically relevant inhibitors result in changes in PI3K/AKT activation .
3 We measure the signalling response using a bead-based ELISA , and use a panel of three cell lines , and isogenic cell lines that express mutant forms of the oncogenes KRAS and BRAF to interrogate the effects of the MEK and RAF inhibitors on signalling .
4 We find that treatment with the RAF inhibitors have opposing effects on AKT phosphorylation depending on the mutational status of two important oncogenes , KRAS and BRAF .
5 If these two genes are in wildtype configuration , RAF inhibitors reduce AKT phosphorylation .
6 In contrast , if BRAF or KRAS are mutant , RAF inhibitors will leave AKT phosphorylation unaffected or lead to an increase of AKT phosphorylation .
7 Down-regulation of phospho-AKT by RAF inhibitors also extends to downstream transcription factors , and correlates with apoptosis induction .
8 Our results show that oncogenes rewire signalling such that targeted therapies can have opposing effects on parallel pathways , which depend on the mutational status of the cell .



PMID: 26799287
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Contribution of KRAS mutations and c.2369C >T ( p.T790M ) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC : a study on circulating tumor DNA .
1 INTRODUCTION :
2 Μ KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer .
3 In non-small cell lung cancer ( NSCLC ) , the efficacy of treatment with EGFR tyrosine kinase inhibitors ( EGFR-TKIs ) depends on activating EGFR mutations ( MUTEGFR ) .
4 However , inhibition of EGFR may select resistant cells displaying alternative signaling , i.e. , KRAS , or restoration of EGFR activity due to additional MUTEGFR , i.e. , the c.2369C >T ( pT790MEGFR ) .
5 AIM :
6 The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance .
7 METHODS :
8 This study used cell -free circulating tumor DNA ( cftDNA ) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI .
9 RESULTS :
10 p .
11 T790MEGFR was detected in 11 ( 333% ) patients , MUTKRAS at codon 12 in 3 ( 91% ) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 ( 394% ) patients .
12 Six patients ( 182% ) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR .
13 In 8 subjects paired tumor re-biopsy/plasma samples were available ; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS .
14 The analysis of time to progression ( TTP ) and overall survival ( OS ) in WTKRAS vs . MUTKRAS were not statistically different , even if there was a better survival with WTKRAS vs . MUTKRAS , i.e. , TTP 14.4 vs. 11.4 months ( p = 097 ) and OS 40.2 vs. 35.0 months ( p = 056 ) , respectively .
15 CONCLUSIONS :
16 MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance .



PMID: 26798444
(None)  
Terms: , mouse models, rat, mice
Sent# Symbols Sentence Mnemonics
0 Impact of RAS and BRAF mutations on carcinoembryonic antigen production and pattern of colorectal metastases .
1 Lung cancer causes more deaths than breast , colorectal and prostate cancers combined .
2 Despite major advances in targeted therapy in a subset of lung adenocarcinomas , the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades .
3 DNA repair deficiency is known to contribute to lung cancer development .
4 In fact , human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C ( XPC ) are highly associated with lung cancer incidence .
5 However , the direct genetic evidence for the role of XPC for lung cancer development is still lacking .
6 Mutations of the rat Kirsten sarcoma viral oncogene homolog ( Kras ) or its downstream effector genes occur in almost all lung cancer cells , and there are a number of mouse models for lung cancer with these mutations .
7 Using activated Kras , Kras ( LA1 ) , as a driver for lung cancer development in mice , we showed for the first time that mice with Kras ( LA1 ) and Xpc knockout had worst outcomes in lung cancer development , and this phenotype was associated with accumulated DNA damage .
8 Μ Using cultured cells , we demonstrated that induced expression of oncogenic KRAS (G12V) led to increased levels of reactive oxygen species ( ROS ) as well as DNA damage , and both can be suppressed by anti-oxidants .
9 Our results suggest that XPC may help repair DNA damage caused by KRAS -mediated production of ROS .



PMID: 26798432
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Quantification of serum MET in non-small - cell lung cancer and its clinical significance .
1 Colorectal cancer ( CRC ) ranked third in cancer related death and its incidence has been increasing worldwide .
2 In recent decades important therapeutic advances have been developed in treatment of metastatic CRC ( mCRC ) , such as monoclonal antibodies against epidermal growth factor receptor ( anti-EGFR ) , which provided additional clinical benefits in mCRC .
3 However , anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment .
4 Thus , KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because ; approximately fifty percent ( 40%-60% ) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment .
5 This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet .
6 Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms .



PMID: 26790710
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 [ What future for circulating tumor DNA? Current data and prospects in colorectal , non-small cell lung and pancreatic cancers ] .
1 Ten years after the discovery of the predictive value of KRAS status for anti-EGFR antibodies , other genes involved in oncogenesis and therapeutic responses were identified and are now systematically sought .
2 Molecular diagnosis often requires invasive procedures , sometimes iatrogenic , and is limited by feasibility problems , quantity and quality of samples .
3 Identifying these mutations from blood biomarkers would reduce costs and diagnostic delay .
4 The circulating tumor DNA ( ctDNA ) is one of the most promising blood biomarkers .
5 In this review , we report and discuss the latest results obtained with ctDNA in colorectal cancer , non-small cell lung cancer , and adenocarcinoma of the pancreas .
6 Μ If the methods highlighting appear very heterogeneous , the correlation between mutations found in tumor and those identified in the blood exceeds 95 % specificity in numerous studies .
7 The detection sensitivity is in turn strongly related to tumor stage patients .
8 The presence of ctDNA appears as a prognostic factor for progression-free survival and overall survival .
9   Finally , recent studies have shown that the changing rate ctDNA during systemic treatments had a predictive value for therapeutic efficacy .
10 These results allow to consider the use of ctDNA in monitoring patients to identify early recurrence or progression .



PMID: 26788852
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Exploiting the CRISPR/Cas9 PAM Constraint for Single - Nucleotide Resolution Interventions .
1 Long-term survival after excision of a giant esophageal gastrointestinal stromal tumor with imatinib mesylate resistance : report of a case .



PMID: 26787892
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Common BRAF (V600E)- directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma .
1 BACKGROUND :
2 Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer .
3 Compared to the other two commercially available epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors , gefitinib and erlotinib , icotinib is similar to them in chemical structure , mechanism of activity and therapeutic effects .
4 To explore the efficacy and side effects of icotinib hydrochloride in the treatment of the advanced non-small cell lung cancer ( NSCLC ) patients with EGFR mutation and wild-type .
5 METHODS :
6 Patients with advanced NSCLC who were treated with icotinib hydrochloride in Beijing Chest Hospital were retrospective analyzed from March 2009 to December 2014 .
7 RESULTS :
8 The clinical data of 124 patients ( 99 with EGFR mutation and 25 with wild type ) with advanced NSCLC were enrolled in this study .
9 The patients' overall objective response rate ( ORR ) was 51.6 % and the disease control rate ( DCR ) was 79.8% ; The patients with EGFR mutation , ORR was 63.6% , DCR was 93.9% .
10 The ORR was 4.0% and the DCR was 24.0% in the wild-type patients .
11   Median progression-free survival ( PFS ) with icotinib treatment in EGFR mutation patients was 10.5 months and 1.0 month in wild-type patients .
12 The major adverse events were mild skin rash ( 306% ) and diarrhea ( 161% ) .
13 CONCLUSIONS :
14   Monotherapy with icotinib hydrochloride is effective and tolerable for the advanced NSCLC EGFR mutation patients .



PMID: 26781010
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Successful Treatment with Modified FOLFOX6 and Panitumumab in a Cecal Cancer Patient Undergoing Hemodialysis .
1 Combination chemotherapy of mFOLFOX6 ( 5-fluorouracil , leucovorin , and oxaliplatin ) plus panitumumab , a fully human monoclonal antibody against epidermal growth factor receptor ( EGFR ) , is one of the standard treatments for metastatic colorectal cancer ( mCRC ) without KRAS mutation .
2 A few reports suggested no need of dose adjustment of cetuximab , a similar chimeric anti-EGFR antibody , in patients with renal impairment .
3 However , panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported .
4   We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy .



PMID: 26780072
(None)  
Terms: phase III
Sent# Symbols Sentence Mnemonics
0 [ Regorafenib in patients with metastatic colorectal cancer : a review and an update ] .
1 Standard chemotherapy in patients with metastatic colorectal cancer is based on a combination of fluoropyrimidines , irinotecan and oxaliplatin .
2 Regorafenib , an oral multikynase inhibitor blocking multiple disease progression-involved pathways , is a new therapeutic option in patients who already received standard therapy .
3 Μ In a phase III randomized , placebo-controlled study regorafenib , as compared to best supportive care , showed a statistically significant improvement in overall survival , irrespective of KRAS mutation status .
4 Safety profile of regorafenib is acceptable , with few severe grade adverse events which can be adequately managed within few weeks after treatment beginning .
5   Regorafenib is a new treatment standard in patients who already received chemotherapy for metastatic colorectal cancer .



PMID: 26775732
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis .
1 BACKGROUND :
2 Clinical trials investigated the potential role of both KRAS and BRAF mutations , as prognostic biomarkers , in colorectal cancer ( CRC ) patients who underwent surgical treatment of CRC-related liver metastases ( CLM ) , showing conflicting results .
3 This meta-analysis aims to review all the studies reporting survival outcomes ( recurrence free survival ( RFS ) , and/or overall survival ( OS ) ) of patients undergoing resection of CLM , stratified according to KRAS and/or BRAF mutation status .
4 MATERIALS AND METHODS :
5 Data from all published studies reporting survival outcomes ( RFS and/or OS ) of CRC patients who received resection of CLM , stratified by KRAS and/or BRAF mutation status were collected , according to the PRISMA guidelines .
6 Pooled HRs were calculated for both the OS and/or RFS .
7 RESULTS :
8 Seven eligible trials ( 1403 patients ) were included .
9 Μ Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS ( HR : 1.65 ; 95% CI : 1.23-2.21 ) and OS ( HR : 1.86 ; 95% CI : 1.51-2.30 ) in patients who underwent surgical resection of CLM .
10 ✓ BRAF mutations were also associated with a significantly worse OS ( HR : 3.90 ; 95% CI : 1.96-7.73 ) in this subgroup of patients . GM-ASS-RO
11 CONCLUSIONS :
12   This meta-analysis suggests both KRAS and BRAF mutations as poor , prognostic biomarkers , associated with worse survival outcomes , in patients undergoing hepatic resection of CLM .



PMID: 26770060
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Profile of panitumumab as first - line treatment in patients with wild-type KRAS metastatic colorectal cancer .
1 BACKGROUND :
2 The epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor gefitinib is an effective treatment for recurrent or advanced lung cancer harboring EGFR gene mutations , and has improved progression-free survival in several clinical trials .
3 However , the effect of gefitinib treatment for recurrent lung cancers with EGFR gene mutations after complete resection and the influence of the timing of such treatment have not been fully elucidated in a practical setting .
4 METHODS :
5 We investigated 64 patients ( median age : 68 years ; men : 22 ; women : 42 ; adenocarcinoma : 61 ; adenosquamous cell carcinoma : 2 ; combined large cell neuroendocrine carcinoma : 1 ) with recurrent lung cancer after complete resection who received gefitinib for the recurrent lesions and in whom the tumors had EGFR gene mutations .
6 Progression-free survival , response rate , and safety were analyzed .
7 RESULTS :
8 Complete response and partial response were achieved in 2 patients and in 42 patients , respectively ( objective response rate : 69 % ) .
9 Stable disease was obtained in 16 patients , the disease control rate was 94 % , and median progression-free survival was 16 months .
10   The timing of gefitinib treatment ( first line , second line , or later ) and the type of EGFR gene mutation present did not influence progression-free survival .
11 However , a smaller number of recurrent sites at the start of gefitinib treatment was linked to better progression-free survival .
12 Hematologic and nonhematologic toxicities were generally mild , but 1 patient experienced interstitial lung disease .
13 CONCLUSIONS :
14 Our results suggest that gefitinib treatment for recurrent lung cancer with gene EGFR mutations is a useful option in a practical setting , irrespective of the timing of such treatment and the type of EGFR gene mutation present .



PMID: 26768652
(Patient)  
Terms: phase III, prospective
Sent# Symbols Sentence Mnemonics
0 Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin , Fluorouracil , and Oxaliplatin With or Without Cetuximab : A Post Hoc Analysis of the PETACC-8 Trial .
1 Importance : The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin , fluorouracil , and oxaliplatin (FOLFOX)- based adjuvant chemotherapy is controversial , possibly owing to a lack of stratification on mismatch repair status .
2 Objective : To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab .
3 Design , Setting , and Participants : This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial .
4 Mismatch repair , BRAF V600E , and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial .
5 The data were analyzed in April 2015 .
6 Intervention : Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer .
7 Main Outcomes and Measures : Associations between these biomarkers and disease-free survival ( DFS ) and overall survival ( OS ) were analyzed with Cox proportional hazards models .
8 Multivariate models were adjusted for covariates ( age , sex , tumor grade , T/N stage , tumor location , Eastern Cooperative Oncology Group performance status ) .
9 Μ Results : Among the 2559 patients enrolled in the PETACC-8 trial ( 42.9% female ; median [range] age , 60.0 [190-750] years ) , microsatellite instability ( MSI ) phenotype , KRAS , and BRAF V600E mutations were detected in , respectively , 9.9% ( 177 of 1791 ) , 33.1% ( 588 of 1776 ) , and 9.0% ( 148 of 1643 ) of cases .
10 ✓ In multivariate analysis , MSI ( hazard ratio [HR] for DFS : 1.10 [95% CI , 073-164] , P = .67 ; HR for OS : 1.02 [95% CI , 061-169] , P = .94 ) and BRAF V600E mutation ( HR for DFS : 1.22 [95% CI , 081-185] , P = .34 ; HR for OS : 1.13 [95% CI , 064-200] , P = .66 ) were not prognostic , whereas KRAS mutation was significantly associated with shorter DFS ( HR , 1.55 [95% CI , 123-195] ; P <.001 ) and OS ( HR , 1.56 [95% CI , 112-215] ; P = .008 ) . GM-ASS-RO
11 ✓ The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS ( HR for DFS : 1.64 [95% CI , 129-208] , P <.001 ; HR for OS : 1.71 [95% CI , 121-241] , P = .002 ) and BRAF V600E mutation ( HR for DFS : 1.74 [95% CI , 114-269] , P = .01 ; HR for OS : 1.84 [95% CI , 101-336] , P = .046 ) were independently associated with worse clinical outcomes . GM-ASS-RO, GE-ASS-RO
12 ✓ In patients with MSI tumors , KRAS status was not prognostic , whereas BRAF V600E mutation was associated with significantly longer DFS ( HR , 0.23 [95% CI , 006-092] ; P = .04 ) but not OS ( HR , 0.19 [95% CI , 003-124] ; P = .08 ) . GM-ASS-RO
13 ✓ Conclusions and Relevance : BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors . GM-ASS-RO
14 Future trials in the adjuvant setting will have to take into account mismatch repair , BRAF , and KRAS status for stratification .
15 Trial Registration : EudraCT 2005-003463-23 .



PMID: 26768497
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Histopathological study using computer database of 10 000 consecutive gastric specimens : (2) malignant lesions .
1 BACKGROUND :
2 The combination of radiotherapy and epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors ( TKIs ) such as erlotinib and gefitinib in patients with advanced or metastatic non-small cell lung cancer ( NSCLC ) has not been widely investigated .
3 For afatinib , a new second generation irreversible pan-EGFR TKI , no clinical trials in this setting have as yet been performed .
4 CASE REPORT :
5 We report a patient with a pretreated metastatic NSCLC receiving afatinib in combination with concomitant palliative radiotherapy to the mediastinum and primary lung tumor .
6 The treatment was feasible and well tolerated .
7 The patient achieved a partial response in the irradiated tumor region and the metastatic sites .
8 CONCLUSION :
9 The combination of afatinib and radiotherapy is promising and should be investigated further .
10   However , because of the limited experience and potential side effects known for other EGFR TKIs , a decision for treatment outside a clinical trial has to be made very carefully , balancing the risk and benefit on an individual patient basis .



PMID: 26768236
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 B-Raf Inhibition in the Clinic : Present and Future .
1 Somatic activating mutations in the B-Raf kinase ( BRAF mutations ) are present in hairy - cell leukemia , cutaneous melanoma , thyroid carcinomas and , less commonly , in ovarian , colon , lung , and other malignancies .
2 These mutations-in particular the most common substitution , V600E-are oncogenic drivers and important therapeutic targets .
3 The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic .
4 In BRAF-mutant melanomas , orally bioavailable B-Raf inhibitors , such as vemurafenib , achieve dramatic responses initially , but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches .
5 In tumors with wild-type B-Raf , vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated , highlighting again the importance of genotype-based clinical decision making .
6 These advances were greatly facilitated by the study of biopsied tumor tissue , especially at the time of drug resistance .
7 Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future .



PMID: 26766738
(None)  
Terms: Phase II study
Sent# Symbols Sentence Mnemonics
0 Phase II study of necitumumab plus modified FOLFOX6 as first - line treatment in patients with locally advanced or metastatic colorectal cancer .
1 Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells .



PMID: 26764183
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers .
1 BACKGROUND & ; AIMS : A long duration of inflammatory bowel disease ( IBD ) increases the risk for colorectal cancer .
2 Μ Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD .
3 We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors .
4 METHODS :
5 We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer ( 15 with ulcerative colitis , 14 with Crohn's disease , and 2 with indeterminate colitis ) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues .
6 Μ We identified somatic alterations by comparing matched specimens .
7 Μ The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies .
8 RESULTS :
9 Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE , MLH1 , and MSH6 and the tumor cells had a hypermutable phenotype .
10 The remaining tumors had , on average , 71 alterations per sample .
11 TP53 was the most commonly mutated gene , with prevalence similar to that of sporadic colorectal tumors ( 63% of cases ) .
12 However , tumors from the patients with IBD had a different mutation spectrum .
13 APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors ( 13% and 20% of cases , respectively ) .
14 Μ Several genes were mutated more frequently or uniquely in tumors from patients with IBD , including SOX9 and EP300 ( which encode proteins in the WNT pathway ) , NRG1 ( which encodes an ERBB ligand ) , and IL16 ( which encodes a cytokine ) .
15 Μ Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network , indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD .
16 CONCLUSIONS :
17 Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors .
18   These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer .



PMID: 26762843
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Quantitative Detection and Resolution of BRAF V600 Status in Colorectal Cancer Using Droplet Digital PCR and a Novel Wild-Type Negative Assay .
1 Sporadic diffuse segmental interstitial cell of Cajal hyperplasia harbouring two gastric gastrointestinal stromal tumours ( GIST ) mimicking hereditary GIST syndromes .



PMID: 26759349
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer .
1 BACKGROUND :
2 Both bevacizumab and anti-epithelial growth factor receptor ( EGFR ) agents ( e.g. cetuximab and panitumumab ) are sequentially used for metastatic colorectal cancer ( mCRC ) .
3 Their co-administration as a first - line treatment does not improve outcome , indicating that there are negative interactions between these agents .
4 A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration .
5 This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti-EGFR therapy .
6 METHODS :
7 We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines , oxaliplatin and irinotecan .
8 We divided patients into two groups ( Group A : the interval between bevacizumab and anti-EGFR agent<6 months ; Group B : the interval >6 months ) .
9 RESULTS :
10 Of the 114 included patients ( median age , 63 years ) , 78 ( 68% ) were male .
11 Most patients ( 88% ) were treated with cetuximab plus irinotecan .
12 Groups A and B consisted of 74 and 40 patients , respectively .
13 There were no significant differences in patient characteristics .
14 Group B patients had significantly longer progression-free survival ( 42 vs. 66 months ; HR , 065 ; 95% CI , 043-098 ; P = 0038 ) and longer overall survival ( 116 vs. 143 months ; HR , 063 ; 95% CI , 041-098 , P = 0039 ) .
15 The response rate was 24.3% in Group A and 47.5% in Group B ( P = 0012 ) .
16 CONCLUSION :
17   A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy .



PMID: 26752111
(Patient)  
Terms: prospective, observational study
Sent# Symbols Sentence Mnemonics
0 Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study .
1 BACKGROUND & ; AIMS : Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers ( CRCs ) are poorly understood .
2 Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability ( E/L ) are more likely to have disease recurrence after treatment .
3 Hypoxia and/or inflammation not only promote metastasis , but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus .
4 Μ We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival .
5 METHODS :
6 We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan .
7 Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity ( LOH ) as possible consequences of MSH3 deficiency .
8 Highly altered loci were examined for association with E/L in liver metastases .
9 We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L .
10 RESULTS :
11 LOH at several loci at chromosome 9p24.2 ( 9p242-LOH ) was associated with E/L in liver metastases ( odds ratio = 10.5 ; 95% confidence interval : 2.69-40.80 ; P = .0007 ) .
12 Μ We found no significant difference in the frequency of E/L , 9p24.2-LOH , mutations in KRAS or BRAF , or the combination of E/L and 9p24.2-LOH , between primary colorectal tumors and their matched metastases .
13 Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence ( hazard ratio = 0.25 ; 95% CI : 0.12-0.50 ; P = .0001 ) , compared with patients without with E/L and 9p24.2-LOH .
14 E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC ( hazard ratio = 0.06 ; 95% CI : 0.01-0.57 ; P = .01 ) .
15 CONCLUSIONS :
16 E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors .



PMID: 26750638
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2 .
1 Although BRAF (V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer ( CRC ) , response and resistance mechanisms for therapeutic BRAF (V600E) inhibitors remains poorly understood .
2 In the present study , we demonstrate that selective BRAF (V600E) inhibition activates AMP-activated protein kinase ( AMPK ) , which induces autophagy as a mechanism of therapeutic resistance in human cancers .
3 The present data show AMPK -dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF (V600E) inhibition , and AMPK was negatively correlated with BRAF (V600E)- dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 ( ULK1 ) , a key initiator of autophagy .
4 Furthermore , selective BRAF (V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis .
5 Taken together , present experiments indicate that AMPK plays a role in the survival of BRAF (V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF (V600E) CRC cells .



PMID: 26749281
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Molecular pathways : targeting NRAS in melanoma and acute myelogenous leukemia .
1 BACKGROUND :
2 Kirsten rat sarcoma virus ( KRAS ) wild-type status determined using a LONGTOKEN predicted response to therapy in the CRYSTAL ( Cetuximab Combined With Irinotecan in First - Line Therapy for Metastatic Colorectal Cancer ) study .
3 A companion KRAS diagnostic tool has been developed for routine clinical use ( QIAGEN therascreen kit ) ( QIAGEN Manchester Ltd , Manchester , UK ) .
4 We wanted to assess the concordance between the validated US Food and Drug Administration ( FDA )- approved therascreen assay and the LNA assay in determining the KRAS status of a subset of patients enrolled in the CRYSTAL study .
5 PATIENTS AND METHODS :
6 DNA extracted from paraffin-embedded tumor sections was tested for KRAS status using the therascreen assay .
7 Efficacy data from the CRYSTAL study were assessed to determine if the overall survival ( OS ) hazard ratio for cetuximab in patients identified as having KRAS wild-type status using the therascreen assay was equivalent to that in patients identified as KRAS wild-type using the LNA assay .
8 This was determined by assessing if the concordance between the therascreen assay and the LNA assay met the minimum threshold ( prespecified as 08 ) to achieve a significant difference in the OS hazard ratio in favor of the cetuximab + FOLFIRI ( 5-fluorouracil , leucovorin [folinic acid] , irinotecan ) arm in the KRAS wild-type population as identified using the therascreen assay .
9 RESULTS :
10 Of the 148 samples determined to be KRAS wild-type ( therascreen assay ) , 141 ( 953% ) samples were also KRAS wild-type (LNA assay) and 7 samples ( 47% ) were KRAS mutant (LNA assay) .
11 The prespecified primary concordance measure p was 141/148 = 0.953 ( 95% confidence interval [CI] , 0.905-0.981 ) .
12 The concordance was statistically significantly higher than the prespecified threshold of 0.8 for concordance between the therascreen assay and the LNA assay .
13 Consistent with the concordance exceeding the prespecified threshold , the OS hazard ratio ( cetuximab + FOLFIRI arm vs . FOLFIRI arm ) in the KRAS wild-type population , determined by the therascreen assay , supported a significant benefit for cetuximab ( ie , the 95% CI excluded 1 ) and was comparable to the OS hazard ratio observed in the CRYSTAL study KRAS wild-type population (LNA assay) even after adjustment for potentially confounding baseline variables .
14 CONCLUSION :
15   These results support the utility of the therascreen assay for identifying patients who may benefit from cetuximab therapy for metastatic colorectal cancer .



PMID: 26747707
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 CDKN2A mutations could influence the dermoscopic pattern of presentation of multiple primary melanoma : a clinical dermoscopic genetic study .
1 BACKGROUND :
2 Colorectal cancers ( CRCs ) that have microsatellite instability ( MSI ) and mutL homolog 1 ( MLH1 ) immunoloss are observed in 3 clinical scenarios : Lynch syndrome ( LS ) , sporadic MSI CRC , and Lynch-like syndrome ( LLS ) .
3 Μ v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC .
4 The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established .
5 The objectives of this study were : 1 ) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing , and 2 ) to assess its role in the differential diagnosis of MLH1-deficient CRCs .
6 METHODS :
7 Μ In total , 165 CRCs were analyzed , including LS ( n = 19 ) , MSI BRAF-mutated CRC ( n = 37 ) , MSI BRAF wild-type CRC ( n = 60 ) , and a control group of CRCs without MSI ( microsatellite stable [MSS] CRC ; n = 49 ) .
8 MLH1 promoter methylation status was analyzed by pyrosequencing , and the ability of different strategies to identify LS was assessed .
9 RESULTS :
10 The average +/- standard deviation methylation in LS ( 9% +/- 7% ) was significantly lower than that in MSI BRAF-mutated CRC ( 42% +/- 17% ; P <001 ) and in MSI BRAF wild-type CRC ( 25% +/- 19% ; P = 002 ) .
11 Somatic MLH1 hypermethylation was detected in 3 patients ( 158% ) with LS , in 34 patients ( 919% ) with MSI BRAF-mutated CRC , and in 37 patients ( 617% ) with MSI BRAF wild-type tumors .
12 Patients with MSI BRAF wild-type , unmethylated tumors ( ie , LLS ) had a stronger family history of CRC than those who had tumors with MLH1 methylation ( P <05 ) .
13 The sensitivity for ruling out LS was 100% for BRAF analysis , 84.2% for MLH1 methylation analysis , and 84.2% for the combination of both analyses .
14 CONCLUSIONS :
15 Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs .
16 Somatic BRAF analysis is the most sensitive strategy for ruling out LS .
17 Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS .



PMID: 26747035
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Validation of targeted next-generation sequencing for RAS mutation detection in FFPE colorectal cancer tissues : comparison with Sanger sequencing and ARMS-Scorpion real-time PCR .
1 OBJECTIVE :
2 To validate the targeted next-generation sequencing ( NGS ) platform-Ion Torrent PGM for KRAS exon 2 and expanded RAS mutations detection in formalin-fixed paraffin-embedded ( FFPE ) colorectal cancer ( CRC ) specimens , with comparison of Sanger sequencing and ARMS-Scorpion real-time PCR .
3 SETTING :
4 Beijing , China .
5 PARTICIPANTS :
6 51 archived FFPE CRC samples ( 36 men , 15 women ) were retrospectively randomly selected and then checked by an experienced pathologist for sequencing based on histological confirmation of CRC and availability of sufficient tissue .
7 METHODS :
8 Μ RAS mutations were detected in the 51 FFPE CRC samples by PGM analysis , Sanger sequencing and the Therascreen KRAS assay , respectively .
9 Agreement among the 3 methods was assessed .
10 Assay sensitivity was further determined by sequencing serially diluted DNA from FFPE cell lines with known mutation statuses .
11 RESULTS :
12 Μ 13 of 51 ( 255% ) cases had a mutation in KRAS exon 2 , as determined by PGM analysis .
13 PGM analysis showed 100% ( 51/51 ) concordance with Sanger sequencing ( kappa = 1000 , 95% CI 1 to 1 ) and 98.04% ( 50/51 ) agreement with the Therascreen assay ( kappa = 0947 , 95% CI 0844 to 1 ) for detecting KRAS exon 2 mutations , respectively .
14 Μ The only discrepant case harboured a KRAS exon 2 mutation ( c37G>T ) that was not covered by the Therascreen kit .
15 Μ The dilution series experiment results showed that PGM was able to detect KRAS mutations at a frequency of as low as 1% .
16 Μ Importantly , RAS mutations other than KRAS exon 2 mutations were also detected in 10 samples by PGM .
17 Μ Furthermore , mutations in other CRC-related genes could be simultaneously detected in a single test by PGM .
18 CONCLUSIONS :
19 The targeted NGS platform is specific and sensitive for KRAS exon 2 mutation detection and is appropriate for use in routine clinical testing .
20 Moreover , it is sample saving and cost-efficient and time-efficient , and has great potential for clinical application to expand testing to include mutations in RAS and other CRC-related genes .



PMID: 26744320
(Cell)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 Oncogenic KRAS activates an embryonic stem cell -like program in human colon cancer initiation .
1 Colorectal cancer is the third most frequently diagnosed cancer worldwide .
2 Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality .
3 Activating KRAS mutation ( KRASmut ) is the most prevalent oncogenic driver in colorectal cancer development , and KRASmut inhibition represents an unmet clinical need .
4 We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues .
5 We find that KRASmut imposes the embryonic stem cell -like program during human colon cancer initiation from colon adenoma to stage I carcinoma .
6 Expression of miR145 , an embryonic SC program inhibitor , promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity .
7 Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell -like program induced by KRASmut to optimize malignant transformation .
8 Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer .



PMID: 26742007
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Loss of CDH1 ( E-cadherin ) expression is associated with infiltrative tumour growth and lymph node metastasis . GE-ASS-RO
1 BACKGROUND :
2 Loss of CDH1 ( E-cadherin ) expression in cancer cells may promote cell migration and invasion .
3 Therefore , we hypothesised that loss of CDH1 expression in colorectal carcinoma might be associated with aggressive features and clinical outcome .
4 METHODS :
5 Utilising molecular pathological epidemiology database of 689 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study , we assessed tumour CDH1 expression by immunohistochemistry .
6 Multivariate logistic regression analysis was conducted to assess association of CDH1 loss with tumour growth pattern ( expansile-intermediate versus infiltrative ) and lymph node metastasis and distant metastasis , controlling for potential confounders including microsatellite instability , CpG island methylator phenotype , LINE-1 methylation , and PIK3CA , BRAF and KRAS mutations .
7 Mortality according to CDH1 status was assessed using Cox proportional hazards model .
8 RESULTS :
9 Μ Loss of tumour CDH1 expression was observed in 356 cases ( 52% ) , and associated with infiltrative tumour growth pattern ( odds ratio ( OR ) , 2.02 ; 95% confidence interval ( CI ) , 1.23-3.34 ; P = 0.006 ) and higher pN stage ( OR , 173 ; 95% CI , 123-243 ; P = 0001 ) .
10 ✓ Tumour CDH1 expression was not significantly associated with distant metastasis or prognosis . GE-ASS-RO
11 CONCLUSIONS :
12 Loss of CDH1 expression in colorectal cancer is associated with infiltrative tumour growth pattern and lymph node metastasis .



PMID: 26735530
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Relationship Between 18F-Fluorodeoxyglucose Uptake and V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Mutation in Colorectal Cancer Patients : Variability Depending on C-Reactive Protein Level .
1 To evaluate clinical values of clinicopathologic and 18F-fluorodeoxyglucose ( 18F-FDG ) positron emission tomography/computed tomography ( PET/CT )- related parameters for prediction of v-Ki-ras2 rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutation in colorectal cancer ( CRC ) and to investigate their variability depending on C-reactive protein ( CRP ) levels .
2 In total , 179 CRC patients who underwent PET/CT scans before curative resection and KRAS mutation evaluation following surgery were enrolled .
3 Maximum standardized uptake value ( SUV max ) , peak standardized uptake value ( SUV peak ) , metabolic tumor volume , and total lesion glycolysis were determined semiquantitatively .
4 Associations between clinicopathologic and PET/CT-related parameters and KRAS expression were analyzed .
5 Elevated CRP ( >60 mg/L ; n = 47 ) was associated with higher primary tumor size , higher SUV max , SUV peak , metabolic tumor volume , and total lesion glycolysis , compared with those for the group with a CRP lower than that the cutoff value ( <60 mg/L ; n = 132 ) .
6 Interestingly , the CRC patients ( having CRP <60 mg/L ) with KRAS mutations had significantly higher ( P <005 ) SUV max and SUV peak values than the patients expressing wild-type KRAS mutations .
7 Multivariate analysis revealed SUV max and SUV peak to be significantly associated with KRAS mutations ( odds ratio = 33 , P = 0005 , and odds ratio = 39 , P = 0004 ) , together with histologic grade and lymph node metastasis. 18F-FDG uptake was significantly higher in CRC patients with KRAS mutations and with normal CRP levels .
8 A severe local inflammation with raised CRP levels , however , might affect accurate 18F-FDG quantification in CRC tumors .
9 Positron emission tomography/computed tomography-related parameters could supplement genomic analysis to determine KRAS expression in CRC ; however , care should be exercised to guarantee proper patient selection .



PMID: 26732779
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 QIAGEN Therascreen KRAS RGQ Assay , QIAGEN KRAS Pyro Assay , and Dideoxy Sequencing for Clinical Laboratory Analysis of KRAS Mutations in Tumor Specimens .
1 OBJECTIVE :
2 To compare the performance of assays used to assess KRAS mutations in tumor specimens .
3 METHODS :
4 We analyzed DNA extracted from 30 formalin-fixed paraffin-embedded ( FFPE ) tumor specimens using the QIAGEN Therascreen KRAS RGQ and QIAGEN Pyro reagents , with dideoxy sequencing ( colloquially considered to be the gold standard ) as the reference method .
5 RESULTS :
6 Μ We detected 22 codon 12 or 13 KRAS mutations using the Pyro assay , whereas the RGQ assay detected 19 mutations .
7 For mutation detection , the clinical sensitivity was 86% for the RGQ assay compared with 100% for the Pyro but 100% for the KRAS mutations that the RGQ was predesigned to detect .
8 Μ The Pyro could detect rare mutations .
9 The RGQ demonstrated a lower limit of detection compared with the Pyro ; However , the Pyro required less DNA input than the RGQ .
10 CONCLUSION :
11 The 2 assays that we tested yielded comparable performance in detecting KRAS mutations , as we had expected based on assay design .
12 Μ Overall , the Pyro assay detects more mutations and requires less DNA input but is less analytically sensitive , compared with the RGQ assay .



PMID: 26719345
(Cell)  
Terms: xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer .
1 BACKGROUND :
2 The antibody cetuximab , targeting epidermal growth factor receptor ( EGFR ) , is used to treat metastatic colorectal cancer ( mCRC ) .
3 Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin .
4 The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin .
5 METHODS :
6 Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions .
7 Reactive oxygen species ( ROS ) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production .
8 Chromatin immunoprecipitation ( ChIP ) measured signal transducer and activator of transcription 1 ( STAT-1 ) binding to dual oxidase 2 ( DUOX2 ) promoter .
9 SW48 , DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab , oxaliplatin , or oxaliplatin + cetuximab ( control [saline] ; n = 3 mice per treatment group ) were used .
10 Statistical tests were two-sided .
11 RESULTS :
12 Cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis ( caspase 3/7 activity reduced by 1.4-fold , 95% confidence interval [CI] = 0.78 to 2.11 , P = .003 ) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38) .
13 Although both oxaliplatin and SN-38 produced ROS , only oxaliplatin-mediated apoptosis was ROS dependent .
14 Production of ROS by oxaliplatin was secondary to STAT1 -mediated transcriptional upregulation of DUOX2 ( 31-fold , 95% CI = 175 to 241 , P <001 ) .
15 Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity .
16 CONCLUSIONS :
17 Inhibition of STAT1 and DUOX2 -mediated ROS generation by cetuximab impairs p38 -dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings .
18   Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR inhibitors with chemotherapeutic agents in future therapeutic use .



PMID: 28626587
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 KRAS testing and first - line treatment among patients diagnosed with metastatic colorectal cancer using population data from ten National Program of Cancer Registries in the United States .
1 BACKGROUND :
2 In 2011 , the National Comprehensive Cancer Network ( NCCN ) recommended KRAS testing for metastatic colorectal cancer ( mCRC ) patients .
3 Our study assessed KRAS testing prevalence and its association with socio-demographic and clinical factors and examined first - line treatment .
4 METHODS :
5 Ten state population-based registries supported by Centers for Disease Control and Prevention's ( CDC ) National Program of Cancer Registries ( NPCR ) collected detailed cancer information on mCRC cases diagnosed in 2011 , including KRAS biomarker testing and first - line treatment from ten central cancer registries .
6 Data were analyzed with Chi-square tests and multivariate logistic regression .
7 RESULTS :
8 Of the 3,608 mCRC cases , 27% ( n = 992 ) had a documented KRAS test .
9 Increased age at diagnosis ( p <00001 ) , racial/ethnic minorities ( p = 00155 ) , public insurance ( p = 00018 ) , and lower census tract education ( p = 00023 ) were associated with less KRAS testing .
10 Significant geographic variation in KRAS testing ( p <00001 ) ranged from 46% in New Hampshire to 18% in California .
11 After adjusting for all covariates , age and residence at diagnosis ( both p <00001 ) remained predictors of KRAS testing .
12 Non-Hispanic Blacks had less KRAS testing than non-Hispanic Whites ( OR = 077 , 95% CI = 061-097 ) .
13 Among those tested and found to have normal ( wild-type ) KRAS , 7% received anti-EGFR treatment ; none received such treatment among those with KRAS mutated gene .
14 CONCLUSIONS :
15 Despite NCCN guideline recommendations , 73% of mCRC cases diagnosed in 2011 had no documented KRAS test .
16 Disparities in KRAS testing existed based on age , race , and residence at diagnosis .
17 IMPACT :
18 These findings show the capacity of monitoring KRAS testing in the US using cancer registry data and suggest the need to understand the low uptake of KRAS testing , and associated treatment choices during the first year since diagnosis .



PMID: 28356789
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Significance of KRAS , NRAS , BRAF and PIK3CA mutations in metastatic colorectal cancer patients receiving Bevacizumab : a single institution experience .
1 The detection of BRAF mutation in colorectal cancer has several clinical applications : enabling the discrimination between sporadic and Lynch syndrome-related colorectal carcinoma , and providing warning of a poorer prognosis .
2 Few immunohistochemical studies using whole - tissue tumor section staining have recently been performed on colorectal cancer .
3 The aim of this study was to evaluate the detection of BRAF mutation by immunohistochemistry ( IHC ) on tissue microarray ( TMA ) .
4 IHC was performed with the BRAF-specific antibody using TMA on a retrospective series of 86 colonic adenocarcinomas with known BRAF status .
5 Μ IHC using BRAF-specific antibody allowed to detect 20/21 BRAF mutated colonic adenocarcinomas and 60/65 BRAF wild-type cases .
6 The staining was equivocal because of equivocal staining in 4 cases and heterogeneity in 3 cases .
7 When compared with TaqMan real-time PCR , the sensitivity and specificity were 95.2% and 92.3% , respectively .
8 Comparison with the whole section immunostaining improved sensitivity to 100% and specificity to 95.4% .
9 Μ Furthermore , in this study we found that BRAF mutated colonic adenocarcinoma were significantly more frequent in women , older patients , and right-sided .
10 Moreover , morphologic features significantly associated with BRAF mutation were : serrated adenocarcinoma subtype , adenocarcinomas with a mucinous component , high histologic grade , pushing margins , stromal inflammation .
11 Μ BRAF-specific antibody can be used on TMA to screen BRAF-mutated colorectal carcinomas .
12 Cases with equivocal or heterogenous staining must be compared with whole section staining .
13 Moreover , BRAF mutated colonic carcinomas have distinct clinical and histopathologic features .



PMID: 26716438
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The prognostic value of Microsatellite Instability , KRAS , BRAF and PIK3CA mutations in stage II colon cancer patients .
1 ✓ ABSTRACT The presence of EGFR mutations predicts the sensitivity to EGF receptor ( EGFR )- tyrosine kinase inhibitors in a molecularly defined subset of non-small-cell lung carcinoma ( NSCLC ) patients .
2 For this reason , EGFR testing of NSCLC is required to provide personalized treatment options and better outcomes for NSCLC patients .
3 As surgery specimens are not available in the majority of NSCLC , other currently available DNA sources are small biopsies and cytological samples , providing however limited and low-quality material .
4 In order to address this issue , the use of surrogate sources of DNA , such as blood , serum and plasma samples , which often contains circulating free tumor DNA or circulating tumor cells , is emerging as a new strategy for tumor genotyping .



PMID: 26715198
(Patient)  
Terms: retrospective, prospective studies
Sent# Symbols Sentence Mnemonics
0 KRAS mutation in lung metastases from colorectal cancer : prognostic implications .
1 Μ KRAS mutant colorectal cancer ( CRC ) patients develop lung and brain metastases more frequently than KRAS wild-type ( WT ) counterpart .
2 We retrospectively investigated the prognostic role of KRAS , BRAF , and PIK3CA ( exon 20 ) mutations and loss of phosphatase and tensin homolog ( PTEN ) in surgically resected lung metastases .
3 Lung specimens from 75 metastatic CRC ( mCRC ) patients treated with one or more metastasectomies with curative intent were analyzed .
4 Sixty-four percent of patients had KRAS WT lung metastases .
5 PTEN loss-of-function was found in 75% .
6 Μ BRAF and PIK3CA exon 20 mutations were not found .
7 Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation .
8 ✓ In univariate analysis , median overall survival ( OS ) for KRAS WT patients was longer , compared to KRAS mutant patients ( median 609 vs. 366 months , P = 0035 ) . RO-ASS-GM
9 ✓ In addition , both progression-free survival ( PFS ) and lung disease-free survival ( LDFS ) between lung surgery and relapse were not associated with KRAS and PTEN status . RO-ASS-GE
10 In multivariate analysis , the risk of death was significantly increased by KRAS mutational status ( OS Hazard ratio ( HR ) 2.17 , 95% IC 1.19-3.96 , P = 0.012 ) and lack of adjuvant chemotherapy ( OS HR 010 , 95% IC 001-074 , P = 0024 ) .
11 The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors .
12 ✓ Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis . RO-ASS-GM
13 Moreover , administration of adjuvant chemotherapy after lung metastasectomy ( LM ) significantly improved both PFS and OS .
14 KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM .
15 Further larger and prospective studies are necessary to confirm these findings .



PMID: 26715116
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A kinome siRNA screen identifies HGS as a potential target for liver cancers with oncogenic mutations in CTNNB1 .
1 BACKGROUND :
2 Aberrant activation of the Wnt/beta-catenin pathway is a major and frequent event in liver cancer , but inhibition of oncogenic beta-catenin signaling has proven challenging .
3 The identification of genes that are synthetically lethal in beta-catenin-activated cancer cells would provide new targets for therapeutic drug design .
4 METHODS :
5 We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 ( gene coding for beta-catenin ) to obtain an isogenic cell line pair with or without aberrant beta-catenin signaling .
6 Using this hepatoblastoma isogenic cell line pair , we performed a human kinome-wide siRNA screen to identify synthetic lethal interactions with oncogenic CTNNB1 .
7 The phenotypic readouts of the screen were cell proliferation , cell cycle arrest and apoptosis , which were assessed by image-based analysis .
8 In addition , apoptosis was assessed by flow cytometric experiments and immunoblotting .
9 The potential synthetic lethal relationship between candidates genes identified in the screen and oncogenic CTNNB1 was also investigated in a different cellular context , a colorectal HCT116 isogenic cell line pair .
10 RESULTS :
11 We first determined the experimental conditions that led to the efficient expression of shRNA against CTNNB1 and maximal reduction of beta-catenin signaling activity in response to doxycycline treatment .
12 Μ Following high throughput screening in which 687 genes coding for kinases and proteins related to kinases ( such as pseudokinases and phosphatases ) were targeted , we identified 52 genes required for HuH6 survival .
13 The silencing of five of these genes selectively impaired the viability of HuH6 cells with high beta-catenin signaling : HGS , STRADA , FES , BRAF and PKMYT1 .
14 Among these candidates , HGS depletion had the strongest inhibitory effect on cell growth and led to apoptosis specifically in HuH6 with high beta-catenin activity , while HuH6 with low beta-catenin activity were spared .
15 In addition , HGS was identified as a potential synthetic lethal partner of oncogenic CTNNB1 in the HCT116 colorectal isogenic cell line pair .
16 CONCLUSIONS :
17 These results demonstrate the existence of crosstalk between beta-catenin signaling and HGS .
18 Importantly , HGS depletion specifically affected cells with uncontrolled beta-catenin signaling activity in two different types of cancer ( Hepatoblastoma HuH6 and colorectal HCT116 ) , and thus may represent a new potential target for novel therapeutic strategies in liver and colorectal cancer .



PMID: 26715098
(None)  
Terms: xenograft, rat
Sent# Symbols Sentence Mnemonics
0 Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation .
1 Metastatic colorectal cancer ( CRC ) patients with v-Ki-ras2 rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab .
2 BKM120 targets phosphatidylinositide-3-kinase ( PIK3CA ) , but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC .
3 Human CRC cell lines with KRAS mutations ( DLD-1 , HCT116 , and LoVo ) were used to test the effect of cetuximab , BKM120 , and cetuximab plus BKM120 on cell proliferation in vitro and in vivo .
4 BKM120 reduced cell proliferation in a concentration -dependent manner in the LoVo ( PI3KCA wild type ) as well as the HCT116 and DLD1 cells ( that carry a PI3KCA mutation ) .
5 BKM120 only inhibited ERK phosphorylation in LoVo cells ( PIK3CA wild type ) , but not in DLD1 or HCT116 cells at a concentration of 1 mumol/L .
6 Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone ( P = 0034 ) .
7 BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation .



PMID: 26714964
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF Mutation Testing and Metastatic Colorectal Cancer in the Community Setting : Is There an Urgent Need for More Education ?
1 BACKGROUND :
2 Patients with metastatic colorectal cancer ( mCRC ) with BRAF mutation ( BRAF MT ) generally have a poorer prognosis .
3 BRAF MT may also have implications for treatment strategy .
4 Despite this , inclusion of BRAF in routine molecular testing varies .
5 Here we report the frequency of BRAF reporting in the South Australian ( SA ) mCRC registry reflecting community practice , together with the survival outcomes based on mutation status .
6 METHODS :
7 The SA population-based mCRC registry was analysed to assess the number of patients where a BRAF MT result was available .
8 The patient characteristics are reported and overall survival was analysed using the Kaplan-Meier method .
9 RESULTS :
10 Of the 3639 patients who have been entered in the registry , only 6.2% ( 227 ) have BRAF MT results available .
11 Of the patients tested , the BRAF MT rate is 12.7% .
12 The mutation rate was highest in rightsided primary ; right colon 23 versus left colon 8.9% and rectum 7% .
13 There was no significant difference in median age or male/female proportion .
14 The median overall survival ( mOS ) for BRAF MT versus wild-type ( WT ) patients is 14.0 versus 32.9 months ( p = 0003 ) .
15   For patients who have chemotherapy ( plus or minus surgery ) the mOS is 14.6 months BRAF MT versus 36.1 months ( p
16 Liver or lung resection was performed on only 8% of the BRAF MT group versus 26.5% of the WT group .
17 CONCLUSION :
18 Results in a population setting confirm our understanding that BRAF MT is more frequently right sided and of lower frequency in rectal cancer .
19   Survival is lower for patients with mCRC that have BRAF MT , regardless of the therapy .
20 BRAF testing is currently performed infrequently in an Australian setting despite its importance as a significant prognostic factor , and the implications for alternate therapeutic approaches .



PMID: 26709701
(Cell)  
Terms: In Vivo, xenograft, in vivo, mouse, mouse xenograft, mouse xenograft models
Sent# Symbols Sentence Mnemonics
0 KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer : Potential Role of Tumor Metabolism .
1 In non-clinical studies , the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro .
2 In contrast , antitumor activity in xenograft tumors is model -dependent , with some solid tumors showing no response to ixazomib .
3 In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models .
4 A survey of 14 non-small cell lung cancer ( NSCLC ) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype ; tumors with wild-type ( WT ) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations .
5 ✓ To confirm the association between KRAS genotype and ixazomib sensitivity , we used SW48 isogenic colon cancer cell lines .
6 Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS .
7 SW48 KRAS WT tumors , but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors , were sensitive to ixazomib in vivo .
8 Since activated KRAS is known to be associated with metabolic reprogramming , we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib .
9 Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors , reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors .
10 Ixazomib treatment resulted in significant metabolic regulation , and some of these changes were specific to KRAS WT tumors .
11 Depletion of free amino acid pools and activation of GCN2-eIF2alpha-pathways were observed both in tumor types .
12 However , changes in lipid beta oxidation were observed in only the KRAS WT tumors .
13 The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition .



PMID: 26706114
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells .
1 Ras converting enzyme 1 ( Rce1 ) is an endoprotease that catalyzes processing of the C - terminus of Ras protein by removing -aaX from the CaaX motif .
2 The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions .
3 Ras is responsible for transmitting signals related to cell proliferation , cell cycle progression , and apoptosis .
4 The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer .
5 Ras , its effectors and regulators , and the enzymes that are involved in its maturation process are all targets for anti-cancer therapeutics .
6 Key enzymes required for Ras maturation and localization are the farnesyltransferase ( FTase ) , Rce1 , and isoprenylcysteine carboxyl methyltransferase ( ICMT ) .
7 Among these proteins , the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been fully explored .
8 Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics .
9 Structure -activity relationship ( SAR ) analysis of a previously reported Rce1 inhibitor , NSC1011 , has been performed to generate a new library of Rce1 inhibitors .
10 Μ The new inhibitors caused a reduction in Rce1 in vitro activity , exhibited low cell toxicity , and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression .
11 Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor ( FTI ) , which is significant because of the preponderance of K-Ras mutations in cancer .



PMID: 26704847
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Relevance of the novel IASLC/ATS/ERS classification of lung adenocarcinoma in advanced disease .
1 Disruption of CRAF -mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors .



PMID: 26702883
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Methylator phenotype in colorectal cancer : A prognostic factor or not ?
1 Colorectal cancer ( CRC ) is due to different types of genetic alterations that are translated into different phenotypes .
2 Among them , CpG island methylator phenotype ( CIMP+ ) is the most recently involved in carcinogenesis of some CRC .
3 The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes .
4 CIMP+ are reported to be more frequently found in the elderly and in women .
5 Μ The tumors are more frequently located in the proximal part of the colon , BRAF mutated and are associated with microsatellite instability ( MSI ) phenotype .
6 All sporadic MSI CRC belong to the methylator phenotype , however some non MSI CRC may also harbor a methylator phenotype .
7 The prognostic value of CIMP is not well known .
8   Most studies show a worse prognosis in CIMP+ CRC , and adjuvant treatments seem to be more efficient .
9 We review here the current knowledge on prognostic and predictive values in CIMP+ CRC .



PMID: 26702772
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin .
1 Multiple proliferation-survival signalling pathways are simultaneously active in BRAF V600E mutated thyroid carcinomas .



PMID: 26701267
(Patient)  
Terms: xenograft, clinical trial, transgenic mice, mice
Sent# Symbols Sentence Mnemonics
0 Identification of T - cell Receptors Targeting Human KRAS-Mutated Tumors .
1 Μ KRAS is one of the most frequently mutated proto-oncogenes in human cancers .
2 The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12 , in particular G12D and G12V present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers .
3 The consistency , frequency , and tumor specificity of these "neoantigens" make them attractive therapeutic targets .
4 Recent data associate T cells that target mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma , lung cancer , or cholangiocarcinoma .
5 Using HLA-peptide prediction algorithms , we noted that HLA-A*11 : 01 could potentially present mutated KRAS variants .
6 By immunizing HLA-A*11 : 01 transgenic mice , we generated murine T cells and subsequently isolated T-cell receptors ( TCR ) highly reactive to the mutated KRAS variants G12V and G12D .
7 Μ Peripheral blood lymphocytes ( PBL ) transduced with these TCRs could recognize multiple HLA-A*11 : 01(+) tumor lines bearing the appropriate KRAS mutations .
8 In a xenograft model of large established tumor , adoptive transfer of these transduced PBLs reactive with an HLA-A*11 : 01 , G12D-mutated pancreatic cell line could significantly reduce its growth in NSG mice ( P = 0002 ) .
9 The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers supports clinical trials with these T cells that recognize mutated KRAS in patients with a variety of common cancer types .



PMID: 26697204
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Hepatic resection , hepatic arterial infusion pump therapy , and genetic biomarkers in the management of hepatic metastases from colorectal cancer .
1 The liver is the most common site of colorectal cancer metastasis .
2 Fortunately , improvements have been made in the care of patients with colorectal liver metastasis ( CRLM ) .
3 Effective management of CRLM requires a multidisciplinary approach that is tailored to individuals in order to achieve long-term survival , and cure .
4 Resection and systemic chemotherapy provides benefit in selected individuals .
5 An adjunct to resection and/or systemic chemotherapy is the use of hepatic arterial infusion pump ( HAIP ) therapy .
6 Many studies show HAIP provides benefit for select patients with CRLM .
7 Added to the crucible of a multidisciplinary approach to managing CRLM is the ever growing understanding of tumor biology and genetic profiling .
8 In this review , we discuss the outcomes of resection , systemic therapies and HAIP therapy for CRLM .
9 Μ We also discuss the impact of recent advances in genetic profiling and mutational analysis , namely mutation of KRAS and BRAF , for this disease .



PMID: 26697201
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Implications of mismatch repair-deficient status on management of early stage colorectal cancer .
1 Innate vs . Adaptive : PD-L1 -mediated immune resistance by melanoma .



PMID: 26697199
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF mutant colorectal cancer as a distinct subset of colorectal cancer : clinical characteristics , clinical behavior , and response to targeted therapies .
1 BACKGROUND :
2 Vascular endothelial growth factor ( VEGF )- mediated angiogenesis plays an important role in non-small cell lung cancer ( NSCLC ) .
3 Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2 .
4 This phase 2 study investigated ramucirumab in combination with first - line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC .
5 METHODS :
6 Eligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1 : 1 to pemetrexed and carboplatin ( or cisplatin ) or ramucirumab ( 10 mg/kg ) plus pemetrexed and carboplatin ( or cisplatin ) once every 3 weeks .
7 Treatment was given for 4 to 6 cycles , and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed .
8 The primary endpoint was progression-free survival ( PFS ) with a sample size of sufficient power to detect an increase from 7 to 10.4 months .
9 RESULTS :
10   From October 2010 to October 2011 , 140 patients were randomized ( pemetrexed-platinum arm , 71 ; ramucirumab-pemetrexed-platinum arm , 69 ) , and most baseline characteristics were similar for the 2 treatment arms .
11 The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm ( hazard ratio , 075 ; P = 132 ) .
12 The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms , respectively ( P = 180 ) .
13 The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm ( P = 032 ) .
14 The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia , neutropenia , fatigue , anemia , nausea , back pain , and hypertension .
15 CONCLUSIONS :
16 The primary endpoint of significant prolongation of PFS was not met ; however , ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients .
17 The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings .



PMID: 26697198
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 New therapeutic strategies for BRAF mutant colorectal cancers .
1 Μ Oncogenic BRAF mutations are found in ~10% of colorectal cancers ( CRCs ) and predict poor prognosis .
2 Although BRAF inhibitors have demonstrated striking efficacy in BRAF mutant melanomas , BRAF inhibitor monotherapy is ineffective in BRAF mutant CRC .
3   Over the past few years , studies have begun to define the molecular mechanisms underlying the relative resistance of BRAF mutant CRC to BRAF inhibitors , leading to the development of novel therapeutic strategies that are showing promising clinical activity in initial clinical trials .
4   Our current understanding of the mechanisms of BRAF inhibitor resistance in BRAF mutant CRC and the therapeutic approaches currently in clinical trials for BRAF mutant CRC are reviewed herein .



PMID: 26697197
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Impact of somatic mutations on patterns of metastasis in colorectal cancer .
1 Assessment of a HER2 scoring system for colorectal cancer : results from a validation study .



PMID: 26697194
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Proficiency of DNA repair genes and microsatellite instability in operated colorectal cancer patients with clinical suspicion of lynch syndrome .
1 BACKGROUND :
2 Lynch syndrome ( LS ) diagnosis is underestimated , and most of the patients remain undetected after colorectal resections .
3 The study aims to assess the frequency of LS in patients undergoing surgical treatment for colorectal cancer ( CRC ) .
4 METHODS :
5 A total of 458 CRC patients were operated from January 2005 to December 2008 .
6 Positive CRC family history ( FH ) was present in 118 ( 258% ) patients .
7 Histologic sections were reviewed for microsatellite instability ( MSI ) criteria ( Bethesda guidelines ) , immunohistochemical ( IHC ) analysis for MLH1 , MSH2 , MSH6 , PMS2 proteins , through the avidin-biotin-peroxidase complex , MSI ( BAT-25 , BAT-26 , NR-21 , NR-24 and MONO-27 ) and BRAF somatic mutation .
8 RESULTS :
9 Of the 118 patients with FH , 61 ( 5169% ) met atleast one of the revised Bethesda criteria .
10 IHC was abnormal in 8 ( 131% ) and MSI in 12 patients ( 20% ) .
11 BRAF was negative in all cases .
12 MSI histopathological included : intratumoral lymphocytes ( 475% ) , expansive tumors ( 295% ) mucinous component ( 278% ) and Crohn's like reaction in ( 147% ) .
13 There was an association between the revised Bethesda criteria with : sex , mucinous histology and Crohn's like reaction ; MSI and IHC with PMS2 and MLH1 .
14 Revised Bethesda criteria 4 had 10.6 increased chances to display positive MSI .
15 We have proposed a score to contribute as a practical tool in the diagnosis of LS .
16 CONCLUSIONS :
17 The frequence of LS in resected CRC patients was 2.6% .
18 The criterion 4 Revised Bethesda was associated more strongly with the presence of MSI .



PMID: 26697123
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer .
1 BACKGROUND :
2 Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas ( CRCs ) , and extensive work has been performed to characterize different methylation profiles of CRC .
3 Less information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC , regardless of the etiopathogenesis .
4 Long interspersed nucleotide element 1 ( LINE-1 ) hypomethylation and gene -specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch ( Lynch colorectal cancer with microsatellite instability ( LS-MSI ) ) , 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded ( early-onset colorectal cancer with microsatellite stability ( EO-MSS ) ) , and 126 sporadic CRCs , comprising 28 cases with microsatellite instability ( S-MSI ) and 98 that were microsatellite stable ( S-MSS ) .
5 All tumor methylation patterns were integrated with clinico-pathological and genetic characteristics , namely chromosomal instability ( CIN ) , TP53 loss , BRAF , and KRAS mutations .
6 RESULTS :
7 LS-MSI mainly showed absence of extensive DNA hypo - and hypermethylation .
8 LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis .
9 Genetically , they commonly displayed G : A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss .
10 S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation .
11 S-MSI were mainly characterized by MLH1 methylation , BRAF mutation , and absence of a CIN phenotype and of TP53 loss .
12 Μ By contrast , S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN , and they were associated with a worse prognosis .
13 EO-MSS were a genetically and epigenetically heterogeneous group of CRCs .
14 Like LS-MSI , some EO-MSS displayed low rates of DNA hypo - or hypermethylation and frequent G : A transitions in the KRAS gene , suggesting that a genetic syndrome might still be unrevealed in these patients .
15 Μ By contrast , some EO-MSS showed similar features to those observed in S-MSS , such as LINE-1 hypomethylation , CIN , and TP53 deletion .
16 In all four classes , hypermethylation of ESR1 , GATA5 , and WT1 was very common .
17 CONCLUSIONS :
18 Aberrant DNA methylation analysis allows the identification of different subsets of CRCs .
19 This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs .



PMID: 26691448
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular spectrum of KRAS , NRAS , BRAF and PIK3CA mutations in Chinese colorectal cancer patients : analysis of 1,110 cases .
1 Mutations in genes such as KRAS , NRAS , BRAF and PIK3CA have become an important part of colorectal carcinoma evaluation .
2 Μ The aim of this study was to screen for mutations in these genes in Chinese patients with colorectal cancer ( CRC ) and to explore their correlations with certain clinicopathological parameters .
3 We tested mutations in the KRAS ( exons 2 , 3 and 4 ) , NRAS ( exons 2 , 3 and 4 ) , PIK3CA ( exon 20 ) and BRAF ( exon 15 ) genes using reverse transcriptase-polymerase chain reaction ( RT-PCR ) and Sanger sequencing in a large cohort of 1,110 Chinese CRC patients who underwent surgical resection at one of three major teaching hospitals located in different regions of China .
4 Μ The prevalence rates of KRAS , NRAS , BRAF and PIK3CA mutations were 45.4% , 3.9% , 3.1% and 3.5% , respectively .
5 Mutant KRAS was associated with the mucinous subtype and greater differentiation , while mutant BRAF was associated with right-sided tumors and poorer differentiation .
6 ✓ Μ Our results revealed differences in the genetic profiles of KRAS , NRAS , PIK3CA and BRAF at mutation hotspots between Chinese CRC patients and those of Western countries , while some of these gene features were shared among patients from other Asian countries . GM-ASS-DS



PMID: 26690310
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer : analysis of 3256 patients enrolled in the QUASAR , FOCUS and PICCOLO colorectal cancer trials .
1 HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers .
2 One suggested anti-EGFR resistance mechanism in colorectal cancer ( CRC ) is aberrant MEK-AKT pathway activation through HER2 up-regulation .
3 We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients , assessing relationships to KRAS/BRAF and outcome .
4 Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials ( FOCUS and PICCOLO ) .
5 Tissue microarrays were created for HER2 immunohistochemistry .
6 HER2-amplification was assessed using FISH and copy number variation .
7 KRAS/BRAF mutation status was assessed by pyrosequencing .
8 Progression-free survival ( PFS ) and overall survival ( OS ) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR ; 29/1342 ( 22% ) stage IV and 25/1914 ( 13% ) stage II-III tumours showed HER2 protein overexpression .
9 Μ Of the HER2-overexpressing cases , 27/28 ( 964% ) stage IV tumours and 20/24 ( 833% ) stage II-III tumours demonstrated HER2 amplification by FISH ; 41/47 ( 872% ) also showed copy number gains .
10 HER2-overexpression was associated with KRAS/BRAF wild-type ( WT ) status at all stages : in 5.2% WT versus 1.0% mutated tumours ( p <00001 ) in stage IV and 2.1% versus 0.2% in stage II-III tumours ( p = 001 ) , respectively .
11 HER2 was not associated with OS or PFS .
12 At stage II-III , there was no significant correlation between HER2 overexpression and 5FU/FA response .
13 A higher proportion of HER2-overexpressing cases experienced recurrence , but the difference was not significant .
14 HER2-amplification/overexpression is identifiable by immunohistochemistry , occurring infrequently in stage II-III CRC , rising in stage IV and further in KRAS/BRAF WT tumours .
15   The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial .
16 (c) 2015 The Authors .
17 Journal of Pathology published by John Wiley & ; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland .



PMID: 26681025
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Mutation profile of KRAS and BRAF genes in patients with colorectal cancer : association with morphological and prognostic criteria . GM-ASS-RO
1 KRAS and BRAF mutations are well-recognized molecular alterations during colorectal carcinogenesis , but there is little agreement on their effect on tumor characteristics .
2 Therefore , we aimed to evaluate the distribution of the most common KRAS and BRAF mutations in Greek patients with colorectal cancer and their possible associations with clinical histopathological parameters .
3 Μ In this study , 322 and 188 colorectal carcinomas were used for the mutation analysis of KRAS ( exon 2 ) and BRAF ( exon 15 ) genes , respectively .
4 The mutational status of both genes was evaluated by polymerase chain reaction and sequencing analysis .
5 Although the overall frequency of KRAS mutations ( 366% ) seemed to be similar to those reported for other populations , the rate of point mutations at codon 13 was significantly lower ( 12% ) in Greek patients with colorectal cancer and associated with male gender ( P <005 ) .
6 ✓ Tumors with G>T codon 12 transversions and G>C transitions showed more frequent lymph node metastasis ( P <005 , P <0005 , respectively ) . GM-ASS-RO
7 The rate of KRAS mutations gradually decreased with increasing histological grade ( P <005 ) , as opposed to BRAF mutations , which were strongly associated with poorly differentiated tumors ( P <0005 ) .
8 Additionally , we found that the histological features of preexisting adenoma were associated with the absence of BRAF mutations , in contrast to KRAS ( P <005 ) .
9 Our data suggested that there seems to be a correlation between morphological criteria and discrete genetic pathways in colorectal carcinogenesis .
10 ✓ Moreover , ethnic or geographic factors may have an impact on genetic background of colorectal carcinomas , and specific types of KRAS mutations may influence the metastatic potential of colorectal tumors . GM-REG-RO



PMID: 26678268
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Multi-Scale Genomic , Transcriptomic and Proteomic Analysis of Colorectal Cancer Cell Lines to Identify Novel Biomarkers .
1 Selecting colorectal cancer ( CRC ) patients likely to respond to therapy remains a clinical challenge .
2 The objectives of this study were to establish which genes were differentially expressed with respect to treatment sensitivity and relate this to copy number in a panel of 15 CRC cell lines .
3 Μ Copy number variations of the identified genes were assessed in a cohort of CRCs .
4 IC50's were measured for 5-fluorouracil , oxaliplatin , and BEZ-235 , a PI3K/mTOR inhibitor .
5 Cell lines were profiled using array comparative genomic hybridisation , Illumina gene expression analysis , reverse phase protein arrays , and targeted sequencing of KRAS hotspot mutations .
6 Frequent gains were observed at 2p , 3q , 5p , 7p , 7q , 8q , 12p , 13q , 14q , and 17q and losses at 2q , 3p , 5q , 8p , 9p , 9q , 14q , 18q , and 20p.Frequently gained regions contained EGFR , PIK3CA , MYC , SMO , TRIB1 , FZD1 , and BRCA2 , while frequently lost regions contained FHIT and MACROD2 .
7 TRIB1 was selected for further study .
8 Gene enrichment analysis showed that differentially expressed genes with respect to treatment response were involved in Wnt signalling , EGF receptor signalling , apoptosis , cell cycle , and angiogenesis .
9 Stepwise integration of copy number and gene expression data yielded 47 candidate genes that were significantly correlated .
10 PDCD6 was differentially expressed in all three treatment responses .
11 Tissue microarrays were constructed for a cohort of 118 CRC patients and TRIB1 and MYC amplifications were measured using fluorescence in situ hybridisation .
12 TRIB1 and MYC were amplified in 14.5% and 7.4% of the cohort , respectively , and these amplifications were significantly correlated ( p
13 TRIB1 protein expression in the patient cohort was significantly correlated with pERK , Akt , and Caspase 3 expression .
14 In conclusion , a set of candidate predictive biomarkers for 5-fluorouracil , oxaliplatin , and BEZ235 are described that warrant further study .
15 Amplification of the putative oncogene TRIB1 has been described for the first time in a cohort of CRC patients .



PMID: 26677401
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma-a step towards personalized therapy .
1 BACKGROUND :
2 Primary pulmonary enteric adenocarcinoma ( PEAC ) is defined as a pulmonary adenocarcinoma with a predominant component of intestinal differentiation and tumor cells positive for atleast one intestinal marker .
3 The aim of the present study was the molecular and histological characterization of a PEAC from a patient with two other family members affected by similar lung tumors , which has never been reported before .
4 FINDINGS :
5 We evaluated the molecular characteristics of the proband's PEAC by using a previously validated 47-microRNA ( miRNA ) cancer-specific array and a predictive method to estimate tissue-of-origin probabilities .
6 Μ Immunohistochemical ( IHC ) staining for thyroid transcription factor ( TTF-1 ) , napsin A , caudal-related homeobox 2 ( CDX2 ) , cytokeratins , and mucins , as well as mutational analyses for epidermal growth factor receptor ( EGFR ) , rat Kirsten sarcoma viral oncogene homolog ( KRAS ) , and anaplastic lymphoma kinase ( ALK ) were performed on formalin-fixed , paraffin-embedded ( FFPE ) tissues .
7 The occurrence of PEAC in two family members was associated with similar clinicopathological features ( age at diagnosis , smoking habit , tumor localization , multiple colonic polyps ) , histologic findings ( TTF-1 negativity and CDX2 positivity ) , and genetic findings ( KRAS ( Gly12Asp ) mutation , but no EGFR/ALK aberrations ) .
8 miRNA profiling revealed similarities with non-small cell lung cancer ( NSCLC ; 7598 % ) and some overlap with pancreatic ductal adenocarcinoma ( PDAC ; 2334 % ) , but not with colorectal cancer ( CRC ; less than 05 % ) .
9 Notably , these PEACs share key PDAC-associated miRNAs associated with tumor aggressiveness ( miR-31*/-126*/-506/-508-3p/-514 ) .
10 CONCLUSIONS :
11 We describe for the first time PEAC in members from the same family , associated with similar clinical and genetic features .
12 miRNA profiling of the PEAC resembled a NSCLC signature , with partial overlap to a PDAC pattern .
13 This could explain its aggressive behavior and therefore help to guide future tailored-therapeutic approaches .



PMID: 26673925
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy .
1 Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer ( CRC ) , but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage .
2 Several drugs and combinations are now available for use in treating patients with advanced CRC , but the optimal sequence of therapy remains unknown .
3 Moreover , the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity , followed by reintroduction of prior full therapy when required , before switching to other drugs .
4 Consequently , randomized strategy trials are needed to define the optimal treatment sequences .
5   Molecular testing for rat Kirsten sarcoma viral oncogene homolog ( KRAS ) and neuroblastoma RAS viral oncogene homolog ( NRAS ) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor ( EGFR ) monoclonal antibody ( MoAb ) therapy .



PMID: 26666825
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients .
1 Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFkappaB signaling pathways .



PMID: 26666244
(Patient)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice .
1 We investigated various phenotypic and genotypic biomarkers of gastric cancer ( GC ) testing the following hypotheses : are these biomarkers suitable for the identification of GC subtypes , are they of prognostic significance , and should any of these biomarkers be considered to tailor patient treatment in the future .
2 The study cohort consisted of 482 patients .
3 pTNM-stage was based on surgical pathologic examination .
4 The Lauren and mucin phenotype was assessed .
5 Helicobacter pylori and Epstein-Barr virus infections were documented .
6 The following biomarkers were determined : BRAF , KRAS , NRAS , and PIK3CA genotype , microsatellite instability , mucin 1 , mucin 2 , mucin 5 , and mucin 6 , CD10 , E-cadherin , beta-catenin , and lysozyme .
7 The histologic phenotype correlated with 10/13 ( 77% ) clinicopathologic patient characteristics and 6/13 ( 46% ) immunohistochemical/molecular biological biomarkers .
8 Inversely , immunohistochemical biomarkers ( mucin phenotype , E-cadherin , beta-catenin , and lysozyme ) were unsuitable for subclassification of GC .
9 It showed too much overlap between the different subtypes .
10 Among the genotypes , only microsatellite instability correlated with tumor type being more prevalent in intestinal and unclassified GCs .
11 Patient survival correlated significantly with 8 ( 62% ) clinicopathologic and 5 ( 36% ) immunohistochemical/molecular biomarkers .
12 ✓ Interestingly , in proximal GCs , KRAS mutation was associated with worse prognosis , as was persistent H . GM-ASS-RO
13 pylori infection in unclassified GCs .
14 Mucin 2 ( all patients , proximal GCs ) and PIK3CA ( exon 20 ; intestinal type GC ) prognosticated independently patient survival .
15 The biomarkers examined herein are unsuitable to aid histologic classification of GC .
16   However , several of them show a correlation with either phenotype and/or prognosis and may be considered to tailor patient treatment in the future , such as KRAS , PIK3CA , MSI , and H .
17 pylori status .



PMID: 26664139
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A metastatic colon adenocarcinoma harboring BRAF V600E has a durable major response to dabrafenib/trametinib and chemotherapy .
1 The subset of metastatic colorectal adenocarcinomas that harbor BRAF V600E mutations are aggressive tumors with significantly shortened survival and limited treatment options .
2 Here we present a colorectal cancer patient whose disease progressed through standard chemotherapy and who developed liver metastasis .
3 Μ Comprehensive genomic profiling ( FoundationOne ( (R) ) ) identified a BRAF V600E mutation in the liver lesion , as well as other genomic alterations consistent with colorectal cancers .
4   Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient .
5 This report illustrates the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas .



PMID: 26662311
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Delphinidin reduces cell proliferation and induces apoptosis of non-small - cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways .
1 BACKGROUND :
2 Various kinase inhibitors are known to be ATP-binding cassette ( ABC ) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression .
3 Here , we investigated the role of the ABC transporters ABCB1 , ABCC1 , and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 ( vemurafenib ) and PLX4720 .
4 PLX4032 had previously been shown to interfere with ABCB1 and ABCG2 .
5 PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032 .
6 FINDINGS :
7 PLX4032 and PLX4720 affected ABCC1 - and ABCG2 -mediated drug transport in a similar fashion .
8 Μ In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub - lines with acquired resistance to PLX4032 , PLX4720 , vincristine ( cytotoxic ABCB1 and ABCC1 substrate ) , or mitoxantrone ( cytotoxic ABCG2 substrate ) , we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate -resistant , 3/4 PLX4720-resistant , and 1/4 PLX4032-resistant melanoma cell lines .
9 CONCLUSION :
10 PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates .
11 Since ABC transporters confer multi - drug resistance , this is of relevance for the design of next - line therapies .



PMID: 26661077
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Rare RAS Mutations in Metastatic Colorectal Cancer Detected During Routine RAS Genotyping Using Next Generation Sequencing .
1 Missense mutations in MLH1 , MSH2 , KRAS , and APC genes in colorectal cancer patients in Malaysia .



PMID: 26657506
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer .
1 Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non-small Cell Lung Cancer .



PMID: 26650777
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies .
1 HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL .



PMID: 26646696
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Signature miRNAs in colorectal cancers were revealed using a bias reduction small RNA deep sequencing protocol .
1 To explore the role of miRNAs in colorectal cancers ( CRC ) , we have deep sequenced 48 pairs of frozen CRC samples , of which 44 pairs produced high quality sequencing data .
2 By using a combined approach of our bias reduction small RNA ( smRNA ) deep sequencing protocol and Illumina small RNA TruSeq method for sample bar coding , we have obtained data from samples of relatively large size with bias reduced digital profile results .
3 This novel approach allowed us to validate many previously published results using various techniques to profile miRNAs in CRC tissues or cell lines and to characterize 'true' miRNA signatures highly expressed in colon/rectum ( CR ) or CRC tissues .
4 According to our results , miR-21 , a miRNA that is up-regulated in CRC , and miR-143 , a miRNA that is down-regulated in CRC , are the two miRNAs that dominated the miRNA population in CR tissues , and probably are also the most important miRNAs in CRCs .
5 These two miRNAs , together with the other eight miRNAs , miR-148a , -194 , -192 , 200b , -200c , -10b , -26a , and -145 , with descending expressing levels , constituted the top 10 highly expressed miRNAs in CR/CRC .
6 Μ Using TaqMan miRNA qPCR , we detected the relative expression of some of the CRC miRNAs in 10 CRC cell lines , validated their dysregulation under cancer condition , and provided possible explanation for their dysregulation , which could be caused by APC , KRAS , or TP53 mutations .
7   We believe these results will provide a new direction in future miRNA-related CRC development studies , and application of miRNAs in CRC diagnosis/prognosis , and therapy .



PMID: 26644411
(None)  
Terms: Phase I Study
Sent# Symbols Sentence Mnemonics
0 A Phase I Study of the Safety , Pharmacokinetics , and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer .
1 A 66-year-old man underwent a sigmoidectomy for advanced sigmoid colon cancer .
2 The pathological examination revealed that the tumor was T3 , N0 , M0 , and KRAS wild type .
3 Fifteen months after surgery , the patient was hospitalized with stenosis of the anastomosis due to recurrent disease that had disseminated to the peritoneum , and which was unresectable .
4 After transverse colostomy , the patient received 8 courses of mFOLFOX6+panitumumab ( Pmab ) , and 39 courses of infusional 5-fluorouracil ( 5-FU ) + Leucovorin ( LV ) + Pmab .
5 A partial remission ( PR ) was maintained for 27 months .
6 The utility of maintenance therapy with an anti-epidermal growth factor receptor ( EGFR ) antibody -based regime has not previously been demonstrated .
7 In this case , a long PR was achieved using infusional 5-FU+LV+Pmab , suggesting that this is a useful maintenance therapy following mFOLFOX6 + Pmab .
8   However , the side effects resulting from Pmab treatment reduced the patient's quality of life ( QOL ) .
9 We suggest that Pmab maintenance therapy can be established by controlling the side effects of the anti-EGFR antibody .



PMID: 26644315
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer .
1 UNLABELLED :
2 How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown .
3 We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses .
4 Μ Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1 (K57T) mutation as a novel mechanism of acquired resistance .
5 This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib .
6   In circulating tumor DNA ( ctDNA ) , mutant MEK1 levels declined with treatment , but a previously unrecognized KRAS (Q61H) mutation was also identified that increased despite therapy .
7 Μ This same KRAS mutation was later found in a separate nonresponding metastasis .
8   In summary , parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient .
9 SIGNIFICANCE :
10 Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies .
11   Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies .
12 ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance .



PMID: 26640390
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells .
1 Regorafenib , an oral multikinase inhibitor , was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer .
2 Since this time , however , few case reports outlining real-world usage have been published in the literature .
3   Here , we detail the clinical history of an elderly woman with KRAS wild-type colon cancer who received regorafenib after prior treatment with other agents .
4   We show that by employing dose modification strategies to address adverse events , this patient was able to remain on therapy for 11 months and achieve stable disease .



PMID: 26637197
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability in pulmonary adenocarcinomas : a comprehensive study of 480 cases .
1 A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency , leading to accumulation of numerous mutations at repetitive DNA sequence stretches ( microsatellites ) , known as high-level microsatellite instability ( MSI-H ) .
2 In colorectal cancer , MSI-H tumors show a clinical behavior different from microsatellite-stable ( MSS ) tumors .
3 Data about the prevalence of MSI among non-small cell lung cancer ( NSCLC ) are conflicting , and clinical relevance of MSI is largely unknown .
4 We analyzed a series of 480 pulmonary adenocarcinomas ( ADC ) for MSI using a sensitive mononucleotide marker panel ( BAT25 , BAT26 , and CAT25 ) .
5 Positive cases were further analyzed by immunohistochemical staining for DNA mismatch repair proteins .
6 Results were correlated with clinicopathological variables .
7 MSI-H was detected in 4/480 ( 08 % ) cases .
8 In none of these , a background of Lynch syndrome was found .
9 Three of the patients developed a metachronous carcinoma ( esophagus , pancreas , and kidney ) .
10 All MSI-H cases were stage I and occurred in smokers/ex-smokers .
11 Μ Mutations were found in EGFR ( n = 2 ) , KRAS ( n = 1 ) , or BRAF ( n = 1 ) .
12 MSI-H neoplasms had a higher proliferative activity ( 387 % ) than MSS neoplasms ( 283 % ) .
13 Mean overall survival for MSS and MSI-H cases was 64.8 ( CI 604-691 ) and 47.1 ( CI 21-732 ) months , respectively .
14 Μ When specific mononucleotide marker panels are applied , the MSI-H phenotype is rare and predominantly found in early stage ADC of smokers .
15 However , the frequency of MSI-H is in the range of other relevant molecular alterations .
16 In the era of precision therapy , associations with distinct clinicopathological variables merit further investigation .



PMID: 26634009
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer .
1 US lung cancer trends by histologic type .



PMID: 26631427
(None)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 Molecular Taxonomy and Tumourigenesis of Colorectal Cancer .
1 Over the last 5 years there has been a surge in interest in the molecular classification of colorectal cancer .
2 The effect of molecular subtyping on current treatment decisions is limited to avoidance of adjuvant 5-fluorouracil chemotherapy in stage II microsatellite unstable-high disease and avoidance of epidermal growth factor receptor -targeted antibodies in extended RAS mutant tumours .
3 The emergence of specific novel combination therapy for the BRAF-mutant cohort and of the microsatellite unstable-high cohort as a responsive group to immune checkpoint inhibition shows the growing importance of a clinically relevant molecular taxonomy .
4 Clinical trials such as the Medical Research Council FOCUS4 trial using biomarkers to select patients for specific therapies are currently open and testing such approaches .
5 Μ The integration of mutation , gene expression and pathological analyses is refining our understanding of the biological subtypes within colorectal cancer .
6 Sharing of data sets of parallel sequencing and gene expression of thousands of cancers among independent groups has allowed the description of disease subsets and the need for a validated consensus classification has become apparent .
7 This biological understanding of the disease is a key step forward in developing a stratified approach to patient management .
8 The discovery of stratifiers that predict a response to existing and emerging therapies will enable better use of these treatments .
9 Improved scientific understanding of the biological characteristics of poorly responsive subgroups will facilitate the design of novel biologically rational combinations .
10   Novel treatment regimens , including the combination of new drugs with radiation , and the discovery and validation of their associated predictive biomarkers will gradually lead to improved outcomes from therapy .



PMID: 26623049
(Patient)  
Terms: retrospective study, rat
Sent# Symbols Sentence Mnemonics
0 [ Overcoming resistance to EGFR-TKI in lung cancer ] .
1 A number of previous studies have reported that 30-50% of patients with rat colorectal cancer ( CRC ) harbor Kirsten sarcoma viral oncogene homolog ( KRAS ) mutations , which is a major predictive biomarker of resistance to epidermal growth factor ( EGFR )- targeted therapy .
2 Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer ( mCRC ) .
3 A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations .
4 Μ The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations .
5 We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August , 2004 and January , 2011 in four hospitals located in Tokyo and Kyushu Island .
6 We also investigated KRAS mutation subtypes and patient characteristics .
7 Μ In the patients who received cetuximab , univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival ( PFS ) and overall survival ( OS ) .
8 Of the 98 patients , 23 ( 235% ) had KRAS p.G13D-mutated tumors , whereas 75 ( 765% ) had tumors harboring other mutations .
9 Of the 31 patients who received cetuximab , 9 ( 290% ) had KRAS p.G13D mutations and 22 ( 710% ) had other mutations .
10 There were no significant differences in age , gender , primary site , pathological type , history of chemotherapy , or the combined use of irinotecan between either of the patient subgroups .
11 ✓ The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations ( median PFS , 45 vs. 28 months , respectively ; P = 065 ; and median OS , 153 vs. 89 months , respectively ; P = 051 ) . RO-ASS-GM
12 Μ However , the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations ( PFS : HR = 0.29 ; 95% CI : 0.08-1.10 ; P = 0.07 ; OS : HR = 0.23 ; 95% CI : 0.04-1.54 ; P = 0.13 ) .
13   In conclusion , treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation , compared with those harboring other mutations .
14   However , further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC .



PMID: 26623045
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Predictability of antitumor efficacy of cetuximab plus irinotecan based on skin rash severity according to observation period in patients with metastatic colorectal cancer following failure of fluorouracil , irinotecan and oxaliplatin .
1 BACKGROUND :
2 The molecular biology and cellular origins of mixed type endometrial carcinomas ( MT-ECs ) are poorly understood , and a Type II component of 10 percent or less may confer poorer prognoses .
3 METHODOLOGY/PRINCIPAL FINDINGS :
4 We studied 10 cases of MT-EC ( containing endometrioid and serous differentiation ) , 5 pure low-grade endometrioid adenocarcinoma ( EAC ) and 5 pure uterine serous carcinoma ( USC ) .
5 Endometrioid and serous components of the MT-ECs were macrodissected and the expression of 60 candidate genes compared between MT-EC , pure USC and pure EAC .
6 Μ We found that four genes were differentially expressed when MT-ECs were compared to pure low-grade EAC : CDKN2A ( P = 0006 ) , H19 ( P = 0010 ) , HOMER2 ( P = 0009 ) and TNNT1 ( P = 0006 ) .
7 Also while we found that even though MT-ECs closely resembled the molecular profiles of pure USCs , they also exhibit lower expression of PAX8 compared to all pure cases combined ( P = 0035 ) .
8 CONCLUSION :
9   Our data suggest that MT-EC exhibits the closest molecular and epidemiological similarities to pure USC and supports clinical observations that suggest patients with MT-EC should receive the same treatment as patients with pure serous carcinoma .
10 Novel specific markers of MT-EC could be of diagnostic utility and could represent novel therapeutic targets in the future .



PMID: 26622882
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Prevalence of KRAS , BRAF , PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer .
1 Mutations in oncogenes along the epidermal growth factor receptor ( EGFR ) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer ( mCRC ) .
2 However , the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear .
3 In the present study , the prevalence of rat Kirsten sarcoma viral oncogene homolog ( KRAS ) , v-Raf murine sarcoma viral oncogene homolog B ( BRAF ) , phosphoinositide 3-kinase ( PI3K ) and EGFR somatic mutations were determined among Singaporean patients with mCRC .
4 DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism .
5 Associations of the genetic mutations with various clinicopathological parameters were further explored .
6 Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients , at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% ( 90% confidence interval , 218-449% ) ] .
7 KRAS mutation was not associated with clinicopathological features , including age , gender and ethnicity of patients , or the tumor site , differentiation and mucinous status .
8 Conversely , the prevalence of BRAF ( 0% ) , PI3K ( 22% ) and EGFR ( 0% ) mutations were low .
9 Μ The results of the present study indicate that KRAS mutations are prevalent among the studied population , and confirm the low prevalence of BRAF , PI3K and EGFR mutations .
10   KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC .



PMID: 26622684
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer .
1 Colorectal cancer ( CRC ) is one of the most common cancers worldwide , with ~700,000 mortalities occurring due to CRC in 2012 .
2 The treatment options are effective in a small percentage of patients , and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial .
3 It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC .
4 In the present study , primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw ( Warsaw , Poland ) .
5 Μ Codons 12 and 13 of exon 1 of KRAS , exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing .
6 The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated .
7 Μ The results revealed that PIK3CA mutations were present in 15 patients ( 96% ) , of whom seven ( 467% ) possessed mutations in codon 9 and eight ( 533% ) possessed mutations in codon 20 .
8 Μ Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations , which accounted for 40% of PIK3CA-mutated tumours , and in one patient with BRAF mutations , which accounted for 6.6% of PIK3CA-mutated tumours .
9 Μ No significant differences were identified between the overall survival ( OS ) rates of patients with PIK3CA mutations ( median OS , 567 months ) and those with wild-type PIK3CA genes ( median OS , 476 months ) ( P = 01270 ) .
10 Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort : Gender , female patients survived for 57.5 months compared with 39.3 months for male patients ( P = 00111 ) ; and lymph node involvement grade , as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases ( P = 00122 ) .
11 The findings of the present analysis indicate that PIK3CA mutation status is not a prognostic factor in CRC patients .
12 In addition , no statistically significant association exists between tumours with PIK3CA mutations and clinical or pathological factors .



PMID: 26619098
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability in colorectal cancer : clinicopathological significance .
1 Although often viewed as a single disease , colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations .
2 Μ Chromosomal instability ( CIN ) , microsatellite instability ( MSI ) and CpG island methylator phenotype ( CIMP ) have been identified as the three major molecular characteristics , which interact with other significant mutations , such as mutations in the KRAS and BRAF genes .
3 High-level MSI ( MSI-H ) is of eminent clinical importance .
4 It is the seminal molecular feature for the identification of individuals with Lynch syndrome , but it may also occur in sporadic cancers with CIMP phenotype , which arise from serrated precursor lesions .
5 MSI-H status is a marker of favorable prognosis and may be used for outcome prediction , that is , molecular grading .
6 Among others , mucinous and medullary histology , signet-ring cell differentiation , and a marked anti-tumoral immune response are histological features suggesting MSI .
7 Universal tumor testing is recommended and may be performed using immunohistochemistry ( mismatch repair protein expression ) or molecular analysis , as has recently been recommended by an international task force .
8 In this review , we consider in detail the molecular pathogenesis of colorectal cancer , focusing on the diagnosis of MSI in both hereditary and sporadic tumors .



PMID: 26617477
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Treatment Individualization in Colorectal Cancer .
1 Colorectal cancer has been characterized as a genetically heterogeneous disease , with a large diversity in molecular pathogenesis resulting in differential responses to therapy .
2 However , the currently available validated biomarkers KRAS , BRAF , and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment .
3 Recent studies have focused on novel targets and rationally designed combination strategies .
4 Furthermore , a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance .
5 Accordingly , patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer .



PMID: 26616508
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting BRAF aberrations in advanced colorectal carcinoma : from bench to bedside .
1   Molecular markers for colon diagnosis , prognosis and targeted therapy .



PMID: 26615988
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Long-term follow-up studies of Gamma Knife surgery for patients with neurofibromatosis Type 2 .
1   KRAS Mutation as a Biomarker for Survival in Patients with Non-Small Cell Lung Cancer , A Meta-Analysis of 12 Randomized Trials .



PMID: 26615134
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overcoming Resistance to Targeted Therapies in Cancer .
1 OBJECTIVE :
2 To study the clinicopathologic features and diagnosis of intraductal papillary mucinous neoplasm ( IPMN ) of the pancreas .
3 METHODS :
4 Nineteen cases of IPMN encountered during the period from 1999 to 2007 were studied by light microscopy and immunohistochemistry .
5 RESULTS :
6 IPMN occurred more often in males ( 68% ) .
7 It affected patients in older age group ( mean age = 59 ) and was located mainly in the head of pancreas ( 60% ) .
8 The mean tumor size was 4.2 cm ( range = 1 to 8 cm ) .
9 The clinical presentation was epigastric pain ( 53% ) , weight loss ( 32% ) , diabetes ( 21% ) , pancreatitis ( 21% ) and jaundice ( 10% ) .
10 Pancreatectomy was performed in 18 cases .
11 The remaining patient received bypass surgery only .
12 Features of in-situ or invasive malignancy were present in 15 of the 19 cases ( 78% ) .
13 Histologically , the tumor consisted of papillary proliferations protruding into and expanding the pancreatic ducts .
14 Invasion into the surrounding pancreatic parenchyma was noted in 12 cases and chronic pancreatitis was present in 16 cases .
15 Follow-up data ( 4 to 48 months ) were available in 13 patients .
16 Apart from 1 patient who died of other disease , all were still alive .
17 Μ Immunohistochemical study showed that p53 was positive in 6 cases , p16 in 5 cases and fascin in 8 cases .
18 The expression of c-erbB-2 was all negative .
19 Ki-67 index ranged from 1% to 80% ( mean = 38% ) .
20 CONCLUSIONS :
21 Malignant changes are not uncommon in IPMN .
22 The prognosis after surgical resection however is better than that of conventional pancreatic adenocarcinoma .
23 The overexpression of p53 , p16 and fascin may be related to tumor progression .
24 The possibility of malignant transformation needs to be considered if the Ki-67 index is over 15% .
25 Early recognition by radiologic examination ( including ERCP ) and pancreatic cytology would be helpful in early diagnosis .
26 Surgical resection represents the mainstay of treatment and long-term post-operative follow up is needed .



PMID: 26613238
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Survivin mRNA expression in blood as a predictor of the response to EGFR-tyrosine kinase inhibitors and prognosis in patients with non-small cell lung cancer .
1 To examine the cytotoxic activity of congeners of 3-amino-isoquinoline , we performed the phenotypic screening using panel of 60 cell lines and found that ( N- ( 6,7-dimethoxy-1-methyl-isoquinolin-3-yl ) -4-{ ; [ ( 1-ethyl-4-methyl-1H-pyrazol-3-y l ) methyl]amino} ; benzamide ( 4d ) ) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells ( IC50 = 18 mum ) and human breast cancer T-47D cells ( GI50 = 19 mum ) .
2 Virtual screening indicated that these compounds target protein kinases and phosphodiesterases ( PDE ) .
3 However , wet screening among panel of protein kinases did not show any significant activity .
4 By contrast , 50 mum of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating ( 3DF ) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture .



PMID: 26610798
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers .
1 CONTEXT :
2 The classification of pulmonary large cell carcinoma has undergone a major revision with the recent World Health Organization ( WHO ) 2015 Classification .
3 Many large cell carcinomas are now reassigned to either adenocarcinoma with solid pattern or nonkeratinizing squamous cell carcinoma based on immunopositivity for adenocarcinoma markers or squamous cell carcinoma markers , respectively .
4 Large cell carcinomas that are negative for adenocarcinoma and squamous cell carcinoma immunomarkers are now classified as large cell carcinoma with null immunohistochemical features ( LCC-N ) .
5 Although a few studies investigated the mutation profile of large cell carcinomas grouped by immunostain profile before the publication of the new WHO classification , investigation of tumors previously diagnosed as large cell carcinoma and reclassified according to the 2015 WHO classification has not , to our knowledge , been reported .
6 OBJECTIVE :
7 To determine the mutation profiles of pulmonary large cell carcinomas reclassified by WHO 2015 criteria .
8 DESIGN :
9 Archival cases of non-small cell lung carcinoma with large cell carcinoma morphology ( n = 17 ) were reclassified according to 2015 WHO criteria .
10 To determine mutation profile , we employed Ion Torrent ( Life Technologies , Carlsbad , California ) -based next-generation sequencing ( 50 genes ; more than 2800 mutations ) in addition to real-time quantitative reverse transcription polymerase chain reaction for ALK translocation detection .
11 RESULTS :
12 Two of 17 cases ( 12% ) were reclassified as LCC-N , and both had mutations-BRAF D594N in one case and KRAS G12C in the other case .
13 Seven of 17 cases ( 41% ) were reclassified in the adenocarcinoma with solid pattern group , which showed one KRAS G12C and one EGFR E709K + G719C double mutation in addition to mutations in TP53 .
14 Μ Eight of 17 cases ( 47% ) were reclassified in the nonkeratinizing squamous cell carcinoma group , which showed mutations in PIK3CA , CDKN2A , and TP53 .
15 Μ No ALK translocations or amplifications were detected .
16 CONCLUSIONS :
17 Μ The adenocarcinoma with solid pattern group showed mutations typical of adenocarcinoma , whereas the nonkeratinizing squamous cell carcinoma group showed mutations typical of squamous cell carcinoma .
18 Both LCC-N cases had mutations associated with adenocarcinoma , supporting the hypothesis that LCC-N is related to adenocarcinoma .



PMID: 26609516
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarker-directed Targeted Therapy in Colorectal Cancer .
1 With advances in the understanding of the biology and genetics of colorectal cancer ( CRC ) , diagnostic biomarkers that may predict the existence or future presence of cancer or a hereditary condition , and prognostic and treatment biomarkers that may direct the approach to therapy have been developed .
2 Biomarkers can be ascertained and assayed from any tissue that may demonstrate the diagnostic or prognostic value , including from blood cells , epithelial cells via buccal swab , fresh or archival cancer tissue , as well as from cells shed into fecal material .
3 For CRC , current examples of biomarkers for screening and surveillance include germline testing for suspected hereditary CRC syndromes , and stool DNA tests for screening average at-risk patients .
4 Molecular biomarkers for CRC that may alter patient care and treatment include the presence or absence of microsatellite instability , the presence or absence of mutant KRAS , BRAF or PIK3CA , and the level of expression of 15-PGDH in the colorectal mucosa .
5   Molecularly targeted therapies and some general therapeutic approaches rely on biomarker information .
6 Additional novel biomarkers are on the horizon that will undoubtedly further the approach to precision or individualized medicine .



PMID: 26607936
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Associations of red and processed meat with survival after colorectal cancer and differences according to timing of dietary assessment .
1 BACKGROUND :
2 Little is known about the prognostic impact of red and processed meat intake or about changes in consumption after a diagnosis of colorectal cancer ( CRC ) .
3 OBJECTIVES :
4 We investigated associations of baseline red and processed meat with survival outcomes and explored changes in intake among CRC survivors 5 y after diagnosis .
5 DESIGN :
6 A total of 3122 patients diagnosed with CRC between 2003 and 2010 were followed for a median of 4.8 y [DACHS ( Darmkrebs : Chancen der Verhutung durch Screening ) study] .
7 Patients provided information on diet and other factors in standardized questionnaires at baseline and at the 5-y follow-up.Cox proportional hazards regression models were used to estimate HRs and 95% CIs .
8 RESULTS :
9 Among patients with stage I-III CRC , baseline red and processed meat intake was not associated with overall ( >1 time/d compared with <1 time/d ; HR : 0.85 ; 95% CI : 0.67 , 1.09 ) , CRC-specific ( HR : 0.83 ; 95% CI : 0.61 , 1.14 ) , cardiovascular disease-specific ( HR : 0.92 ; 95% CI : 0.51 , 1.68 ) , non-CRC-specific ( HR : 0.88 ; 95% CI : 0.59 , 1.30 ) , and recurrence-free ( HR : 1.03 ; 95% CI : 0.80 , 1.33 ) survival ; results among stage IV patients were comparable .
10 Μ An association with worse overall survival was found among patients with rat Kirsten sarcoma viral oncogene homolog ( KRAS )- mutated CRC ( HR : 1.99 ; 95% CI : 1.10 , 3.56 ) but not with microsatellite instability or CpG island methylator phenotype ( CIMP ) positivity .
11 A much lower proportion of survivors reported daily consumption of red and processed meat at the 5-y follow-up than at baseline ( concordance rate : 39% ; kappa-value : 0.10 ; 95% CI : 0.07 , 0.13 ) .
12 CONCLUSIONS :
13 Our findings suggest that baseline red and processed meat intake is not associated with poorer survival among patients with CRC .
14 The potential interaction with KRAS mutation status warrants further evaluation .
15 Major changes in consumption measured at the 5-y follow-up may have had an impact on our survival estimates .



PMID: 26604793
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gefitinib , an EGFR tyrosine kinase inhibitor , activates autophagy through AMPK in human lung cancer cells .
1 ✓ Epidermal growth factor receptor ( EGFR )- tyrosine kinase inhibitors ( TKIs ) , including gefitinib , are the first - line treatment of choice for nonsmall cell lung cancer patients who harbor activating EGFR mutations , however , acquired resistance to EGFR-TKIs is inevitable .
2 The main objective of this study was to identify informative protein signatures of extracellular vesicles ( EV ) derived from gefitinib-resistant nonsmall cell lung cancer cells using proteomics analysis .
3 Μ Nano-LC-MS/MS analysis identified with high confidence ( false discovery rate <005 , fold change >/ = 2 ) 664 EV proteins enriched in PC9R cells , which are resistant to gefitinib due to EGFR T790M mutation .
4 Computational analyses suggested components of several signal transduction mechanisms including the AKT ( also PKB , protein kinase B ) /mTOR ( mechanistic target of rapamycin ) pathway are overrepresented in EV from PC9R cells .
5 Treatment of recipient cells with EV harvested from PC9R cells increased phosphorylation of signaling molecules , and enhanced proliferation , invasion , and drug resistance to gefitinib-induced apoptosis .
6 Dose - and time -dependent pharmaceutical inhibition of AKT/mTOR pathway overcame drug resistance of PC9R cells and those of H1975 exhibiting EGFR T790M mutation .
7 Our findings provide new insight into an oncogenic EV protein signature regulating tumor microenvironment , and will aid in the development of novel diagnostic strategies for prediction and assessment of gefitinib resistance .



PMID: 26602406
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A Case of Complete Pathological Response in a Patient with Locally Advanced Sigmoid Colon Cancer after FOLFOX IRI Chemotherapy ] .
1 A 61-year-old man with advanced sigmoid colon cancer was admitted to our hospital .
2 Abdominal computed tomography ( CT ) revealed locally advanced sigmoid colon cancer , with suspected invasion of the bladder and small intestine .
3 The clinical stage of the disease was T4b , N1 , M0 , and Stage III a , with wild-type KRAS expression .
4 A transverse colostomy was performed because of the presence of a bowel obstruction .
5 The patient received 4 courses of Leucovorin , 5-fluorouracil , oxaliplatin , and irinotecan ( FOLFOXIRI ) .
6 The size of the tumor and lymph nodes decreased noticeably after chemotherapy and laparoscopic high anterior resection with lymph node dissection .
7 During this phase , the pathological stage of the disease was ypT0 , N0 , and Stage 0 ( no viable carcinoma cells , Grade 3 ) .
8   This result suggested that preoperative FOLFOXIRI chemotherapy is a useful regimen for the treatment of locally advanced colon cancer .



PMID: 26598515
(Patient)  
Terms: case, prospective, control
Sent# Symbols Sentence Mnemonics
0 ERCC1 expression correlated with EGFR and clinicopathological variables in patients with non-small cell lung cancer . An immunocytochemical study on fine-needle aspiration biopsies samples .
1 BACKGROUND :
2 Low levels of adiponectin ( ADIPOQ ; HGNC ID ; HGNC : 13633 ) , an adipokine , are associated with obesity , adiposity , excess energy balance , and increased risk of colorectal neoplasia .
3 Given the reported association of increased body mass index ( BMI ) and low-level physical activity with KRAS-mutated colorectal tumor , we hypothesized that low-level plasma adiponectin might be associated with increased risk of KRAS-mutant colorectal carcinoma but not with risk of KRAS wild-type carcinoma .
4 METHODS :
5 We conducted molecular pathological epidemiology research using a nested case-control study design ( 307 incident rectal and colon cancer case patients and 593 matched control individuals ) within prospective cohort studies , the Nurses' Health Study ( 152 case patients and 297 control individuals , with blood collection in 1989-1990 ) and the Health Professionals Follow-up Study ( 155 case patients and 296 control individuals , with blood collection in 1993-1995 ) .
6 Multivariable conditional logistic regression models and two-sided likelihood ratio tests were used to assess etiologic heterogeneity of the associations .
7 RESULTS :
8 The association of low-level plasma adiponectin with colorectal cancer risk statistically significantly differed by KRAS mutation status ( P heterogeneity = 004 ) .
9 Low levels of plasma adiponectin were associated with KRAS-mutant colorectal cancer ( for the lowest versus highest tertile : multivariable odds ratio [OR] = 2.83 , 95% confidence interval [CI] = 1.50 to 5.34 , P trend = .002 ) but not with KRAS wild-type cancer ( for the lowest versus highest tertile : multivariable OR = 0.83 , 95% CI = 0.49 to 1.43 , P trend = .48 ) .
10 In secondary analyses , the association between plasma adiponectin and colorectal cancer did not appreciably differ by BRAF or PIK3CA oncogene mutation status .
11 CONCLUSIONS :
12 Low-level plasma adiponectin is associated with KRAS-mutant colorectal cancer risk but not with KRAS wild-type cancer risk .



PMID: 26597160
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification and characterization of a new G-quadruplex forming region within the kRAS promoter as a transcriptional regulator .
1 kRAS is one of the most prevalent oncogenic aberrations .
2 It is either upregulated or mutationally activated in a multitude of cancers , including pancreatic , lung , and colon cancers .
3 While a significant effort has been made to develop drugs that target kRAS , their clinical activity has been disappointing due to a variety of mechanistic hurdles .
4 The presented works describe a novel mechanism and molecular target to downregulate kRAS expression--a previously undescribed G-quadruplex ( G4 ) secondary structure within the proximal promoter acting as a transcriptional silencer .
5 There are three distinct guanine-rich regions within the core kRAS promoter , including a previously examined region ( G4near ) .
6 Of these regions , the most distal region does not form an inducible and stable structure , whereas the two more proximal regions ( termed near and mid ) do form strong G4s .
7 G4near is predominantly a tri-stacked structure with a discontinuous guanine run incorporated ; G4mid consists of seven distinct runs of continuous guanines and forms numerous competing isoforms , including a stable three-tetrad stacked mixed parallel and antiparallel loop structures with longer loops of up to 10 nucleotides .
8 Comprehensive analysis of the regulation of transcription by higher order structures has revealed that the guanine-rich region in the middle of the core promoter , termed G4mid , is a stronger repressor of promoter activity than G4near .
9   Using the extensive guanine-rich region of the kRAS core promoter , and particularly the G4mid structure , as the primary target , future drug discovery programs will have potential to develop a potent , specifically targeted small molecule to be used in the treatment of pancreatic , ovarian , lung , and colon cancers .



PMID: 26589793
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oxaliplatin in the era of personalized medicine : from mechanistic studies to clinical efficacy .
1 Oxaliplatin is a third-generation platinum compound approved for clinical use relatively recently as compared to other drugs of the same class .
2 Its main cellular target is DNA , where similarly to cisplatin and carboplatin it forms cross-links .
3 However , due to a unique indication for colorectal cancer , synergistic interaction with fluoropyrimidines and peculiar toxicity profile , oxaliplatin is different from those compounds .
4 Multiple lines of evidence indicate differences in transport and metabolism , consequences of DNA platination , as well as DNA repair and transduction of DNA damage .
5 Here , we explore the preclinical features that may explain the unique properties of oxaliplatin in the clinics .
6 Among them , the capability to accumulate in tumor cells via organic cation transporters , to kill KRAS mutant cells and to activate immunogenic cell death appears helpful to explain in part its clinical behavior .
7 The continuous investigation of the molecular pharmacology of oxaliplatin is expected to provide clues to the definitions of predictors of drug activity and toxicity to translate to the clinical setting .



PMID: 26588428
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Immunohistochemical detection of the BRAF V600E mutant protein in colorectal cancers in Taiwan is highly concordant with the molecular test .
1 Is laparoscopic resection the appropriate management of a jejunal gastrointestinal stromal tumor ( GIST ) ? Report of a case .



PMID: 26586952
(None)  
Terms: in vitro, xenograft, tumor xenografts
Sent# Symbols Sentence Mnemonics
0 Combination of cetuximab and PP242 synergistically suppress the progression of wild-type KRAS colorectal carcinoma .
1 Mammalian target of rapamycin ( mTOR ) has been shown to be overactive in human colorectal cancer , but the first-generation mTOR inhibitor , rapamycin , has failed to show clinical efficacy against colorectal cancer .
2 Μ On the other hand , although the second-generation mTOR inhibitor , PP242 , has exerted substantial efficacy , it was revealed that independent inhibition by PP242 was transient , which could lead to positive-feedback loop to EGFR .
3 Using wild-type KRAS colorectal cancer cells as models , we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody , cetuximab , and PP242 , alone or in combination in vitro and in vivo .
4 Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells .
5 Moreover , the ability of cancer - cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone .
6 Interestingly , the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting .
7 The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy , in terms of either diameter or number .
8 More importantly , the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts .
9   These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas .



PMID: 26581910
(Patient)  
Terms: in vitro, in vivo
Sent# Symbols Sentence Mnemonics
0 A mutant BRAF V600E-specific immunohistochemical assay : correlation with molecular mutation status and clinical outcome in colorectal cancer .
1 Colorectal cancer ( CRC ) global incidence is one of the highest among cancers .
2 The KRAS gene has been shown as a robust biomarker for poor prognosis and drug resistance .
3 MicroRNA-143 ( miR-143 ) and let-7 are families of tumor suppressor microRNAs that are often downregulated in CRC , especially with coexistent KRAS mutations .
4 In order to evaluate if miR-143 and/or let-7b replenishment would re-sensitize CRC cells to paclitaxel treatment , we investigated in effect of miR-143 and let-7b replenishments on sensitivity to paclitaxel treatment in KRAS mutant LoVo and wild-type SW48 CRC cell lines .
5 Our results showed that miR-143 , but not let-7b , increased sensitization of KRAS mutant tumor cells to paclitaxel .
6 Furthermore , transfection of miR-143 , but not let-7b , mimic negatively regulated the expression of mutant but not wild-type KRAS .
7 Combination of miR-143 mimic and paclitaxel induced the onset of apoptosis , and reverted in vitro metastatic properties ( migration and invasion ) in KRAS mutant tumor cells .
8 MiR-143 thus can be used as a chemosensitizer for the treatment of KRAS mutant tumors and warrants further investigations in in vitro and pre-clinical in vivo models .



PMID: 26581653
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation .
1 Biomarkers that currently affect clinical practice : EGFR , ALK , MET , KRAS .



PMID: 26579439
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Bile acid nuclear receptor FXR and digestive system diseases .
1 Bile acids ( BAs ) are not only digestive surfactants but also important cell signaling molecules , which stimulate several signaling pathways to regulate some important biological processes .
2 The bile-acid -activated nuclear receptor , farnesoid X receptor ( FXR ) , plays a pivotal role in regulating bile acid , lipid and glucose homeostasis as well as in regulating the inflammatory responses , barrier function and prevention of bacterial translocation in the intestinal tract .
3 As expected , FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract , including inflammatory bowel disease , colorectal cancer and type 2 diabetes .
4 In this review , we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases .
5 Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases .



PMID: 26578731
(Patient)  
Terms: NCT00852228
Sent# Symbols Sentence Mnemonics
0 Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV .
1 BACKGROUND :
2 Systemic chemotherapy typically converts previously unresectable liver metastases ( LM ) from colorectal cancer to curative intent resection in approximately 15% of patients .
3 This European multicenter phase II trial tested whether hepatic artery infusion ( HAI ) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients .
4 PATIENTS AND METHODS :
5 Participants had unresectable LM from wt KRAS colorectal cancer .
6 Main non-inclusion criteria were advanced extra hepatic disease , prior HAI and grade 3 neuropathy .
7 Irinotecan ( 180 mg/m(2) ) , oxaliplatin ( 85 mg/m(2) ) and 5-fluorouracil ( 2800 mg/m(2) ) were delivered via an implanted HAI access port and combined with i .
8 v .
9 cetuximab ( 500 mg/m(2) ) every 14 days .
10 Multidisciplinary decisions to resect LM were taken after every three courses .
11 The rate of macroscopic complete resections ( R0 + R1 ) of LM , progression-free survival ( PFS ) and overall survival ( OS ) were computed according to intent to treat .
12 RESULTS :
13 The patient population consisted of 42 men and 22 women , aged 33-76 years , with a median of 10 LM involving a median of six segments .
14 Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients .
15 A median of six courses was delivered .
16 The primary end point was met , with R0-R1 hepatectomy for 19 of the 64 previously treated patients , 29.7% ( 95% confidence interval 185-409 ) .
17 Grade 3-4 neutropenia ( 426% ) , abdominal pain ( 262% ) , fatigue ( 18% ) and diarrhea ( 164% ) were frequent .
18 Objective response rate was 40.6% ( 286-523 ) .
19 Median PFS and OS reached 9.3 ( 78-109 ) and 25.5 months ( 188-321 ) respectively .
20 Those with R0-R1 hepatectomy had a median OS of 35.2 months ( 326-378 ) , with 37.4% ( 236-512 ) alive at 4 years .
21 CONCLUSION :
22   The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing .
23 PROTOCOL NUMBERS :
24 EUDRACT 2007-004632-24 , NCT00852228 .



PMID: 26577117
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer .
1 Increased frequency of 20q gain and copy-neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas .



PMID: 26575603
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer .
1 BACKGROUND :
2 In metastatic colorectal cancer ( mCRC ) , BRAFV600E mutation has been variously associated to specific clinico-pathological features .
3 METHODS :
4 Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set ( TS ) and validation-set ( VS ) for developing a nomogram predictive of BRAFV600E status .
5 The model was internally and externally validated .
6 RESULTS :
7 In the TS , data from 596 mCRC patients were gathered ( RAS wild-type ( wt ) 281 ( 471% ) ; BRAFV600E mutated 54 ( 91% ) ) ; RAS and BRAFV600E mutations were mutually exclusive .
8 In the RAS-wt population , right-sided primary ( odds ratio ( OR ) : 7.80 , 95% confidence interval ( CI ) 3.05-19.92 ) , female gender ( OR : 2.90 , 95% CI 1.14-7.37 ) and mucinous histology ( OR : 4.95 , 95% CI 1.90-12.90 ) were independent predictors of BRAFV600E mutation , with high replication at internal validation ( 100% , 93% and 98% , respectively ) .
9 A predictive nomogram was calculated : patients with the highest score ( right-sided primary , female and mucinous ) had a 81% chance to bear a BRAFV600E-mutant tumour ; accuracy measures : AUC = 0.812 , SE : 0.034 , sensitivity : 81.2% ; specificity : 72.1% .
10 In the VS ( 508 pts , RAS wt : 262 ( 516% ) , BRAFV600E mutated : 49 ( 96% ) ) , right-sided primary , female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy .
11 CONCLUSIONS :
12 Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity .



PMID: 26573425
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS testing in metastatic colorectal cancer : advances in Europe .
1 Personalized medicine shows promise for maximizing efficacy and minimizing toxicity of anti-cancer treatment .
2 KRAS exon 2 mutations are predictive of resistance to epidermal growth factor receptor -directed monoclonal antibodies in patients with metastatic colorectal cancer .
3 Recent studies have shown that broader RAS testing ( KRAS and NRAS ) is needed to select patients for treatment .
4 While Sanger sequencing is still used , approaches based on various methodologies are available .
5 Μ Few CE-approved kits , however , detect the full spectrum of RAS mutations .
6 More recently , "next-generation" sequencing has been developed for research use , including parallel semiconductor sequencing and reversible termination .
7 These techniques have high technical sensitivities for detecting mutations , although the ideal threshold is currently unknown .
8 Finally , liquid biopsy has the potential to become an additional tool to assess tumor-derived DNA .
9 For accurate and timely RAS testing , appropriate sampling and prompt delivery of material is critical .
10 Processes to ensure efficient turnaround from sample request to RAS evaluation must be implemented so that patients receive the most appropriate treatment .
11 Given the variety of methodologies , external quality assurance programs are important to ensure a high standard of RAS testing .
12 Here , we review technical and practical aspects of RAS testing for pathologists working with metastatic colorectal cancer tumor samples .
13 The extension of markers from KRAS to RAS testing is the new paradigm for biomarker testing in colorectal cancer .



PMID: 26572750
(None)  
Terms: Phase I, Phase II, Phase III
Sent# Symbols Sentence Mnemonics
0 Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction .
1 INTRODUCTION :
2 Integration of targeted therapy and additional chemotherapy options has improved median overall survival ( OS ) in patients with unresectable metastatic colorectal cancer ( mCRC ) .
3 Cetuximab and panitumumab are examples of targeted therapies , specifically against the epidermal growth factor receptor ( EGFR ) .
4 This review focuses on Panitumumab , a fully human IgG2 monoclonal antibody , which inhibits key oncogenic downstream cell signalling pathways .
5 Panitumumab and cetuximab have improved tumour response rate , progression-free survival , and OS in mCRC patients in whom the Rat RAS ( Sarcoma ) gene is of Wild Type ( WT ) status .
6 AREAS COVERED :
7 The EGFR signalling pathway and preclinical , Phase I and Phase II clinical studies on the pharmacokinetic , pharmacodynamic and safety evaluation of panitumumab are presented .
8 Phase III studies utilising panitumumab in the first , second and third line setting in mCRC are also described .
9 EXPERT OPINION :
10 Panitumumab exhibits excellent pharmacokinetics and pharmacodynamics by way of uncomplicated dosing , non-existent drug interactions , minimal infusion reactions and manageable side effects , making it a suitable target for combination treatments .
11 However , innate and acquired resistances are still obstacles .
12 To overcome this , experimented strategies are ongoing , particularly in patients with Her-2 and BRAF gene alterations .
13   Novel biomarkers to improve patient selection and second-generation targeted antibodies are in development .



PMID: 26566372
(Patient)  
Terms: Prospective, prospective
Sent# Symbols Sentence Mnemonics
0 Prospective noninterventional study on the use of panitumumab monotherapy in patients with recurrent or progressive colorectal cancer : the VECTIS study .
1 PURPOSE :
2 Epidermal growth factor receptor -targeted monoclonal antibodies are active as monotherapy beyond second - line treatment .
3 Skin toxicities ( STs ) are common during treatment , and a positive association between ST severity and patient outcome has been reported .
4 This study collected information on panitumumab monotherapy use in patients with KRAS exon 2 wild-type metastatic colorectal cancer in clinical practice .
5 METHODS :
6 This open-label , prospective , observational , noninterventional study included adult patients who had failed prior chemotherapy with 5-fluorouracil , oxaliplatin , and irinotecan .
7 Patients received panitumumab monotherapy ( 6 mg/kg every 2 weeks ) for
8 Effectiveness was assessed as disease control rate ( DCR ) , tumor response , and freedom from progression .
9 The incidence of ST and other adverse drug reactions ( ADRs ) was recorded , as were Eastern Cooperative Oncology Group performance status ( ECOG PS ) and quality of life .
10 The KRAS analysis process was also evaluated .
11 FINDINGS :
12 The full analysis set included 632 patients ( 646% male ; mean age , 623 years ) , who completed a mean of 9.6 panitumumab cycles .
13 ST , mainly grade 1/2 , occurred in 84.3% of patients , 82.7% of whom required treatment .
14 Nonskin ADRs occurred in 3.5% of patients .
15 By the end of treatment , the DCR was 58.9% overall , and was 53.8% and 62.7% , respectively in patients with ST grade 0/1 and grade 2/3 .
16 Significant associations were observed between maximum ST grade and best response ( P = 00009 ) , DCR ( P = 00046 ) , tumor response ( P = 00002 ) , and freedom from progression ( P = 00084 ) .
17 At the end of the study , 67.4% of the patients had an ECOG PS of 0/1 .
18 Quality of life was rated as "very good" or "good" in 70.3% of patients .
19 Mean time to obtain KRAS results was 18.2 days ; satisfaction with different aspects of KRAS testing was "very good" or "good" in 80%-97% of patients .
20 CONCLUSION :
21   Panitumumab monotherapy showed adequate effectiveness and safety in patients with heavily pretreated KRAS exon 2 wild-type metastatic colorectal cancer .
22 The most common ADR was grade 1/2 ST .



PMID: 26561209
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy .
1 Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors .



PMID: 26560143
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Absolute Quantification of Endogenous Ras Isoform Abundance .
1 Ras proteins are important signalling hubs situated near the top of networks controlling cell proliferation , differentiation and survival .
2 Three almost identical isoforms , HRAS , KRAS and NRAS , are ubiquitously expressed yet have differing biological and oncogenic properties .
3 In order to help understand the relative biological contributions of each isoform we have optimised a quantitative proteomics method for accurately measuring Ras isoform protein copy number per cell .
4 The use of isotopic protein standards together with selected reaction monitoring for diagnostic peptides is sensitive , robust and suitable for application to sub-milligram quantities of lysates .
5 We find that in a panel of isogenic SW48 colorectal cancer cells , endogenous Ras proteins are highly abundant with >/ = 260,000 total Ras protein copies per cell and the rank order of isoform abundance is KRAS>NRAS>/ = HRAS .
6 A subset of oncogenic KRAS mutants exhibit increased total cellular Ras abundance and altered the ratio of mutant versus wild type KRAS protein .
7 These data and methodology are significant because Ras protein copy number is required to parameterise models of signalling networks and informs interpretation of isoform-specific Ras functional data .



PMID: 26557847
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Molecular Features and Methylation Status in Early Onset ( Colorectal Cancer : A Population Based , Case-Control Study .
1 Colorectal cancer is usually considered a disease of the elderly .
2 However , a small fraction of patients develops colorectal cancer earlier .
3 The aim of our study was to define the frequency of known hereditary colorectal syndromes and to characterise genetic and epigenetic features of early nonhereditary tumors .
4 Thirty-three patients colorectal cancer and 41 patients with disease at >60 years of age were investigated for MSI , Mismatch Repair proteins expression , KRAS and BRAF mutations , hypermethylation , and LINE-1 hypomethylation .
5 Detection of germline mutations was performed in Mismatch Repair , APC and MUTYH genes .
6 Μ Early onset colorectal cancer showed a high incidence of hereditary forms ( 18% ) .
7 Μ KRAS mutations were detected in 36% of early nonhereditary tumors .
8 Early onset colorectal cancer disclosed an average number of methylated genes significantly lower when compared to the controls ( p = 002 ) .
9 Finally both of the two groups were highly methylated in ESR1 , GATA5 , and WT1 genes and were similar for LINE-1 hypomethylation .
10 The genetic make-up of carcinomas differs from young to elderly patients .
11 Early onset tumors showed more frequently a constitutional defective of Mismatch Repair System and a minor number of methylated genes .
12 Hypermethylation of ESR1 , GATA5 , and WT1 genes suggests possible markers in the earlier diagnosis of colorectal tumorigenesis .



PMID: 26553611
(None)  
Terms: prospective studies
Sent# Symbols Sentence Mnemonics
0 Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites .
1 Metastatic colorectal cancer ( mCRC ) carries a poor prognosis with an overall 5-year survival of 13.1% .
2 Therapies guided by tumor profiling have suggested benefit in advanced cancer .
3 We used a multiplatform molecular profiling ( MP ) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC .
4 We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing ( Sanger/NGS ) , immunohistochemistry ( IHC ) and in-situ hybridization ( ISH ) .
5 Μ mCRC metastases to liver , brain , ovary or lung ( n = 1507 ) showed differential expression of markers including high protein expression of TOPO1 ( 52% ) and/or low RRM1 ( 57% ) , TS ( 71% ) and MGMT ( 39% ) , suggesting possible benefit from irinotecan , gemcitabine , 5FU/capecitabine and temozolomide , respectively .
6 Μ Lung metastases harbored a higher Her2 protein expression than the primary colon tumors ( 4% vs. 18% , p = 0028 ) .
7 Brain and lung metastases had higher KRAS mutations than other sites ( 65% versus 59% versus 47% , respectively , p = 007 , <001 ) , suggesting poor response to anti-EGFR therapies .
8 Μ BRAF-mutated CRC ( n = 455 ) showed coincident high protein expression of RRM1 ( 56% ) , TS ( 53% ) and low PDGFR ( 22% ) as compared with BRAF wild-type tumors .
9 KRAS-mutated mCRC had higher protein expression of c-MET ( 47% vs. 36% ) and lower MGMT ( 56% vs. 63% ) , suggesting consideration of c-MET inhibitors and temozolomide .
10 KRAS-mutated CRC had high TUBB3 ( 42% vs. 33% ) and low Her2 by IHC ( 05% ) and HER2 by FISH ( 3% , p <005 ) .
11 CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer ( 10% and 33% , respectively ) .
12 MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types .
13 Our findings are hypothesis generating and need to be examined in prospective studies .
14 Specific therapies may be considered for different actionable targets in mCRC as revealed by MP .



PMID: 26553291
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer .
1   Histogram analysis of iodine maps from dual energy computed tomography for monitoring targeted therapy of melanoma patients .



PMID: 26552951
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer : Targeting BRAF mutations equally ?
1 Comparison of KRAS genotype : therascreen assay vs . LNA -mediated qPCR clamping assay .



PMID: 26551156
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparative net cost impact of the utilization of panitumumab versus cetuximab for the treatment of patients with metastatic colorectal cancer in Canada .
1 The most challenging task in colorectal cancer research nowadays is to understand the development of acquired resistance to anti-EGFR drugs .
2 The key reason for this problem is the KRAS mutations appearance after the treatment with monoclonal antibodies ( moAb ) .
3 Here we present a mathematical model for the analysis of KRAS mutations behavior in colorectal cancer with respect to moAb treatments .
4 To evaluate the drug performance we have developed equations for two types of tumors cells , KRAS mutated and KRAS wild-type .
5 Both tumor cell populations were treated with a combination of moAb and chemotherapy drugs .
6 Μ It was observed that even the minimal initial concentration of KRAS mutation before the treatment has the ability to make the tumor refractory to the treatment .
7 Minor population of KRAS mutations has strong influence on large number of wild-type cells as well rendering them resistant to chemotherapy .
8 Μ Patients immune responses are specifically taken into considerations and it is found that , in case of KRAS mutations , the immune strength does not affect medication efficacy .
9   Finally , cetuximab ( moAb ) and irinotecan ( chemotherapy ) drugs are analyzed as first - line treatment of colorectal cancer with few KRAS mutated cells .
10   Results show that this combined treatment could be only effective for patients with high immune strengths and it should not be recommended as first - line therapy for patients with moderate immune strengths or weak immune systems because of a potential risk of relapse , with KRAS mutant cells acquired resistance involved with them .



PMID: 26543374
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ rs712 polymorphism within let-7 microRNA -binding site might be involved in the initiation and progression of colorectal cancer in Chinese population . GM-INV-RO
1 Assessment of molecular testing in fine-needle aspiration biopsy samples : an experience in a Chinese population .



PMID: 26541605
(Cell)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH .
1 More than half of human colorectal cancers ( CRCs ) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies .
2 Μ We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C .
3 This effect is due to increased uptake of the oxidized form of vitamin C , dehydroascorbate ( DHA ) , via the GLUT1 glucose transporter .
4 Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C , depleting glutathione .
5 Thus , reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ) .
6 Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells .
7 High-dose vitamin C impairs tumor growth in Apc/Kras (G12D) mutant mice .
8 These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations .



PMID: 26538496
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer .
1 BACKGROUND :
2 In a phase II study , we showed that temozolomide ( TMZ ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer ( CRC ) and MGMT methylation .
3 A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion , even in resistant tumors .
4 METHODS :
5 Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m(2) for 21 consecutive days every 4 weeks , for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity .
6 The primary endpoint was treatment activity in terms of objective response rate ( ORR ) .
7 MGMT protein expression was tested by immunohistochemistry ( IHC ) on two pooled cohorts : patients from the previous study of standard-dose TMZ and those from the current investigation .
8 RESULTS :
9 From November 2013 to December 2014 , 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori .
10 We observed only three episodes of grade 3 asthenia and no significant myelotoxicity .
11 The ORR was 16 % ( all partial responses occurring in RAS-BRAF-mutated tumors ) .
12 Median progression-free survival ( PFS ) and overall survival ( OS ) were 2.3 and 6.7 months , respectively .
13 Patients with MGMT-low expression by IHC had a significantly higher ORR ( p <00001 ) and PFS ( p = 0001 ) compared to those with MGMT-high expression , while no difference was observed in OS .
14 CONCLUSIONS :
15 Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing , even in the RAS-BRAF-mutated population .
16   The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation .



PMID: 26537294
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Automated PCR detection of BRAF mutations in colorectal adenocarcinoma : a diagnostic test accuracy study .
1 BACKGROUND :
2 Μ Testing for BRAF mutations in colorectal carcinoma ( CRC ) is important in the screening pathway for Lynch syndrome and is of prognostic value to guide management .
3 This is a diagnostic accuracy study of the Idylla system , a novel and automated alternative PCR system .
4 METHODS :
5 100 consecutive formalin-fixed , paraffin-embedded CRC resection cases were tested for BRAF mutations using the Idylla automated platform and compared with standard ( Cobas ) PCR .
6 RESULTS :
7 The sensitivity of the Idylla BRAF test was 100% and the specificity was 96% .
8 ✓ Μ Only one discordant Idylla positive/standard PCR negative result occurred and on Droplet Digital PCR demonstrated a mutation not identified by traditional PCR in this case . RO-ASS-GM
9 CONCLUSION :
10 This study has validated the Idylla system for BRAF testing in CRC and demonstrated a possibly greater sensitivity , in addition to cost effectiveness and shorter turnaround time , when compared with standard PCR .



PMID: 26536055
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Next-Generation Sequencing of Matched Primary and Metastatic Rectal Adenocarcinomas Demonstrates Minimal Mutation Gain and Concordance to Colonic Adenocarcinomas .
1 CONTEXT :
2 -Colorectal carcinoma is the third most common cause of cancer death in males and females in the United States .
3 Rectal adenocarcinoma can have distinct therapeutic and surgical management from colonic adenocarcinoma owing to its location and anatomic considerations .
4 OBJECTIVE :
5 -To determine the oncologic driver mutations and better understand the molecular pathogenesis of rectal adenocarcinoma in relation to colon adenocarcinoma .
6 DESIGN :
7 Μ -Next-generation sequencing was performed on 20 cases of primary rectal adenocarcinoma with a paired lymph node or solid organ metastasis by using an amplicon-based assay of more than 2800 Catalogue of Somatic Mutations in Cancer ( COSMIC )- identified somatic mutations .
8 RESULTS :
9 -Next-generation sequencing data were obtained on both the primary tumor and metastasis from 16 patients .
10 Μ Most rectal adenocarcinoma cases demonstrated identical mutations in the primary tumor and metastasis ( 13 of 16 , 81% ) .
11 Μ The mutations identified , listed in order of frequency , included TP53 , KRAS , APC , FBXW7 , GNAS , FGFR3 , BRAF , NRAS , PIK3CA , and SMAD4 .
12 CONCLUSIONS :
13 Μ -The somatic mutations identified in our rectal adenocarcinoma cohort showed a strong correlation to those previously characterized in colonic adenocarcinoma .
14 Μ In addition , most rectal adenocarcinomas harbored identical somatic mutations in both the primary tumor and metastasis .
15 These findings demonstrate evidence that rectal adenocarcinoma follows a similar molecular pathogenesis as colonic adenocarcinoma and that sampling either the primary or metastatic lesion is valid for initial evaluation of somatic mutations and selection of possible targeted therapy .



PMID: 26532584
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HER2 gene mutations in non-small cell lung carcinomas : concurrence with Her2 gene amplification and Her2 protein expression and phosphorylation .
1 AIM :
2 To profile expression of microRNAs ( miRNAs ) in gastric cancer cells and investigate the effect of miR-374b-5p on gastric cancer cell invasion and metastasis .
3 METHODS :
4 An miRNA microarray assay was performed to identify miRNAs differentially expressed in gastric cancer cell lines ( MGC-803 and SGC-7901 ) compared with a normal gastric epithelial cell line .
5 Upregulation of miR-374b-5p was newly identified and confirmed via quantitative real-time reverse transcription-PCR ( qRT-PCR ) .
6 MGC-803 cells were transfected with a synthesized anti-miR-374b-5p sequence or a control vector using Lipofectamine reagent , or treated with transfection reagent alone or phosphate-buffered saline as controls .
7 Rate of transfection was verified after 48 h by qRT-PCR .
8 Cells were then subjected to transwell migration , wound scratch and cell counting kit-8 assays .
9 A bioinformatic analysis to identify miR-374b-5p target genes was performed using miRanda , PicTar and TargetScan software .
10 A dual luciferase reporter assay was performed to evaluate the influence of miR-374b-5p on target gene activation , and qRT-PCR and Western blot were used to evaluate the levels of target mRNA and protein following transfection with miR-374b-5p antisense oligonucleotides .
11 RESULTS :
12 The microarray profiling revealed downregulation of 14 ( fold change <0667 ; P <005 ) and upregulation of 12 ( fold change >150 ; P <005 ) miRNAs in MGC-803 and SGC-7901 cells compared with GES-1 controls .
13 The upregulation of miR-374b-5p ( fold change = 175 and 164 in MGC-803 and SGC-7901 , respectively ; P <005 ) was confirmed by qRT-PCR .
14 Compared with the control groups , the restoration of miR-374b-5p expression with anti-miR-374b-5p significantly suppressed the metastasis , invasion and proliferation of MGC-803 cells .
15 The bioinformatic analysis predicted that the 3' untranslated region ( UTR ) of reversion-inducing cysteine-rich protein with Kazal motif ( RECK ) contains three miR-374b-5p target sequences .
16 RECK was verified as a target gene in a dual luciferase reporter assay showing that activation of RECK 3'UTR-pmirGLO was increased by co-transfection with miR-374b-5p .
17 Finally , transfection of miR-374b-5p antisense oligonucleotides increased mRNA and protein levels of RECK in MGC-803 cells ( P <005 ) .
18 CONCLUSION :
19 These findings indicate that upregulation of miR-374b-5p contributes to gastric cancer cell metastasis and invasion through inhibition of RECK expression .



PMID: 26532065
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison Of Kras Tested And Not-Tested Metastatic Colorectal Cancer ( Mcrc ) Patient Cohorts In Europe .
1   Afatinib as first - line treatment for patients with advanced non-small - cell lung cancer harboring EGFR mutations : focus on LUX-Lung 3 and LUX-Lung 6 phase III trials .



PMID: 26530529
(Patient)  
Terms: in vivo, xenograft, animal models, zebrafish
Sent# Symbols Sentence Mnemonics
0 Molecular pathological epidemiology of colorectal cancer in Chinese patients with KRAS and BRAF mutations .
1 Pancreatic cancer is one of the most aggressive human cancers , and the pharmaceutical outcomes for its treatment remain disappointing .
2 Proper animal models will provide an efficient platform for investigating novel drugs , and the zebrafish has become one of the most promising and comprehensive model animal in cancer research .
3 In the present study , we used a novel xenograft model in zebrafish by transplanting human pancreatic cancer cells to study the progression and metastasis of pancreatic cancer cells and to assay the pharmacological effects of new drug U0126 in vivo .
4 We first established a primary xenograft model of pancreatic cancer by injecting human pancreatic cancer cells into both live larval and adult zebrafish , and then investigated the behaviors of CM-DiIlabeled human pancreatic cancer cells .
5 Subsequently , we tested the potential of this model for drug screening by evaluating a known small-molecule inhibitor , U0126 , which targets the KRAS signaling pathway .
6 Cells with KRAS mutations exhibited significant proliferative and migratory behaviors and invaded the zebrafish vasculature system .
7 In contrast , the proliferation and migration of Mia PaCa-2 cells in zebrafish larvae were substantially repressed following U0126 treatment .
8 These results suggest that zebrafish xenotransplantation can be used as a simple and efficient tool to screen and identify new anti-pancreatic cancer compounds .



PMID: 26528862
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer .
1 BACKGROUND :
2 The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 The response rate , progression-free survival ( PFS ) and overall survival of the patients were analyzed .
5 RESULTS :
6 In total , 45 patients were included in the study .
7 The overall response rate for the combination of cetuximab and FOLFOX , FOLFIRI and CAPOX was 20 , 46 and 30% , respectively , but the differences were not statistically significant .
8 The median PFS for the three groups were 8 , 6 and 3.5 months , respectively , but again these differences were not significant .
9 All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens .
10 CONCLUSION :
11   Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC , with higher hematologic toxicities among the FOLFOX subgroup .



PMID: 26527776
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Adjuvant Fluorouracil , Leucovorin , and Oxaliplatin in Stage II to III Colon Cancer : Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study .
1 BACKGROUND :
2 Gefitinib and cetuximab are both epidermal growth factor receptor ( EGFR ) target therapies used to treat patients with non-small-cell lung cancer ( NSCLC ) with different mechanisms .
3 To clarify the effectiveness of cetuximab after failure of gefitinib treatment , we investigated the clinical features of patients with NSCLC who received cetuximab-containing chemotherapy after failure of gefitinib .
4 PATIENTS AND METHODS :
5 We analyzed the clinical data and mutational studies of patients with NSCLC in the National Taiwan University Hospital who had received gefitinib and , after failure of gefitinib , cetuximab-containing chemotherapy .
6 RESULTS :
7   Fifteen patients who received cetuximab-containing chemotherapy after failure of gefitinib were identified .
8 Four were responders to gefitinib therapy , and 3 were responders to cetuximab-containing chemotherapy .
9 Ten were sequenced for EGFR and KRAS mutations .
10 Six of the 10 patients had EGFR mutations , and all 10 patients had wild-type ( WT ) KRAS .
11   In the 4 patients who had the gefitinib-resistant EGFR T790M mutation , 2 were responders to cetuximab-containing chemotherapy .
12 The other cetuximab responder had WT EGFR .
13 CONCLUSION :
14 Cetuximab might add benefit in treatment after failure of gefitinib , regardless of EGFR mutational status .
15   Treatment with cetuximab should be further explored , even in patients who have previously received gefitinib treatment .



PMID: 26525741
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ High SLFN11 expression predicts better survival for patients with KRAS exon 2 wild type colorectal cancer after treated with adjuvant oxaliplatin-based treatment . GE-REG-RO, RO-ASS-GE
1 BACKGROUND :
2 SLFN11 was reported to be a predictive marker for DNA damage drugs .
3 The study was to investigate whether SLFN11 expression is related to sensitivity to adjuvant oxaliplatin-based treatment in colorectal cancer .
4 METHODS :
5 A tissue microarray , made with specimens from consecutive 261 patients who received oxaliplatin based adjuvant chemotherapy , was stained with anti-SLFN11 antibody .
6 The staining was dichotomized as high or low expression .
7 SLFN11 expression was correlated to clinicopathological factors , KRAS exon 2 mutation and survival .
8 RESULTS :
9 Μ SLFN11 high expression was found in 16.9 % of patients , and KRAS exon 2 mutation was detected in 32.2 % of patients .
10 SLFN11 was expressed more common in well/moderate differentiation tumors ( comparing to poor differentiation ones , 21 % v 4.9 % , P = 0.003 ) and stage II tumors ( comparing to stage III tumors , 26.1 % v 11.4 % , p = 0.006 ) .
11 23 out of 153 patients with KRAS exon 2 wild-type CRC had SLFN11 high expression , no death events was recorded in the 23 patients until last follow up .
12 These patients had significantly better overall survival ( OS ) than those with SLFN11 low expression tumors ( 100 % versus 782 % , log rank P = 0048 ) .
13 However , among patients with KRAS exon 2 mutant tumors , OS did not significantly differ between those with SLFN11 high and SLFN11 low tumors ( Log rank P = 0709 ) .
14 CONCLUSIONS :
15 ✓ SLFN11 expression predicts good better survival in colorectal cancer patients with KRAS exon 2 wild type who have received oxaliplatin based adjuvant chemotherapy . GE-REG-RO, RO-ASS-GE



PMID: 26524859
(Patient)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 [ Fecal Biomarker for Colorectal Cancer Diagnosis ] .
1 The fecal occult blood test ( FOBT ) is widely used for colorectal cancer ( CRC ) screening to reduce the mortality rate associated with this cancer .
2 However , several problems exist , as FOBT results can contain some false-negative CRC patients and some-false positive healthy subjects .
3 Thus , to resolve these problems , several fecal biomarkers based on fecal protein , fecal DNA , and fecal RNA have been reported .
4 Fecal calprotectin , which indicates intestinal bleeding or inflammation of the colon mucosa , and fecal tumor M2-PK , which is produced by cancer cells , have been extensively investigated as fecal protein biomarkers .
5 To detect small amounts of CRC-specific proteins , the chemiluminescent enzyme immunoassay ( CLEIA ) , which is a highly sensitive protein detection method using immunomagnetic beads , will be used .
6 DNA mutation of APC , KRAS , and TP53 genes and DNA methylation of VIM , TFPI2 , BMP3 , NDRG4 , and SFRP2 genes were reported as fecal DNA biomarkers .
7 Consequently , a fecal DNA test named Cologuard from Exact Sciences was approved by the FDA in August 2014 .
8 Fecal COX2 , MMP7 , miR-106a , miR-92a , and miR-223 were also reported as fecal RNA biomarkers .
9 This review article summarizes fecal biomarkers using fecal samples for CRC diagnosis .



PMID: 26523369
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 MicroRNA-20b promotes cell growth of breast cancer cells partly via targeting phosphatase and tensin homologue ( PTEN ) .
1 BACKGROUND :
2 Telomeres are TTAGGG tandem repeats capping chromosomal ends and partially controlled by the telomerase enzyme .
3 The EGFR pathway putatively regulates telomerase function , prompting an investigation of telomere length ( TL ) and its association with anti-epidermal growth factor receptor ( EGFR ) therapy in metastatic colorectal cancer ( mCRC ) .
4 METHODS :
5 Colorectal cancer cell lines were treated with multiple drugs and sensitivity determined .
6 Clinical information was gathered from 75 patients who had received anti-EGFR drugs .
7 Telomere length was measured using a validated qRT-PCR technique .
8 RESULTS :
9 In CRC cell lines , TL independently predicted cetuximab sensitivity .
10 Cells with shorter TL had growth inhibition of 18.6+/-3.41% as compared with 41.39+/-8.58% in longer TL ( P = 002 ) .
11 These in vitro findings were validated clinically , in a robust multivariate model .
12 ✓ Among patients with KRas WT tumours , those with longer TL had a superior median progression-free survival ( PFS ) of 24.9 weeks than those with shorter TL ; median 11.1 weeks , HR 0.31 ; P = 0.048 . GE-ASS-RO, RO-ASS-GE
13 CONCLUSION :
14   Telomere length could be a potential unique biomarker predictive of clinical benefit ( PFS ) of mCRC patients treated with anti-EGFR therapy .
15 This is the novel demonstration of a complex hitherto undescribed interaction , placing anti-EGFR therapy , EGFR pathway , and the telomerase complex within a clinical context .



PMID: 26517354
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutational profiling of colorectal cancers with microsatellite instability .
1 Microsatellite instability ( MSI ) is caused by defective mismatch repair in 15-20% of colorectal cancers ( CRCs ) .
2 Higher mutation loads in tumors with mismatch repair deficiency can predict response to pembrolizumab , an anti-programmed death 1 ( PD-1 ) immune checkpoint inhibitor .
3 Μ We analyzed the mutations in 113 CRCs without MSI ( MSS ) and 29 CRCs with MSI-High ( MSI-H ) using the 50 - gene AmpliSeq cancer panel .
4 ✓ Μ Overall , MSI-H CRCs showed significantly higher mutations than MSS CRCs , including insertion/deletion mutations at repeat regions . GM-ASS-DS
5 ✓ Μ MSI-H CRCs showed higher incidences of mutations in the BRAF , PIK3CA , and PTEN genes as well as mutations in the receptor tyrosine kinase families . GM-ASS-DS
6 While the increased mutations in BRAF and PTEN in MSI-H CRCs are well accepted , we also support findings of mutations in the mTOR pathway and receptor tyrosine kinase family genes .
7 ✓ Μ MSS CRCs showed higher incidences of mutations in the APC , KRAS and TP53 genes , confirming previous findings . GM-ASS-DS
8   Μ NGS assays may be designed to detect driver mutations for targeted therapeutics and to identify tumors with high mutation loads for potential treatment with immune checkpoint blockade therapies .
9   Further studies may be warranted to elucidate potential targeted therapeutics against mutations in the mTOR pathway and the receptor tyrosine kinase family in MSI-H CRCs as well as the benefit of anti-PD-1 immunotherapy in hypermutated MSS CRCs or other cancers .



PMID: 26515606
(Patient)  
Terms: prospective study
Sent# Symbols Sentence Mnemonics
0 NDRG4 stratifies the prognostic value of body mass index in colorectal cancer .
1 NDRG4 is a novel candidate tumor suppressor and can inhibit PI3K/AKT signal which is related with energy balance and related carcinogenesis .
2 In the present study , we investigated whether NDRG4 status could modify the association of obesity with clinical outcome of colorectal cancer .
3 For this purpose , a hospital-based prospective study cohort of 226 colorectal cancer patients was involved .
4 NDRG4 mRNA levels were determined by real-time PCR .
5 Association of NDRG4 mRNA expression with disease-free and overall survival was studied first .
6 Then , the association of obesity with clinical outcome was determined according to NDRG4 level .
7 Multivariate Cox proportional hazards model was used to compute hazard ratio , adjusting for covariates including microsatellite instability , KRAS , BRAF and PIK3CA mutation .
8 Μ Results showed that NDRG4 mRNA expression was decreased in tumor specimens and significantly correlated with tumor differentiation , invasion and metastasis .
9 Patients with tumor of reduced NDRG4 mRNA level had unfavorable disease-free and overall survival .
10 Obesity was found to be adversely associated with disease-free and overall survival in tumors with reduced NDRG4 level , not in preserved NDRG4 level group , in both univariate and multivariate analysis .
11 These data provided the first evidence that NDRG4 level in colorectal cancer could effectively stratify the prognostic value of obesity , which would better the understanding of the prognostic role of obesity in colorectal cancer .
12 Our results also support the notion that the host-tumor interactions in colorectal cancer might influence tumor aggressiveness .



PMID: 26515332
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS polymorphisms are associated with survival of CRC in Chinese population . GM-ASS-RO
1 rs12245 , rs12587 , rs9266 , rs1137282 , rs61764370 , and rs712 of KRAS oncogene are characterized in the 3'UTR .
2 The study highlights the important role of these polymorphisms playing in the susceptibility , oxaliplatin-based chemotherapy sensitivity , progression , and prognosis of CRC .
3 Improved multiplex ligation detection reaction ( iMLDR ) technique is used for genotyping .
4 An unconditional logistic regression model was used to estimate the association of certain polymorphism and CRC risk .
5 Μ The Kaplan-Meier method , log-rank test , and Cox regression model were used to evaluate the effects of polymorphisms on survival analysis .
6 ✓ Μ Results demonstrated that TT genotype and T allele of rs712 were associated with the increased risk of CRC ; the patients with GG genotype and G allele of rs61764370 had a shorter survival and a higher risk of relapse or metastasis of CRC . GM-ASS-RO, RO-ASS-GM
7   Our studies supported the conclusions that rs61764370 and rs712 polymorphisms of the KRAS are functional and it may play an important role in the development of CRC and oxaliplatin-based chemotherapy efficiency and prognosis of CRC .



PMID: 26512054
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors .
1 BACKGROUND :
2 The CpG island methylator phenotype ( CIMP ) is a major molecular pathway in colorectal cancer .
3 Approximately 25% to 60% of CIMP tumors are microsatellite unstable ( MSI-H ) due to DNA hypermethylation of the MLH1 gene promoter .
4 Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1 .
5 METHODS :
6 We assessed the associations between age , sex , tumor - site , MSI status BRAF and KRAS mutations , and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables .
7 RESULTS :
8 Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger , more likely to be male , and more likely to have distal colon or rectal primaries and the MSI-L phenotype .
9 CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation .
10 MLH1 methylation was associated with significantly better overall survival ( HR , 050 ; 95% confidence interval , 031-082 ) .
11 CONCLUSIONS :
12 These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis .
13 IMPACT : MLH1 DNA methylation status should be taken into account in etiologic studies .



PMID: 26510091
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MGMT inhibition suppresses survivin expression in pancreatic cancer .
1 To clarify molecular alterations in serrated pathway of colorectal cancer ( CRC ) , we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps ( SSA/P ) , traditional serrated adenomas ( TSAs ) and high-methylation CRC .
2 The methylation levels of six Group-1 and 14 Group-2 markers , established in our previous studies , were analyzed quantitatively using pyrosequencing .
3 Μ Subsequently , we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development .
4 Μ SSA/P showed high methylation levels of both Group-1 and Group-2 markers , frequent BRAF mutation and occurrence in proximal colon , which were features of high-methylation CRC .
5 Μ But TSA showed low-methylation levels of Group-1 markers , less frequent BRAF mutation and occurrence at distal colon .
6 SSA/P , but not TSA , is thus considered to be precursor of high-methylation CRC .
7 High-methylation CRC had even higher methylation levels of some genes , e.g. , MLH1 , than SSA/P , and significant frequency of somatic mutations in nonsynonymous mutations ( p <00001 ) and insertion/deletions ( p = 0002 ) .
8 Μ MLH1-methylated SSA/P showed lower methylation level of MLH1 compared with high-methylation CRC , and rarely accompanied silencing of MLH1 expression .
9 The mutation frequencies were not different between MLH1-methylated and MLH1-unmethylated SSA/P , suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype .
10 Mutations of mismatch repair genes , e.g. , MSH3 and MSH6 , and genes in PI3K , WNT , TGF-beta and BMP signaling ( but not in TP53 signaling ) were significantly involved in high-methylation CRC compared with adenoma , suggesting importance of abrogation of these genes in serrated pathway .



PMID: 26508880
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular profiling in the treatment of colorectal cancer : focus on regorafenib .
1 Metastatic colorectal cancer ( mCRC ) is a highly heterogeneous disease .
2 Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies , including anti-EGFR antibodies , cetuximab and panitumumab , and VEGF inhibitors , bevacizumab , ramucirumab , and aflibercept .
3 The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments , such as RAS mutation profiling for EGFR antibodies .
4 Regorafenib is a multikinase inhibitor currently used as late line therapy for mCRC .
5 The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized .
6   Here , we review currently available clinical evidence of mCRC molecular profiling , such as RAS , BRAF , and MMR testing , and its role in targeted therapies with special focus on regorafenib treatment .



PMID: 26508446
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prediction of response to anti-EGFR antibody -based therapies by multigene sequencing in colorectal cancer patients .
1 BACKGROUND :
2 The anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies ( moAbs ) cetuximab or panitumumab are administered to colorectal cancer ( CRC ) patients who harbor wild-type RAS proto-oncogenes .
3 However , a percentage of patients do not respond to this treatment .
4 In addition to mutations in the RAS genes , mutations in other genes , such as BRAF , PI3KCA , or PTEN , could be involved in the resistance to anti-EGFR moAb therapy .
5 METHODS :
6 In order to develop a comprehensive approach for the detection of mutations and to eventually identify other genes responsible for resistance to anti-EGFR moAbs , we investigated a panel of 21 genes by parallel sequencing on the Ion Torrent Personal Genome Machine platform .
7 We sequenced 65 CRCs that were treated with cetuximab or panitumumab .
8 Among these , 37 samples were responsive and 28 were resistant .
9 RESULTS :
10 ✓ We confirmed that mutations in EGFR-pathway genes ( KRAS , NRAS , BRAF , PI3KCA ) were relevant for conferring resistance to therapy and could predict response ( p = 0001 ) . GM-REG-RO
11 After exclusion of KRAS , NRAS , BRAF and PI3KCA combined mutations could still significantly associate to resistant phenotype ( p = 0045 , by Fisher exact test ) .
12 In addition , mutations in FBXW7 and SMAD4 were prevalent in cases that were non-responsive to anti-EGFR moAb .
13 After we combined the mutations of all genes ( excluding KRAS ) , the ability to predict response to therapy improved significantly ( p = 0002 , by Fisher exact test ) .
14 CONCLUSIONS :
15 The combination of mutations at KRAS and at the five gene panel demonstrates the usefulness and feasibility of multigene sequencing to assess response to anti-EGFR moAbs .
16 The application of parallel sequencing technology in clinical practice , in addition to its innate ability to simultaneously examine the genetic status of several cancer genes , proved to be more accurate and sensitive than the presently in use traditional approaches .



PMID: 26508156
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy .
1 Μ Endometrial Carcinomas With Clear Cells : A Study of a Heterogeneous Group of Tumors Including Interobserver Variability , Mutation Analysis , and Immunohistochemistry With HNF-1beta .



PMID: 26499143
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Molecular phenotypes of colorectal cancer is critical in clinical individual treatment ] .
1 Gastrointestinal stromal tumors ( GISTs ) are relatively rare neoplasms of the gastrointestinal tract originating from the pluripotential mesenchymal stem cells , which differentiate into interstitial Cajal cells .
2 They are usually located in the upper gastrointestinal track .
3 These tumors are typically defined by the expression of c-KIT ( CD117 ) and CD34 proteins in the tumor cells .
4 A small percentage of these tumors is negative for c-KIT .
5 The neoplasms are positive for platelet-derived growth factor alpha ( PDGFalpha ) mutations .
6 In addition to PDGFRalpha mutations , wild-type c-KIT mutations can also be present .
7 The therapeutic approach to locally developed gastrointestinal stromal tumors is surgical resection , either with open or laparoscopic surgery .
8 In case of systemic disease , molecular pharmacologic agents such as imatinib and sunitinib are used for treatment .
9 These agents block the signaling pathways of neoplastic - cell tyrosine kinases , interfering in their proliferation and causing apoptosis .



PMID: 26498038
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical detection and categorization of uncommon and concomitant mutations involving BRAF .
1 BACKGROUND :
2 Selective BRAF inhibitors , vemurafenib and dabrafenib , and the MEK inhibitor , trametinib , have been approved for treatment of metastatic melanomas with a BRAF p.V600E mutation .
3 The clinical significance of non - codon 600 mutations remains unclear , in part , due to variation of kinase activity for different mutants .
4 METHODS :
5 In this study , we categorized BRAF mutations according to the reported mutant kinase activity .
6 A total of 1027 lung cancer , colorectal cancer or melanoma specimens were submitted for clinical mutation detection by next generation sequencing .
7 RESULTS :
8 Μ Non - codon 600 mutations were observed in 37% of BRAF-mutated tumors .
9 Of all BRAF mutants , 75% were kinase -activated , 15% kinase -impaired and 10% kinase -unknown .
10 The most common kinase -impaired mutant involves codon 594 , specifically , p .
11 D594G ( c1781A >G ) and p.D594N ( c1780G >A ) .
12 Lung cancers showed significantly higher incidences of kinase -impaired or kinase -unknown mutants .
13 Μ Kinase -impaired BRAF mutants showed a significant association with concomitant activating KRAS or NRAS mutations , but not PIK3CA mutations , supporting the reported interaction of these mutations .
14 CONCLUSIONS :
15 BRAF mutants with impaired or unknown kinase activity as well as concomitant kinase -impaired BRAF mutations and RAS mutations were detected in lung cancers , colorectal cancers and melanomas .
16 Different therapeutic strategies based on the BRAF mutant kinase activity and the concomitant mutations may be worthwhile .



PMID: 26497852
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab .
1 The aim of our study was to investigate whether microRNAs ( miRNAs ) could serve as predictive biomarkers to anti-EGFR therapy ( cetuximab , panitumumab ) in patients with RAS wild-type ( wt-RAS ) metastatic colorectal cancer ( mCRC ) .
2 Historical cohort of 93 patients with mCRC ( 2006-2009 ) was included and further divided into exploratory and validation cohorts .
3 MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression ( TTP ) .
4 The validation was performed on two independent cohorts : 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab .
5 Μ We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy ( P
6 These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p ( P <0001 ) and miR-31-5p ( P <0001 ) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab .
7 When evaluated on the complete cohort of cetuximab patients ( N = 69 ) , miR-31-3p ( HR , 510 ; 95% CI , 252-1032 ; P <0001 ) and miR-31-5p ( HR , 480 ; 95% CI , 250-924 ; P <0001 ) were correlated with TTP on the comparable level of significance .
8 There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples .
9   MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients .



PMID: 26496853
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Traditional serrated adenoma with BRAF mutation is associated with synchronous/metachronous BRAF-mutated serrated lesions .
1 AIMS :
2 To determine whether traditional serrated adenoma ( TSA ) results in an increased risk of developing subsequent serrated polyps or colorectal cancer ( CRC ) .
3 METHODS AND RESULTS :
4 We recruited 111 patients with an index TSA , and analysed the pathological and molecular features of their synchronous/metachronous serrated lesions .
5 Fifty hyperplastic polyps , 14 sessile serrated adenomas , an additional 27 TSAs and 17 CRCs were identified from 46 patients .
6 Twenty-seven percent of TSAs showed a precursor serrated polyp in the periphery and were strongly correlated with BRAF mutation ( P <0001 ) .
7 Serrated polyps occurred more commonly in patients with BRAF-mutated index TSAs than in patients with KRAS-mutated index TSAs .
8 BRAF-mutated index TSAs were strongly associated with a right-sided location and BRAF mutation of synchronous/metachronous serrated polyps ( P = 0013 and P = 0005 , respectively ) .
9 Μ The 17 CRCs occurred more frequently in women , and were characterized by a high BRAF mutation rate ( 59% ) , a positive CpG island methylator phenotype ( 59% ) , and stable or low levels of microsatellite instability ( 77% ) .
10 CONCLUSIONS :
11 BRAF-mutated TSA is distinct from KRAS-mutated TSA in predisposing to the acquisition of subsequent serrated neoplasia .
12 This indicates the presence of an intestinal field defect in the tumour microenvironment that results in tumour initiation and malignant progression .



PMID: 26496026
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer .
1 AIM :
2 VE1 is a monoclonal antibody detecting mutant BRAFV (600E) protein by immunohistochemistry .
3 Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status , investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients .
4 METHODS :
5 Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers ( n = 34 ) , melanomas ( n = 23 ) and thyroid cancers ( n = 8 ) .
6 Two prognostic cohorts were evaluated ( n = 259 , Cohort 1 and n = 226 , Cohort 2 ) by multiple-punch tissue microarrays .
7 VE1 staining on preoperative biopsies ( n = 118 patients ) was compared to expression in resections .
8 Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks ( n = 100 blocks ) .
9 RESULTS :
10 Inter-observer agreement was 100% ( kappa = 10 ) .
11 Concordance between VE1 and V600E mutation was 98.5% .
12 Cohort 1 : VE1 positivity ( seen in 135% ) was associated with older age ( p = 00175 ) and MLH1 deficiency ( p <00001 ) .
13 Cohort 2 : VE1 positivity ( seen in 128% ) was associated with female gender ( p = 00016 ) , right-sided tumor location ( p <00001 ) , higher tumor grade ( p <00001 ) and mismatch repair ( MMR )- deficiency ( p <00001 ) .
14 In survival analysis , MMR status and postoperative therapy were identified as possible confounding factors .
15 Adjusting for these features , VE1 was an unfavorable prognostic factor .
16 Preoperative biopsy staining matched resections in all cases except one .
17 No heterogeneity was found across any primary/metastatic tumor blocks .
18 CONCLUSION :
19 VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens , preoperative biopsies , metastatic lesions and tissue microarrays .



PMID: 26495974
(Patient)  
Terms: retrospective studies
Sent# Symbols Sentence Mnemonics
0 Assessment of DDR2 , BRAF , EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients .
1 The clinical significance of KRAS gene testing prior to using anti-epidermal growth factor receptor ( EGFR ) antibodies for colorectal cancer patients has been established in past randomized clinical trials .
2 Thus , testing for the 7 most common mutations of KRAS codons 12 and 13 is now recommended as a clinical practice .
3 However , pooled analysis of randomized controlled studies in Western countries in patients treated with cetuximab has suggested that patients with tumors showing the KRAS p.G13D mutation[a glycine(G) to aspartate(D) transition mutation] have longer overall survival and progression-free survival when compared to patients with other KRAS mutations .
4 Furthermore , even among patients whose tumors are wild-type for KRAS codons 12 and 13 , response rates are only 13~17% for anti-EGFR antibody monotherapy .
5 ✓ These facts suggest that additional activating mutations in the RAS-RAF-MAPK or PI3K-AKT-mTOR pathways may also confer resistance to anti-EGFR antibody therapies .
6 ✓ Indeed , recent retrospective studies have shown that mutations in KRAS codon 61 and 146 , BRAF , NRAS , and PIK3CA may also predict resistance to anti-EGFR antibodies in colorectal cancer patients .
7   On the other hand , the continuous use of anti-EGFR therapies for KRAS wild-type patients may lead to secondary resistance .
8 Μ Acquired EGFR or KRAS mutations have occasionally been detected among specimens from these patients .
9   We review the latest personalized therapy available for colorectal cancer patients using KRAS mutational testing .
10 We also illustrate future perspectives for patient selection using KRAS , BRAF , NRAS , PIK3CA , and other mutations .



PMID: 26491871
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing : Results from a Europe-Wide Physician Survey and Medical Records Review .
1 BACKGROUND :
2 From 2008-2013 , the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment .
3 To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer ( mCRC ) , two European multi-country , cross-sectional , observational studies were initiated in 2012 : a physician survey and a medical records review .
4 The first two out of three planned rounds for each study are reported .
5 METHODS :
6 The primary objective in the physician survey was to estimate the prevalence of KRAS testing , and in the medical records review , it was to evaluate the effect of test results on patterns of panitumumab use .
7 The medical records review study also included a pathologists' survey .
8 RESULTS :
9   In the physician survey , nearly all oncologists ( 299/301 ) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab .
10 Nearly all oncologists ( 283/301 ) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status .
11 In the medical records review , 97.5% of participating oncologists ( 77/79 ) conducted a KRAS test for all of their patients prior to prescribing panitumumab .
12   Four patients ( 13% ) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment .
13   Approximately one-quarter of patients ( 85/306 ) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy ; of these , 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment .
14 All 56 referred laboratories that participated used a Conformite Europeenne-marked or otherwise validated KRAS detection method , and nearly all ( 55/56 ) participated in a quality assurance scheme .
15 CONCLUSIONS :
16   There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab , with or without concurrent oxaliplatin-containing therapy .



PMID: 26490659
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Does anti-p53 antibody status predict for clinical outcomes in metastatic colorectal cancer patients treated with fluoropyrimidine , oxaliplatin , plus bevacizumab as first - line chemotherapy ?
1 The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma .



PMID: 26490308
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Individualization of therapy for colorectal cancer based on clinical and molecular parameters .
1 PURPOSE :
2 We hypothesized that adverse prognostic associations of specific tumor molecular factors vary by patient age at colorectal cancer diagnosis .
3 EXPERIMENTAL DESIGN :
4 We examined the prognostic associations and interactions by age at colorectal cancer diagnosis ( <60 vs. 60-74 vs. >/ = 75 years old ) of key molecular factors-CpG island methylator phenotype ( CIMP ) , microsatellite instability ( MSI ) , KRAS , BRAF , and PIK3CA mutations , and nuclear CTNNB1 expression status-on colorectal cancer-specific survival ( CSS ) and overall survival ( OS ) , using 1,280 incident colorectal cancer cases ( median age , 69 years ; range , 38-91 years ) within the Nurses' Health Study and Health Professionals Follow-up Study cohorts .
5 RESULTS :
6 ✓ MSI-high was associated with better survival , whereas BRAF mutation was associated with worse survival , but these associations did not appreciably differ by age group . GM-ASS-RO
7 ✓ Status of CIMP , KRAS mutation , or PIK3CA mutation was not associated with prognosis regardless of age . GM-ASS-RO
8 ✓ Nuclear CTNNB1 expression was associated with a trend toward worse prognosis among older adults [age >/= 75 years ; multivariate HR , 1.67 ; 95% confidence interval ( CI ) , 0.89-3.13 ( for CSS ) ; multivariate HR , 1.44 ; 95% CI , 0.93-2.24 ( for OS ) ] but not among younger patients , and there was a statistically significant interaction by age ( Pinteraction = 003 for CSS ; Pinteraction = 0007 for OS ) . GE-ASS-RO
9 CONCLUSIONS :
10 Tumor nuclear CTNNB1 expression may be associated with higher mortality among older patients with colorectal cancer but not among younger patients .
11 Our findings need to be confirmed in independent datasets .
12 Detailed exploration of tumor molecular signatures in older patients with colorectal cancer in large populations is warranted .



PMID: 26489582
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ [ Relationship between Polymorphisms and the Efficacy of Cetuximab ] . GM-ASS-RO
1 Differential expression of connexin 43 in gastrointestinal stromal tumours of gastric and small intestinal origin .



PMID: 26489551
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Long-Term Survival of a Patient with KRAS Mutated Colon Cancer Successfully Treated with Regorafenib ] .
1 Targeted therapy in lung cancer : IPASS and beyond , keeping abreast of the explosion of targeted therapies for lung cancer .



PMID: 26488212
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells .
1 Epidermal growth factor receptor ( EGFR ) gene mutations ( G719X , exon 19 deletions/insertions , L858R , and L861Q ) predict favorable responses to EGFR tyrosine kinase inhibitors ( TKIs ) in advanced non-small cell lung cancer ( NSCLC ) .
2 However , EGFR exon 20 insertion mutations ( ~10% of all EGFR mutations ) are generally associated with insensitivity to available TKIs ( gefitinib , erlotinib , and afatinib ) .
3 The basis of this primary resistance is poorly understood .
4 We studied a broad subset of exon 20 insertion mutations , comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients , and found that most are resistant to EGFR TKIs .
5 The crystal structure of a representative TKI-insensitive mutant (D770 N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket , and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation .
6 Unlike EGFR-L858R , D770 N771insNPG activates EGFR without increasing its affinity for EGFR TKIs .
7 Unexpectedly , we find that EGFR-A763 Y764insFQEA is highly sensitive to EGFR TKIs in vitro , and patients whose NSCLCs harbor this mutation respond to erlotinib .
8 Analysis of the A763 Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction , altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R .
9 ✓ Μ Our studies reveal intricate differences between EGFR mutations , their biology , and their response to EGFR TKIs . GM-ASS-RO



PMID: 26486455
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan .
1 BACKGROUND :
2 More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer ( mCRC ) .
3 We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC .
4 METHODS :
5 We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan ( CI ) .
6 We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes .
7 RESULTS :
8 Μ BRAF mutation was detected in 5.1 % ( 3/58 ) of patients .
9 All 50 patients showed wild type PIK3CA .
10 Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis .
11 PSKH1 , TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC .
12 The higher expression value of PSKH1 ( r = 0462 , p <0001 ) and TLK2 ( r = 0361 , p = 0005 ) had the significant correlation to prolonged PFS .
13 CONCLUSION :
14 Μ The result of this work demonstrated that expression nature of kinase genes such as PSKH1 , TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC .
15 Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC .



PMID: 26484206
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Global gene expression profiling analysis reveals reduction of stemness after B-RAF inhibition in colorectal cancer cell lines .
1 Cancer cell differentiation is an important field of discussion in the light of cancer stem cells .
2 In a recent study by Herr et al. ( 2015 ) "B-RAF inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells" we described how inhibition of mutant BRAF in colorectal cancer cell lines induces cell re-differentiation that is correlated with the loss of tumor growth in vitro and in vivo .
3 We used Illumina HumanHT-12 v4 Expression BeadChip to characterize the gain of differentiation of PLX4720-treated 3D cultures of HT29 and Colo-205 cells .
4 Here , we describe the experimental design and statistical analysis that were performed on the data set leading to the above hypothesis .
5 The data are publicly available at the Gene Expression Omnibus ( GEO ) database under the accession number GSE50791 .



PMID: 26483874
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Role of retinoids in the prevention and treatment of colorectal cancer .
1 Vitamin A and its derivatives , retinoids , have been widely studied for their use as cancer chemotherapeutic agents .
2 With respect to colorectal cancer ( CRC ) , several critical mutations dysregulate pathways implicated in progression and metastasis , resulting in aberrant Wnt/beta-catenin signaling , gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt , cyclooxygenase-2 over-expression , reduction of peroxisome proliferator-activated receptor gamma activation , and loss of p53 function .
3 Dysregulation leads to increased cellular proliferation and invasion and decreased cell - cell interaction and differentiation .
4 Retinoids affect these pathways by various mechanisms , many involving retinoic acid receptors ( RAR ) .
5 RAR bind to all-trans-retinoic acid ( ATRA ) to induce the transcription of genes responsible for cellular differentiation .
6   Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation , increase differentiation , or promote apoptosis ; as CRC progresses , RAR expression is often lost , rendering treatment of CRCs with ATRA ineffective .
7 Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways .
8 This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR -dependent and RAR-independent mechanisms .



PMID: 26483047
(Patient)  
Terms: NCT01229813
Sent# Symbols Sentence Mnemonics
0 A randomized study of KRAS-guided maintenance therapy with bevacizumab , erlotinib or metronomic capecitabine after first - line induction treatment of metastatic colorectal cancer : the Nordic ACT2 trial .
1 BACKGROUND :
2 Maintenance treatment ( mt ) with bevacizumab ( bev ) +/-erlotinib ( erlo ) has modest effect after induction chemotherapy in metastatic colorectal cancer ( mCRC ) .
3 We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev +/- erlo and low-dose capecitabine ( cap ) .
4 PATIENTS AND METHODS :
5 Included patients had mCRC scheduled for first - line therapy , Eastern Cooperative Oncology Group ( ECOG ) 0-1 and no major comorbidities .
6 Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks .
7 After induction , patients without progression were eligible for randomization to mt ; KRAS wild-type ( wt ) patients were randomized to bev +/- erlo ( arms wt-BE , N = 36 versus wt-B , N = 35 ) , KRAS mutated ( mut ) patients were randomized to bev or metronomic cap ( arms mut-B , N = 34 versus mut-C , N = 33 ) .
8 Primary end point was progression-free survival ( PFS ) rate ( PFSr ) at 3 months after start of mt .
9 A pooled analysis of KRAS wt patients from the previous ACT study was performed .
10 RESULTS :
11 We included 233 patients .
12 Median age was 64 years , 62% male , 68% ECOG 0 , 52% with primary tumor in situ .
13 A total of 138 patients started mt after randomization .
14 ✓ PFSr was 64.7% versus 63.6% in wt-B versus wt-BE , P = 1.000 ; and 75% versus 66.7% in mut-B versus mut-C , P = 0.579 , with no significant difference in median PFS and overall survival ( OS ) . GE-ASS-RO
15 ✓ In the pooled cohort , median PFS was 3.7 months in wt-B ( N = 64 ) and 5.7 months in wt-BE ( N = 62 ) ( hazard ratios 103 , 95% confidence interval 070-150 , P = 0867 ) . GE-ASS-RO
16 The frequency of any grade 3/4 toxicities during mt was : 28%/58%/18%/15% ( wt-B/wt-BE/mut-B/mut-C ) .
17 CONCLUSIONS :
18 Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS , but it did increase toxicity .
19 ✓ KRAS status does not seem to influence the outcome of treatment with erlotinib . GE-REG-RO
20 Metronomic cap warrants further investigation in mt strategies , given our explorative results .
21 CLINICALTRIALSGOV : NCT01229813 .



PMID: 26476438
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mitochondrial DNA copy number in colorectal cancer : between tissue comparisons , clinicopathological characteristics and survival .
1 Low mitochondrial DNA ( mtDNA ) copy number in tumors has been associated with worse prognosis in colorectal cancer ( CRC ) .
2 This study further deciphers the role of mtDNA copy number in CRC by comparing mtDNA copy number between healthy , adenoma and carcinoma tissue , by investigating its association according to several clinicopathological characteristics in CRC , and by relating it to CRC-specific survival in CRC patients .
3 A hospital-based series of samples including cancer , adenoma and adjacent histologically normal tissue from primary CRC patients ( n = 56 ) and recurrent CRC ( n = 16 ) was studied as well as colon mucosa samples from healthy subjects ( n = 76 ) .
4 Furthermore , mtDNA copy number was assessed in carcinomas of 693 CRC cases identified from the population-based Netherlands Cohort Study ( NLCS ) .
5 MtDNA copy number was significantly lower in carcinoma tissue ( P = 0011 ) and adjacent tissue ( P <0001 ) compared to earlier resected adenoma tissue and in primary CRC tissue compared to recurrent CRC tissue ( P = 0011 ) .
6 Within both study populations , mtDNA copy number was significantly lower in mutated BRAF ( P = 0027 and P = 0006 ) and in microsatellite unstable ( MSI ) tumors ( P = 0033 and P <0001 ) and higher in KRAS mutated tumors ( P = 0004 ) .
7 Furthermore , the association between mtDNA and survival seemed to follow an inverse U-shape with the highest HR observed in the second quintile of mtDNA copy number ( HR = 170 , 95% CI = 118 , 244 ) compared to the first quintile .
8 These results might reflect an association of mtDNA copy number with various malignant processes in cancer cells and warrants further research on tumor energy metabolism in CRC prognosis .



PMID: 26476272
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The serrated neoplasia pathway of colorectal tumors : Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential .
1 The serrated neoplasia pathway accounts for 20-30% of colorectal cancers ( CRC ) , which are characterized by extensive methylation ( CpG island methylation phenotype , CIMP ) , frequent BRAF mutation and high microsatellite instability ( MSI ) .
2 Μ We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC .
3 The early identification of preneoplastic lesions among serrated polyps is currently challenging .
4 Here , we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential .
5 Μ A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell -rich hyperplastic polyps ( GCHP ) , 68 microvesicular hyperplastic polyps ( MVHP ) , 100 sessile serrated adenoma ( SSA ) and eight traditional serrated adenoma ( TSA ) ] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations , MSI , CIMP , MLH1 and MGMT methylation , and MUC2 and MUC5AC expression and methylation .
6 We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway , and specifically detects MVHP and SSA , arguing for a filiation between MVHP , SSA and CIMP-H/MSI CRC , whereas GCHP and TSA arise from a distinct pathway .
7 Μ Moreover , MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation , CIMP-H or MSI , suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions .
8 Our data suggest that MVHP should be recognized among HP and require particular attention .



PMID: 26475632
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma .
1 OBJECTIVE :
2 Sessile serrated adenomas ( SSAs ) are the precursors of atleast 15% of colorectal carcinomas , but their biology is incompletely understood .
3 We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma .
4 DESIGN :
5 A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted .
6 Samples were examined for BRAF and KRAS mutations , the CpG island methylator phenotype ( CIMP ) and immunostained for MLH1 , p53 , p16 , beta-catenin and 0-6-methylguanine DNA methyltransferase ( MGMT ) .
7 RESULTS :
8 The median polyp size was 9 mm and 86.5% were proximal .
9 Most were BRAF mutated ( 927% ) and 94.0% showed CIMP .
10 Mismatch repair deficiency , evidenced by loss of MLH1 ( 745% ) is associated with older age ( 767 versus 710 ; p<00029 ) , female gender ( 70% versus 36% ; p<00008 ) , proximal location ( 91% versus 72% ; p<002 ) , CIMP ( 98% versus 80% ; p<002 ) and lack of aberrant p53 ( 7% versus 34% ; p<0001 ) when compared with the mismatch repair-proficient cases .
11 Loss of p16 ( 431% ) and gain of nuclear beta-catenin ( 555% ) were common in areas of dysplasia/cancer , irrespective of mismatch repair status .
12 CONCLUSIONS :
13 SSAs containing dysplasia/carcinoma are predominantly small ( <10 mm ) and proximal .
14 The mismatch repair status separates these lesions into distinct clinicopathological subgroups , although WNT activation and p16 silencing are common to both .
15 Cases with dysplasia occur at a similar age to cases with carcinoma .
16 This , together with the rarity of these 'caught in the act' lesions , suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia .



PMID: 26474549
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Retreatment with anti-EGFR based therapies in metastatic colorectal cancer : impact of intervening time interval and prior anti-EGFR response .
1 Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations .



PMID: 26473412
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA-27b suppresses tumor progression by regulating ARFGEF1 and focal adhesion signaling .
1 The non - receptor tyrosine kinase c-Src is frequently activated during progression of colon cancers .
2 In this study , we found that among the c-Src-regulated microRNAs ( miRNAs ) , miR-27b is also repressed by activation of K-Ras/H-Ras .
3 Inhibitor studies suggested that the phosphatidylinositol 3 - kinase pathway is involved in the repression of miR-27b .
4 MicroRNA-27b was repressed in various colon cancer cell lines and tumor tissues .
5 Re-expression of miR-27b in human colon cancer HCT116 cells caused morphological changes and suppressed tumor growth , cell adhesion , and invasion .
6 We also identified ARFGEF1 and paxillin as novel targets of miR-27b , and found that miR-27b -mediated regulation of ARFGEF1 is crucial for controlling anchorage -independent growth , and that of paxillin is important for controlling cell adhesion and invasion .
7 Re-expression of miR-27b suppressed the activation of c-Src induced by integrin-mediated cell adhesion , suggesting that repression of miR-27b may contribute to c-Src activation in cancer cells .
8 These findings show that miR-27b functions as a tumor suppressor by controlling ARFGEF1 and the paxillin/c-Src circuit at focal adhesions .



PMID: 26471487
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Diagnosis of metachronous multiple lung adenocarcinoma at the cut-end by epidermal growth factor receptor mutation status discordance 4 years after sublobar resection for adenocarcinoma in situ : report of a case .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is a heterogeneous disease caused by genetic and epigenetic alterations .
3 This study aimed to describe the mutation frequency of 12 genes in different CRC phenotypes .
4 METHODS :
5 Patients who underwent surgery at the Taipei Veterans General Hospital during 2000-2010 for CRC ( n = 1249 ) were enrolled .
6 The endpoint was overall survival .
7 The prognostic value was determined with the log-rank test and Cox regression analysis .
8 RESULTS :
9 Μ We found 1836 mutations of 12 genes in 997 ( 798% ) tumors .
10 Μ Mutations were most frequently in KRAS ( 485 , 388% ) , TP53 ( 373 , 299% ) , APC ( 363 , 290% ) , and PIK3CA ( 179 , 143% ) ; 137 ( 110% ) cancers had high microsatellite instability ( MSI ) .
11 Women had significantly higher high MSI ( 143% ) and BRAF mutation ( 63% ) frequencies .
12 The abnormal MSI ( 217% ) and KRAS ( 446% ) , BRAF ( 86% ) , PIK3CA ( 194% ) , AKT1 ( 22% ) , and TGF - betaR ( 96% ) mutation frequencies were significantly higher in proximal colon cancer .
13 The high MSI ( 356% ) and BRAF ( 203% ) , TGF - betaR ( 186% ) , PTEN ( 51% ) , and AKT1 ( 34% ) mutation frequencies were significantly higher in 59 ( 47% ) poorly differentiated tumors .
14 The high MSI ( 213% ) and KRAS ( 519% ) , BRAF ( 83% ) , PIK3CA ( 250% ) , AKT1 ( 46% ) , and SMAD4 ( 83% ) mutation frequencies were significantly higher in 108 mucinous tumors .
15 TNM stage , lymphovascular invasion , and mucinous histology were significantly associated with patient outcomes in univariate and multivariate analyses .
16 Only NRAS mutation ( hazard ratio 159 , 95% confidence interval 106-238 ) affected patient survival .
17 CONCLUSIONS :
18 Mutational spectra differ significantly between CRC subtypes , implying diverse carcinogenetic pathways .
19 The NRAS mutation is important , despite its low frequency .



PMID: 26469098
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Large Bowel Genetic Background and Inflammatory Processes in Carcinogenesis--Systematic Review .
1 Colorectal cancer ( CRC ) has become the third most common cancer in developed countries .
2 Each year more and more people die from CRC .
3 CRC is also one of the most effectively studied topics in recent years .
4 It has been found that the key phenomena in CRC development are genetic and inflammatory processes .
5 Well-known genetic bases for the carcinogenesis of CRC include chromosomal changes characteristic of the chromosomal instability pathway which correlates with specific and well-defined genetic alterations ( such as APC , K-RAS , DCC and p53 ) and genomic instability characteristics for the mutator pathway focused on KRAS and BRAF mutations .
6 Recent studies have highlighted the impact of inflammation in CRC , especially elevated levels of pro-inflammatory cytokines .
7 Among important risk factors of colon carcinogenesis are colorectal polyps , which are currently the subject of intense research .
8 Recent studies have shown that different adenomas are characterized by different pathways of carcinogenesis as well as diverse COX-2 expression in various polyps .
9   Understanding the mechanism of inflammatory processes in CRC parallel to basic genetic alterations might allow for effective and targeted treatment .



PMID: 26468218
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Survival of patients with KRAS wild-type metastatic colorectal cancer is identical after sequential treatment with cetuximab and bevacizumab regardless of the sequence - A retrospective single-center study .
1 OBJECTIVE :
2 To investigate the overall survival of patients with KRAS wild-type metastatic colorectal cancer ( mCRC ) after sequentially receiving both bevacizumab and cetuximab during the course of treatment .
3 METHODS :
4 Twenty-six mCRC patients who received both bevacizumab and cetuximab at the Sun Yat-sen University Gastrointestinal Hospital were retrospectively analyzed .
5 Group A ( n = 8 ) comprised patients who received bevacizumab first , and group B ( n = 18 ) comprised those who received cetuximab first .
6 The objective response rate , progression-free survival , and overall survival were compared .
7 RESULTS :
8 Baseline characteristics between the two groups were statistically similar .
9 The objective response in groups A and B patients was 62.5% and 66.6% , respectively ( P = 0132 ) .
10 The median progression-free survival for groups A and B patients was 13 and 10 months , respectively ( P = 0798 ) .
11 The median overall survival for the entire cohort was 42 months , 44 months for group A and 39 months for group p B ( P = 0862 ) patients , respectively .
12 Patients aged <40 years had worse survival than those aged >/ = 40 years ( 22 versus 44 months ; P = 0029 ) .
13 Patients with synchronous metastasis had worse survival than those with metachronous metastasis ( unreached and 36 months , respectively ) .
14 In multivariate analyses , synchronous metastasis and age remained statistically significant .
15 The hazard ratio for synchronous metastasis was 4.548 , and the HR for patients aged >/ = 40 years was 0.237 .
16 CONCLUSION :
17 A longer median survival time was observed in patients regardless of the targeted therapy sequence , which warrants further investigation .



PMID: 26467662
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Structural , biochemical , and clinical characterization of epidermal growth factor receptor ( EGFR ) exon 20 insertion mutations in lung cancer .
1 PURPOSE :
2 Μ The prevalence of anaplastic lymphoma kinase ( ALK ) gene fusion ( ALK positivity ) in early-stage non-small-cell lung cancer ( NSCLC ) varies by population examined and detection method used .
3 The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population .
4 METHODS :
5 Analysis of ALK status was performed by immunohistochemistry ( IHC ) and fluorescent in situ hybridization ( FISH ) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank .
6 Positive patients were matched with negative patients in a 1 : 2 ratio , both for IHC and for FISH testing .
7 Testing was performed in 16 participating centers , using the same protocol after passing external quality assessment .
8 RESULTS :
9 Positive ALK IHC staining was present in 80 patients ( prevalence of 62% ; 95% CI , 49% to 76% ) .
10 Of these , 28 patients were ALK FISH positive , corresponding to a lower bound for the prevalence of FISH positivity of 2.2% .
11 FISH specificity was 100% , and FISH sensitivity was 35.0% ( 95% CI , 247% to 465% ) , with a sensitivity value of 81.3% ( 95% CI , 636% to 928% ) for IHC 2+/3+ patients .
12 The hazard of death for FISH-positive patients was lower than for IHC-negative patients ( P = 022 ) .
13 Multivariable models , adjusted for patient , tumor , and treatment characteristics , and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival ( OS ) .
14 CONCLUSION :
15 In this large cohort of surgically resected lung adenocarcinomas , the prevalence of ALK positivity was 6.2% using IHC and atleast 2.2% using FISH .
16 A screening strategy based on IHC or H-score could be envisaged .
17 ALK positivity ( by either IHC or FISH ) was related to better OS .



PMID: 26463710
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Optimizing Anti-EGFR Therapy in Colorectal Cancer .
1 Treatment with anti-EGFR monoclonal antibodies has been successfully integrated in the continuum of care for metastatic colorectal cancer .
2 The major challenge is the identification of patients who would benefit from treatment .
3 Currently , the best predictor of efficacy is the absence of mutations in KRAS and NRAS genes .
4 Clin Cancer Res ; 21 ( 24 ) ; 5415-6 .
5 (c) 2015 AACR .
6 See related article by Peeters et al. , p. 5469 .



PMID: 26461472
(Cell)  
Terms: xenograft, mouse, mouse xenograft, mouse xenograft model
Sent# Symbols Sentence Mnemonics
0 Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer .
1 Here , we showed the antibiotic salinomycin ( SAL ) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status , with a relatively low toxicity to normal cells .
2 Additionally , combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF .
3 Further , we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species ( ROS ) , loss of mitochondrial membrane potential ( MMP ) and lysosomal membrane potential ( LMP ) .
4 And the ROS contributed the loss of MMP and LMP .
5 We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase -independent pathway triggered by cathepsin B and D .
6 Lastly , SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model .
7   This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer .



PMID: 26460303
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sensitization of human pancreatic cancer cells harboring mutated K-ras to apoptosis .
1 The revolution in individualized therapy for patients with advanced non-small cell lung cancer ( NSCLC ) has seen the emergence of a number of molecularly targeted therapies for distinct patient molecular subgroups .
2 Activating anaplastic lymphoma kinase ( ALK )- gene rearrangement has been detected in 3-7 % of NSCLC cases , and the ALK inhibitor crizotinib is now an approved treatment for patients with tumors harboring this event .
3 However , resistance to ALK-targeted therapies is a ubiquitous problem in the management of advanced ALK-positive NSCLC and can be mediated by secondary kinase mutations or the activation of compensatory alternative oncogenic drivers .
4 New , more potent ALK inhibitors such as ceritinib ( LDK378 ) , alectinib ( CH5424802 ) , and AP26113 are now emerging , together with an increased knowledge of the molecular basis of resistance .
5   There is a need to evaluate the optimal clinical application of these new agents , either as sequential therapies or in combination with other targeted agents , to combat resistance and prolong survival in patients with ALK-positive NSCLC .
6   The remarkable clinical activity of ALK inhibitors also emphasizes the importance of optimal diagnostic testing algorithms , to ensure that all eligible patients receive these breakthrough therapies .



PMID: 26460302
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hitting the Target in BRAF-Mutant Colorectal Cancer .
1 Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations ( or so-called driver mutations ) and histological subtypes ( the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS] ) .
2 Although both these classifications are essential for personalized treatment , their integrated clinical effect remains unclear .
3 Μ Therefore , we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis .
4 Μ Analysis for oncogenic mutations included the direct sequencing of EGFR , KRAS , HER2 , BRAF , PIK3CA , ALK , and RET for oncogenic mutations/rearrangements , and a rereview of the IASLC/ATS/ERS classification was undertaken .
5 Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ , 20 minimally invasive adenocarcinomas , 901 invasive adenocarcinomas , 44 invasive mucinous adenocarcinomas , and three other variants .
6 Μ The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS , ALK , and HER2 mutations than invasive adenocarcinomas .
7 Smoking , a solid predominant pattern , and a mucinous component were independently associated with fewer EGFR mutations .
8 Μ The ALK rearrangements were more frequently observed in tumors with a minor mucinous component , while the KRAS mutations were more prevalent in smokers .
9 In addition , 503 patients with stage I-IIIA tumors were analyzed for overall survival ( OS ) and relapse-free survival .
10 The stage and histological pattern were independent predictors of relapse-free survival , and the pathological stage was the only independent predictor for the OS .
11 ✓ Although patients with the EGFR mutations had better OS than those without the mutations , no oncogenic mutation was an independent predictor of survival . GM-MRK-RO, GM-ASS-RO, RO-ASS-GM
12 Μ Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification , which facilitates a morphology-based mutational analysis strategy .
13   The combination of these two classifications might not increase the prognostic ability , but it provides essential information for personalized treatment .



PMID: 26456957
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical influence of cancer stem cells on residual disease after preoperative chemoradiotherapy for rectal cancer .
1 We evaluated the clinical influence of cancer stem cells ( CSCs ) on residual disease after preoperative chemoradiotherapy ( CRT ) in patients with rectal cancer .
2 The surgical specimens of 145 patients with residual rectal cancer after preoperative CRT were assessed .
3 To identify CSCs , immunohistochemistry was performed using their surrogate makers ( CD44 and aldehyde dehydrogenase 1 [ALDH1] ) in full section tissues .
4 Μ Of the 145 cases , ALDH1 and CD44 positivity was found in 80.0 % ( n = 116 ) and 47.6 % ( n = 69 ) , respectively ; ALDH1 positivity showed weakly positive correlation with CD44 ( r s = 0269 , P = 0002 ) .
5 ALDH1 and CD44 positivity was related to lower tumor regression grade ( TRG ) ( P = 0009 and 0003 , respectively ) .
6 Additionally , ALDH1 positivity was associated with positive circumferential resection margin ( P = 0019 ) .
7 Μ However , ALDH1 and CD44 positivity showed no relationship with KRAS or BRAF mutation .
8 In univariate analysis , ALDH1 positivity was associated with short recurrence-free survival ( RFS ) ( P = 0005 ) and rectal cancer-specific survival ( RCSS ) ( P = 0043 ) , but not CD44 positivity ( RFS , P = 0725 ; RCSS , P = 0280 ) .
9 In multivariate analysis , ALDH1 positivity was an independent prognostic factor for poor RFS ( P = 0039 ; hazard ratio = 2997 ; 95 % confidence interval = 1059-8478 ) , but not RCSS ( P = 0571 ) .
10 The expression of ALDH1 assessment independently predicts RFS in patients with residual disease after CRT .
11 These results suggest that targeting CSCs could be an effective therapeutic approach to rectal cancer patients receiving preoperative CRT .



PMID: 26452385
(None)  
Terms: clinical trial, this review
Sent# Symbols Sentence Mnemonics
0 Mitogen -Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation .
1 Colorectal cancer ( CRC ) is the second largest cause of cancer mortality in Western countries , mostly due to metastasis .
2 Understanding the natural history and prognostic factors in patients with metastatic CRC ( mCRC ) is essential for the optimal design of clinical trials .
3 The main prognostic factors currently used in clinical practice are related to tumor behavior ( e.g. , white blood counts , levels of lactate dehydrogenase , levels of alkaline phosphatase ) disease extension ( e.g. , presence of extrahepatic spread , number of organs affected ) and general functional status ( e.g. , performance status as defined by the Eastern Cooperative Oncology Group ) .
4 However , these parameters are not always sufficient to establish appropriate therapeutic strategies .
5 First - line therapy in mCRC combines conventional chemotherapy ( CHT ) ( e.g. , FOLFOX , FOLFIRI , CAPOX ) with a number of agents targeted to specific signaling pathways ( TA ) ( e.g. , panitumumab and cetuximab for cases KRAS/NRAS WT , and bevacizumab ) .
6 Although the response rate to this combination regime exceeds 50% , progression of the disease is almost universal and only less than 10% of patients are free of disease at 2 years .
7 Current clinical trials with second and third line therapy include new TA , such as tyrosin-kinase receptors inhibitors ( MET , HER2 , IGF-1R ) , inhibitors of BRAF , MEK , PI3K , AKT , mTORC , NOTCH and JAK1/JAK2 , immunotherapy modulators and check point inhibitors ( anti-PD-L1 and anti - PD1 ) .
8   Despite the identification of multiple prognostic and predictive biomarkers and signatures , it is still unclear how expression of many of these biomarkers is modulated by CHT and/or TA , thus potentially affecting response to treatment .
9   In this review we analyzed how certain biomarkers in tumor cells and microenvironment influence the response to new TA and immune-therapies strategies in mCRC pre-treated patients .



PMID: 26449765
(Patient)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Assessment of a HER2 scoring system for colorectal cancer : results from a validation study .
1 We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a phase II trial of ERBB2-targeted therapy ( HERACLES trial ) .
2 A two-step approach was used .
3 In step 1 , a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification .
4 Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer .
5 In step 2 , from September 2012 to January 2015 , colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial ( clinical validation cohort ) .
6 Μ In both archival test ( N = 256 ) and clinical validation ( N = 830 ) cohorts , a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria .
7 Μ ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression , corresponding to homogenous ERBB2 amplification , in >50% of cells .
8 None of the immunohistochemistry 0 or 1+ cases was amplified .
9 Concordance between SISH and FISH was 100% .
10 In conclusion , we propose specific criteria for defining ERBB2-positivity in colorectal cancer ( HERACLES Diagnostic Criteria ) .
11   In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population , HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer .



PMID: 26449693
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Establishment , characterization and chemosensitivity of three mismatch repair deficient cell lines from sporadic and inherited colorectal carcinomas .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is one of the most common types of cancer , affecting 3 - 5% of the global population .
3 Μ K-ras protooncogene and TP53 tumour suppressor gene mutations are among the most common genetic alterations detected in advanced colorectal tumours .
4 OBJECTIVE :
5 To investigate the role of K-ras codon 12 and TP53 exons 5 - 9 mutations in late-stage CRC patients .
6 METHODS :
7 Blood samples were collected from 249 CRC patients , of whom 147 presented with advanced carcinoma .
8 Μ K-ras codon 12 mutations were analysed using polymerase chain reaction-restriction fragment length polymorphism , while direct sequencing was used in screening for TP53 exons 5 - 9 mutations .
9 RESULTS :
10 Μ No significant changes were observed in TP53 exons 5 - 9 , except for two cases in which nucleotide replacements were observed in the non-coding regions in intron 4 ( c376-19C& ; gt ; T ) and intron 9 ( c993+12T& ; gt ; C ) .
11 Μ Heterozygous mutations in K-ras codon 12 were observed in 79 individuals suffering from advanced CRC ( 537% ) .
12 Colon and rectal tumours were equally distributed among the heterozygotes , but colon tumours were mostly present in wild-type homozygotes ( 846% ) .
13 There was also a predominance of Caucasians among heterozygotes and a predominance of Asians among the wild-type homozygotes .
14 CONCLUSION :
15 Analysis of peripheral blood samples of CRC patients suffering from advanced carcinoma has prognostic value only for K-ras codon 12 mutations , and not for TP53 mutations .



PMID: 26448020
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Combined Analysis of EGFR and PTEN Status in Patients With KRAS Wild-Type Metastatic Colorectal Cancer .
1 To determine the relationship between the expression of phosphatase and tensin homologue ( PTEN ) and epidermal growth factor receptor ( EGFR ) in metastatic colorectal cancer ( mCRC ) and the clinical outcome of cetuximab-containing chemotherapy .
2 A total of 158 consecutive mCRC patients with wild-type KRAS status who received chemotherapy with or without cetuximab , and for whom tumor tissue was available , were enrolled .
3 The EGFR and PTEN expression was determined by immunohistochemistry ( IHC ) .
4 A total of 158 mCRC patients with wild-type KRAS status were enrolled in the study ; 51 patients received chemotherapy combined with cetuximab , 107 patients received chemotherapy alone .
5 Patients who received chemotherapy combined with cetuximab had longer overall survival ( OS ) compared with patients who received chemotherapy alone .
6 Μ High EGFR expression was detected in 60 patients ( 380% ) , while normal PTEN expression was detected in 60 patients ( 595% ) .
7 The PTEN status was significantly related with the histological grade .
8   For patients who received chemotherapy combined with cetuximab the median OS of patients with high-expression of EGFR was longer than the OS of patients with low EGRF expression ; 25.0 versus 19.0 months , P = 0.002 .
9 For patient with normal PTEN the median OS were longer than the median OS for patients with loss of PTEN ; 24.0 versus 19.0 months , P = 0.026 .
10 ✓ The overall response rate ( ORR ) had a borderline association with EGFR and PTEN expression ( P = 0055 and 0048 , respectively ) . RO-ASS-GE
11   In a multivariate analysis , ECOG PS , EGFR status , chemotherapy +/- cetuximab , and the interaction of EGFR or PTEN and chemotherapy +/- cetuximab were independent prognostic factors for OS .
12   Our findings show that chemotherapy combined with cetuximab demonstrated encouraging antitumor activity for mCRC patients with wild-type KRAS status .
13 Especially , those who have high EGFR expression or normal PTEN expression were more likely to benefit from such a treatment strategy .
14 Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers .



PMID: 26446234
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer : Challenging Drug Label to Light Up New Hope .
1 BACKGROUND :
2 No prospective trials have specifically addressed the efficacy and safety of panitumumab in elderly patients with metastatic colorectal cancer ( CRC ) .
3 We aimed at assessing the efficacy and safety of single agent panitumumab in "frail" elderly patients diagnosed with metastatic RAS and BRAF wild-type CRC .
4 MATERIALS AND METHODS :
5 Forty elderly patients ( aged >/= 75 years ) with metastatic RAS-BRAF wild-type CRC received off-label prescriptions of single-agent panitumumab at seven Italian institutions .
6 Treatment was administered as first line in patients with absolute contraindication to any chemotherapy or as second - line treatment after failure of a fluoropyrimidine-based treatment , in the presence of contraindication to irinotecan .
7 The outcome measures included objective response rate ( ORR ) , as well as progression-free survival ( PFS ) , disease control rate ( DCR ) , overall survival ( OS ) , and safety .
8 RESULTS :
9 The median PFS and OS were 6.4 months ( 95% confidence interval [CI] : 4.9-8 months ) and 14.3 months ( 95% CI : 10.9-17.7 months ) , respectively .
10 ORR was 32.5% , and DCR was 72.5% .
11   Dose reductions related to adverse events ( AEs ) were reported in 9 ( 23% ) patients , but no permanent treatment discontinuation caused by was reported .
12 The most frequent grade 3 AE was skin rash , with an incidence of 20% .
13 CONCLUSION :
14   Panitumumab is effective and well-tolerated in frail elderly patients with RAS-BRAF wild-type metastatic CRC and deemed unfit for chemotherapy .
15 A randomized study is needed to confirm these data .
16 IMPLICATIONS FOR PRACTICE :
17   Treatment of elderly patients with metastatic colorectal cancer represents a difficult challenge in clinical practice .
18   A significant proportion of frail elderly patients do not receive treatment , reflecting ongoing uncertainty of clinical benefit and toxicity of chemotherapy .
19 Unfit condition in this cohort of patients further limits antineoplastic prescription and consequently patient survival .
20   RAS and BRAF wild-type status could help select an elderly and unfit population that could benefit from anti-epidermal growth factor receptor single agent therapy .
21   In the present study , single-agent off-label panitumumab was effective and well-tolerated as first - line treatment in frail elderly patients deemed unfit for chemotherapy for metastatic RAS and BRAF wild-type colorectal cancer .



PMID: 26442575
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparative net cost impact of the utilization of panitumumab versus cetuximab for the treatment of patients with metastatic colorectal cancer in Canada .
1 OBJECTIVE :
2 Clinical practice guidelines support the use of the epidermal growth factor receptor ( EGFR ) inhibitors panitumumab and cetuximab for the treatment of metastatic colorectal cancer ( mCRC ) after failure of other chemotherapy regimens , based on significant clinical benefits in patients with wild-type KRAS .
3 The purpose of the analysis was to compare provincial hospital costs when using panitumumab versus cetuximab with or without irinotecan in this patient population using a Net Impact Analysis ( NIA ) approach .
4 METHODS :
5 The NIA determined the total per patient cost of the reimbursed regimens of panitumumab versus cetuximab in British Columbia , Alberta , Manitoba , Ontario , and Quebec .
6 Utilization of healthcare resources related to EGFR inhibitor infusions , follow-up monitoring , and treatment of adverse events ( AEs ) were also included .
7 Healthcare resource use including drugs , medical supplies , laboratory testing , oncology infusion time , and healthcare professionals' time was obtained through expert consultation and the use was then multiplied by the province-specific cost of each resource .
8 Numerous sensitivity analyses were conducted .
9 RESULTS :
10   Based on the dosing regimens in place in each province , the total annual per patient cost of panitumumab ranged from $22,203-$32,600 , while the total annual per patient cost of cetuximab treatment varied from $30,321-$40,908 .
11   Treatment with panitumumab resulted in lower costs in all cost categories including drug acquisition , infusion preparation/administration , patient monitoring , and AE management .
12 Per patient savings with panitumumab ranged from a low of $3815 in British Columbia to a high of $10,603 in Ontario .
13 In sensitivity analyses , panitumumab remained cost saving in all scenarios where the savings ranged from $150-$16,006 per patient .
14 CONCLUSIONS :
15 Treating chemorefractory mCRC patients with panitumumab rather than cetuximab reduced healthcare resource costs .
16   Provincial healthcare savings achieved with the use of panitumumab could potentially be re-allocated to other cancer treatments , although further study would be needed to validate this assumption .



PMID: 26439693
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Antitumor activity of a potent MEK inhibitor , TAK-733 , against colorectal cancer cell lines and patient derived xenografts .
1 Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase -positive lung cancer .



PMID: 26439033
(Patient)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Tegafur gimeracil oter combined with oxaliplatin for advanced colorectal cancer .
1 OBJECTIVE :
2 To analyze the therapeutic actions of tegafur gimeracil oteracil combined with oxaliplatin for treating patients with advanced colorectal cancer , and its effects on the K-ras gene mutation and the CK20 mRNA .
3 PATIENTS AND METHODS :
4 Forty-one patients with advanced colorectal cancer from our hospital , from October 2013 to October 2014 , were enrolled in this study .
5 After obtaining consent from the hospital Ethics Committee and the patients as well as their relatives , all 41 patients were divided into two groups .
6 The control group , which consisted of 20 cases , were treated with capecitabine combined with oxaliplatin .
7 The study group , which comprised of 21 cases , were treated with tegafur gimeracil oteracil combined with oxaliplatin .
8 Both groups were followed-up after six months to evaluate the treatment outcomes .
9 RESULTS :
10 The survival rate in the observation group was higher than that in the control group .
11 The progression-free survival time ( PFS ) in the observation group was longer than that in the control group .
12 The objective response rate ( ORR ) and disease control rate ( DCR ) were higher for the observation group .
13 The differences had statistical significance ( p <005 ) .
14 The proportion of K-ras gene mutation in the observation group was substantially superior to that in the control group .
15 The positive expression rate of CK 20 mRNA in the observation group was significantly lower than that in the control group .
16 The differences had statistical significance ( p <005 ) .
17 The incidence of adverse reaction in the observation group was lower than that of the control group , and the differences had statistical significance ( p <005 ) .
18 CONCLUSIONS :
19   Tegafur/gimeracil/oteracil combined with oxaliplatin therapy had better treatment outcomes than capecitabine combined oxaliplatin for advanced colorectal cancer .
20 This maybe related to K-ras gene mutation and the reduction of CK20 mRNA expression .



PMID: 26438111
(None)  
Terms: phase II, clinical trial, retrospective, meta-analyses
Sent# Symbols Sentence Mnemonics
0 Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy : American Society of Clinical Oncology Provisional Clinical Opinion Update 2015 .
1 PURPOSE :
2 An American Society of Clinical Oncology Provisional Clinical Opinion ( PCO ) offers timely clinical direction after publication or presentation of potentially practice-changing data from major studies .
3 This PCO update addresses the utility of extended RAS gene mutation testing in patients with metastatic colorectal cancer ( mCRC ) to detect resistance to anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody ( MoAb ) therapy .
4 CLINICAL CONTEXT :
5   Recent results from phase II and III clinical trials in mCRC demonstrate that patients whose tumors harbor RAS mutations in exons 2 ( codons 12 and 13 ) , 3 ( codons 59 and 61 ) , and 4 ( codons 117 and 146 ) are unlikely to benefit from therapy with MoAbs directed against EGFR , when used as monotherapy or combined with chemotherapy .
6 RECENT DATA :
7 In addition to the evidence reviewed in the original PCO , 11 systematic reviews with meta-analyses , two retrospective analyses , and two health technology assessments based on a systematic review were obtained .
8 Μ These evaluated the outcomes for patients with mCRC with no mutation detected or presence of mutation in additional exons in KRAS and NRAS .
9 PCO :
10   All patients with mCRC who are candidates for anti-EGFR antibody therapy should have their tumor tested in a Clinical Laboratory Improvement Amendments-certified laboratory for mutations in both KRAS and NRAS exons 2 ( codons 12 and 13 ) , 3 ( codons 59 and 61 ) , and 4 ( codons 117 and 146 ) .
11   Μ The weight of current evidence indicates that anti-EGFR MoAb therapy should only be considered for treatment of patients whose tumor is determined to not have mutations detected after such extended RAS testing .



PMID: 26437179
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status .
1 Stage-specific prognostic biomarkers in melanoma .



PMID: 26429158
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 KRAS gene mutations - prognostic factor in colorectal cancer ?
1 The colorectal cancer ( CRC ) modern therapy is using adjuvant and neoadjuvant companion therapeutic agents , part of them having an anti-angiogenic action .
2 Their benefic effect can be annulated by some gene mutations , which are interfering in signal transduction pathways .
3 One of the more frequent activating mutations is occurring in the KRAS gene .
4 We assessed the KRAS mutations by two molecular methods , in a group of patients with a follow-up until 144 months , aiming to establish eventual correlations between the presence of mutations and the evolution of patients .
5 We tried to appreciate the prognostic value of these mutations .
6 A retrospective study was conducted on 74 patients treated by radical surgery ; the surgical specimens were analyzed macroscopically and the histopathological type and degree were established .
7 PCR-RFLP ( polymerase chain reaction-restriction fragment length polymorphism ) and pyrosequencing were performed on paraffin-embedded tumor specimens .
8 ✓ Statistical analysis showed significant differences in survival between patients with wild type gene and patients with mutation in codon 13 ; the same results were also obtained regarding TNM I , II stages or Dukes type A and B cases . RO-ASS-GM
9 However , for the patients in stage IV pTNM , the evolution was slightly better in association with a KRAS mutation than in wild type cases .



PMID: 26426996
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 c-MYC Copy-Number Gain Is an Independent Prognostic Factor in Patients with Colorectal Cancer .
1 Detection of Crizotinib-Sensitive Lung Adenocarcinomas With MET , ALK , and ROS1 Genomic Alterations via Comprehensive Genomic Profiling .



PMID: 26426205
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer .
1 Anti-epidermal growth factor receptor ( EGFR ) treatment is an effective option for metastatic colorectal cancer ( CRC ) treatment .
2 However , there are few reliable biomarkers to predict the clinical response to anti-EGFR treatment .
3 We investigated the genome -wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti-EGFR antibody .
4 We retrospectively reviewed the medical records of 97 patients ( 45 patients for the first cohort and 52 patients for the second cohort ) who received anti-EGFR treatment for KRAS wild-type metastatic CRC .
5 Then we analyzed the associations between genome -wide DNA methylation status and clinical response to anti-EGFR treatment , and evaluated the predictive power and value of the methylation status statistically .
6 As a result , each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses .
7 In the first cohort , clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup ( response rate , 357% versus 63% , P = 003 ; disease control rate , 75% versus 313% , P = 0005 ; hazard ratio for progression-free survival , 027 ; 95% confidence interval , 013-057 , P <0001 ; overall survival , 019 ; 95% confidence interval , 006-054 , P <0001 ) .
8 These results were reproducible in the second cohort .
9 The genome -wide methylation status was a predictive factor of progression-free survival and overall survival independently of RAS mutation status .
10   In conclusion , we found that the genome -wide DNA methylation status is a powerful epigenetic predictor of anti-EGFR treatment in patients with KRAS wild-type metastatic colorectal cancer (UMIN000005490) .



PMID: 26425687
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes , Inhibiting Signaling Pathways , and Reprogramming Gene Expression .
1 Occurrence of both neurofibromatoses 1 and 2 in the same individual with a rapidly progressive course .



PMID: 26425654
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Crizotinib-associated erythema multiforme in a lung cancer patient .
1 Trail resistance induces epithelial-mesenchymal transition and enhances invasiveness by suppressing PTEN via miR-221 in breast cancer .



PMID: 26423386
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein ( ABCB1 ) and breast cancer resistance protein ( ABCG2 ) inhibitor elacridar .
1 BACKGROUND :
2 Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas .
3 In contrast , results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia .
4 OBJECTIVE :
5 We tested the hypothesis that higher total folate intake ( including food folate and folic acid from fortified foods and supplements ) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer .
6 DESIGN :
7 We used rectal and colon cancer cases within the following 2 US prospective cohort studies : the Nurses' Health Study and the Health Professionals Follow-Up Study .
8 Biennial questionnaires were used to gather information on medical history and lifestyle factors , including smoking and alcohol consumption .
9 B-vitamin and methionine intakes were derived from food-frequency questionnaires .
10 Data on tumor molecular characteristics ( including microsatellite instability , CpG island methylator phenotype , KRAS , BRAF , and PIK3CA mutations , and long interspersed nucleotide element 1 methylation level ) were available for a subset of cases .
11 We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models .
12 RESULTS :
13 In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y , we documented 641 deaths including 176 colorectal cancer-specific deaths .
14 No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality ( multivariate P-trend >/= 021 ) .
15 In an exploratory molecular pathologic epidemiology survival analysis , there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular biomarkers examined .
16 CONCLUSIONS :
17 Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I-III colorectal cancer .
18 Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death .



PMID: 26419959
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA MIR21 and T Cells in Colorectal Cancer .
1 The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated .
2 Experimental evidence suggests that microRNA MIR21 ( miR-21 ) suppresses antitumor T-cell -mediated immunity .
3 Thus , we hypothesized that tumor MIR21 expression might be inversely associated with T - cell density in colorectal carcinoma tissue .
4 Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study , we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay .
5 Densities of CD3(+) , CD8(+) , CD45RO (PTPRC) (+) , and FOXP3(+) cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis .
6 Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression ( ordinal quartiles as a predictor variable ) with T - cell density ( ordinal quartiles as an outcome variable ) , adjusting for tumor molecular features , including microsatellite instability ; CpG island methylator phenotype ; KRAS , BRAF , and PIK3CA mutations ; and LINE-1 methylation .
7 We adjusted the two-sided alpha level to 0.012 for multiple hypothesis testing .
8 Tumor MIR21 expression was inversely associated with densities of CD3(+) and CD45RO(+) cells ( Ptrend <00005 ) .
9 The multivariate odds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3(+) or CD45RO(+) cells was 0.44 [95% confidence interval ( CI ) , 0.28 to 0.68] or 0.41 ( 95% CI , 026-064 ) , respectively .
10 Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell -mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer .



PMID: 26419617
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ALK inhibition for non-small cell lung cancer : from discovery to therapy in record time .
1 In this study , we investigate effect of PI3K gene silencing on growth , migration and related proteins expression of CD40 signal-mediated gastric cancer cells .
2 We observed that combination of sCD40L with PI3K siRNA could significantly inhibit AGS cells growth , block cells in G1 phase , and promote tumour cells apoptosis after 24 h treatment .
3 Transwell test showed that numbers of cells per visual field in group PI3K siRNA or group sCD40L ( after 24 h PI3K siRNA or sCD40L alone treatment ) were fewer than that ( 3254 +/- 422 ) in control group .
4 Numbers of cells per visual field in ( after 24 h combination treatment of PI3K siRNA with sCD40L ) were significantly fewer than that in group PI3K siRNA or group sCD40L .
5 Compared with group sCD40L , expression level of Fas protein in group sCD40L + PI3K siRNA was significantly increased .
6 The findings suggest that PI3K siRNA may strengthen CD40 -induced specific antitumour effect via blocking PI3K/Akt signal pathway , resisting tumour immunoediting regulated by CD40 signal .
7 Combination of sCD40L and PI3K siRNA is an important mechanism of gastric cancer therapy .



PMID: 26418750
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy .
1 The aim of this study was to determine whether or not the addition of anti-epidermal growth factor receptor ( anti-EGFR ) monoclonal antibody ( mAb ) to standard chemotherapy or best supportive care ( BSC ) , compared with chemotherapy or BSC alone , can improve overall survival ( OS ) and progression-free survival ( PFS ) in patients with metastatic colorectal cancer ( mCRC ) , and evaluate the influence of KRAS mutant status on the efficacy of anti-EGFR mAb .
2 Medline , Embase , the Cochrane controlled trials register , and the Science Citation Index were searched .
3 Nine trials were identified , covering a total of 7941 patients .
4   The treatment of mCRC with a combination of anti-EGFR mAb and chemotherapy or BSC , as compared with chemotherapy or BSC alone , improved the OS [hazard ratio ( HR ) , 0.90 ( 084-096 ) ; P = 0.002] .
5 The benefit of anti-EGFR mAb in patients with KRAS wild-type tumors was apparent in relation to a marginal trend toward improved OS [HR , 0.84 ( 070-101 ) ; P = 0.06] , and significantly improved PFS [HR , 0.64 ( 051-081 ) ; P<0.001] .
6 No benefit for the addition of anti-EGFR mAb was detected for any efficacy end-point in patients with KRAS mutant tumors .
7 ✓ The summary HRs ( anti-EGFR mAb versus control ) were 0.98 ( 088-108 ) ( P = 071 ) for OS and 1.08 ( 094-125 ) ( P = 027 ) for PFS , respectively . GE-ASS-RO
8 In conclusion , this analysis provides confirmation that , compared with chemotherapy or BSC alone , anti-EGFR mAb with chemotherapy or BSC reduces the risk of progression and death of mCRC and that this benefit is seen only in patients with wild-type KRAS tumors .



PMID: 26418570
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study .
1 The surprising results published by FIRE-3 revealed that the overall survival ( OS ) of RAS wild-type metastatic colorectal cancer ( mCRC ) patients treated with Cetuximab ( Cmab ) and FOLFIRI combination was prolonged to 33.1 months .
2 The substantial increase in testing and treatment costs , however , impose a considerable health burden on patients and society .
3 Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies ( mAbs ) therapy based on FIRE-3 study .
4   Four groups were analyzed : group 1 , patients with KRAS testing treated with Cmab and FOLFIRI ; group 2 , patients with RAS testing treated with Cmab and FOLFIRI ; group 3 , patients with KRAS testing treated with bevacizumab ( Bmab ) and FOLFIRI ; group 4 , patients with RAS testing treated with Bmab and FOLFIRI .
5 A Markov model comprising 3 health states ( progression-free survival , progressive disease and death ) was built .
6 The costs were calculated from a Chinese payer perspective , and survival was reported in quality-adjusted life-months ( QALMs ) .
7 Average total lifetime costs ranged from $104,682.44 ( RAS-Bmab ) to $136,867.44 ( RAS-Cmab ) , while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab .
8 The cost per QALM was $6,263.86 for RAS-Cmab , $6,145.84 for KRAS-Bmab , $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively .
9 The KRAS-Cmab strategy was dominated by the other 3 groups .
10 The first-treatment cost of RAS-Cmab was the most influential one to the model .
11   In all , the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies ( mAbs ) therapy with the most gained QALMs .



PMID: 26416897
(Patient)  
Terms: NCT00433927, NCT00719797
Sent# Symbols Sentence Mnemonics
0 Variations in genes regulating tumor-associated macrophages ( TAMs ) to predict outcomes of bevacizumab-based treatment in patients with metastatic colorectal cancer : results from TRIBE and FIRE3 trials .
1 BACKGROUND :
2 Tumor-associated macrophages ( TAMs ) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1 , which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor .
3 The CCL2/CCR2 axis , histidine-rich glycoprotein ( HRG ) , and placenta growth factor ( PIGF ) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment .
4 We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer ( mCRC ) .
5 PATIENTS AND METHODS :
6 We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first - line treatment using PCR-based direct sequencing .
7 Twelve functional single - nucleotide polymorphisms in eight genes ( CCL2 , CCR2 , HRG , PIGF , NFKB1 , TBK1 , CCL18 , and IRF3 ) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial ( NCT00719797 ) , then validated in 248 KRAS exon2 ( KRAS ) wild-type participants in FIRE3 trial ( NCT00433927 ) .
8 FIRE3-cetuximab cohort served as a negative control .
9 RESULTS :
10 ✓ Μ TBK1 rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis ; furthermore , the association of the T allele was observed for progression-free survival ( PFS ) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort . GM-ASS-RO
11 ✓ CCL2 rs4586 , CCL18 rs14304 , and IRF3 rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort , whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort . GM-ASS-RO
12 No association was seen in control cohort .
13 CONCLUSIONS :
14   Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy .
15 ✓ These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status -dependent manner . GM-REG-RO



PMID: 26416732
(Patient)  
Terms: , tumour graft models
Sent# Symbols Sentence Mnemonics
0 The genomic landscape of response to EGFR blockade in colorectal cancer .
1 Colorectal cancer is the third most common cancer worldwide , with 1.2 million patients diagnosed annually .
2 In late-stage colorectal cancer , the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab , which prevent epidermal growth factor receptor ( EGFR ) activation .
3 Μ Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy .
4 Despite these efforts , additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy .
5 To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy , here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours , all of which were KRAS wild-type .
6 We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data .
7   Μ In addition to previously identified genes , we detected mutations in ERBB2 , EGFR , FGFR1 , PDGFRA , and MAP2K1 as potential mechanisms of primary resistance to this therapy .
8 Μ Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade .
9 Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy .
10 Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes .
11 These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer , highlight new mechanisms of responsiveness to anti-EGFR therapies , and delineate new avenues for intervention in managing colorectal cancer .



PMID: 26415565
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Factors associated with reclassification of hyperplastic polyps after pathological reassessment from screening and surveillance colonoscopies .
1 INTRODUCTION :
2 A substantial interobserver variation in the differential diagnosis of hyperplastic polyps ( HPs ) and sessile or traditional serrated adenomas ( SSAs/TSAs ) has been described .
3 METHODS :
4 The aim of this study is to determine the magnitude of reclassification of HPs and associated factors after pathological reassessment of specimens from screening and surveillance colonoscopies , and to estimate its consequences for follow-up recommendations .
5 RESULTS :
6 Among 1694 screening and surveillance colonoscopies , a total of 536 polyps were initially diagnosed as HPs and remained unchanged in 88.5% ( n = 474 ) , whereas 7.6 ( n = 41 ) and 1.1% ( n = 6 ) were reclassified as SSA and TSA , respectively .
7 Compared to definite HPs , SSAs were found more frequently in men than in women ( 829 vs. 612% , p <005 ) , and in individuals >/ = 65.0 years ( 512 vs. 316% , p = 005 ) .
8 Also , more SSAs were >5 mm in size ( 366 vs. 63% , p <005 ) and were localized in the proximal colon ( 317 vs. 118% , p <005 ) .
9 In a mixed model analysis , age >/ = 65.0 years ( OR 413 , 95% CI 122-142 ) , snare polypectomy ( OR 236 , 95% CI 486-115 ) , and coincident advanced adenomas ( OR 756 , 95% CI 131-435 ) were significantly ( p <005 ) associated with reclassification to SSAs .
10 Only 0.53% of patients had received false recommendations for follow-up visits based on the incorrect HP diagnosis .
11 A c.1799T>A , p .
12 Μ V600E BRAF mutation was detected in 21.9 % ( n = 9 ) of reclassified SSAs .
13 CONCLUSION :
14 Considering these factors may be helpful in serrated lesions that are difficult to allocate .
15 Incorrect recommendations regarding control colonoscopy intervals due to misdiagnosed HPs can explain only a small fraction of interval colorectal cancers .



PMID: 26406410
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Current status of chemotherapy use and clinical outcome in octogenarians with advanced non-small cell lung cancer .
1 BACKGROUND :
2 Bevacizumab , an angiogenesis inhibitor is used in regimens for metastatic colorectal cancer ( CRC ) .
3 A minority of cancer cells with characteristics of cancer stem cells ( CSC ) may be responsible for progression and development of chemotherapy resistance in this disease .
4 CD133 is a well-known CSC marker and is associated with angiogenesis , poor prognosis and resistance to chemotherapy .
5 OBJECTIVE :
6 The purpose of our study was to evaluate the association between the rs3130 and rs2286455 polymorphisms of the CD133 gene and the response , toxicity , and overall survival of patients with CRC on bevacizumab-based treatment .
7 METHODS :
8 Forty-three patients receiving bevacizumab , irinotecan and capecitabine and 15 patients receiving bevacizumab , irinotecan and 5-FU were included .
9 Efficacy and toxicity were evaluated .
10 Μ KRAS mutation analysis and rs3130 and rs2286455 polymorphisms genotyping in the tumors and peripheral blood respectively were performed with PCR-RFLP .
11 RESULTS :
12 ✓ Μ No association between KRAS mutated alleles and response was found . GM-ASS-RO
13 The rs3130 CC genotype was associated with reduced toxicity of treatments ( p= 00017 ) , and with lower overall survival on bevacizumab ( p= 0002 ) .
14 CONCLUSIONS :
15 ✓ The CC genotype of rs3130 polymorphism in the CD133 gene can predict poorer overall survival in patients with metastatic CRC on bevacizumab which cannot be attributed to increased treatment toxicity . GM-REG-RO



PMID: 26405092
(None)  
Terms: Phase II/III Study
Sent# Symbols Sentence Mnemonics
0 A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory , KRAS Wild-Type , Metastatic Colorectal Cancer .
1 Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors .



PMID: 26404261
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers .
1 Colorectal cancer ( CRC ) is a heterogeneous disease with multiple underlying causative genetic mutations .
2 Genetic mutations in the phosphatidylinositol-3 kinase ( PI3K ) and the mitogen activated protein kinase ( MAPK ) pathways are frequently implicated in CRC .
3 Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC .
4 Several selective inhibitors of MEK have entered clinical trial evaluation ; however , clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable .
5 Amplification of the driving oncogene KRAS (13D) , which increases signaling through the ERK1/2 pathway , upregulation of the noncanonical wingless/calcium signaling pathway ( Wnt ) , and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC .
6 The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations .
7   Thus , dual targeted inhibition of MEK and PI3K pathway effectors ( mTOR , PI3K , AKT , IGF-1R or PI3K/mTOR inhibitors ) presents a potential strategy to overcome resistance to MEK inhibitor therapy .
8 Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors .



PMID: 26401070
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Stool DNA methylation assays in colorectal cancer screening .
1 Colorectal cancer ( CRC ) is fourth most common cancer in men and third in women worldwide .
2 Developing a diagnostic panel of sensitive and specific biomarkers for the early detection of CRC is recognised as to be crucial for early initial diagnosis , which in turn leads to better long term survival .
3 Most of the research on novel potential CRC biomarkers in the last 2 decades has been focussed on stool DNA analysis .
4 In this paper , we describe the recent advances in non-invasive CRC screening and more specifically in molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions .
5 In several research papers these markers showed superior rates for sensitivity and specificity in comparison to previously described assays .
6 These tests detected the majority of adenomas >/= 1 cm in size and the detection rates progressively increased with larger adenomas .
7 The methylation status of the BMP3 and NDRG4 promoters demonstrated effective detection of neoplasms at all sites throughout the colon and was not affected by common clinical variables .
8 Recently , a multitarget stool DNA test consisting of molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions , mutant KRAS and immunochemical assay for human haemoglobin has been made commercially available and is currently reimbursed in the United States .
9 Although this is the most sensitive non-invasive CRC screening test , there is the need for further research in several areas - establishment of the best timeframe for repeated DNA stool testing ; validation of the results in populations outside of North America ; usefulness for surveillance and prognosis of patients ; cost-effectiveness of DNA stool testing in real-life populations .



PMID: 26398184
(None)  
Terms: clinical trial, phase III
Sent# Symbols Sentence Mnemonics
0 Cost-Effectiveness of Cetuximab as First - line Treatment for Metastatic Colorectal Cancer in the United States .
1 PURPOSE :
2 We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial ( FIRE-3 ) data to evaluate clinical and economic tradeoffs associated with first - line treatments of KRAS wild-type ( WT ) metastatic colorectal cancer ( mCRC ) .
3 MATERIALS AND METHODS :
4 A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab .
5 Hypothetical KRAS-WT mCRC patients initiated first - line treatment and could experience adverse events , disease progression warranting second - line treatment , or clinical response and hepatic metastasectomy .
6 Model inputs were derived from FIRE-3 and published literature .
7 Incremental cost-effectiveness ratios ( ICERs ) were reported as US$ per life year ( LY ) and quality-adjusted life year ( QALY ) .
8 Μ Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data ; 1-way and probabilistic sensitivity analyses were conducted .
9 RESULTS :
10   Compared with bevacizumab , KRAS-WT patients receiving first - line cetuximab gained 5.7 months of life at a cost of $46,266 , for an ICER of $97,223/LY ( $122,610/QALY ) .
11 For extended RAS-WT patients , the ICER was $77,339/LY ( $99,584/QALY ) .
12 Cetuximab treatment was cost-effective 80.3% of the time , given a willingness-to-pay threshold of $150,000/LY .
13 Results were sensitive to changes in survival , treatment duration , and product costs .
14 CONCLUSIONS :
15   Our analysis of FIRE-3 data suggests that first - line treatment with cetuximab and FOLFIRI in KRAS ( and extended RAS ) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI .
16   This information , in combination with other studies investigating comparative effectiveness of first - line options , can be useful to clinicians , payers , and policymakers in making treatment and resource allocation decisions for mCRC patients .



PMID: 26396549
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 BRAF Mutation in Colorectal Cancer : An Update .
1 Colorectal cancer ( CRC ) is still one of the deadliest cancer-related diseases .
2 About 10% of CRC patients are characterized by a mutation in the B-Raf proto - oncogene serine/threonine kinase (BRAF) gene resulting in a valine-to-glutamate change at the residue 600 ( V600E ) .
3 This mutation is also present in more than 60% of melanoma patients .
4 BRAF inhibitors were developed and found to improve patient survival ; however , most patients at the end of the track ultimately develop resistance to these inhibitors .
5 Melanoma patients benefit from the combination of BRAF inhibitors with mitogen/extracellular signal-regulated kinase ( MEK ) inhibitors , among others .
6 Unfortunately , colorectal patients do not respond much efficiently , which suggests different resistance mechanisms between the two cancer types .
7 This review aims at shedding light on recent discoveries that improve our understanding of the BRAF mutation biology in CRC .



PMID: 26396545
(None)  
Terms: , Mouse Model
Sent# Symbols Sentence Mnemonics
0 Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography .
1 Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A -dependent mechanism .



PMID: 26392102
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer .
1 BACKGROUND :
2 Approximately 20% of all colorectal cancers are hypothesized to arise from the "serrated pathway" characterized by mutation in BRAF , high-level CpG Island Methylator Phenotype , and microsatellite instability/mismatch repair ( MMR )- deficiency .
3 MMR-deficient cancers show frequent losses of Cdx2 , a homeodomain transcription factor .
4 Here , we determine the predictive value of Cdx2 expression for MMR-deficiency and investigate changes in expression between primary cancers and matched lymph node metastases .
5 METHODS :
6 Immunohistochemistry for Cdx2 , Mlh1 , Msh2 , Msh6 , and Pms2 was performed on whole tissue sections from 201 patients with primary colorectal cancer and 59 cases of matched lymph node metastases .
7 Receiver operating characteristic curve analysis and Area under the Curve ( AUC ) were investigated ; association of Cdx2 with clinicopathological features and patient survival was carried out .
8 RESULTS :
9 ✓ Loss of Cdx2 expression was associated with higher tumor grade ( p = 00002 ) , advanced pT ( p = 00166 ) , and perineural invasion ( p = 00228 ) . GE-ASS-RO
10 Cdx2 loss was an unfavorable prognostic factor in univariate ( p = 00145 ) and multivariate [p = 0.0427 ; HR ( 95% CI ) : 0.58 ( 034-098 ) ] analysis .
11 The accuracy ( AUC ) for discriminating MMR-proficient and - deficient cancers was 87% [OR ( 95% CI ) : 0.96 ( 095-098 ) ; p <0.0001] .
12 Specificity and negative predictive value for MMR-deficiency was 99.1 and 96.3% .
13 One hundred and seventy-four patients had MMR-proficient cancers , of which 60 ( 345% ) showed Cdx2 loss .
14 Cdx2 loss in metastases was related to MMR-deficiency ( p <00001 ) .
15 There was no difference in expression between primary tumors and matched metastases .
16 CONCLUSION :
17 Loss of Cdx2 is a sensitive and specific predictor of MMR-deficiency , but is not limited to these tumors , suggesting that events "upstream" of the development of microsatellite instability may impact Cdx2 expression .



PMID: 26386973
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations .
1 A perspective on the current management of advanced colorectal cancer .



PMID: 26386083
(None)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 BRAF mutations : signaling , epidemiology , and clinical experience in multiple malignancies .
1 Only 10% to 15% of patients with pancreatic ductal adenocarcinoma ( PDAC ) are candidates for potentially curative surgery due to the location or spread of disease at the time of diagnosis .
2 Despite rapid progress in the understanding of the molecular mechanisms underlying PDAC , translation to effective therapies has been modest at best .
3 One of the key tools available for studying biology and developing more effective therapeutics is the laboratory mouse , mus musculus .
4 This article explores new and innovative approaches to mouse modeling and how these approaches can be utilized to move the field forward .



PMID: 26384309
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients .
1 INTRODUCTION :
2 Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer ( mCRC ) patients .
3 Their prognostic value is controversial , and no data regarding the prognostic value of mutation rate , defined as the percentage of mutated alleles/tumor sample , are available .
4 We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first - line doublet plus bevacizumab .
5 PATIENTS AND METHODS :
6 This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers , and 263 patients were fully evaluable for our analysis .
7 K-Ras mutation rate was assessed by pyrosequencing .
8 Patients with less than 60% of cancer cells in tumor tissue were excluded .
9 No patients received anti-EGFR containing anticancer therapy , at any time .
10 Median mutation rate was 40% and was adopted as cut-off .
11 The primary and secondary endpoints were PFS and OS respectively .
12 RESULTS :
13 ✓ At univariate analysis , K-Ras mutation rate higher than 40% was significantly associated with lower PFS ( 73 versus 91 months ; P <00001 ) and OS ( 21 versus 31 months ; P = 0004 ) . GM-ASS-RO
14 ✓ Μ A multivariate model adjusted for age at diagnosis , site of origin of tumor tissue ( primary versus metastases ) , referral center , number of metastatic sites , and first - line chemotherapy backbone , showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population . GM-MRK-RO
15 DISCUSSION :
16 ✓ Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first - line therapy . GM-ASS-RO
17 These data deserve to be verified in an independent validation set .



PMID: 26379353
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 K-ras Mutation in Colorectal Cancer , A Report from Southern Iran .
1 Sequence -dependent antiproliferative effects of gefitinib and docetaxel on non-small cell lung cancer ( NSCLC ) cells and the possible mechanism .



PMID: 26376292
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers .
1 Microsatellite instability ( MSI ) has been associated with favourable survival in early stage colorectal cancer ( CRC ) compared to microsatellite stable ( MSS ) CRC .
2 The BRAF V600E mutation has been associated with worse survival in MSS CRC .
3 This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting .
4 The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear .
5 We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients .
6 BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II ( n = 85 ) and III ( n = 58 ) MSI colon cancers by high resolution melting analysis and sequencing .
7 Μ The relation between mutation status and cancer-specific ( CSS ) and overall survival ( OS ) was analyzed using Kaplan-Meier and Cox regression analysis .
8 Μ BRAF V600E mutations were observed in 51% ( n = 73 ) and KRAS mutations in 16% of cases ( n = 23 ) .
9 ✓ Patients with double wild-type cancers ( dWT ; i.e. , BRAF and KRAS wild-type ) had a highly favourable survival with 5-year CSS of 93% ( 95% CI 84-100% ) , while patients with cancers harbouring mutations in either BRAF or KRAS , had 5-year CSS of 76% ( 95% CI 67-85% ) . GM-ASS-RO
10 In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed .
11 On multivariate analysis , mutation in either BRAF or KRAS vs . dWT remained significantly prognostic .
12 Μ Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers .



PMID: 26375816
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer .
1 BACKGROUND :
2 Cancer is caused by somatic DNA alterations such as gene point mutations , DNA copy number aberrations ( CNA ) and structural variants ( SVs ) .
3 Genome -wide analyses of SVs in large sample series with well-documented clinical information are still scarce .
4 Consequently , the impact of SVs on carcinogenesis and patient outcome remains poorly understood .
5 This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer ( CRC ) and to determine the clinical relevance of recurrent breakpoint genes .
6 METHODS :
7 Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization .
8 These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples .
9 In addition , mutation status of the commonly affected APC , TP53 , KRAS , PIK3CA , FBXW7 , SMAD4 , BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing .
10 Μ Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases .
11 RESULTS :
12 In total , 748 genes were identified that were recurrently affected by chromosomal breaks ( FDR <01 ) .
13 Μ MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases , indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations .
14   Μ Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis .
15 CONCLUSIONS :
16 We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC .



PMID: 26372699
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comment on : 'KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer.' Variation in survival associated with proto-oncongenes is not evidence for effectiveness of lung metastasectomy .
1 MEK inhibition in non-small cell lung cancer .



PMID: 26371285
(None)  
Terms: Phase II study, mice, transgenic TMPRSS2-ERG mice
Sent# Symbols Sentence Mnemonics
0 Phase II study of single-agent cetuximab in KRAS G13D mutant metastatic colorectal cancer .
1 The TMPRSS2-ERG fusion , present in approximately 50% of prostate cancers , is less common in prostatic intraepithelial neoplasia ( PIN ) , raising questions about whether TMPRSS2-ERG contributes to disease initiation .
2 Μ We identified the translational start site of a common TMPRSS2-ERG fusion and showed that transgenic TMPRSS2-ERG mice develop PIN , but only in the context of PI3-kinase pathway activation .
3 TMPRSS2-ERG-positive human tumors are also enriched for PTEN loss , suggesting cooperation in prostate tumorigenesis .



PMID: 26369631
(None)  
Terms: xenograft, in vitro, in vivo, PDX, tumor model
Sent# Symbols Sentence Mnemonics
0 Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6 .
1 PURPOSE :
2 The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant ( KRAS ( mt ) ) colorectal cancers , where upregulated CDK4 and hyperphosphorylated retinoblastoma ( RB ) typify the vast majority of tumors .
3 EXPERIMENTAL DESIGN :
4 Initial testing was carried out in the HCT-116 tumor model , which is known to harbor a KRAS mutation .
5 Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models , genomically diverse with respect to KRAS , BRAF , and PIK3CA mutational status .
6 Tolerance , efficacy , and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration .
7 RESULTS :
8 Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib .
9 Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment .
10 Testing of colorectal patient-derived xenograft ( PDX ) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS ( mt ) models tested .
11 Stasis was observed in a KRAS/BRAF wild-type and a BRAF ( mt ) model .
12 CONCLUSIONS :
13 Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested .
14   Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer .



PMID: 26366557
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Clinical Validation of Targeted Next Generation Sequencing for Colon and Lung Cancers .
1 OBJECTIVE :
2 Recently , Next Generation Sequencing ( NGS ) has begun to supplant other technologies for gene mutation testing that is now required for targeted therapies .
3 However , transfer of NGS technology to clinical daily practice requires validation .
4 METHODS :
5 We validated the Ion Torrent AmpliSeq Colon and Lung cancer panel interrogating 1850 hotspots in 22 genes using the Ion Torrent Personal Genome Machine .
6 First , we used commercial reference standards that carry mutations at defined allelic frequency ( AF ) .
7 Then , 51 colorectal adenocarcinomas ( CRC ) and 39 non small cell lung carcinomas ( NSCLC ) were retrospectively analyzed .
8 RESULTS :
9 Sensitivity and accuracy for detecting variants at an AF >4% was 100% for commercial reference standards .
10 Among the 90 cases , 89 ( 989% ) were successfully sequenced .
11 Among the 86 samples for which NGS and the reference test were both informative , 83 showed concordant results between NGS and the reference test ; i.e . KRAS and BRAF for CRC and EGFR for NSCLC , with the 3 discordant cases each characterized by an AF <10% .
12 CONCLUSIONS :
13 Μ Overall , the AmpliSeq colon/lung cancer panel was specific and sensitive for mutation analysis of gene panels and can be incorporated into clinical daily practice .



PMID: 26365186
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs .
1 ✓ Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors , but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR .
2 We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition .
3 We found that suppression of protein tyrosine phosphatase non-receptor type 11 ( PTPN11 ) confers sensitivity to BRAF inhibitors in colon cancer .
4 Mechanistically , we found that inhibition of PTPN11 blocks signaling from receptor tyrosine kinases ( RTKs ) to the RAS-MEK-ERK pathway .
5 ✓ PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation .
6 Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs .
7 Moreover , activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation .



PMID: 26363448
(Patient)  
Terms: meta-analysis, retrospective study
Sent# Symbols Sentence Mnemonics
0 FCGR2A , FCGR3A polymorphisms and therapeutic efficacy of anti-EGFR monoclonal antibody in metastatic colorectal cancer .
1 Anti-EGFR monoclonal antibodies ( mAb ) such as cetuximab , panitumumab are one kind of efficacious targeted drugs in treatment of metastatic colorectal cancer ( mCRC ) .
2 However , only a small proportion of patients harbored wild-KRAS genotype can benefit from it .
3 We hypothesized that personal genetic heterogeneity might be the main cause leading to obvious difference in its clinical efficacy .
4 ✓ A retrospective study including 82 mCRC patients treated with chemotherapy plus cetuximab and a comprehensive meta-analysis containing 2831 cases within sixteen eligible studies were conducted to investigate the possible association between FCGR2A H131R and FCGR3A V158F and clinical outcome of mCRC patients treated with anti-EGFR mAb based therapy . GM-ASS-RO
5 ✓ Results of the retrospective study showed that H131R within FCGR2A or V158F within FCGR3A were not associated with clinical outcome in 82 KRAS wild chemorefractory mCRC patients in co-dominant , dominant , recessive , over-dominant , allele genetic models . GM-ASS-RO
6 However , the comprehensive meta-analysis with the largest of sample size obtained the significant result between FCGR3A V158F and PFS ( FV/VV vs . FF : Ph = 0.027 , MSR = 0.680 , 95%CI = 0.549-0.842 in overall population ; Ph = 0.12 , MSR = 0.728 , 95%CI = 0.648-0.818 in KRAS wild population ) and OS ( VV vs . FF : Ph <0.001 , MSR = 0.733 , 95%CI = 0.578-0.930 in overall population ) .
7 ✓ These findings indicate that KRAS wild chemorefractory mCRC individual harbored genotype FF of V158Fcan benefit from anti-EGFR mAb adjuvant therapy in terms of PFS and OS , and it may be useful genetic biomarker to predict clinical survival of mCRC individuals with anti-EGFR mAb based therapy . GM-REG-RO



PMID: 26361962
(Cell)  
Terms: in vitro, mice, genetically engineered mice, mouse models, mouse, mouse model
Sent# Symbols Sentence Mnemonics
0 [ New targets and new drugs in thoracic oncology ] .
1 BACKGROUND :
2 Μ KRAS gene mutations are found in 40-50% of colorectal cancer cases , but their functional contribution is not fully understood .
3 To address this issue , we generated genetically engineered mice with colon tumors expressing an oncogenic Kras ( G12D ) allele in the context of the Adenomatous polyposis coli ( Apc ) deficiency to compare them to tumors harboring Apc deficiency alone .
4 METHODS :
5 Μ CDX2P9.5-G22Cre ( referred to as G22Cre ) mice showing inducible Cre recombinase transgene expression in the proximal colon controlled under the CDX2 gene promoter were intercrossed with Apc ( flox/flox ) mice and LSL-Kras (G12D) mice carrying loxP-flanked Apc and Lox-Stop-Lox oncogenic Kras ( G12D ) alleles , respectively , to generate G22Cre ; Apc ( flox/flox ) ; Kras ( G12D ) and G22Cre ; Apc ( flox/flox ) ; KrasWT mice .
6 Gene expression profiles of the tumors were analyzed using high-density oligonucleotide arrays .
7 RESULTS :
8 Morphologically , minimal difference in proximal colon tumor was observed between the two mouse models .
9 Consistent with previous findings in vitro , Glut1 transcript and protein expression was up-regulated in the tumors of G22Cre ; Apc ( flox/flox ) ; Kras ( G12D ) mice .
10 Μ Immunohistochemical staining analysis revealed that GLUT1 protein expression correlated with KRAS mutations in human colorectal cancer .
11 Microarray analysis identified 11 candidate genes upregulated more than fivefold and quantitative PCR analysis confirmed that Aqp8 , Ttr , Qpct , and Slc26a3 genes were upregulated 3.7 - to 30.2-fold in tumors with mutant Kras .
12 CONCLUSIONS :
13 These results demonstrated the validity of the G22Cre ; Apc ( flox/flox ) ; Kras ( G12D ) mice as a new mouse model with oncogenic Kras activation .
14 We believe that this model can facilitate efforts to define novel factors that contribute to the pathogenesis of human colorectal cancer with KRAS mutations .



PMID: 26361422
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Annexin A10 expression in colorectal cancers with emphasis on the serrated neoplasia pathway .
1 AIM :
2 To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers ( CRCs ) .
3 METHODS :
4 A total of 1133 primary CRC patients who underwent surgical resection at Seoul National University Hospital between January 2004 and December 2007 were enrolled .
5 Expression of Annexin A10 was evaluated by immunohistochemistry using tissue microarray and paired to our findings on clinicopathologic and molecular characteristics of each individual .
6 CpG island methylator phenotype was determined by MethyLight assay and microsatellite instability was determined by high performance liquid chromatography .
7 KRAS and BRAF mutation status was evaluated by direct sequencing and allele -specific PCR .
8 Μ Univariate and stage-specific survival analyses were performed to reveal the prognostic value of Annexin A10 expression .
9 RESULTS :
10 Μ Annexin A10 expression was observed in 66 ( 58% ) of the 1133 patients .
11 Μ Annexin A10 expression was more commonly found in females and was associated with proximal location , ulcerative gross type , advanced T category , N category and TNM stage .
12 CRCs with Annexin A10 expression showed an absence of luminal necrosis , luminal serration and mucin production .
13 CRCs with Annexin A10 expression were associated with CpG island methylator phenotype , microsatellite instability and BRAF mutation .
14 ✓ In survival analysis , Annexin A10 expression was associated with poor overall survival and progression-free survival , especially in stage IV CRCs . GE-ASS-RO
15 CONCLUSION :
16 Annexin A10 expression is associated with poor clinical behavior and can be used a supportive surrogate marker of the serrated neoplasia pathway in invasive CRCs .



PMID: 26359417
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Co-existence of BRAF V600E Gene Mutation in Tumor and Non-tumoral Surrounding Tissues in Colorectal Cancer .
1 BACKGROUND/AIM :
2 The murine sarcoma viral ( V-Raf ) oncogene homolog B ( BRAF ) V600E mutation , which increases protein kinase activity in BRAF-mitogen-activated protein kinase kinase ( MEK ) - extracellular signal-regulated kinases ( ERK ) ( mitogen -activated protein kinase ( MAPK ) ) signaling , is found in 5-40% of all colorectal carcinoma cases .
3 Proteins with this mutation are reported to be 130-fold more active , which results in induced proliferation , differentiation , cellular survival , and angiogenesis .
4 The aim of the present study was to investigate tumor tissues , together with the surrounding non-tumoral tissues , for BRAF mutation presence , which may be an indicator for possible recurrence or prognosis as in the 'field carcinogenesis' model .
5 MATERIALS AND METHODS :
6 The BRAF V600E genotype of 152 colorectal adenocarcinoma paraffin-embedded specimens were determined by mutant-allele -specific amplification-polymerase chain reaction .
7 RESULTS :
8 THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
9 Μ We also found that females are more prone to having the mutation and that being female increases the risk of having this mutation by 1.54-fold ( chi(2) =358 , p = 005 , OR = 154 , 95% CI = 097-244 ) .
10 CONCLUSION :
11 ✓ BRAF V600E mutation in non-tumoral surrounding tissue in patients with colorectal cancer may be used as a valuable marker to foresee clinical outcome or a possible recurrence . GM-MRK-RO
12 To our knowledge , this was the first study to take into consideration the non-tumoral surrounding tissues in addition to the tumor tissue .



PMID: 26358176
(None)  
Terms: this review, clinical trial
Sent# Symbols Sentence Mnemonics
0 BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood .
1 In April 2013 our group published a review on predictive molecular pathology in this journal .
2 Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic molecular pathology rendering it worthwhile to present an up-date on this topic .
3 A major technical improvement is certainly given by the introduction of next-generation sequencing ( NGS ; amplicon , whole exome , whole genome ) and its application to formalin-fixed paraffin-embedded ( FFPE ) tissue in routine diagnostics .
4 Μ Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs .
5 In the near future this will open new strategies to apply 'off-label' targeted therapies , e.g.for rare tumors , otherwise resistant tumors etc .
6 Μ The clinically relevant genetic aberrations described in this review include mutation analyses of RAS ( KRAS and NRAS ) , BRAF and PI3K in colorectal cancer , KIT or PDGFR alpha as well as BRAF , NRAS and KIT in malignant melanoma .
7 Moreover , we present several recent advances in the molecular characterization of malignant lymphoma .
8 Beside the well-known mutations in NSCLC ( EGFR , ALK ) a number of chromosomal aberrations ( KRAS , ROS1 , MET ) have become relevant .
9 Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution .
10 The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible .
11 As another aspect of the increasing number of druggable mutations , we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy .
12 Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval , e.g.by the FDA or EMA .
13 Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible .
14 Although it is yet to be shown , which levels of biological information are most informative for predictive pathology , an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches .
15 To optimize cancer treatment we need to understand tumor biology in much more detail on morphological , genetic , proteomic as well as epigenetic grounds .
16 Finally , the complex challenges on the level of drug design , molecular diagnostics , and clinical trials make necessary a close collaboration among academic institutions , regulatory authorities and pharmaceutical companies .



PMID: 26358068
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Young age of onset colorectal cancers .
1 BACKGROUND :
2 Colorectal cancer is typically a condition of older patients with only 10 % diagnosed under the age of 50 years .
3 Often , diagnosis is delayed , but certain factors such as inherited syndromes , inflammatory bowel disease , or a family history of colorectal cancer should heighten the clinician's awareness .
4 This study of young colorectal cancers describes the incidence of potential contributory factors that warrant early investigations and their effect on survival outcomes .
5 METHODS :
6 A single-institution colorectal cancer database was queried for patients diagnosed with colorectal cancer under the age of 50 .
7 Medical records were reviewed , and patients were grouped into familial , inflammatory bowel disease-related , or sporadic cancers .
8 Sporadic cancers without existing family history were further evaluated for genetic and molecular changes including mutations in the oncogenes KRAS and BRAF , microsatellite instability , and methylator phenotype .
9 RESULTS :
10 One hundred thirty-five patients under the age of 50 with colorectal cancer diagnosed between 1994 and 2004 were identified .
11 Slightly under half , ( 444 % ) were women .
12 Mean age at surgery was 42.1 +/- 6.7 years .
13 Nineteen patients ( 14 % ) had a hereditary colorectal cancer syndrome ( 11 hereditary non-polyposis colorectal cancer ( HNPCC ) , 8 familial adenomatous polyposis ( FAP ) ) , and 19 ( 14 % ) had inflammatory bowel disease ( 14 ulcerative colitis , 5 Crohn's ) .
14 Three patients had other cancers ( brain , breast , and endometrial ) and 20 % of patients had a family history of colorectal cancer outside of a defined syndrome .
15 Overall , age-standardized 5-year survival was 66.8 % ( stage I 100 % , stage II 765 % , stage III 630 % , and stage IV 0 % ) .
16 Patients with genetic predisposition and inflammatory bowel disease had better 5-year survival when compared to the sporadic group ( p = 0025 ) .
17 Molecular profiles were available for 71 of the 77 sporadic cancers .
18 All 71 tumors were microsatellite stable , and none had CpG island methylator phenotype .
19 Twenty-three ( 324 % ) were KRAS mutant .
20 CONCLUSION :
21 In our cohort , a family history of colorectal cancer , known hereditary colorectal cancer syndrome , and inflammatory bowel disease account for nearly half of all cases of young colorectal cancer .
22 Prompt investigation of symptoms is essential in patients with Sporadic early-onset colorectal cancers , which appear to arise through the classical adenoma-to-carcinoma sequence .



PMID: 26355232
(None)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first - line setting .
1 Laparoscopic resection of schwannoma of the ascending colon .



PMID: 26352110
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism .
1 A novel grading system based on the counting of poorly differentiated clusters ( PDC ) of neoplastic cells at the invasive margin and in the tumour stroma was recently introduced among the histological parameters predictive of adverse clinical outcome in colorectal cancer ( CRC ) .
2 The aim of this study was to correlate the histological grade based on PDC and the mutational status of KRAS , NRAS and BRAF genes in 175 consecutive CRCs .
3 The highest PDC count under the objective lens of a x20 microscopic field in each tumour was considered for grading assessment , so that PDC counts <5 , 5-9 and >/ = 10 PDCs were defined grade 1 , grade 2 and grade 3 , respectively .
4 Μ Hotspots mutations were identified using the MassArray platform .
5 Overall , there were 42 ( 24% ) mutated tumours .
6 Mutational status was significantly associated with high pT stage ( p = 00021 ) , advanced pTNM stage ( p = 00018 ) , nodal metastases ( p = 0006 ) , tumour budding ( p = 0022 ) and high PDC grade ( p = 00022 ) .
7 KRAS mutations were significantly associated with PDC grade ( p = 00379 ) , while BRAF mutations were associated with PDC-G3 although statistical significance was not reached .
8 No significant associations were found between NRAS and PDC .
9 The significant association between mutated KRAS and PDC grade suggests that KRAS mutations may be involved in the formation of PDC .



PMID: 26351322
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype .
1 Functional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer .



PMID: 26351067
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Expression of the hyaluronan-mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers .
1 Expression of the hyaluronan-mediated motility receptor ( RHAMM , CD168 ) predicts adverse clinicopathological features and decreased survival for colorectal cancer ( CRC ) patients .
2 Using full tissue sections , we investigated the expression of RHAMM in tumor budding cells of 103 primary CRCs to characterize the biological processes driving single - cell invasion and early metastatic dissemination .
3 RHAMM expression in tumor buds was analyzed with clinicopathological data , molecular features and survival .
4 Tumor budding cells at the invasive front of CRC expressed RHAMM in 68% of cases .
5 Detection of RHAMM-positive tumor budding cells was significantly associated with poor survival outcome ( P = 0312 ) , independent of TNM stage and adjuvant therapy in multivariate analysis ( P = 0201 ) .
6 RHAMM-positive tumor buds were associated with frequent lymphatic invasion ( P = 0007 ) , higher tumor grade ( P = 0296 ) , and nodal metastasis ( P = 0364 ) .
7 Importantly , the prognostic impact of RHAMM expression in tumor buds was maintained independently of the number of tumor buds found in an individual case ( P = 0246 ) .
8 Μ No impact of KRAS/BRAF mutation , mismatch repair deficiency and CpG island methylation was observed .
9 ✓ RHAMM expression identifies an aggressive subpopulation of tumor budding cells and is an independent adverse prognostic factor for CRC patients . GE-MRK-DS
10 These data support ongoing efforts to develop RHAMM as a target for precision therapy .



PMID: 26350752
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial .
1 INTRODUCTION :
2 Molecular characterisation of tumours is increasing personalisation of cancer therapy , tailored to an individual and their cancer .
3 FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer .
4 During an initial 16-week period of standard first - line chemotherapy , tumour tissue will undergo several molecular assays , with the results used for cohort allocation , then randomisation .
5 Laboratories in Leeds and Cardiff will perform the molecular testing .
6 The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed .
7 METHODS :
8 Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research .
9 Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol , reporting results directly to the MRC Trial Management Group for independent cross-referencing .
10 RESULTS :
11 Pyrosequencing analysis of mutation status at KRAS codons12/13/61/146 , NRAS codons12/13/61 , BRAF codon600 and PIK3CA codons542/545/546/1047 , generated highly concordant results .
12 Μ Two samples gave discrepant results ; in one a PIK3CA mutation was detected only in Leeds , and in the other , a PIK3CA mutation was only detected in Cardiff .
13 pTEN and mismatch repair ( MMR ) protein expression was assessed by immunohistochemistry ( IHC ) resulting in 6/97 discordant results for pTEN and 5/388 for MMR , resolved upon joint review .
14 Tumour heterogeneity was likely responsible for pyrosequencing discrepancies .
15 The presence of signet-ring cells , necrosis , mucin , edge-effects and over-counterstaining influenced IHC discrepancies .
16 CONCLUSIONS :
17   Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies .
18 This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials .
19 TRIAL REGISTRATION NUMBER :
20 ISRCTN90061564 .



PMID: 26350096
(None)  
Terms: This review, genetically engineered mouse, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 RAS signaling and anti-RAS therapy : lessons learned from genetically engineered mouse models , human cancer cells , and patient-related studies .
1 Μ Activating mutations of oncogenic RAS genes are frequently detected in human cancers .
2 Μ The studies in genetically engineered mouse models ( GEMMs ) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung , pancreas , and gastrointestinal tract .
3 Nevertheless , most of these tumors do not have metastatic phenotypes .
4 Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes .
5 Μ Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes , including TP53 , STK11 , CDKN2A , and KMT2C in lung cancer ; APC , TP53 , and PIK3CA in colon cancer ; and TP53 , CDKN2A , SMAD4 , and MED12 in pancreatic cancer .
6 Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications , that inhibit downstream effectors of RAS signaling pathways , and that kill RAS mutant cancer cells through synthetic lethality .
7 Recent clinical studies have revealed that sorafenib , a pan-RAF and VEGFR inhibitor , has impressive benefits for KRAS mutant lung cancer patients .
8 Combination therapy of MEK inhibitors with either docetaxel , AKT inhibitors , or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients .
9 This review discusses knowledge gained from GEMMs , human cancer cells , and patient-related studies on RAS -mediated tumorigenesis and anti-RAS therapy .
10 Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes .
11 Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine .



PMID: 26348463
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Advances in Molecular Pathology and Treatment of Periampullary Cancers .
1 OBJECTIVES :
2 Periampullary cancers ( PACs ) include the following 4 traditional anatomic subtypes : pancreatic , ampullary , biliary , or duodenal cancers .
3 This review was performed to highlight recent advances in the genomic and molecular understanding of each PAC subtype and the advances in chemotherapeutic and molecular trials in these cancer subtypes .
4 RESULTS :
5 Recent advances have highlighted differences in the genomic and molecular features within each PAC subtype .
6 Ampullary cancers can now be further defined accurately into their intestinal and pancreatobiliary subtypes using histomolecular profiling .
7 Μ K-ras mutation , which occurs in most pancreatic cancers , is found to occur less frequently in ampullary ( 42%-52% ) , biliary ( 22%-23% ) , and duodenal cancers ( 32%-35% ) , suggesting crucial differences in targetable mutations in these cancer subtypes .
8 Ampullary cancers of intestinal subtype and duodenal cancers seem to share similarities with colorectal cancer , given that they respond to similar chemotherapeutic regimens .
9   This has potential implications for clinical trials and treatment selection , where PACs are often considered together .
10 CONCLUSIONS :
11 Future trials should be designed in view of our increased understanding of the different anatomic and histomolecularly profiled subtypes of PAC cancers , which respects their individual molecular characteristics , phenotype , and response to treatment .



PMID: 26347132
(Patient)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer : Moving Beyond KRAS Exon 2 .
1   The advent of anti-EGFR ( epidermal growth factor receptor ) therapy resulted in significant progress in the treatment of metastatic colorectal cancer patients .
2   However , many patients do not respond to this therapy or develop acquired resistance within a few months after the start of treatment .
3   Since 2008 , anti-EGFR therapy is restricted to KRAS wild-type patients as it has been shown that KRAS exon 2-mutated patients do not respond to this therapy .
4   Still , up to 60 % of KRAS exon 2 wild-type patients show primary resistance to this treatment .
5 ✓ Μ Recently , several studies investigating the predictive and prognostic role of RAS mutations other than in KRAS exon 2 demonstrated that patients with these mutations are not responding to therapy . RO-ASS-GM
6   However , the role of these mutations has long been questioned as The National Comprehensive Cancer Network Guidelines in Oncology and the European Medicines Agency indications had already been changed in order to restrict anti-EGFR therapy to all RAS wild-type colorectal cancer patients , while the Food and Drug Administration guidelines remained unchanged .
7 Recently , the Food and Drug Administration guidelines have also been changed , which implies the importance of RAS mutations beyond KRAS exon 2 in colorectal cancer .
8 ✓ In this review , we discuss the most important studies regarding the predictive and prognostic role of RAS mutations other than in KRAS exon 2 in order to demonstrate the importance of these RAS mutations in patients with metastatic colorectal cancer treated with anti-EGFR therapy . RO-ASS-GM



PMID: 26343581
(None)  
Terms: , mouse
Sent# Symbols Sentence Mnemonics
0 Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity .
1 The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood .
2 Here , we show that the growth of tumors formed by mutant Braf (V600E) mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2 , which suppresses immunity and fuels tumor-promoting inflammation .
3 Genetic ablation of cyclooxygenases ( COX ) or prostaglandin E synthases in Braf ( V600E ) mouse melanoma cells , as well as in Nras ( G12D ) melanoma or in breast or colorectal cancer cells , renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways .
4 This mouse COX -dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies , arguing for COX activity as a driver of immune suppression across species .
5   Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors , implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients .



PMID: 26341920
(Patient)  
Terms: Phase III Study, prospective, phase III study, retrospective, NCT0039183
Sent# Symbols Sentence Mnemonics
0 Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second - line Treatment for Metastatic Colorectal Cancer .
1 PURPOSE :
2 We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized , multicenter phase III study of panitumumab plus fluorouracil , leucovorin , and irinotecan ( FOLFIRI ) versus FOLFIRI alone as second - line therapy in patients with metastatic colorectal cancer ( mCRC ; ClinicalTrialsgov , NCT0039183 ) .
3 EXPERIMENTAL DESIGN :
4 Outcomes were from the study's primary analysis .
5 RAS mutations beyond KRAS exon 2 ( KRAS exons 3 , 4 ; NRAS exons 2 , 3 , 4 ; BRAF exon 15 ) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens .
6 Progression-free survival ( PFS ) and overall survival ( OS ) were coprimary endpoints .
7 RESULTS :
8 Μ The RAS ascertainment rate was 85% ; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations .
9 For PFS and OS , the hazard ratio ( HR ) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR , 0.70 ( 95% confidence interval [CI] , 0.54-0.91 ) ; P = 0.007 vs. 0.73 ( 95% CI , 059-090 ) ; P = 0.004 ; OS HR , 0.81 ( 95% CI , 063-103 ) ; P = 0.08 vs. 0.85 ( 95% CI , 070-104 ) ; P = 0.12] .
10   Patients with RAS mutations were unlikely to benefit from panitumumab .
11 Among RAS wild-type patients , the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group .
12 CONCLUSIONS :
13   Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population .
14 These findings support RAS testing for patients with mCRC .
15 Clin Cancer Res ; 21 ( 24 ) ; 5469-79 .
16 (c) 2015 AACR .
17 See related commentary by Salazar and Ciardiello , p. 5415 .



PMID: 26341689
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Expression of tumor-related Rac1b antagonizes B-Raf-induced senescence in colorectal cells .
1 Μ Mutations in the BRAF oncogene have been identified as a tumor-initiating genetic event in mainly melanoma , thyroid and colon cancer , resulting in an initial proliferative stimulus that is followed by a growth arrest period known as oncogene -induced senescence ( OIS ) .
2 It remains unknown what triggers subsequent escape from OIS to allow further tumor progression .
3 Μ A previous analysis revealed that around 80% of colorectal tumors carrying a mutation in BRAF also overexpress splice variant Rac1b .
4 We used normal NCM460 colonocytes as a model to express oncogenic B-Raf-V600E in the presence or absence of co-transfected Rac1b and then analyzed the effect on expression of senescence markers .
5 When oncogenic B-Raf-V600E was expressed we observed the induction of the senescence-associated beta-galactosidase and of the cell -cycle inhibitors p14 , p15 and p21 whereas proliferation marker Ki67 was suppressed .
6 Upon co-expression of splice variant Rac1b , but not of Rac1 , the B-Raf-induced senescence phenotype was reverted and expression of the cell -cycle inhibitors downregulated in a reactive oxygen-species dependent manner .
7 We thus provide evidence that co-expression of splice variant Rac1b counteracts B-Raf-induced senescence , indicating the selection for increased Rac1b expression as one potential mechanism by which colorectal tumor cells can escape from B-Raf-induced OIS .



PMID: 26341080
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic Value of BRAF , PI3K , PTEN , EGFR Copy Number , Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First - Line Chemotherapy with Anti-EGFR Therapy .
1 INTRODUCTION :
2 Μ Mutational analysis of RAS is required for anti-epidermal growth factor receptor ( EGFR ) treatment for patients with metastatic colorectal cancer ( mCRC ) .
3 However , most patients with KRAS wild-type tumors still do not respond .
4 Other molecules downstream of the EGFR may also play a role in resistance to EGFR therapies .
5 OBJECTIVE :
6 Our objective was to investigate the clinical importance of biomarkers in relation to response , progression-free survival , and overall survival in patients with mCRC receiving first - line treatment with anti-EGFR therapy plus chemotherapy .
7 METHODS :
8 We studied the EGFR pathway [EGFR , NRAS , BRAF , PIK3CA , phosphatase and tensin homolog ( PTEN ) , amphiregulin (AREG) , and epiregulin (EREG) ] in 105 patients with mCRC KRAS codon 12 wild type .
9 We analysed objective response , progression-free survival , and overall survival in molecularly defined subgroups of the patients receiving anti-EGFR therapy plus chemotherapy as first - line treatment .
10 RESULTS :
11 We found a significant association between RAS wild-type , BRAF wild-type , EREG , and AREG overexpression and response to anti-EGFR therapy ( p = 0003 , p = 0015 , p = 005 , and p = 0009 , respectively ) .
12 Progression-free survival and overall survival were lower in patients with RAS ( p = 036 and p BRAF ( p = 0003 and p = 0002 , respectively ) mutant tumors .
13 ✓ Patients with EREG and AREG messenger RNA ( mRNA ) expression had longer survival than those with low-expression tumors ; progression-free survival and overall survival were significant for AREG ( p = 0001 and p = 005 , respectively ) . GE-ASS-RO, RO-ASS-GE
14   Patients with EGFR amplification tumors responded better to treatment and had better survival rates , although this was not significant .
15 PIK3CA and PTEN were not associated with either response or survival .
16 The multivariate logistic regression model for response showed only BRAF as a significant predictor after adjustment for the other covariates ( p = 004 , odds ratio 83 , 95 % confidence interval 081-860 ) .
17 CONCLUSIONS :
18 ✓ RAS , BRAF , AREG , and EREG predict for efficacy of first - line anti-EGFR therapy in patients with mCRC . GE-REG-RO



PMID: 26338658
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Precision medicine in colorectal cancer : evolving genomic landscape and emerging consensus .
1 Colorectal cancer is the third most lethal cancer in men and women in the USA .
2 Although surgical resection is the mainstay of treatment , many patients develop local and widely metastatic disease and become resistant to conventional chemotherapeutics .
3 Recent comprehensive molecular characterization has led to subclassification of colorectal adenocarcinoma based on molecular properties , such as microsatellite instability and high CpG island methylation .
4 These emerging subclassifications are associate with varying frequencies of RAS , BRAF , APC and other genetic events and have the ability to redefine therapeutic regimens .
5   In this review , we examine how molecular diagnostics are currently used while providing insight into emerging implications for molecular analysis for personalized therapy in colorectal cancer .



PMID: 26338525
(Patient)  
Terms: NCT00719797
Sent# Symbols Sentence Mnemonics
0 FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first - line treatment of patients with metastatic colorectal cancer : updated overall survival and molecular subgroup analyses of the open-label , phase 3 TRIBE study .
1 BACKGROUND :
2 In the TRIBE study , FOLFOXIRI ( fluorouracil , leucovorin , oxaliplatin , and irinotecan ) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI ( fluorouracil , leucovorin , and irinotecan ) plus bevacizumab .
3 In this updated analysis , we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups .
4 METHODS :
5 TRIBE was an open-label , multicentre , phase 3 randomised study of patients ( aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0 ) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units .
6 Patients were randomly assigned ( 1 : 1 ) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab .
7 Bevacizumab was given as a 5 mg/kg intravenous dose .
8 FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min , a 400 mg/m(2) intravenous bolus of fluorouracil , and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h .
9 FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min , followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min , followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h .
10 Μ Tissue samples for RAS and BRAF mutational status analyses were centrally collected .
11 In this updated analysis , we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups .
12 All analyses were by intention to treat .
13 TRIBE was concluded on Nov 30 , 2014 .
14 The trial is registered with ClinicalTrials .
15 gov , number NCT00719797 .
16 FINDINGS :
17 Between July 17 , 2008 , and May 31 , 2011 , 508 patients were randomly assigned .
18 ✓ At a median follow-up of 48.1 months ( IQR 417-556 ) , median overall survival was 29.8 months ( 95% CI 260-343 ) in the FOLFOXIRI plus bevacizumab group compared with 25.8 months ( 225-291 ) in the FOLFIRI plus bevacizumab group ( hazard ratio [HR] 0.80 , 95% CI 0.65-0.98 ; p = 0.03 ) . GE-ASS-RO
19 Median overall survival was 37.1 months ( 95% CI 297-427 ) in the RAS and BRAF wild-type subgroup compared with 25.6 months ( 224-286 ) in the RAS-mutation-positive subgroup ( HR 149 , 95% CI 111-199 ) and 13.4 months ( 82-241 ) in the BRAF-mutation-positive subgroup ( HR 279 , 95% CI 175-446 ; likelihood-ratio test p<00001 ) .
20 Treatment effect was not significantly different across molecular subgroups ( pinteraction = 052 ) .
21   INTERPRETATION : FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study , irrespective of baseline clinical characteristics and RAS or BRAF mutational status .



PMID: 26337942
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Molecular phenotypes of colorectal cancer and potential clinical applications .
1 Colorectal cancer ( CRC ) is a heterogeneous disease , arising from many possible etiological pathways .
2 This heterogeneity can have important implications for CRC prognosis and clinical management .
3 Epidemiological studies of CRC risk and prognosis-as well as clinical trials for the treatment of CRC-must therefore be sensitive to the molecular phenotype of colorectal tumors in patients under study .
4 In this review , we describe four tumor markers that have been widely studied as reflections of CRC heterogeneity : (i) microsatellite instability ( MSI ) or DNA mismatch repair ( MMR ) deficiency , ( ii ) the CpG island methylator phenotype ( CIMP ) , and somatic mutations in ( iii ) BRAF and ( iv ) KRAS .
5 These tumor markers have been used to better characterize CRC epidemiology and , increasingly , may be used to guide clinical decision-making .
6 Going beyond these traditional tumor markers , we also briefly review some more novel markers likely to be of clinical significance .
7 Lastly , recognizing that none of these individual tumor markers are isolated attributes but , rather , a reflection of broader tumor phenotypes , we review some of the hypothesized etiological pathways of CRC development and their associated clinical differences .



PMID: 26336987
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma .
1 Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model , the evolution of the mutational landscape underlying this model is not fully understood .
2 In this study , we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas , four microsatellite-unstable ( MSU ) and four-stable ( MSS ) pairs , using whole-exome sequencing .
3 Μ In the MSU adenoma-carcinoma pairs , we observed no subclonal mutations in adenomas that became fixed in paired carcinomas , suggesting a 'parallel' evolution of synchronous adenoma-to-carcinoma , rather than a 'stepwise' evolution .
4 The abundance of indel ( in MSU and MSS pairs ) and microsatellite instability ( in MSU pairs ) was noted in the later adenoma - or carcinoma-specific mutations , indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different .
5 All MSU cases exhibited clonal , truncating mutations in ACVR2A , TGFBR2 , and DNA mismatch repair genes , but none were present in APC or KRAS .
6 Μ In three MSS pairs , both APC and KRAS mutations were identified as both early and clonal events , often accompanying clonal copy number changes .
7 An MSS case uniquely exhibited clonal ERBB2 amplification , followed by APC and TP53 mutations as carcinoma-specific events .
8 Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs , our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context -dependent .



PMID: 26335936
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Italian external quality assessment for RAS testing in colorectal carcinoma identifies methods-related inter-laboratory differences .
1 BACKGROUND :
2 In 2014 the European Medicines Agency included exon 2 , 3 and 4 KRAS and NRAS testing for the selection of metastatic colorectal cancer ( mCRC ) patients eligible for the therapy with anti-EGFR monoclonal antibodies .
3 The Italian Association of Medical Oncology ( AIOM ) and the Italian Society of Pathology and Cytology ( SIAPEC ) organized an external quality assessment ( EQA ) scheme for CRC to evaluate inter-laboratory consistency and to ensure standardization of the results in the transition from KRAS to all-RAS testing .
4 METHODS :
5 Ten formalin fixed paraffin embedded specimens including KRAS/NRAS ( exons 2 , 3 , 4 ) and BRAF ( codon 600 ) mutations were validated by three referral laboratories and sent to 88 participant centers .
6 Molecular pathology sample reports were also requested to each laboratory .
7 A board of assessors from AIOM and SIAPEC evaluated the results according to a predefined scoring system .
8 The scheme was composed of two rounds .
9 RESULTS :
10 In the first round 36% of the 88 participants failed , with 23 centers having atleast one false positive or false negative while 9 centers did not meet the deadline .
11 The genotyping error rate was higher when Sanger sequencing was employed for testing as compared with pyrosequencing ( 3 versus 13% ; p = 001 ; Pearson Chi Square test ) .
12 In the second round , the laboratories improved their performance , with 23/32 laboratories passing the round .
13 Overall , 79/88 participants passed the RAS EQA scheme .
14 Μ Standardized Human Genome Variation Society nomenclature was incorrectly used to describe the mutations identified and relevant variations were noticed in the genotype specification .
15 CONCLUSION :
16 Μ The results of the Italian RAS EQA scheme indicate that the mutational analyses are performed with good quality in many Italian centers , although significant differences in the methods used were highlighted .
17 The relatively high number of centers failing the first round underlines the fundamental role in continued education covered by EQA schemes .



PMID: 26334293
(Patient)  
Terms: Phase II Trial
Sent# Symbols Sentence Mnemonics
0 Phase II Trial of S-1 and Oxaliplatin Plus Cetuximab for Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases (KSCC1002) .
1 BACKGROUND :
2 The Kyushu Study Group of Clinical Cancer ( KSCC ) conducted phase II trials of KSCC1002 (UMIN000001308) concerning liver resectability after first - line treatment of initially unresectable or not optimally resectable colorectal liver metastases in a prospective , multicenter study .
3 METHODS :
4 Patients with wild-type KRAS received 4-6 cycles of S-1 and oxaliplatin ( SOX ) plus cetuximab .
5 Liver resectability was evaluated subsequently with the liver resection rate as the primary endpoint .
6 RESULTS :
7 Of the 33 patients enrolled between March 2010 and July 2013 , the median number of administration cycles was 4 ( range 0-10 ) .
8 The overall response rate was 63.6 % ( 95 % confidence interval [CI] 45.1-79.6 % ) .
9 Liver resection was possible in 16 of 33 ( 485 % ) patients , and there were 13 R0 cases ( 394 % ) .
10 We conducted a central review of liver resectability evaluated by five liver surgeons , and the resectability increased from 18.2 to 66.7 % after chemotherapy , based on imaging .
11 The median overall survival for all 33 cases was 31.6 months ( 95 % CI 148-not reached ) .
12 The median progression-free survival was 9.7 months ( 95 % CI 62-118 ) .
13 CONCLUSIONS :
14 SOX plus cetuximab is safe and effective for advanced colorectal cancer with limited liver metastasis , and may lead to high liver resectability .



PMID: 26333174
(Cell)  
Terms: in vitro, xenograft, rat, tumor model
Sent# Symbols Sentence Mnemonics
0 MiR-622 inhibited colorectal cancer occurrence and metastasis by suppressing K-Ras .
1 Colorectal cancer ( CRC ) is one of the leading causes of cancer death worldwide , with many oncogenes and anti - oncogenes involved .
2 MicroRNAs ( miRNAs ) are a class of small , noncoding RNA molecules that can adjust downstream targets .
3 Accumulating evidence has revealed that microRNAs govern the occurrence and development of cancer .
4 Here , we studied the role of miR-622 in CRC and clarified the underlying mechanism .
5 We detected that miR-622 was down-regulated in colorectal tumor tissues and cell lines and that miR-622 was lower in metastatic CRC tissues compared with that in non-metastatic specimens .
6 Furthermore , we confirmed that miR-622 inhibited tumor proliferation and migration in vitro .
7 Through dual-luciferase reporter assay , we found kirsten rat sarcoma ( K-Ras ) gene was the direct target of miR-622 .
8 More importantly , K-Ras overexpression can rescue the inhibitory effect of miR-622 on CRC development .
9 All these data were validated in colon xenograft tumor model .
10   MiR-622-K-Ras signal pathway was a potentially new direction in the development of screening target and therapeutic treatments for CRC .
11 (c) 2015 Wiley Periodicals , Inc .



PMID: 26327923
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Precision medicine in colorectal cancer : the molecular profile alters treatment strategies .
1 When considering treatment options for patients with metastatic colorectal cancer ( mCRC ) , molecular profiling has become a pivotal component in guiding clinical decisions .
2 FOLFOX and FOLFIRI ( fluorouracuil , leucovorin plus oxaliplatin or ininotecan , respectively ) are the standard base regimens used for the treatment of mCRC .
3 Biologic agents , such as the epidermal growth factor receptor ( EGFR ) targeted therapies , cetuximab and panitumumab and the vascular endothelial growth factor monoclonal antibody , bevacizumab , are safe and effective in the first - line setting .
4 The most efficacious use of these agents in terms of timing and selection of the right patient population continues to be debated .
5 Here we review multiple investigations into the effectiveness of treatment options as a function of the mutations present in colon cancers .
6 ✓ Early studies have reported that KRAS mutations at exon 2 predict resistance to EGFR targeted therapies .
7   More recently the data have expanded to include KRAS mutations at exons 3 and 4 and NRAS mutations at exons 2 , 3 and 4 as well as other biomarkers including BRAF and PIK3CA , leading to the evolution of the treatment of mCRC to a more precision-based approach .
8 As our understanding of relevant biomarkers increases , and data from both molecular profiling and treatment response become more readily available , treatment options will become more precise and their outcomes more effective .



PMID: 26327919
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Management of regorafenib-related toxicities : a review .
1 Regorafenib ( Stivarga , BAY 73-4506 ; Bayer Pharma AG , Berlin , Germany ) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 ( VEGFR2 ) , VEGFR1 , VEGFR3 , fibroblast growth factor receptor 1 ( FGFR1 ) , RAF , KIT , RET and BRAF .
2 Its antiangiogenic effect is greater than that of its related drug , sorafenib .
3 Regorafenib has been approved by the US Food and Drug Administration ( FDA ) for the treatment of metastatic colorectal cancer ( mCRC ) in patients who have failed treatment with fluoropyrimidine , oxaliplatin and irinotecan based chemotherapy , an anti-VEGF therapy and , if KRAS wild type , an anti-EGFR therapy .
4 The FDA based this approval on data from the CORRECT trial , which showed the efficacy of regorafenib compared with placebo .
5 The most common grade 3-4 adverse reactions with the drug are hand foot skin reactions ( HFSR ) , diarrhea , hypertension and fatigue .
6 This review discusses the efficacy data , and the incidence and management of regorafenib's toxicities .



PMID: 26325103
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS , NRAS , BRAF mutation comparison of endoscopic and surgically removed primary CRC paired samples : is endoscopy biopsy material adequate for molecular evaluation ?
1 Langerhans cell sarcoma : case report and review of world literature .



PMID: 26322950
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MSIplus for Integrated Colorectal Cancer Molecular Testing by Next-Generation Sequencing .
1 Pyrosequencing evaluation of low-frequency KRAS mutant alleles for EGF receptor therapy selection in metastatic colorectal carcinoma .



PMID: 26321889
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Increasing Relevance of Tumour Histology in Determining Oncological Outcomes in Colorectal Cancer .
1 Colorectal cancer is not just one type of cancer .
2 Differences in outcome and reaction to treatment can atleast be partly explained by different histological and molecular subtypes .
3 Recognition of these differences may influence treatment decisions .
4 However , there is huge variation in the amount of information that is available .
5 Several tumour types such as mucinous carcinoma , signet ring cell carcinoma , neuroendocrine carcinoma and adenosquamous carcinoma have such a distinct phenotype that they are readily recognised .
6 However , due to the rarity of signet ring cell carcinoma and adenosquamous carcinoma , limited data are available .
7 More recently defined subtypes , like medullary carcinoma , serrated adenocarcinoma and micropapillary carcinoma , are not adequately diagnosed , which limits research possibilities using large-scale data from registries .
8 In the current review , we systematically describe the histologic subtypes with the clinical and molecular background .
9 We evaluate their prognosis compared to adenocarcinoma not otherwise specified and speculate about the clinical relevance .



PMID: 26318998
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Probing a 3,4'-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway .
1 Mutations in the Ras-pathway occur in 40-45% of colorectal cancer patients and these are refractory to treatment with anti-EGFR-targeted therapies .
2 With this in mind , we have studied novel guanidinium-based compounds with demonstrated ability to inhibit protein kinases .
3 We have performed docking studies with several proteins involved in the Ras-pathway and evaluated 3,4'-bis-guanidinium derivatives as inhibitors of B-Raf .
4 Compound 3 , the most potent in this series , demonstrated strong cytotoxicity in ( WT ) B-Raf colorectal cancer cells and also cells with ( V600E ) B-Raf mutations .
5 Cell death was induced by apoptosis , detected by cleavage of PARP .
6 Compound 3 also potently inhibited ERK1/2 signalling , inhibited EGFR activation , as well as Src , STAT3 and AKT phosphorylation .
7 Mechanistically , compound 3 did not inhibit ATP binding to B-Raf , but direct assay of B-Raf activity was inhibited in vitro .
8 Summarizing , we have identified a novel B-Raf type-III inhibitor that exhibits potent cellular cytotoxicity .



PMID: 26318427
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer : do all roads lead to RAS ?
1 Advances towards the design and development of personalized non-small - cell lung cancer drug therapy .



PMID: 26314551
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The distribution of BRAF gene fusions in solid tumors and response to targeted therapy .
1 Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma , BRAF gene fusions have not been investigated as anticancer drug targets .
2 In our study , a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne or FoundationOne Heme comprehensive genomic profiling assays .
3 BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 ( 03% ) of 20,573 tumors , across 12 distinct tumor types , including 20 novel BRAF fusions .
4 These comprised 29 unique 5' fusion partners , of which 31% (9) were known and 69% ( 20 ) were novel .
5 BRAF fusions included 3% ( 14/531 ) of melanomas ; 2% ( 15/701 ) of gliomas ; 1.0% ( 3/294 ) of thyroid cancers ; 0.3% ( 3/1,062 ) pancreatic carcinomas ; 0.2% ( 8/4,013 ) nonsmall - cell lung cancers and 0.2% ( 4/2,154 ) of colorectal cancers , and were enriched in pilocytic ( 30% ) vs.nonpilocytic gliomas ( 1% ; p <00001 ) , Spitzoid ( 75% ) vs.nonSpitzoid melanomas ( 1% ; p = 00001 ) , acinar ( 67% ) vs.nonacinar pancreatic cancers ( <1% ; p <00001 ) and papillary ( 3% ) vs.nonpapillary thyroid cancers ( 0% ; p <003 ) .
6 Clinical responses to trametinib and sorafenib are presented .
7 In conclusion , BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms , but enriched in Spitzoid melanoma , pilocytic astrocytomas , pancreatic acinar and papillary thyroid cancers .



PMID: 26311717
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis .
1   Μ Predictors of outcome for patients with lung adenocarcinoma carrying the epidermal growth factor receptor mutation receiving 1st - line tyrosine kinase inhibitors : Sensitivity and meta-regression analysis of randomized trials .



PMID: 26311588
(Patient)  
Terms: phase II trial, Clinical Trial
Sent# Symbols Sentence Mnemonics
0 A single-arm phase II trial of combined chemotherapy with S-1 , oral leucovorin , and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer .
1 BACKGROUND :
2 The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer ( mCRC ) necessitates more effective treatments for refractory mCRC .
3 For untreated mCRC , S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity .
4 The ML18147 trial demonstrated that bevacizumab ( Bev ) prolongs overall survival after mCRC progression .
5 We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy .
6 METHODS :
7 Major eligibility criteria were confirmed adenocarcinoma diagnosis ; age >20 years ; Eastern Cooperative Oncology Group performance status , 0-2 ; and progression after administration/intolerance of/to approved drugs for mCRC. ( 5-FU , oxaliplatin , irinotecan , Bev , and anti-EGFR antibody , if KRAS wild-type ) .
8 S-1 ( 80-120 mg/body ) and leucovorin ( 25 mg ) were orally administered in a 1-week-on/1-week-off schedule .
9 Bev ( 5 mg/kg ) was administered on day 1 of every 2-week cycle .
10 The primary endpoint was disease control rate ( DCR ) .
11 RESULTS :
12 A total of 31 patients were enrolled .
13 DCR was 65% [95% confidence interval ( CI ) , 48-100%] and the response rate was 7% ( 95% CI , 07-22% ) .
14 One patient showing partial response to SL/Bev had a BRAF-mutant tumor .
15 Median progression-free survival and overall survivals were 5.3 [95% CI , 21-93] and 9.9 [95% CI , 74-NA] months , respectively .
16 The most-frequent grade-3/4 adverse events were mucositis ( 26% ) and diarrhea ( 11% ) , which were manageable by dose reduction/interruption .
17 CONCLUSIONS :
18   SL/Bev showed impressive activity in refractory mCRC and was tolerable , suggesting its potential as an alternative chemotherapy for refractory mCRC .
19 TRIAL REGISTRATION :
20 This study has been registered in University Hospital Medical Information Network ( UMIN ) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012 .



PMID: 26309716
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 K-ras genetic mutation and influencing factor analysis for Han and Uygur nationality colorectal cancer patients .
1 THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
2 Μ Single factor analysis and multiple factor logistic regression analysis were utilized to analyze the influencing factor for K-ras genetic mutation. 33 cases of patients with K-ras genetic mutation were found from the 91 cases colorectal cancer patients and the total mutation rate was 36.3% .
3 Μ Among them , 24 cases ( 727% ) were found with mutation only in the 12th code , 9 cases ( 273% ) were found with mutation only in the 13th code and no one case was found with mutation in both the two codes .
4 Mutation rate of the 12th code in the Uygur nationality was significantly higher than that in the Han nationality ( P<005 ) , but there were no significant difference in the comparison of the total mutation rate and the 13th code mutation rate between the two groups ( P>005 ) .
5 There were no associativity ( P>005 ) between the K-ras genetic mutation and sex , age , smoking history , drinking history , tumor location , macropathology type , differentiation level , staging , invasive depth , lymph nodes transferring and metastasis in colorectal cancer patients ( P>005 ) .
6 K-ras genetic mutation rate is high in colorectal cancer patients .
7 The mutation rate of 12th code in Uygur nationality is higher than that in Han nationality .
8 There is no significant associativity between K-ras genetic mutation rate and patients' clinical pathology characteristic .



PMID: 26309164
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 89Zr-cetuximab PET imaging in patients with advanced colorectal cancer .
1 Monoclonal antibodies ( mAbs ) against the epidermal growth factor receptor ( EGFR ) are used in the treatment of advanced colorectal cancer ( mCRC ) .
2 Approximately 50% of patients benefit despite patient selection for RAS wild type ( wt ) tumors .
3 Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment , biodistribution and tumor uptake of ( 89 ) Zr-cetuximab by Positron Emission Tomography ( PET ) , combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated .
4 Ten patients with wt K-RAS mCRC received 37 +/- 1 MBq ( 89 ) Zr-cetuximab directly ( <2 h ) after the first therapeutic dose of cetuximab .
5 PET-scans were performed from 1 hour to 10 days post injection ( pi ) .
6 Biodistribution was determined for blood and organs .
7 Uptake in tumor lesions was quantified by Standardized Uptake Value ( SUV ) and related to response .
8 In 6 of 10 patients ( 89 ) Zr-cetuximab uptake in tumor lesions was detected .
9 Four of 6 patients with ( 89 ) Zr-cetuximab uptake had clinical benefit , while progressive disease was observed in 3 of 4 patients without ( 89 ) Zr-cetuximab uptake .
10 Taken together , tumor uptake of 89Zr-cetuximab can be visualized by PET imaging .
11   The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC .



PMID: 26305864
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer .
1 BACKGROUND :
2 APC mutations ( APC-mt ) occur in approximately 70% of colorectal cancers ( CRCs ) , but their relationship to prognosis is unclear .
3 METHODS :
4 APC prognostic value was evaluated in 746 stage I-IV CRC patients , stratifying for tumour location and microsatellite instability ( MSI ) .
5 Μ Microarrays were used to identify a gene signature that could classify APC mutation status , and classifier ability to predict prognosis was examined in an independent cohort .
6 RESULTS :
7 Wild-type APC microsatellite stable ( APC-wt/MSS ) tumours from the proximal colon showed poorer overall and recurrence-free survival ( OS , RFS ) than APC-mt/MSS proximal , APC-wt/MSS distal and APC-mt/MSS distal tumours ( OS HR179 , P0015 ; RFS HR188 , P0026 ) .
8 APC was a stronger prognostic indicator than BRAF , KRAS , PIK3CA , TP53 , CpG island methylator phenotype or chromosomal instability status ( P0036 ) .
9 Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature ( P = 0019 ) .
10 APC status did not affect outcomes in MSI tumours .
11 In a validation on 206 patients with proximal colon cancer , APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases ( OS HR250 , P0010 ; RFS HR214 , P0025 ) .
12 Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway ( P0016 ) .
13 CONCLUSIONS :
14 APC-wt status is a marker of poor prognosis in MSS proximal colon cancer .



PMID: 26300630
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 The efficacy and safety of panitumumab in the treatment of patients with metastatic colorectal cancer : a meta-analysis from five randomized controlled trials .
1 BACKGROUND :
2 The efficacy of adding panitumumab to chemotherapy remains controversial in the treatment of metastatic colorectal cancer ( mCRC ) .
3 Thus , we conducted this meta-analysis to assess the efficacy and safety of this combination regimen in patients with mCRC .
4 METHODS :
5 The PubMed , Embase , and Web of Science databases were comprehensively searched .
6 Eligible studies included randomized controlled trials ( RCTs ) that estimated the efficacy of panitumumab with or without chemotherapy in the treatment of patients with mCRC .
7 Hazard ratio ( HR ) , risk ratio ( RR ) , and 95% confidence intervals ( CIs ) were calculated , and heterogeneity was tested using I (2) statistics .
8 RESULTS :
9 Four studies involving a total of 3,066 patients were included in this meta-analysis .
10 The addition of panitumumab to chemotherapy significantly improved progression-free survival ( PFS ) ( HR =084 , 95% CI =078-091 , P = 0000 ) and the objective response rate ( ORR ) ( RR =218 , 95% CI =113-422 , P = 0021 ) compared to chemotherapy alone , but no effect was noted on overall survival ( OS ) ( HR =097 , 95% CI =089-105 , P = 0402 ) .
11   Subgroup analysis based on KRAS gene status revealed that the combined therapy significantly improved PFS ( HR =071 , 95% CI =057-088 , P = 0002 ) and ORR ( RR =243 , 95% CI =121-490 , P = 0013 ) in patients with wild-type KRAS tumors .
12   Irinotecan-based chemotherapy plus panitumumab significantly prolonged PFS in patients with mCRC ( HR =084 , 95% CI =076-094 , P = 0002 ) .
13 The combined treatment also increased the incidence of grade 3/4 adverse events .
14 CONCLUSION :
15 This meta-analysis indicates that the combination of panitumumab and chemotherapy effectively improved PFS and ORR , but it did not prolong OS .
16 However , as the number of studies in the meta-analysis was limited , more large-scale , better-designed RCTs are needed to assess the combination of panitumumab and chemotherapy .



PMID: 26299862
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Biochip detection of KRAS , BRAF , and PIK3CA somatic mutations in colorectal cancer patients ] .
1 Somatic mutations of KRAS , PIK3CA , and BRAF cause insensitivity of colorectal tumors to therapy with anti-EGFR monoclonal antibodies , necessitating a genetic testing prior to therapy .
2 A biological microchip was developed and validated to allow detection of 19 somatic mutations in KRAS , PIK3CA , and BRAF genes .
3 The method combines LNA-clamp PCR and allele -specific hybridization on a microchip and detects mutant DNA in 100 times wild-type background ( 1% ) .
4 A total of 66 DNA samples isolated from colorectal tumors were tested with the biochip.Possible associations between the genetic status of the tumor and the patient's characteristics ( age , sex , tumor localization , stage , and TMN ) were assessed statistically .
5 KRAS mutations were more common in females ( P = 002 ) and in patients with distant metastasis ( P = 004 ) .
6 Μ Other associations between the presence of mutations and patient characteristics were not observed .
7   The method proved highly sensitive and can be used in oncology to select patients who sensitive to therapy with anti-EGFR monoclonal antibodies .



PMID: 26299805
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 4-Hydroxynonenal promotes growth and angiogenesis of breast cancer cells through HIF-1alpha stabilization .
1 Chromosomal inversions within chromosome 2p , resulting in fusions between the echinoderm microtubule-associated protein -like 4 ( EML4 ) and anaplastic lymphoma kinase ( ALK ) genes , are a recent focus of treatment options for non-small cell lung cancer .
2 Μ Thirteen EML4-ALK fusion variants have been identified , affecting eight EML4 exons .
3 We have developed an exon scanning approach using multiplex reverse transcriptase-polymerase chain reaction ( RT-PCR ) to amplify known and potential variants involving the first 22 EML4 exons .
4 A total of 55 formalin-fixed , paraffin-embedded lung cancer tumors were screened , of which 5 ( 9% ) were positive for EML4-ALK fusions .
5 Μ Four positive cases harbored known fusion variants : variant 3a , 3b , or both in three cases and variant 1 in one case .
6 Μ The fifth positive specimen harbored two novel variants , designated 8a and 8b , involving exon 17 of EML4 .
7 Fluorescence in situ hybridization confirmed the presence of EML4-ALK fusions in three of the four RT-PCR-positive specimens with sufficient tissue for examination , and also confirmed absence of fusions in all 19 RT-PCR-negative specimens tested .
8 Immunohistochemistry analysis confirmed ALK protein expression in the sample containing the novel 8a and 8b variants .
9 Μ This RT-PCR-based exon scanning approach avoids the limitations of screening only for previously identified EML4-ALK fusions and provides a simple molecular assay for fusion detection in a clinical diagnostics setting .



PMID: 26298837
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cystic brain metastasis in non-small - cell lung cancer with ALK rearrangement .
1 PURPOSE :
2 Microsatellite instability ( MSI ) in human endometrial cancer ( EC ) was analysed using a unique fluorescent technique .
3 MSI is associated with various human neoplasms .
4 However , the reported frequency of MSI differs widely in each malignancy .
5 Methodological difficulties have in fact been pointed out in its assay techniques .
6 METHODS :
7 We previously established a sensitive fluorescent technique in which the major methodological problems are overcome .
8 Μ Application of this technique has revealed two distinct modes of microsatellite alterations , i.e . Type A and Type B .
9 In the present study , we have applied this technique to 94 ECs .
10 RESULTS :
11 Μ Significant microsatellite alterations were observed in 38 ( 404% ) tumours of the panel .
12 The two modes , Type A and Type B , were indeed observed in this malignancy .
13 More importantly , we found that the modes more closely correlated with the molecular and clinicopathological backgrounds of the tumours than the established and widely used MSI grades , MSI-H and MSI-L .
14 Type B MSI widely correlated with family history of hereditary non-polyposis colorectal cancer-associated cancers , whereas MSI-H only did with that of colorectal cancer .
15 Furthermore , mutation in the KRAS oncogene , which has been regarded as generally infrequent in microsatellite-unstable tumours , was clearly associated with Type A MSI .
16 CONCLUSIONS :
17 Our observations may suggest a biological relevance and a potential utility of the modal classification of MSI and , furthermore , added complexities to genomic instability underlying tumourigenesis in human endometrium .



PMID: 26296467
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Fentanyl inhibits the invasion and migration of colorectal cancer cells via inhibiting the negative regulation of Ets-1 on BANCR .
1 BACKGROUND :
2 Recent studies have shown the potential anti-tumor effect of fentanyl on colorectal cancer ( CRC ) .
3 However , its underling mechanism is still unclear .
4 Since studies indicates the abnormal expression of transcription factor Ets-1 and BRAF -activated lncRNA (BANCR) in CRC progress , the relationship between Ets-1 and BANCR was investigated here to illustrate the fentanyl -induced mechanism on CRC in vitro .
5 METHODS :
6 Μ The expression levels of Ets-1 and BANCR were first detected in fentanyl-treated CRC cells .
7 The interaction between Ets-1 and BANCR promoter was verified with chromatin immunoprecipitation assays , as well as corresponding acetylation of histones .
8 The regulation of Ets-1 on BANCR expression was confirmed through luciferase assays and RT-PCR analysis .
9 And , cell clone formation , cell migration and invasion were observed to evaluate the anti-tumor effects of fentanyl .
10 Ets-1 overexpression or co-overexpression with BANCR was further performed by plasmids transfection to show the regulatory role of Ets-1 in fentanyl -induced mechanism .
11 RESULTS :
12 Fentanyl induced BANCR upregulation and Ets-1 downregulation in CRC cells .
13 Μ Further studies showed that Ets-1 negatively regulated BANCR expression via the deacetylation of histones H3 within BANCR promoter .
14 Moreover , fentanyl induced less cell clone formation , as well as inhibited cell migration and invasion in vitro , while Ets-1 overexpression inhibited fentanyl -induced effects that could be reversed by BANCR co-overexpression .
15 CONCLUSION :
16 Fentanyl showed anti-tumor like effects on CRC cells , including less cell clone formation and inhibited cell migration and invasion .
17   Furthermore , the regulatory role of Ets-1 on BANCR influenced fentanyl -induced mechanism , indicating their potential application in the therapeutic treatment of CRC .



PMID: 26291085
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Comprehensive DNA Methylation Analysis Reveals a Common Ten - Gene Methylation Signature in Colorectal Adenomas and Carcinomas .
1 Microarray analysis of promoter hypermethylation provides insight into the role and extent of DNA methylation in the development of colorectal cancer ( CRC ) and may be co-monitored with the appearance of driver mutations .
2 Colonic biopsy samples were obtained endoscopically from 10 normal , 23 adenoma ( 17 low-grade ( LGD ) and 6 high-grade dysplasia ( HGD ) ) , and 8 ulcerative colitis ( UC ) patients ( 4 active and 4 inactive ) .
3 CRC samples were obtained from 24 patients ( 17 primary , 7 metastatic ( MCRC ) ) , 7 of them with synchronous LGD .
4 Field effects were analyzed in tissues 1 cm ( n = 5 ) and 10 cm ( n = 5 ) from the margin of CRC .
5 Tissue materials were studied for DNA methylation status using a 96 gene panel and for KRAS and BRAF mutations .
6 Expression levels were assayed using whole genomic mRNA arrays .
7 SFRP1 was further examined by immunohistochemistry .
8 HT29 cells were treated with 5-aza-2' deoxycytidine to analyze the reversal possibility of DNA methylation .
9 More than 85% of tumor samples showed hypermethylation in 10 genes ( SFRP1 , SST , BNC1 , MAL , SLIT2 , SFRP2 , SLIT3 , ALDH1A3 , TMEFF2 , WIF1 ) , whereas the frequency of examined mutations were below 25% .
10 These genes distinguished precancerous and cancerous lesions from inflamed and healthy tissue .
11 The mRNA alterations that might be caused by systematic methylation could be partly reversed by demethylation treatment .
12 Systematic changes in methylation patterns were observed early in CRC carcinogenesis , occuring in precursor lesions and CRC .
13   Thus we conclude that DNA hypermethylation is an early and systematic event in colorectal carcinogenesis , and it could be potentially reversed by systematic demethylation therapy , but it would need more in vitro and in vivo experiments to support this theory .



PMID: 26287849
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation .
1 Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas .



PMID: 26284133
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hypothesis : Obesity Is Associated with a Lower Mutation Threshold in Colon Cancer .
1 Neoplastic progression requires accumulation of several mutations ( mutation threshold ) .
2 We hypothesize that obesity raises the risk of microsatellite stable ( MSS ) colon cancer ( CC ) atleast in part by decreasing the mutation threshold .
3 Thus , we posit that obese patients require fewer mutations , particularly driver mutations , compared to their normal BMI counterparts .
4 Further , we suggest that the reduced number of required mutations in obese patients could be due to several factors , including the high levels of cytokines that accompany obesity .
5 Cytokine-activated ERK , AKT , and JAK/STAT signaling could synergize with CC-initiating mutations to promote intestinal neoplastic development .
6 Therefore , driver mutations that induce these specific pathways may not be "required" for neoplastic development in obesity ; alteration in cell signaling consequent to obesity can substitute for some driver mutations in neoplastic progression .
7 This hypothesis is supported by preliminary analyses of data from The Cancer Genome Atlas ( TCGA ) .
8 Thus , we observed that , compared to normal weight patients , cancer genomes of obese MSS CC patients exhibit fewer somatic mutations , and correspondingly lower numbers of mutations in driver genes ( P = 0026 ) .
9 Μ The most striking observation was the lower number of KRAS mutations detected in patients with high body-mass index ( BMI ) .
10 These intriguing observations require further validation with increased number of patients , taking into account all possible confounding factors .
11 Μ If the hypothesis is confirmed , future studies should also address several possible explanations for the observed lower mutation threshold in obese MSS CC patients .



PMID: 26283684
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer . GE-MRK-RO
1 PURPOSE :
2 EphA2 , a member of the Eph receptor tyrosine kinases family , is an important regulator of tumor initiation , neovascularization , and metastasis in a wide range of epithelial and mesenchymal cancers ; however , its role in colorectal cancer recurrence and progression is unclear .
3 EXPERIMENTAL DESIGN :
4 EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors ( N = 338 ) , and findings correlated with clinical outcome .
5 The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined .
6 The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type ( WT ) and mutant ( MT ) parental and invasive colorectal cancer cell line models .
7 RESULTS :
8 Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue , which positively correlated with high CD44 and Lgr5 expression levels .
9 ✓ Μ Moreover , high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues , in both univariate and multivariate analyses . GE-ASS-RO
10 Preclinically , we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways .
11 Moreover , EphA2 levels were elevated in several invasive daughter cell lines , and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells .
12 CONCLUSIONS :
13   These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer , which may be due to its ability to promote cell migration and invasion , providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target .



PMID: 26281864
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Correlation between DPYD gene variation and KRAS wild type status in colorectal cancer .
1 AIMS :
2 Failure and side effects of combined cytotoxic therapy are challenges in the treatment of metastatic colorectal cancer ( CRC ) .
3 DPYD gene variations can potentially predict toxicity to 5-fluorouracil ( FU )- based therapy and KRAS - , NRAS - , BRAF - , PIK3CA-wild type status is a known prerequisite for epidermal growth factor receptor ( EGFR ) inhibitor therapy .
4 This study was performed to search for a possible link between these therapeutic markers .
5 METHODS :
6 The DPYD gene variations c.496A>G , c.1679T>G , c.2846A>T and KRAS/NRAS/BRAF/PIK3CA mutational status were determined in non-neoplastic , primary CRC and metastatic CRC tissue from 115 patients .
7 RESULTS :
8 The polymorphism c.496A>G was the DPYD gene variant with the highest detection rate ( 129% ) , occurred predominantly in females ( 867% , p = 00044 ) and was exclusively seen in KRAS wild type primary CRC ( 15/65 ( 231% ) versus 0/51 ( 0% ) in KRAS-mutated primary CRC , respectively , p = 0.0001 ) .
9 CONCLUSIONS :
10 This genetic profile could define a patient group requiring alternative combined therapeutic approaches .
11 Global testing of large patient cohorts is necessary to prove this concept .



PMID: 26281694
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Targeted therapies for metastatic colorectal cancer ] .
1 Targeted therapies against vascular endothelial growth factor ( VEGF ) , VEGF receptor and epidermal growth factor receptor ( EGFR ) have improved survival in patients with metastatic colorectal cancer ( mCRC ) .
2 Clinical studies have demonstrated that the following 6 targeted agents showed antitumor activity in patients with mCRC : bevacizumab , aflibercept , ramucirumab , cetuximab , panitumumab and regorafenib .
3 ✓ KRAS exon 2 ( codons 12 and 13 ) mutations were negative predictive biomarkers for efficacy of anti-EGFR antibody therapy . GM-MRK-RO
4 Expanded RAS mutations ( including KRAS exon 2 , exon 3 and exon 4 mutations as well as NRAS mutations ) can further predict the therapeutic effects of this therapy .
5   It seems to be necessary to identify new predictive biomarkers and develop new targeted agents for personalized treatment for mCRC .



PMID: 26276752
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colon Tumors with the Simultaneous Induction of Driver Mutations in APC , KRAS , and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence .
1 Despite the widespread availability of immunohistochemical and other methodologies for screening and early detection of lung and breast cancer biomarkers , diagnosis of the early stage of cancers can be difficult and prone to error .
2 The identification and validation of early biomarkers specific to lung and breast cancers , which would permit the development of more sensitive methods for detection of early disease onset , is urgently needed .
3 In this paper , ultra-small and bright nanoprobes based on quantum dots ( QDs ) conjugated to single human domain anti-HER2 ( epidermal growth factor receptor 2 ) antibodies ( sdAbs ) were applied for immunolabeling of breast and lung cancer cell lines , and their performance was compared to that of anti-HER2 monoclonal antibodies conjugated to conventional organic dyes Alexa Fluor 488 and Alexa Fluor 568 .
4 The sdAbs-QD conjugates achieved superior staining in a panel of lung cancer cell lines with differential HER2 expression .
5 This shows their outstanding potential for the development of more sensitive assays for early detection of cancer biomarkers .



PMID: 26275292
(None)  
Terms: Meta-Analysis
Sent# Symbols Sentence Mnemonics
0 Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature .
1 IMPORTANCE :
2 The EGFR inhibitors ( EGFR-I ) cetuximab and panitumumab and the angiogenesis inhibitors ( AIs ) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC .
3 OBJECTIVE :
4 To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC .
5 DATA SOURCES :
6 MEDLINE , EMBASE and Cochrane databases were searched to 2014 , supplemented by hand-searching ASCO/ESMO conference abstracts .
7 STUDY SELECTION :
8 Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1 ) chemotherapy with or without a biological agent or 2 ) different chemotherapy regimens with the same biological agent .
9 EGFR-I trials were restricted to KRAS exon 2 wild-type ( WT ) populations .
10 DATA EXTRACTION AND SYNTHESIS :
11 Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria .
12 The primary outcome was overall survival with secondary endpoints progression free survival ( PFS ) , overall response rate ( ORR ) and toxicity .
13 RESULTS :
14 EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 ( 95% CI 081-100 , p = 004 ) , but more so PFS with HR 0.77 ( 95% CI 069-086 , p<000001 ) .
15 No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy ( OS HR 0.97 ( 95% CI 087-109 ) and PFS HR 0.92 ( 95% CI 083-102 ) ) .
16 Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82% , p = 0.02 .
17 Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens ( PFS HR 082 , 95% CI 072-094 ) compared to capecitabine ( HR 109 ; 95% CI 091-130 ) and bolus 5FU ( HR 107 ; 95% CI 079-145 ) ; subgroup interaction was present with I2 = 72% , p = 0.03 .
18 The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens .
19 For AIs , OS benefit was observed with both oxaliplatin-based ( HR 083 ) and irinotecan-based ( HR 077 ) regimens without significant subgroup interactions .
20 Oxaliplatin+AI trials showed no subgroup interactions by type of FP , whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP ( I2 = 897% , p = 0002 ) .
21 CONCLUSION AND RELEVANCE : The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy , regardless of FP regimen , whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU .
22 No such differential activity was observed with the varying chemotherapy schedules when combined with AIs .



PMID: 26272063
(Cell)  
Terms: xenograft, tumor xenografts
Sent# Symbols Sentence Mnemonics
0 MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer .
1 PURPOSE :
2 ✓ PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer , limiting the sensitivity to targeted therapies .
3 Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors .
4 EXPERIMENTAL DESIGN :
5 In the present study , we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways .
6 Moreover , we investigated if TP53 mutation affects the response to this therapy .
7 RESULTS :
8 Μ Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN .
9   Although the on-treatment cell -cycle effects were not affected by the TP53 status , a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models .
10 Μ We further interrogated two independent panels of KRAS/BRAF - and PIK3CA/PTEN-altered cell line - and patient-derived tumor xenografts for the antitumor response toward this combination of agents .
11 A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models ( two out of five , 40% ) , but there was no such response across the eight mutant TP53 models ( 0% ) .
12 Interestingly , within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease , two patients with long-lasting responses ( 32 weeks ) had TP53 wild-type tumors .
13 CONCLUSIONS :
14 Our data support that , in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations , MEK blockade results in potent p21 induction , preventing apoptosis to occur .
15 In turn , mTORC1/2 inhibition blocks MEK inhibitor -mediated p21 induction , unleashing apoptosis .
16 Clin Cancer Res ; 21 ( 24 ) ; 5499-510 .
17 (c) 2015 AACR .



PMID: 26261259
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial : First - Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer .
1 PURPOSE :
2 We investigated choice and efficacy of subsequent treatment , with special focus on second - line therapy , in the FIRE-3 trial ( FOLFIRI plus cetuximab [arm A] or bevacizumab [arm B] ) for patients with KRAS wild-type metastatic colorectal cancer .
3 PATIENTS AND METHODS :
4 Start of subsequent - line ( second or third ) therapy was defined as use of an antitumor drug that was not part of the previous regimen .
5 We evaluated choice , duration , and efficacy of subsequent therapy and determined the impact of subsequent - line treatment on outcome of patients in FIRE-3 .
6 RESULTS :
7   Of 592 patients in the intent-to-treat population , 414 ( 699% ) received second - line and 256 ( 432% ) received third - line therapy .
8   In subsequent treatment lines , 47.1% of patients originally assigned to arm A received bevacizumab , and 52.2% originally assigned to arm B received either cetuximab or panitumumab .
9 Oxaliplatin was subsequently used in 55.9% ( arm A ) and 53.2% ( arm B ) of patients .
10 Second - line therapy was administered for a median duration of 5.0 versus 3.2 months ( P <001 ) in study arm A versus B .
11   Progression-free ( 65 v 47 months ; hazard ratio , 068 ; 95% CI , 054 to 085 ; P <001 ) and overall survival ( 163 v 132 months ; hazard ratio , 070 ; 95% CI , 055 to 088 ; P = 0021 ) from start of second - line therapy were longer in patients in arm A compared with arm B .
12 CONCLUSION :
13 Our data suggest that the sequence of drug application might be more important than exposure to single agents .
14   In patients with RAS wild-type tumors , first - line application of anti-epidermal growth factor receptor -directed therapy may represent a favorable condition for promoting effective subsequent therapy including antiangiogenic agents .



PMID: 26260912
(None)  
Terms: , transgenic lung cancer model, transgenic mice, mice, mouse model, mouse, transgenic mouse
Sent# Symbols Sentence Mnemonics
0 ✓ Colorectal cancer metastatic to the brain : analysis of prognostic factors and impact of KRAS mutations on presentation and outcome . GM-ASS-RO
1 Trichostatin A ( TSA ) is a histone deacetylase inhibitor and a potential therapeutic for various malignancies .
2 The in vivo effect of TSA , however , has not been investigated in a transgenic lung cancer model .
3 Previously , we generated transgenic mice with overexpression of Groucho-related-gene 1 ( Grg1 ) and these mice all developed mucinous lung adenocarcinoma .
4 Grg1 is a transcriptional co - repressor protein , the function of which is thought to depend on HDAC activity .
5 However , functions outside the nucleus have also been proposed .
6 We tested the supposition that Grg1 -induced tumorigenesis is HDAC -dependent by assaying the therapeutic effect of TSA in the Grg1 transgenic mouse model .
7 We found that TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice ( p <001 ) .
8 TSA did not affect overall Grg1 protein levels , but instead reduced ErbB1 and ErbB2 expression , which are upregulated by Grg1 in the absence of TSA .
9 We confirmed this effect in A549 cells .
10 Furthermore , lapatinib , an inhibitor of both ErbB1 and ErbB2 , effectively masked the effect of TSA on the inhibition of A549 cell proliferation and migration , suggesting TSA does work , atleast in part , by downregulating ErbB receptors .
11 Μ We additionally found that TSA reduced the expression of VEGF and VEGFR2 , but not basic FGF and FGFR1 .
12 Our findings indicate that TSA effectively inhibits Grg1 -induced lung tumorigenesis through the down-regulation of ErbB1 and ErbB2 , as well as reduced VEGF signaling .
13   This suggests TSA and other HDAC inhibitors could have therapeutic value in the treatment of lung cancers with Grg1 overexpression .



PMID: 26258891
(Patient)  
Terms: in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression .
1 Colorectal cancer ( CRC ) is the third most common cancer in the world , and second leading cause of cancer deaths in the US .
2 Although , anti-EGFR therapy is commonly prescribed for CRC , patients harboring mutations in KRAS or BRAF show poor treatment response , indicating an ardent demand for new therapeutic targets discovery .
3 SPINK1 ( serine peptidase inhibitor , Kazal type 1 ) overexpression has been identified in many cancers including the colon , lung , breast and prostate .
4 Our study demonstrates the functional significance of SPINK1 in CRC progression and metastases .
5 Stable knockdown of SPINK1 significantly decreases cell proliferation , invasion and soft agar colony formation in the colon adenocarcinoma WiDr cells .
6 Conversely , an increase in these oncogenic phenotypes was observed on stimulation with SPINK1-enriched conditioned media ( CM ) in multiple benign models such as murine colonic epithelial cell lines , MSIE and YAMC (SPINK3-negative) .
7 Mechanistically , SPINK1 promotes tumorigenic phenotype by activating phosphatidylinositol 3-kinase ( PI3K/AKT ) and LONGTOKEN signaling pathways , and the SPINK1-positive WiDr cells are sensitive to AKT and MEK inhibitors .
8 Importantly , SPINK1 silencing mediated upregulation of various Metallothionein isoforms , considered as tumor suppressors in CRC , confer sensitivity to doxorubicin , which strengthens the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients .
9 Furthermore , in vivo studies using chicken chorioallantoic membrane assay , murine xenograft studies and metastasis models further suggest a pivotal role of SPINK1 in CRC progression and metastasis .
10 Taken together , our study demonstrates an important role for the overexpressed SPINK1 in CRC disease progression , a phenomenon that needs careful evaluation towards effective therapeutic target development .



PMID: 26252300
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS Mutation Status Is Not a Predictor for Tumor Response and Survival in Rectal Cancer Patients Who Received Preoperative Radiotherapy With 5-Fluoropyrimidine Followed by Curative Surgery . GM-MRK-RO
1 We evaluated the tumor response and survival according to the KRAS oncogene status in locally advanced rectal cancer .
2 One hundred patients with locally advanced rectal cancer ( cT3-4N0-2M0 ) received preoperative radiation of 50.4 Gy in 28 fractions with 5-fluorouracil and total mesorectal excision .
3 Tumor DNA from each patient was obtained from pretreatment biopsy tissues .
4 Μ A rat Kirsten sarcoma viral oncogene homolog ( KRAS ) mutation was found in 26 ( 26% ) of the 100 patients .
5 Downstaging ( ypT0-2N0M0 ) rates after preoperative chemoradiotheray were not statistically different between the wild-type and mutant -type KRAS groups ( 308% versus 270% , P = 0715 , respectively ) .
6 After a median follow-up time of 34 months , there was no statistically significant difference in the 3-year relapse-free survival ( 822% versus 826% , P = 0512 ) and overall survival ( 947% versus 923% , P = 0249 ) rates between wild-type and mutant -type KRAS groups , respectively .
7 ✓ The KRAS mutation status does not influence the tumor response to the radiotherapy and survival in locally advanced rectal cancer patients who received preoperative chemoradiotherapy and curative surgery . GM-REG-RO



PMID: 26252055
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer .
1 BACKGROUND :
2 Quantification of Circulating Tumor Cells ( CTCs ) as a prognostic marker in metastatic colorectal cancer ( mCRC ) has already been validated and approved for routine use .
3 However , more than quantification , qualification or characterization of CTCs is gaining importance , since the genetic characterization of CTCs may reflect , in a real time fashion , genetic profile of the disease .
4 OBJECTIVE :
5 To characterize KRAS mutations ( codon 12 and 13 ) in CTCs from patients with mCRC and to compare with matched primary tumor .
6 Additionally , correlate these mutations with clinical and pathological features of patients .
7 METHODS :
8 Blood samples were collected from 26 patients with mCRC from the AC Camargo Cancer Center ( Sao Paulo-Brazil ) .
9 CTCs were isolated by ISET technology ( Isolation by Size of Epithelial Tumors ; Rarecells Diagnostics , France ) and mutations analyzes were performed by pyrosequencing ( QIAGEN ) .
10 RESULTS :
11 Μ KRAS mutation was detected in 7 of the 21 cases ( 33% ) of samples from CTCs .
12 Μ In matched primary tumors , 9 of the 24 cases ( 375% ) were found KRAS mutated .
13 Μ We observed that 5 of the 9 samples with KRAS mutation in their primary tumor had also KRAS mutation in CTCs , meaning a concordance of 71% of matched cases ( P = 0017 ) .
14 KRAS mutation neither on primary tumor nor in CTCs was associated with clinical-pathological parameters analyzed .
15 CONCLUSION :
16   Faced with a polyclonal disease like colorectal cancer , which is often treated with alternating and successive lines of chemotherapy , real time genetic characterization of CTCs , in a fast and feasible fashion , can provide important information to clinical management of metastatic patients .
17 Although our cohort was limited , it was possible to show a high grade of concordance between primary tumor and CTCs , which suggests that CTCs can be used as surrogate of primary tumors in clinical practice , when the knowledge of mutation profile is necessary and the primary tumor is not available .



PMID: 26251082
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Differentiation of high-risk stage I and II colon tumors based on evaluation of CAV1 gene expression .
1 BACKGROUND :
2 Several molecular markers are currently being investigated for their prognostic or predictive value in colorectal cancer .
3 One of the genes proposed , as a potential molecular marker in CRC is CAV1 .
4 METHODS :
5 The level of CAV1 expression was investigated in low-stage ( I and II TNM ) colon cancers using Real-Time PCR and immunohistochemistry .
6 RESULTS :
7 The level of CAV1 expression increased in tumors characterized by greater depths of invasiveness .
8 Μ The CAV1 expression level detected in tumors with a depth of invasion at stage T4 was significantly higher compared to that in T2 ( P = 001 ) and T3 ( P = 0003 ) lesions .
9 The length of a patient's survival depended on CAV1 expression level ; the 10-year survival rate for patients with elevated expression of CAV1 was approximately 59% compared with 91% for patients with reduced or unchanged expression of CAV1 ( P = 0007 ) .
10 ✓ The overall survival rate of patients with T3 + T4 lesions was significantly lower ( P = 0006 ) for patients with tumor displaying elevated CAV1 expression compared with patients with reduced or unchanged CAV1 expression . RO-ASS-GE
11 CONCLUSIONS :
12   Evaluation of CAV1 expression offers valuable prognostic information for patients with colorectal cancer , and could be used to select patients with stage I or II disease , who are at increased risk of unfavorable outcomes .



PMID: 26249337
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lower prevalence of Lynch syndrome in colorectal cancer patients in a Japanese hospital-based population .
1 PURPOSE :
2 The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution .
3 METHODS :
4 Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010 , immunohistochemistry analyses for mismatch repair proteins ( MLH1 , MSH2 , MSH6 , and PMS2 ) and microsatellite instability ( MSI ) testing for surgically resected , formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60 years of age were undertaken .
5 Μ Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary .
6 RESULTS :
7 Seven patients were identified as candidates for genetic testing by mismatch repair protein loss ( n = 7 ) or MSI-H ( n = 6 ) .
8 Methylation of MLH1 was detected in one case .
9 Three patients were diagnosed with Lynch syndrome , comprising 2.2 % of the total colorectal cancer patients younger than 60 years of age .
10 CONCLUSION :
11 The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations .



PMID: 26247523
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Can the histological type of colorectal cancer determine the carcinogenesis pathway ?
1 Colorectal cancer ( CRC ) is the most common type of gastrointestinal cancer and has three major pathways of carcinogenesis .
2 About 80% of genomic instability concerns chromosomal instability ( CIN ) ; the rest is connected with either microsatellite instability ( MSI ) or CpG island methylation .
3 Some MSI-related cancers are associated with Lynch syndrome , whereas others are caused by sporadic , acquired hypermethylation of the promoter of the MLH1 gene .
4 These tumours have distinctive clinical and histopathological features .
5 They may be poorly differentiated , accompanied by Crohn's-like lymphocytic infiltration and have a pushing margin .
6 MSI-high ( MSI-H ) phenotype has a slightly better prognosis .
7 We investigated 46 classic CRCs using histochemical and immunohistochemical methods ( p53 , MLH1 , MSH2 , MSH6 ) .
8 Based on the results , we divided patients into 4 groups .
9 Tumours from the first and second group ( 27 cases ) expressed the loss of MSI markers and presented a characteristic clinical and morphological image .
10 The other 19 cases lacked significant immunohistochemical or microscopic features .
11 These require further molecular studies to evaluate their carcinogenesis .
12 Discovery of MSI in colorectal tumours should be taken into account in the management of patients .
13 They do not respond to 5-fluorouracil or anti-EGFR therapy , especially the sporadic ones with BRAF mutations .



PMID: 26245900
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism .
1 Among hydroxycinnamic acids , caffeic , ferulic and p-coumaric acids have received considerable attention due to their biological activities .
2 However , studies related to the biological activities of o-coumaric acid ( OCA ) are limited .
3 In this regard , this study was designed to determine the chemopreventive potential of OCA in human breast cancer cells (MCF-7) .
4 The EC50 value of OCA was found to be 4.95 mM and was used throughout the study .
5 Caspase-3 protein and mRNA levels increased by 59% and 72% .
6 Similarly , protein and mRNA levels of Bax were increased by 115% and 152% .
7 However , OCA treatment caused 48% and 35% decreases in Bcl-2 protein and mRNA levels .
8 Cyclin D1 and cyclin dependent kinase -2 protein and mRNA levels decreased significantly .
9 Moreover , p53 protein and mRNA levels increased by 178% and 245% , respectively .
10 In addition to p53 , PTEN protein and mRNA levels were induced .
11 Although , CYP1A1 , CYP1A2 and CY2E1 mRNA levels increased , CYP3A4 and CYP2C9 mRNA levels decreased in response to OCA treatment .
12 These results suggest that OCA demonstrates anticarcinogenic activity on MCF-7 cells by activating multiple pathways .
13 However , it also has high carcinogen activating and drug interaction potential .
14 Therefore , serious precautions must be taken before using OCA .



PMID: 26245851
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Platelet-Derived Growth Factor Receptor -alpha Regulates Proliferation of Gastrointestinal Stromal Tumor Cells With Mutations in KIT by Stabilizing ETV1 .
1 BACKGROUND & ; AIMS : The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma ( HCC ) , but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation ( H3K27me3 and H3K4me3 ) in HCC remains poorly understood .
2 Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients .
3 METHODS :
4 We used chromatin immunoprecipitation ( ChIP ) assays and a ChIP-on-chip screen to analyse HCC .
5 RESULTS :
6 We found that the EZH2 occupancy coincides with the H3K27me3 at promoters and directly silences the transcription of target genes in HCC .
7 The H3K27me3-related gene network of EZH2 contains well-established genes , such as CDKN2A , as well as previously unappreciated genes , including FOXO3 , E2F1 , and NOTCH2 , among others .
8 We further observed independently increasing profiles of H3K27me3 and H3K4me3 at the promoters of certain target genes in HCC specimens .
9 Importantly , Kaplan-Meier analysis reveals that 3-year overall and tumour-free survival rates are dramatically reduced in patients that simultaneously express EZH2 and menin , compared to rates in the EZH2 or menin under expressing patients .
10 Furthermore , an inhibitor of H3K27me3 alone , or in combination with an H3K4me3 inhibitor , effectively blocked the aggressive phenotype of HCC cells .
11 CONCLUSIONS :
12   Our results indicate that a combined analysis of both H3K27me3 and H3K4me3 may serve as powerful diagnostic biomarkers of HCC , and targeting both might benefit anti-HCC therapy .



PMID: 26243863
(Patient)  
Terms: PDX, xenograft, clinical trial
Sent# Symbols Sentence Mnemonics
0 HER2 activating mutations are targets for colorectal cancer treatment .
1 UNLABELLED :
2 Μ The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer .
3 Introduction of the HER2 mutations S310F , L755S , V777L , V842I , and L866M into colon epithelial cells increased signaling pathways and anchorage -independent cell growth , indicating that they are activating mutations .
4 Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation .
5 HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib .
6 Μ HER2 gene sequencing of 48 cetuximab-resistant , quadruple ( KRAS , NRAS , BRAF , and PIK3CA ) wild-type ( WT ) colorectal cancer patient-derived xenografts ( PDX ) identified 4 PDXs with HER2 mutations .
7 HER2-targeted therapies were tested on two PDXs .
8   Treatment with a single HER2-targeted drug ( trastuzumab , neratinib , or lapatinib ) delayed tumor growth , but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs .
9 SIGNIFICANCE :
10 ✓ HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines , and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy .
11 These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer .



PMID: 26237292
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular biomarkers in colorectal carcinoma .
1 Colorectal cancer is a tumor with increasing incidence which represents one of the first leading causes of death worldwide .
2 Gene alterations described for colorectal cancer include genome instability ( microsatellite and chromosomal instability ) , CpG islands methylator phenotype , microRNA , histone modification , protein biomarkers , gene mutations ( RAS , BRAF , PI3K , TP53 , PTEN ) and polymorphisms ( APC , CTNNB1 , DCC ) .
3 In this article , biomarkers with prognostic value commonly found in colorectal cancer will be reviewed .



PMID: 26235176
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 How can we identify new biomarkers for patients with for lung metastasectomy in colorectal cancer .
1 Impact of NRAS Mutations on the Diagnosis of Follicular Neoplasm of the Thyroid .



PMID: 26231173
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Durable recurrence-free survival after pneumonectomy for late lung metastasis from rectal cancer : case report with genetic and epigenetic analyses .
1 BACKGROUND :
2 Treatment of pulmonary recurrence from colorectal cancer involving the main bronchus usually entails palliation using interventional bronchoscopy , because the prognosis is generally very poor .
3 Surgical experience has clarified that in this setting pneumonectomy should only be performed in carefully selected patients showing favorable prognostic profiles ( defined by low carcinoembryonic antigen serum levels pre-thoracotomy ) , solitary and completely resectable pulmonary metastasis , and long disease-free intervals .
4 In the few long-term survivors after pneumonectomy for late-recurrent colorectal cancer , the disease has a relatively indolent metastatic course and genetic and epigenetic profiling may provide further insight regarding tumor evolution .
5 CASE PRESENTATION :
6 We describe a rare case of late hilar-endobronchial and lymph nodal recurrence of rectal cancer , sequential to hepatic metastasectomy , that we successfully treated with pneumonectomy and chemotherapy ( leucovorin , 5-fluorouracil and oxaliplatin regimen ) ; the patient achieved 7-year relapse-free survival after lung metastasectomy and 24-year overall survival after primary rectal cancer resection .
7 To our knowledge , this is the longest survival reported after sequential liver resection and pneumonectomy for recurrent colorectal cancer .
8 In our case the primary rectal cancer and its recurrences showed identical immunohistochemical patterns .
9 Μ The primary rectal cancer and the matched metastases ( hepatic , pulmonary and lymph nodal ) demonstrated no KRAS , NRAS , BRAF and PIK3CA mutations , a microsatellite stable phenotype , and no tumor protein p53 alterations or recurrent copy number alterations on chromosome 8 .
10 High genetic concordances between the paired primary tumor and metastases suggest that the key tumor biological traits remained relatively conserved in the three metastatic sites .
11 Minor differences in gene specific hypermethylation were observed between the primary tumor and lung and nodal metastases .
12 These differences suggest that epigenetic mechanisms may be causally involved in the microenvironmental regulation of cancer metastasis .
13 CONCLUSION :
14   The exceptionally long survival of the patient in our case study involving favorable clinical features was related to an excellent response to surgery and adjuvant chemotherapy ; however , genetic or epigenetic factors that remain unidentified cannot be excluded as contributory factors .
15 Our findings support the concept of a common clonal origin of the primary cancer and synchronous and late metastases , and suggest that aberrant DNA methylation may regulate tumor dormancy mechanisms .



PMID: 26227479
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Small - cell lung cancer with a rare epidermal growth factor receptor gene mutation showing "wax-and-wane" transformation .
1 The exocrine pancreas can undergo acinar-to-ductal metaplasia ( ADM ) , as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma ( PDAC ) can arise .
2 The NAD(+)- dependent protein deacetylase Sirtuin-1 ( Sirt1 ) has been implicated in carcinogenesis with dual roles depending on its subcellular localization .
3 In this study , we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis , i.e . ADM models and established PDAC .
4 In addition , we analyzed the expression of KIAA1967 , a key mediator of Sirt1 function , along with potential Sirt1 downstream targets .
5 Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells .
6 In ADM , Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling .
7 Experiments where during ADM , we enforced repression of Sirt1 shuttling , inhibition of Sirt1 activity or modulation of its expression , all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM .
8 Our results further underscore that important transcriptional regulators of acinar differentiation , that is , Pancreatic transcription factor -1a and beta-catenin can be deacetylated by Sirt1 .
9 Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors .
10 ✓ KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6 .
11 In PDAC , acetylation of beta-catenin is not affected , unlike p53 , a well-characterized Sirt1 -regulated protein in tumor cells .
12 Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis .



PMID: 26226847
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers .
1 Activating mutations in downstream genes of the epidermal growth factor receptor ( EGFR ) pathway may cause anti-EGFR resistance in patients with colorectal cancers .
2 Μ We present performance characteristics of a next-generation sequencing assay designed to detect such mutations .
3 Μ In this retrospective quality assessment study , we analyzed mutation detected in the KRAS , NRAS , BRAF , and PIK3CA genes by a clinically validated next-generation sequencing assay in 310 colorectal cancer specimens .
4 Μ Tumor cellularity and mutant allele frequency were analyzed to identify tumor heterogeneity and mutant allele -specific imbalance .
5 Μ Next-generation sequencing showed precise measurement of mutant allele frequencies and detected 23% of mutations with 2-20% mutant allele frequencies .
6 Μ Of the KRAS mutations detected , 17% were outside of codons 12 and 13 .
7 Among PIK3CA mutations , 48% were outside of codons 542 , 545 , and 1047 .
8 The percentage of tumors with predicted resistance to anti-EGFR therapy increased from 40% when testing for only mutations in KRAS exon 2 to 47% when testing for KRAS exons 2-4 , 48% when testing for KRAS and NRAS exons 2-4 , 58% when including BRAF codon 600 mutations , and 59% when adding PIK3CA exon 20 mutations .
9 Right-sided colorectal cancers carried a higher risk of predicted anti-EGFR resistance .
10 Μ A concomitant KRAS mutation was detected in 51% of PIK3CA , 23% of NRAS , and 33% of kinase -impaired BRAF-mutated tumors .
11 Lower than expected mutant allele frequency indicated tumor heterogeneity , while higher than expected mutant allele frequency indicated mutant allele -specific imbalance .
12 Μ Two paired neuroendocrine carcinomas and adjacent adenomas showed identical KRAS mutations , but only PIK3CA mutations in neuroendocrine carcinomas .
13 Next-generation sequencing is a robust tool for mutation detection in clinical laboratories .
14 It demonstrates high analytic sensitivity and broad reportable range , and it provides simultaneous detection of concomitant mutations and a quantitative measurement of mutant allele frequencies to predict tumor heterogeneity and mutant allele -specific imbalance .



PMID: 26224873
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tankyrase Inhibition Blocks Wnt/beta-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer .
1   Molecular Targeted Drugs and Biomarkers in NSCLC , the Evolving Role of Individualized Therapy .



PMID: 28162292
(None)  
Terms: in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 The Development Of RRx-001 , A Novel Nitric-Oxide-Mediated Epigenetically Active Anticancer Agent .
1 Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors ( BRAFi ) , most tumors become resistant .
2 Here , we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens .
3 Sox10/MITF expression correlated with and contributed to RNF125 transcription .
4 Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases ( RTKs ) , including EGFR .
5 Μ Notably , RNF125 altered RTK expression through JAK1 , which we identified as an RNF125 substrate .
6 RNF125 bound to and ubiquitinated JAK1 , prompting its degradation and suppressing RTK expression .
7 Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression , as shown in culture and in in vivo xenografts .
8 Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression .



PMID: 26222778
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 An Integrative Approach for Mapping Differentially Expressed Genes and Network Components Using Novel Parameters to Elucidate Key Regulatory Genes in Colorectal Cancer .
1 For examining the intricate biological processes concerned with colorectal cancer ( CRC ) , a systems biology approach integrating several biological components and other influencing factors is essential to understand .
2 We performed a comprehensive system level analysis for CRC which assisted in unravelling crucial network components and many regulatory elements through a coordinated view .
3 Using this integrative approach , the perceptive of complexity hidden in a biological phenomenon is extensively simplified .
4 The microarray analyses facilitated differential expression of 631 significant genes employed in the progression of disease and supplied interesting associated up and down regulated genes like jun , fos and mapk1 .
5 The transcriptional regulation of these genes was deliberated widely by examining transcription factors such as hnf4 , nr2f1 , znf219 and dr1 which directly influence the expression .
6 Further , interactions of these genes/proteins were evaluated and crucial network motifs were detected to associate with the pathophysiology of CRC .
7 The available standard statistical parameters such as z-score , p-value and significance profile were explored for the identification of key signatures from CRC pathway whereas a few novel parameters representing over-represented structures were also designed in the study .
8 The applied approach revealed 5 key genes i.e.kras , araf , pik3r5 , ralgds and akt3 via our novel designed parameters illustrating high statistical significance .
9 These novel parameters can assist in scrutinizing candidate markers for diseases having known biological pathways .
10 Further , investigating and targeting these proposed genes for experimental validations , instead being spellbound by the complicated pathway will certainly endow valuable insight in a well-timed systematic understanding of CRC .



PMID: 26222184
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Focus on 16p13.3 Locus in Colon Cancer .
1 Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma : IHC score algorithm for FISH .



PMID: 26220423
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of KRAS , NRAS and BRAF by mass spectrometry - a sensitive , reliable , fast and cost-effective technique .
1 BACKGROUND :
2 Μ According to current clinical guidelines mutational analysis for KRAS and NRAS is recommended prior to EGFR -directed therapy of colorectal cancer ( CRC ) in the metastatic setting .
3 Therefore , reliable , fast , sensitive and cost-effective methods for routine tissue based molecular diagnostics are required that allow the assessment of the CRC mutational status in a high throughput fashion .
4 METHODS :
5 We have developed a custom designed assay for routine mass-spectrometric ( MS ) ( MassARRAY , Agena Bioscience ) analysis to test the presence/absence of 18 KRAS , 14 NRAS and 4 BRAF mutations .
6 We have applied this assay to 93 samples from patients with CRC and have compared the results with Sanger sequencing and a chip hybridization assay ( KRAS LCD-array Kit , Chipron ) .
7 In cases with discordant results , next-generation sequencing ( NGS ) was performed .
8 RESULTS :
9 Μ MS detected a KRAS mutation in 46/93 ( 49% ) , a NRAS mutation in 2/93 ( 2% ) and a BRAF mutation in 1/93 ( 1% ) of the cases .
10 MS results were in agreement with results obtained by combination of the two other methods in 92 ( 99% ) of 93 cases .
11 Μ In 1/93 ( 1% ) of the cases a G12V mutation has been detected by Sanger sequencing and MS , but not by the chip assay .
12 In this case , NGS has confirmed the G12V mutation in KRAS .
13 CONCLUSIONS :
14 Μ Mutational analysis by MS is a reliable method for routine diagnostic use , which can be easily extended for testing of additional mutations .



PMID: 26220150
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer .
1 RAS family proteins ( including KRAS and NRAS ) play important roles in the epidermal growth factor receptor ( EGFR ) signaling pathway .
2 Mutations in RAS genes ( occurring at loci in exons 2 , 3 , and 4 ) often result in constitutive activation of RAS proteins and persistent downstream signaling .
3   Mutations in KRAS exon 2 ( codon 12/13 ) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer ( mCRC ) , and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies .
4 Μ However , a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes .
5   Μ Recent studies have demonstrated that evaluation of an extended panel of RAS mutations-including mutations in KRAS exon 2 , 3 , and 4 and NRAS exons 2 , 3 , and 4-can better define the patient population that is unlikely to benefit from anti-EGFR therapy , with concomitant improvements in outcomes in the more highly selected RAS wild-type group .
6   This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy .
7   In the near future , it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment .



PMID: 26218848
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular markers and pathway analysis of colorectal carcinoma in the Middle East .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is one of the most common cancers in the world .
3 A newly proposed integrated pathway comprising traditional , alternate , and serrated pathways by genetic and epigenetic factors was defined recently and hypothesized to play a role in the pathogenesis of CRC ; however , to the authors' knowledge , there is a paucity of information regarding these proposed molecular pathways in different ethnic groups .
4 METHODS :
5 Molecular characterization of 770 CRC specimens was performed for microsatellite instability , BRAF , and KRAS by polymerase chain reaction and 500 cases for CpG island methylator phenotype ( CIMP ) high phenotype by MethyLight technology .
6 Tumors were assigned to different molecular pathways and examined for clinicopathological correlation and survival analysis .
7 RESULTS :
8 The traditional pathway constituted 33.4% of CRC cases , the alternate pathway comprised 11.6% , and the serrated molecular pathway accounted for only 0.8% of Middle Eastern CRC cases .
9 Approximately 54.2% of CRC cases did not qualify to fit into any pathway and thus were designated as an unassigned group .
10 Molecular pathways were found to be significantly associated with tumor site and grade .
11 A subset of cases with an uncategorized pathway demonstrated a significant survival difference ( P = 0079 ) .
12 CONCLUSIONS :
13 Μ The serrated pathway was found to account for a very low percentage of the CRC patient cohort in the current study .
14 The unassigned group accounted for the majority of Middle Eastern CRC cases , and therefore methods of CRC pathway analysis might not be applicable to this ethnic group .
15 The current study demonstrates the need to unravel the molecular genetic basis of this disease to further subcategorize these CRC cases .
16 It also identifies a need for further studies on different populations for a better understanding of their exact role and incidence .



PMID: 26216840
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer .
1 Sporadic colorectal cancer ( CRC ) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient's genetic background .
2 Consolidating the knowledge of genetic and epigenetic events that occur with initiation , progression , and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging , and inform treatment approaches .
3 Μ Modern next-generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations and has classified new alterations .
4 Each patient's CRC is genetically unique , propelled by 2-8 driver gene alterations that have accumulated within the CRC since initiation .
5 Μ Commonly observed alterations across sporadic CRCs have allowed classification into a (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability and POLE mutations in approximately 15% , containing multiple frameshifted genes and BRAF (V600E) ; (2) nonhypermutated group with multiple somatic copy number alterations and aneuploidy in approximately 85% , containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes , such as APC and TP53 ; (3) CpG island methylator phenotype CRCs in approximately 20% that overlap greatly with microsatellite instability CRCs and some nonhypermutated CRCs ; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in approximately 60% that associates with metastatic behavior in both hypermutated and nonhypermutated groups .
6   Components from these classifications are now used as diagnostic , prognostic , and treatment biomarkers .
7 Additional common biomarkers may come from genome -wide association studies and microRNAs among other sources , as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care .



PMID: 26210240
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS Status as an Independent Prognostic Factor for Survival after Yttrium-90 Radioembolization Therapy for Unresectable Colorectal Cancer Liver Metastases . GE-MRK-RO
1 PURPOSE :
2 To evaluate Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation status as a prognostic factor for survival after yttrium-90 ( ( 90 ) Y ) radioembolization for colorectal cancer ( CRC ) liver metastases .
3 MATERIALS AND METHODS :
4 Consecutive patients with unresectable CRC liver metastases and documented KRAS mutation status who were treated with ( 90 ) Y radioembolization during the period 2007-2014 were investigated .
5 Patient demographics , disease characteristics , therapy regimens , and overall survival ( OS ) from first ( 90 ) Y radioembolization were compared between patients with KRAS wild-type ( wt ) and mutant status .
6 Kaplan-Meier estimation and Cox regression were used for survival analysis and to assess independent prognostic factors for OS .
7 RESULTS :
8 Μ Of 186 patients , 104 underwent KRAS mutation analysis before ( 90 ) Y radioembolization , with 45 ( 433% ) identified as mutant .
9 The wt and mutant groups were similar in demographics , liver status , overall performance status , and tumor characteristics ( all P >05 ) .
10 Mean time from liver metastasis to ( 90 ) Y radioembolization was greater in patients with KRAS wt status ( P = 033 ) .
11   A greater percentage of wt patients received anti-epidermal growth factor receptor therapies before ( 90 ) Y radioembolization ( 661% versus 89% ; P <001 ) .
12 Median OS from first ( 90 ) Y radioembolization was significantly greater in KRAS wt patients ( 95 mo versus 48 mo ; P = 041 ) .
13   Univariate analysis identified Child-Pugh class , carcinoembryonic antigen ( CEA ) , chemotherapy after ( 90 ) Y radioembolization , KRAS status , and treatment-induced toxicity as prognostic factors for OS .
14   Multivariate Cox regression analysis demonstrated Child-Pugh class , CEA , and KRAS status to be independent prognostic factors for OS , even when correcting for the effect of chemotherapy after ( 90 ) Y radioembolization .
15 CONCLUSIONS :
16 ✓ Patients with CRC and KRAS wt may derive greater survival benefit from ( 90 ) Y radioembolization therapy than patients with KRAS mutant . RO-ASS-GM



PMID: 26208524
(Cell)  
Terms: In vitro, In vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 BGB-283 , a Novel RAF Kinase and EGFR Inhibitor , Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers .
1 Oncogenic BRAF , which drives cell transformation and proliferation , has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers .
2 Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF (V600E) metastatic melanoma , their clinical efficacy in BRAF (V600E) colorectal cancer is far less impressive .
3 Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors .
4 Here , we report characterization of a dual RAF kinase/EGFR inhibitor , BGB-283 , which is currently under clinical investigation .
5 In vitro , BGB-283 potently inhibits BRAF (V600E)- activated ERK phosphorylation and cell proliferation .
6 It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF (V600E) and EGFR mutation/amplification .
7 In BRAF (V600E) colorectal cancer cell lines , BGB-283 effectively inhibits the reactivation of EGFR and EGFR -mediated cell proliferation .
8 Μ In vivo , BGB-283 treatment leads to dose -dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line -derived and primary human colorectal tumor xenografts bearing BRAF (V600E) mutation .
9 These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF (V600E) mutation .



PMID: 26207614
(None)  
Terms: Phase I/II trial
Sent# Symbols Sentence Mnemonics
0 Phase I/II trial of capecitabine , oxaliplatin , and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer .
1 Detection of B7-H4 and p53 in pancreatic cancer : potential role as a cytological diagnostic adjunct .



PMID: 26206338
(None)  
Terms: In Vivo, mouse models, mouse, mice, genetically engineered mouse
Sent# Symbols Sentence Mnemonics
0 Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer .
1 The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy .
2 Nevertheless , this approach has been limited , in part , due to the lack of predictive and informative preclinical studies .
3 Herein , we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial .
4 Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten ; Apc and Kras ; and Apc , Pten and Kras .
5 MEK inhibition was effective in the combinatorial Apc and Kras setting , but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants .
6 Furthermore , we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice , combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice .
7   This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic .



PMID: 26206335
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer .
1 BACKGROUND :
2 Cyclin-dependent kinase inhibitor 2A ( CDKN2A ) is the major high-risk susceptibility gene for melanoma .
3 OBJECTIVE :
4 We sought to evaluate the effect of CDKN2A mutations in Spanish patients with a high risk of developing melanoma and the association with clinical and family history features .
5 METHODS :
6 A cross-sectional study design was used to analyze the CDKN2A impact in 702 Spanish patients with a high risk of developing melanoma .
7 RESULTS :
8 The CDKN2A mutation prevalence was 8.5% in patients with sporadic multiple primary melanoma and 14.1% in familial melanoma .
9 Number of cases in the family , number of primary melanomas , and age of onset were associated with the presence of CDKN2A mutation .
10 Having a CDKN2A mutation in the family increased the prevalence of other cancers ( prevalence ratio [PR] 2.99 , P = .012 ) and prevalence of pancreatic ( PR 297 , P = 006 ) , lung ( PR 304 , P<001 ) , and breast ( PR 219 , P = 018 ) cancers but not nephrourologic or colon cancer .
11 LIMITATIONS :
12 Smoking status was not assessed in the individuals with lung cancer .
13 CONCLUSIONS :
14 Melanoma-prone families with mutations in CDKN2A have an increased prevalence of a broad spectrum of cancers including lung , pancreatic , and breast cancer .
15 This information should be included in genetic counseling and cancer prevention programs for CDKN2A mutation carriers .



PMID: 26206254
(Patient)  
Terms: Meta-analysis, Phase II
Sent# Symbols Sentence Mnemonics
0 Meta-analysis of KRAS mutations and survival after resection of colorectal liver metastases .
1 INTRODUCTION :
2 Vorinostat is a small molecule inhibitor of class I and II histone deacetylases with preclinical activity in melanoma .
3 METHODS :
4 We evaluated 32 patients with advanced primary cutaneous or ocular melanoma in a multi-institutional setting ( PMH Phase II Consortium ) with continuous daily oral vorinostat 400 mg .
5 The primary endpoint was response rate by RECIST , with time to progression as a secondary endpoint .
6 The study was designed to distinguish a response rate of 20 % from a RR of 5 % and to distinguish a 2 month median progression-free survival ( PFS ) , from one of 3.1 months .
7 The study proceeded to stage 2 following 2 of 16 responses . .
8 We also assessed VEGF , FGF levels , P52 polymorphisms and chromatin-associated proteins as potential biomarkers .
9 RESULTS :
10 Therapy was associated with significant side effects , including fatigue , nausea , lymphopenia , and hyperglycemia .
11 Eleven patients experienced atleast one grade 3 or higher adverse event .
12 There were two confirmed PRs in patients with cutaneous melanoma .
13 Sixteen patients had stable disease and 14 patients had progressive disease for best response .
14 In addition , two patients with cutaneous melanoma scored as stable disease had early unconfirmed partial responses with subsequent progression .
15 Patients with stable disease or partial response ( n = 18 ) had a median progression free survival of 5 months. ( range 2-12 months ) .
16 CONCLUSIONS :
17 Μ Vorinostat demonstrated some early responses and a high proportion of patients with stable disease , but did not meet its primary endpoint of response .
18 Different schedules of this agent with BRAF mutation status and markers of histone acetylation could be explored in melanoma .



PMID: 26201544
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Screening for Lynch syndrome and referral to clinical genetics by selective mismatch repair protein immunohistochemistry testing : an audit and cost analysis .
1 Lynch syndrome ( LS ) accounts for around 3% of colorectal cancers ( CRCs ) and is caused by germline mutations in mismatch repair ( MMR ) genes .
2 Recently , screening strategies to identify patients with LS have become popular .
3 ✓ Μ We audited CRCs screened with MMR immunohistochemistry ( IHC ) in 2013. 209 tumours had MMR IHC performed at a cost of pound12 540. 47/209 ( 21% ) cases showed IHC loss of expression in atleast one MMR protein. 28/44 cases with loss of MLH1 had additional BRAF V600E testing , at a cost of pound5040 . RO-ASS-GM
4 MMR IHC reduced the number of potential clinical genetics referrals from 209 to 47 .
5 BRAF mutation testing , performed in a subset of cases with MLH1 loss , further reduced this to 21 .
6 At a cost of pound1340 per referral , this model of LS screening for clinical genetics referral had significant potential savings ( pound234 340 ) and can be easily implemented in parallel with MMR IHC done for prognostication in CRCs .



PMID: 26197754
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Efficacy and safety of motesanib , an oral inhibitor of VEGF , PDGF , and Kit receptors , in patients with imatinib-resistant gastrointestinal stromal tumors .
1 The patient was a 66-year-old man with progressive rectal cancer and portal vein tumor thrombosis near the porta hepatis .
2 A subileus further complicated the situation .
3 Therefore , an abdominoperineal resection was performed .
4 As the KRAS gene was the wild-type gene , we administered panitumumab monotherapy every 2 weeks after the operation .
5 Two months after the operation , the tumor marker levels were normal and the tumor size was reduced .
6 Hence , oral capecitabine , with 1-week administration followed by 1-week of rest , was added to the therapy .
7 In the 12 months after the operation , panitumumab was stopped once , and treatment with capecitabine alone was continued in the same schedule .
8 As of 26 months , the disease showed a partial response using capecitabine alone .
9 We report our experience of a case of rectal cancer with portal vein tumor thrombosis that was successfully treated with panitumumab .



PMID: 26196590
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Moving from histological subtyping to molecular characterization : new treatment opportunities in advanced non-small - cell lung cancer .
1 SLC22A18 , solute carrier family 22 , member 18 , has been proposed to function as a tumor suppressor based on its chromosomal location at 11p15.5 , mutations and aberrant splicing in several types of cancer and down-regulation in glioblastoma .
2 In this study , we sought to demonstrate the significance of SLC22A18 as a tumor suppressor in colorectal cancer ( CRC ) and provide mechanistic bases for its function .
3 Μ We first showed that the expression of SLC22A18 is significantly down-regulated in tumor tissues using matched normal-tumor samples from CRC patients .
4 This finding was also supported by publically accessible data from The Cancer Genome Atlas ( TCGA ) .
5 Functionally , SLC22A18 inhibits colony formation and induces of G2/M arrest consistent with being a tumor suppressor .
6 Interestingly , suppression of KRAS by RNA interference promotes SLC22A18 expression , and expression of SLC22A18 in turn inhibits KRAS (G12D)- mediated anchorage independent growth of NIH3T3 cells indicating a mutual negative interaction .
7 Μ Finally , we evaluated diagnostic and prognostic values of SLC22A18 using clinical and gene expression data from TCGA which revealed a significantly worse long-term prognosis for patients with low level SLC22A18 expression .
8 In sum , we established SLC22A18 as a tumor suppressor in colon epithelial cells and propose that SLC22A18 is potentially a marker of diagnostic and prognostic values .



PMID: 26190239
(Patient)  
Terms: phase II
Sent# Symbols Sentence Mnemonics
0 Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer : a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme .
1 BACKGROUND :
2 Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors ( GIST ) .
3 The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression .
4 However , imatinib can be associated with diverse adverse events , which has limited its use .
5 We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST .
6 CASE PRESENTATION : A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant .
7 An abdominal CT scan revealed a 20 x 19 cm intraabdominal mass with tumor invasion into the peritoneum .
8 Μ Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT .
9 The patient was diagnosed with unresectable GIST .
10 Imatinib 400 mg/day was started .
11   The patient tolerated the first eight weeks of treatment .
12 However , about three months later , the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash .
13 The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care .
14 However , the skin lesions recurred whenever the patient received imatinib over 100 mg/day .
15 Therefore , imatinib 100 mg/day was maintained .
16 Despite the low dose imatinib , follow up CT showed a marked partial response without grade 3 or 4 toxicities .
17 CONCLUSION :
18   The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses .
19   Individualized treatment is needed for such patients , and we may also try sunitinib as a alternative drug .



PMID: 26189770
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping .
1 In metastatic colorectal cancer , KRAS and NRAS genotyping is mandatory before prescription of panitumumab or cetuximab .
2 In order to perform such molecular tests , the French National Cancer Institute has set up a nationwide network of molecular centers .
3 We report here the percentage of these mutations according to a prospective nonselected cohort of incident metastatic colorectal carcinoma patients .
4 A total of 6,803 patients were tested between July 1 , 2013 , and December 31 , 2013 .
5 Μ Overall , 49.06% of patients harbored a mutation in either KRAS or NRAS .
6 Mutations of NRAS exons 3 and 4 were very rare .
7 Μ No NRAS exon 3 at c.59 or exon 4 at c.117 mutations were retrieved , and only 1 NRAS exon 4 at c.146 mutation was detected .
8 This present cohort is likely to represent most of the incident cases of metastatic colorectal adenocarcinomas arising in France over 6 months and is to our knowledge the largest population set genotyped for these genes in this condition .
9 This is a unique opportunity to observe the frequency of RAS mutations regardless of most inclusion bias .



PMID: 26189563
(Cell)  
Terms: in vitro, in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 Comparison of high-resolution melting analysis , Sanger sequencing and ARMS for KRAS mutation detection in metastatic colorectal cancer .
1 The stress-upregulated catecholamines -activated beta1 - and beta2-adrenergic receptors ( beta1/2-ARs ) have been shown to accelerate the progression of cancers such as colorectal cancer ( CRC ) .
2 We investigated the underlying mechanism of the inhibition of beta1/2-ARs signaling for the treatment of CRC and elucidated the significance of beta2-AR expression in CRC in vitro and in clinical samples .
3 The impacts of beta1/2-AR antagonists in CRC in vitro and CRC-xenograft in vivo were examined .
4 We found that repression of beta2-AR but not beta1-AR signaling selectively suppressed cell viability , induced G1-phase cell cycle arrest , caused both intrinsic and extrinsic pathways-mediated apoptosis of specific CRC cells and inhibited CRC-xenograft growth in vivo .
5 Moreover , the expression of beta2-AR was not consistent with the progression of CRC in vitro or in clinical samples .
6 Our data evidence that the expression profiles , signaling , and blockage of beta2-AR have a unique pattern in CRC comparing to other cancers .
7 beta2-AR antagonism selectively suppresses the growth of CRC accompanying active beta2-AR signaling , which potentially carries wild-type KRAS , in vitro and in vivo via the inhibition of beta2-AR transactivated EFGR-Akt/ERK1/2 signaling pathway .
8 Thus , beta2-AR blockage might be a potential therapeutic strategy for combating the progressions of beta2-AR -dependent CRC .



PMID: 26189482
(Cell)  
Terms: in-vitro
Sent# Symbols Sentence Mnemonics
0 The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation .
1 Human cutaneous melanoma is an aggressive and chemotherapy-resistant type of cancer .
2 AM251 is a cannabinoid type 1 ( CB1 ) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells .
3 The current study aimed to characterize the in-vitro antimelanoma activity of AM251 .
4 The BRAF V600E mutant melanoma cell line , A375 , was used as an in-vitro model system .
5 Characterization tools included a cell viability assay , nuclear morphology assessment , gene expression , western blot , flow cytometry with Annexin V-FITC/7-AAD double staining , cell cycle analyses , and measurements of changes in intracellular cAMP and calcium concentrations .
6 AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability .
7 AM251 , at a concentration that approximates the IC50 , downregulated genes encoding antiapoptotic proteins ( BCL2 and survivin ) and increased transcription levels of proapoptotic BAX , induced alteration of Annexin V reactivity , DNA fragmentation , chromatin condensation in the cell nuclei , and G2/M phase arrest .
8 AM251 also induced a 40% increase in the basal cAMP levels , but it did not affect intracellular calcium concentrations .
9 The involvement of GPR55 , TRPA1 , and COX-2 in the AM251 mechanism of action was excluded .
10 The combination of AM251 with celecoxib produced a synergistic antitumor activity , although the mechanism underlying this effect remains to be elucidated .
11 This study provides the first evidence of a proapoptotic effect and G2/M cell cycle arrest of AM251 on A375 cells .
12 This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma .



PMID: 26187617
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Analysis of Molecular Markers by Anatomic Tumor Site in Stage III Colon Carcinomas from Adjuvant Chemotherapy Trial NCCTG N0147 ( Alliance ) .
1 PURPOSE :
2 To determine the frequency and prognostic association of molecular markers by anatomic tumor site in patients with stage III colon carcinomas .
3 EXPERIMENTAL DESIGN :
4 Μ In a randomized trial of adjuvant FOLFOX +/- cetuximab , BRAF (V600E) and KRAS ( exon 2 ) mutations and DNA mismatch repair ( MMR ) proteins were analyzed in tumors ( N = 3,018 ) in relationship to tumor location , including subsite .
5 Cox models were used to assess clinical outcome , including overall survival ( OS ) .
6 RESULTS :
7 KRAS codon 12 mutations were most frequent at the splenic flexure and cecum ; codon 13 mutations were evenly distributed .
8 BRAF mutation frequency sharply increased from transverse colon to cecum in parallel with deficient (d) MMR .
9 Nonmutated BRAF and KRAS tumors progressively decreased from sigmoid to transverse ( all P <00001 ) .
10 Significantly , poorer OS was found for mutant KRAS in distal [HR , 1.98 ; 95% confidence interval ( CI ) , 1.49-2.63 ; P <0.0001] versus proximal ( 125 ; 95% CI , 097-160 ; P = 0079 ) cancers .
11 BRAF status and outcome were not significantly associated with tumor site .
12 Proximal versus distal dMMR tumors had significantly better outcome .
13 An interaction test was significant for tumor site by KRAS ( P ( adjusted ) = 0.043 ) and MMR ( P ( adjusted ) = 0.010 ) for OS .
14   Significant prognostic differences for biomarkers by tumor site were maintained in the FOLFOX arm .
15 Tumor site was independently prognostic with a stepwise improvement from cecum to sigmoid ( OS : P ( adjusted ) = 0.001 ) .
16 CONCLUSIONS :
17 Mutation in BRAF or KRAS codon 12 was enriched in proximal cancers whereas nonmutated BRAF/KRAS was increased in distal tumors .
18 Μ Significant differences in outcome for KRAS mutations and dMMR were found by tumor site , indicating that their interpretation should occur in the context of tumor location .



PMID: 26185002
(Patient)  
Terms: in vitro, xenograft
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer-derived tumor spheroids retain the characteristics of original tumors .
1 Primary cultures of cancer cells are useful for developing personalized medicine .
2 In this study , we characterized three lines of three-dimensional ( 3D ) tumor spheroids established directly from tumor tissues of patients with colorectal cancers ( CRCs ) .
3 Each line mainly included EpCAM-positive cells and cells expressing putative cancer stem cell markers such as CD133 , CD44 , CD24 , ALDH1 , and LGR5 .
4 These characteristic stem cell markers remained identically for months in vitro .
5 Short tandem repeat genotyping suggested that genetic fingerprints of these tumor spheroids were similar to those of the original tumor tissues from which they were derived .
6 Μ Mutational analysis showed that each line had the same mutation profile for APC , KRAS , MLH1 , serine-threonine kinase 11 , and TP53 as its parental tumor tissue .
7 ✓ One line harboring an activating KRAS mutation was resistant to cetuximab while the remaining two lines harboring wild-type KRAS showed different responses to cetuximab . GM-ASS-RO
8 Immunohistochemical analysis showed that xenograft tumors derived from these lines retained the histopathological and mutational patterns of their parental tumors .
9 Collectively , these results clearly showed that 3D tumor spheroids directly generated from tumor tissues of patients with CRCs preserved the characteristics of their parental tumor tissues and could be used for developing personalized medicines for CRCs .



PMID: 26184520
(Patient)  
Terms: NCT01103323
Sent# Symbols Sentence Mnemonics
0 BRAF and NRAS mutations are heterogeneous and not mutually exclusive in nodular melanoma .
1 BACKGROUND :
2 Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments .
3 However , the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment .
4 This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels .
5 METHODS :
6 Μ We used BEAMing technology to identify KRAS , PIK3CA , and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial .
7 We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 ( LINE -1 ) quantitive real-time PCR .
8 We also measured the concentration of 15 proteins of interest-angiopoietin 2 , interleukin 6 , interleukin 8 , placental growth factor , soluble TIE-1 , soluble VEGFR1 , VEGF-A , VEGF-C , VEGF-D , VEGF-A isoform 121 , bone morphogenetic protein 7 , macrophage colony-stimulating factor , stromal cell -derived factor-1 , tissue inhibitor of metalloproteinase 2 , and von Willebrand factor -in plasma samples from 611 patients .
9 We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status , circulating DNA concentration , and protein concentrations .
10 The CORRECT trial was registered with ClinicalTrials .
11 gov , number NCT01103323 .
12 FINDINGS :
13 Μ Tumour-associated mutations were readily detected with BEAMing of plasma DNA , with KRAS mutations identified in 349 ( 69% ) of 503 patients , PIK3CA mutations in 84 ( 17% ) of 503 patients , and BRAF mutations in 17 ( 3% ) of 502 patients .
14 Μ We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene .
15 Μ Some of the most prevalent individual hot-spot mutations we identified included : KRAS ( KRAS G12D , 116 [28%] of 413 mutations ; G12V , 72 [17%] ; and G13D , 67 [16%] ) and PIK3CA ( PIK3CA E542K , 27 [30%] of 89 mutations ; E545K , 37 [42%] ; and H1047R , 12 [14%] ) .
16   Μ 41 ( 48% ) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA .
17 Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status ( progression-free survival with regorafenib versus placebo : hazard ratio [HR] 0.52 , 95% CI 0.35-0.76 for KRAS wild-type ; HR 0.51 , 95% CI 0.40-0.65 for KRAS mutant [KRAS wild type versus mutant , pinteraction = 074] ; HR 0.50 , 95% CI 0.40-0.63 for PIK3CA wild-type ; HR 0.54 , 95% CI 0.32-0.89 for PIK3CA mutant [PIK3CA wild-type versus mutant , pinteraction = 085] ) or circulating DNA concentration ( progression-free survival with regorafenib versus placebo : HR 0.53 , 95% CI 0.40-0.71 , for low circulating DNA concentrations ; HR 0.52 , 95% CI 0.40-0.70 , for high circulating DNA concentrations ; low versus high circulating DNA , pinteraction = 0.601 ) .
18 With the exception of von Willebrand factor , assessed with the median cutoff method , plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival .
19 In univariable analyses , the only plasma protein that was associated with overall survival was TIE-1 , high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations .
20 This association was not significant in multivariable analyses .
21 Μ INTERPRETATION : BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue .
22   Additionally , the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations .
23 FUNDING : Bayer HealthCare Pharmaceuticals .



PMID: 26184500
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prophylactic versus reactive treatment of acneiform skin rashes from epidermal growth factor receptor inhibitors in metastatic colorectal cancer .
1 Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer .



PMID: 26183044
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Computed tomography assessment of early response to neoadjuvant therapy in colon cancer .
1 INTRODUCTION :
2 Using multidetector computed tomography , we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer .
3 METHODS :
4 Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment .
5 All patients had histologically confirmed colon cancer , a T4 or T3 tumour with extramural invasion >/= 5 mm and no distant metastases or peritoneal nodules .
6 The patients were treated with oxaliplatin and capecitabine .
7 In addition , those with no mutations in the KRAS , BRAF and PIK3CA genes were also treated with panitumumab .
8 Before and after treatment , we measured the tumour diameter in two different planes , the extension of the extramural tumour invasion , and the number and size of enlarged lymph nodes .
9 RESULTS :
10 The mean tumour length was 7.8 cm ( 95% confidence interval ( CI ) : 5.3-10.4 ) at baseline and 4.34 cm ( 95% CI : 4.0-4.9 ) after treatment .
11 The mean extramural tumour invasion was 10.6 mm ( 95% CI : 9.5-11.8 ) at baseline and 5.7 mm ( 95% CI : 4.7-6.7 ) after treatment .
12 The mean number of enlarged lymph nodes was 4.1 ( 95% CI : 3.4-4.9 ) at baseline and 2.1 ( 95% CI : 1.4-2.7 ) after treatment .
13 According to RECIST 1.1 , 45% ( 95% CI : 34-57 ) of the patients had a response and 55% ( 95% CI : 43-67 ) had stable disease .
14 None of the patients showed progressive disease .
15 CONCLUSION :
16 Using CT , we demonstrated a significant reduction in tumour size , extramural tumour invasion , number and size of enlarged lymph nodes following neoadjuvant treatment .
17 FUNDING :
18 not relevant .
19 TRIAL REGISTRATION :
20 Registered with ClinicalTrials .
21 gov ( NCT 01108107 ) .



PMID: 26182332
(None)  
Terms: Pdx, ex vivo, Ex vivo, mouse model, mouse, transgenic mouse, Transgenic mice, mice, transgenic mice
Sent# Symbols Sentence Mnemonics
0 Axillary Lymph Node Involvement , a Unique Pattern of Metastasis in BRAF-Mutant Colorectal Cancer .
1 PURPOSE :
2 To test ultrasonographic ( US ) imaging with vascular endothelial growth factor receptor type 2 ( VEGFR2 )- targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma ( PDAC ) in a transgenic mouse model of pancreatic cancer development .
3 MATERIALS AND METHODS :
4 Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University .
5 Transgenic mice ( n = 44 ; Pdx1-Cre , KRas (G12D) , Ink4a(-/-) ) that spontaneously develop PDAC starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 x 10(7) clinical-grade VEGFR2-targeted microbubble contrast material .
6 The pancreata in wild-type ( WT ) mice ( n = 64 ) were scanned as controls .
7 Pancreatic tissue was analyzed ex vivo by means of histologic examination ( with hematoxylin-eosin staining ) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2 .
8 The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis .
9 RESULTS :
10 VEGFR2-targeted US of PDAC showed significantly higher signal intensities ( 26.8-fold higher ; mean intensity +/- standard deviation , 6.7 linear arbitrary units [lau] +/- 8.5 ; P <.001 ) in transgenic mice compared with normal , control pancreata of WT mice ( mean intensity , 025 lau +/- 025 ) .
11 The highest VEGFR2-targeted US signal intensities were observed in smaller tumors , less than 3 mm in diameter ( 30.8-fold higher than control tissue with mean intensity of 7.7 lau +/- 9.3 [P <001] ; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau +/- 5.8 [P <024] ) .
12 Μ Ex vivo quantitative VEGFR2 immunofluorescence demonstrated that VEGFR2 expression was significantly higher in pancreatic tumors ( P <.001 ; mean fluorescent intensity , 499.4 arbitrary units [au] +/- 179.1 ) compared with normal pancreas ( mean fluorescent intensity , 2329 au +/- 837 ) .
13 CONCLUSION :
14 US with clinical-grade VEGFR2-targeted microbubbles allows detection of small foci of PDAC in transgenic mice .



PMID: 26181352
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Recombinant expression of hepatoma associated gene and its protein function ] .
1 Oncologists' attitudes toward KRAS testing : a multisite study .



PMID: 26172302
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ MGL ligand expression is correlated to BRAF mutation and associated with poor survival of stage III colon cancer patients . GE-ASS-RO
1 The epigenetic regulator I-BET151 induces BIM -dependent apoptosis and cell cycle arrest of human melanoma cells .



PMID: 26172297
(Patient)  
Terms: in vivo, in vitro, mouse model, mouse, mice
Sent# Symbols Sentence Mnemonics
0 BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis .
1 Matrix metalloproteinase 10 ( MMP-10 ; stromelysin 2 ) is a member of a large family of structurally related matrix metalloproteinases , many of which have been implicated in tumor progression , invasion and metastasis .
2 We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells ( BASCs ) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma .
3 However , the potential role of Mmp10 in lung tumorigenesis has not been addressed .
4 Here , we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras .
5 In addition , we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null ( Mmp10(-/-) ) mice .
6 This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro , demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells .
7 To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers .
8 Our analysis reveals that MMP10 is highly overexpressed in human lung tumors .
9 Gene set enhancement analysis ( GSEA ) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer .
10 Finally , Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy .
11 We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic , cancer-initiating , stem-like cell population , and that Mmp10 expression is associated with stem-like , highly metastatic genotypes in human lung cancers .
12 These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells .



PMID: 26171935
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Expression of pEGFR and pAKT as response-predictive biomarkers for RAS wild-type patients to anti-EGFR monoclonal antibodies in metastatic colorectal cancers .
1 BACKGROUND :
2 RAS wild-type ( RASw/t ) tumours have been associated with better outcomes in patients with metastatic colorectal cancer ( mCRC ) treated with anti-EGFR monoclonal antibodies ( mAb ) .
3 We investigated the expression of EGFR downstream proteins under their active phosphorylated forms as potential markers in response to these patients .
4 METHODS :
5 One-hundred tumour samples were collected from patients with mCRC refractory to FOLFOX and/or FOLFIRI and treated by a combination of chemotherapy with anti-EGFR mAb .
6 The outcomes were measured on response evaluation criteria in solid tumour ( RECIST ) , progression-free survival ( PFS ) and overall survival ( OS ) .
7 Μ All samples were assessed for RAS and BRAF mutations , and the key phosphorylated proteins of EGFR downstream signalling were quantitatively analysed using the BioPlex Protein array .
8 RESULTS :
9 Among the 60 RASw/t patients , 45.0% achieved a complete or partial response when treated with anti-EGFR mAb .
10 Expression of pAKT , pERK1/2 and pMEK1 was significantly lower in RASw/t patients ( P = 00246 ; P = 0004 ; P = 00110 , respectively ) .
11 The response rate was significantly higher for RASw/t patients who express pEGFR and pAKT ( P = 00258 ; P = 00277 , respectively ) .
12 CONCLUSIONS :
13 Overexpression of pEGFR and pAKT may predict the response rate in RASw/t patients treated with anti-EGFR mAb .
14 On the basis of our results , we hypothesise that the association of anti-EGFR mAb and anti-AKT therapies could be of interest .



PMID: 26171582
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gene expression in colon cancer : A focus on tumor site and molecular phenotype .
1 Hundreds to thousands of genes are differentially expressed in tumors when compared to nontumor colonic tissue samples .
2 We evaluated gene expression patterns to better understand differences in colon cancer by tumor site and tumor molecular phenotype .
3 We analyzed RNA-seq data from tumor/normal paired samples from 175 colon cancer patients .
4 Μ We implemented a cross validation strategy with nonparametric tests to identify genes which displayed varying expression characteristics related to paired tumor/nontumor tissue across proximal and distal colon sites and by tumor molecular phenotypes , that is , TP53 , KRAS , CpG Island Methylator Phenotype ( CIMP ) , and microsatellite instability ( MSI ) .
5 We used Ingenuity Pathway Analysis ( IPA ) to determine networks associated with deregulated genes in our data .
6 Μ Genes showed significant differences in expression characteristics at the 0.01 level in both validation groups between tumor subsite ( 116 genes ) , CIMP high versus CIMP low ( 79 genes ) , MSI versus microsatellite stable ( MSS ) ( 49 genes ) , TP53-mutated versus not mutated ( 17genes ) , and KRAS-mutated versus not mutated ( 1 gene ) .
7 Deregulated genes for CIMP high and MSI tumors were often down-regulated .
8 In contrast to CIMP high and MSI tumors , genes that were deregulated in TP53 were likely to be up-regulated .
9 ERK1 , WNT , growth factors and inflammation-related factors were focal points of both CIMP and MSI IPA networks .
10 The MUC family of genes was up-regulated MSI networks .
11 Μ Numerous genes showed differences in expression between proximal and distal tumors , nontumor proximal and distal tissue , and tumor molecular phenotype .
12 Deregulated mucin genes appear to play an important role in MSI tumors .



PMID: 26169242
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of low-level DNA mutation by ARMS-blocker-Tm PCR .
1 Isoalantolactone , a sesquiterpene lactone , induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways .



PMID: 26168967
(Cell)  
Terms: In vitro, in vitro
Sent# Symbols Sentence Mnemonics
0 In vitro prediction of the efficacy of molecularly targeted cancer therapy by Raman spectral imaging .
1 Mutational acquired resistance is a major challenge in cancer therapy .
2 Somatic tumours harbouring some oncogenic mutations are characterised by a high mortality rate .
3 Surprisingly , preclinical evaluation methods do not show clearly resistance of mutated cancers to some drugs .
4 Here , we implemented Raman spectral imaging to investigate the oncogenic mutation resistance to epidermal growth factor receptor targeting therapy .
5 Μ Colon cancer cells with and without oncogenic mutations such as KRAS and BRAF mutations were treated with erlotinib , an inhibitor of epidermal growth factor receptor , in order to detect the impact of these mutations on Raman spectra of the cells .
6 Μ Clinical studies suggested that oncogenic KRAS and BRAF mutations inhibit the response to erlotinib therapy in patients , but this effect is not observed in vitro .
7 The Raman results indicate that erlotinib induces large spectral changes in SW-48 cells that harbour wild-type KRAS and BRAF .
8 These spectral changes can be used as a marker of response to therapy .
9 HT-29 cells ( BRAF mutated ) and SW-480 cells ( KRAS mutated ) display a smaller and no significant response , respectively .
10 However , the erlotinib effect on these cells is not observed when phosphorylation of extracellular-signal-regulated kinase and AKT is monitored by Western blot , where this phosphorylation is the conventional in vitro test .
11 Lipid droplets show a large response to erlotinib only in the case of cells harbouring wild-type KRAS and BRAF , as indicated by Raman difference spectra .
12 This study shows the great potential of Raman spectral imaging as an in vitro tool for detecting mutational drug resistance .



PMID: 26168486
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Establishment of a Three-dimensional Floating Cell Culture System for Screening Drugs Targeting KRAS -mediated Signaling Molecules .
1 BACKGROUND/AIM :
2 Oncogenic mutations in the KRAS gene are critically involved in many human tumors but drugs targeting oncogenic KRAS have not yet been clinically developed .
3 Herein , we established a three-dimensional floating ( 3DF ) culture system for screening drugs that target KRAS -mediated signaling molecules .
4 MATERIALS AND METHODS :
5 HKe3 cells , derived from colorectal cancer HCT116 cells and disrupted at mutated ( mt ) KRAS gene , were infected with a retrovirus expressing wild-type ( wt ) KRAS or mtKRAS to establish HKe3-derived cells expressing wtKRAS or mtKRAS .
6 Established cells were cultured in 96-well plates with an ultra-low attachment surface and round bottom for 3DF culture .
7 RESULTS :
8 HKe3-wtKRAS and HKe3-mtKRAS cells in 3DF culture rapidly assembled into respective single spherical structures ( spheroids ) .
9 Furthermore , mtKRAS but not wtKRAS expression inhibited luminal apoptosis in spheroids indicating that the 3DF culture was compatible with the 3D matrigel culture .
10 CONCLUSION :
11 This 3DF culture system could be useful for screening drugs that target KRAS -mediated signaling molecules .



PMID: 26166616
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer .
1 The role of biomarker assessment in determining the best therapeutic options for patients with metastatic colorectal cancer has become increasingly complex and important .
2   Biomarkers that predict the efficacy and/or toxicity of such treatments can affect medical decision making , leading to decreased harm and/or costs associated with treatment and improvements in therapeutic outcomes for patients .
3   This review discusses traditional and emerging biomarkers of potential clinical utility for patients with metastatic colorectal cancer , current assays and methods used in clinical practice , technologies that have allowed the identification of new biomarkers and key considerations for oncologists and pathologists when determining appropriate biomarker evaluations to be undertaken for their patients .



PMID: 26163603
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Colorectal Cancer Patient Characteristics , Treatment and Survival in Oman--a Single Center Study .
1 BACKGROUND :
2 Colorectal cancer is the most common gastrointestinal cancer in Oman with an increasing incidence .
3 We here report the presenting features , treatment outcomes and survival in a University hospital in Oman and compare our data with regional and international studies .
4 MATERIALS AND METHODS :
5 Medical records of patients with colorectal cancer were reviewed retrospectively between June 2000 and December 2013 and were followed until June 2014 .
6 RESULTS :
7 A total of 162 patients were diagnosed with colorectal cancer .
8 The majority were males ( 586% ) , with a median age of 56 years .
9 Rectum was involved in 29.6% of patients , followed by ascending and sigmoid colon .
10 The majority of patients had stage III ( 426% ) and stage IV ( 327% ) disease at presentation .
11 K-Ras status was checked for 79 patients , and 41 ( 519% ) featured the wild type .
12 Median relapse free survival was 22 months .
13 Median overall survival for all patients was 43 months .
14 Observed 5 year overall survival ( OS ) for stages I , II and III was 100% , 60% and 60% respectively .
15 On Log rank univariate analysis , age , BMI , diabetes , hypertension , metformin use , stage , clinical nodal status for rectal cancer , pathological T and nodal status , site of metastasis , surgical intervention , chemotherapy , radiotherapy , chemotherapy regimen , no of cycles of chemotherapy , response , RFS , site of recurrence and administration of 2nd line chemotherapy were significant factors affecting OS .
16 On Cox regression multivariate analysis none of the factors independently affected the OS .
17 CONCLUSIONS :
18 The majority of patients present with advanced disease and at young age .
19 The survival rates are comparable to the published regional and international literature .



PMID: 26162609
(Patient)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer : results of the EXPERT-C trial .
1 BACKGROUND :
2 Lethal-7 ( let-7 ) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS .
3 A single - nucleotide polymorphism ( rs61764370 , T >G base substitution ) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer ( CRC ) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC .
4 PATIENTS AND METHODS :
5 We analysed rs61764370 in EXPERT-C , a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy , surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer .
6 DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay .
7 Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms .
8 RESULTS :
9 A total of 155/164 ( 945% ) patients were successfully analysed , of whom 123 ( 794% ) and 32 ( 206% ) had the LCS-6 TT and LCS-6 TG genotype , respectively .
10 Μ Carriers of the G allele were found to have a statistically significantly higher rate of complete response ( CR ) after neoadjuvant therapy ( 281% versus 106% ; P = 0020 ) and a trend for better 5-year progression-free survival ( PFS ) [77.4% versus 64.5% : hazard ratio ( HR ) 0.56 ; P = 0.152] and overall survival ( OS ) rates ( 80.3% versus 71.9% : HR 0.59 ; P = 0.234 ) .
11 Both CR and survival outcomes were independent of the use of cetuximab .
12 ✓ The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype ( HR PFS 170 , P = 0078 ; HR OS 179 , P = 0082 ) compared with those with the LCS-6 TG genotype ( HR PFS 133 , P = 0713 ; HR OS 101 , P = 0995 ) . RO-ASS-GM
13 CONCLUSION :
14 ✓ This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation . GM-MRK-RO
15 In this setting , however , this polymorphism does not appear to predict cetuximab benefit .



PMID: 26161928
(Cell)  
Terms: in vivo, xenograft, in vitro, In vivo, mice
Sent# Symbols Sentence Mnemonics
0 KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancer .
1 AIM :
2 To investigate the impact of KRAS mutation variants on the activity of regorafenib in SW48 colorectal cancer cells .
3 MATERIALS & ; METHODS : Activity of regorafenib was evaluated in isogenic SW48 KRAS wild-type ( WT ) and mutant cells .
4 Μ Subcutaneous xenografts ( KRAS WT and G12C mutant variants ) in NOD/SCID mice were analyzed to elucidate the effect of regorafenib treatment in vivo .
5 RESULTS :
6 Compared with KRAS WT cells , all mutant variants seemed associated with some degree of resistance to regorafenib-treatment in vitro .
7 In vivo , activation of apoptosis ( TUNEL ) and reduction of proliferation ( Ki67 ) after treatment with regorafenib were more pronounced in KRAS WT tumors as compared with G12C variants .
8 CONCLUSION :
9 In SW48 cells , exon 2 mutations of the KRAS gene may influence antitumor effects of regorafenib .



PMID: 26160882
(None)  
Terms: case, control
Sent# Symbols Sentence Mnemonics
0 Stage-specific prognostic biomarkers in melanoma .
1 Pancreatic phospholipase A2 , product of PLA2G1B , catalyzes the release of fatty acids from dietary phospholipids .
2 Diet is the ultimate source of arachidonic acid in cellular phospholipids , precursor of eicosanoid signaling molecules , linked to inflammation , cell proliferation and colorectal carcinogenesis .
3 We evaluated the association of PLA2G1B tagging single - nucleotide polymorphisms with colorectal neoplasia risk .
4 A linkage-disequilibrium-based tagSNP algorithm ( r(2) =090 , MAF>/ = 4% ) identified three tagSNPs .
5 The SNPs were genotyped on the Illumina platform in three population-based , case-control studies : colon cancer ( 1424 cases/1780 controls ) ; rectal cancer ( 583/775 ) ; colorectal adenomas ( 485/578 ) .
6 Evaluating gene -wide associations , principal-component and haplotype analysis were conducted , individual SNPs were evaluated by logistic regression .
7 Μ Two PLA2G1B variants were statistically significantly associated with reduced risk of rectal cancer ( rs5637 , 3702 G>A Ser98Ser , p-trend = 003 ; rs9657930 , 1593 C>T , p-trend = 001 ) ; principal component analysis showed that genetic variation in the gene overall was statistically significantly associated with rectal cancer ( p = 002 ) .
8 NSAID users with the rs2070873 variant had a reduced rectal cancer risk ( P-inter = 002 ) .
9 Specific associations were observed with tumor subtypes ( TP53/KRAS ) .
10 The results suggest that genetic polymorphisms in PLA2G1B affect susceptibility to rectal cancer .



PMID: 26160848
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ErbB-3 activation by NRG-1beta sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells ( CSCs ) .
1 Cancers acquire mutations in cooperating pathways that sustain their growth and survival .
2 To support continued proliferation , tumor cells adapt their metabolism to balance energy production with their augmented biosynthetic needs .
3 Although most normal differentiated cells use mitochondrial oxidative phosphorylation ( OXPHOS ) as the bioenergetic source , cancer cells have been proposed to rely principally on cytoplasmic glycolysis .
4 The molecular basis for this shift , termed the Warburg effect , is the subject of intense investigation , because mechanistic understanding may lead to novel approaches to target the altered metabolism of cancer cells .
5 Recently , mutations BRAF ( V600E ) have emerged as a major regulator of metabolic homeostasis .
6 Melanoma cells may use a metabolic shift to circumvent BRAF (V600E)- induced senescence though limiting their reliance on OXPHOS and promote proliferation .
7 Furthermore , BRAF (V600E) acts to suppress expression of the melanocyte master regulator microphthalmia-associated transcription factor ( MITF ) and the mitochondrial biogenesis coactivator PGC1alpha .
8 Accordingly , therapeutic inhibition of BRAF (V600E) reverses metabolic reprogramming in melanoma cells and elevates OXPHOS through increased MITF-PGC1alpha levels .
9   BRAF-targeted drugs modulate the metabolic state of malignant melanoma cells , and counteracting these adaptive responses using pharmacologic agents may prove useful in combinatorial therapeutic strategies .
10 Clin Cancer Res ; 20(9) ; 2257-63 .
11 (c) 2014 AACR .



PMID: 26160682
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 The Hippo pathway in colorectal cancer .
1 Colorectal cancer ( CRC ) is one the most frequently diagnosed neoplastic diseases worldwide .
2 Currently , aside from traditional chemotherapy , advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor ( EGFR ) .
3 Since up to 70% of metastasized CRCs are drug resistant , the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment .
4 The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation , differentiation , apoptosis and tumourigenesis .
5 Components of the Hippo pathway are deregulated in various human malignancies , and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer .
6 In this review we focused on recent data regarding Hippo pathway , its up-stream signals and down-stream effectors .
7 Hippo negatively regulates its major effectors , YAP1 and TAZ kinases , which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression .
8 The deregulation of Hippo pathway components was found in many malignancies .
9 The interactions between Hippo and Wnt/beta-catenin signalling , crucial in the maintenance of cell homeostasis , have been described in relation to the control of intestinal stem cell proliferation and CRC development .
10 Μ The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal , ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy .



PMID: 26160607
(Patient)  
Terms: meta-analysis, clinical trial
Sent# Symbols Sentence Mnemonics
0 Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens : A meta-analysis of 18 randomized controlled clinical trials .
1 The anti-Epidermal Growth Factor Receptor monoclonal antibodies (anti-EGFR MoAbs) are beneficial in the treatment of wild type ( WT ) KRAS colorectal cancer , but are burdened by serious toxicities .
2 We conducted a systematic review and meta-analysis to determine incidence and relative risk ( RR ) of severe and life-threatening diarrhoea and mucositis in colorectal cancer patients and WT-KRAS subpopulation .
3 PubMed and Embase were searched for trials comparing the same therapeutic regimens with or without anti-EGFR for colorectal cancer .
4 Data on severe and life-threatening diarrhoea and mucositis were extracted from 18 studies involving 13,382 patients .
5 Statistical analyses calculated incidence of AEs , RRs and 95% confidence intervals by using either random or fixed effects models .
6 Patients receiving anti-EGFR MoAbs showed an increased risk of diarrhoea ( RR : 1.66 , CI 1.52-1.80 ) and mucositis ( RR : 3.44 , CI 2.66-4.44 ) .
7 The risk was similar among WT-KRAS patients .
8 Prevention and risk reduction strategies of these AEs are mandatory to optimize clinical outcomes .



PMID: 26160500
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical value of chip-based digital-PCR platform for the detection of circulating DNA in metastatic colorectal cancer .
1 BACKGROUND :
2 The detection of circulating DNA is considered a promising strategy in cancer patients .
3 Digital PCR has emerged as a sensitive method able to quantify both circulating free and tumour DNA .
4 AIM :
5 The aim of this study was to prospectively evaluate the clinical value of a chip-based digital PCR for the detection of circulating DNA .
6 METHODS :
7 Digital PCR was used in 34 metastatic colorectal cancer patients to detect and quantify circulating free and tumour DNA based on K-ras mutational status .
8 Clinical outcomes were analyzed according to circulating DNA measurements .
9 RESULTS :
10 Digital PCR yielded a detection rate of 69% for circulating tumour DNA .
11 The median concentrations of circulating free and tumour DNA were 20 and 6.8 ng/mL , respectively , with significant correlation between both biomarkers ( p<0001 ) .
12 Median overall survival was 4.8 months in patients with high circulating free DNA ( >75% quartile ) versus not reached in patients with a low level ( <25% quartile ) ( p = 0029 ) .
13 Moreover , median overall survival was significantly decreased in patients with detectable circulating tumour DNA compared to those without ( respectively 118 months versus not reached , p = 004 ) .
14 CONCLUSIONS :
15 Chip-based digital PCR is a simple and non-invasive method allowing the efficient detection of circulating DNA .
16 Our results highlight that levels of these circulating markers may have a potential prognostic value .



PMID: 26153495
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis .
1 BACKGROUND :
2 While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer ( mCRC ) is well established , the impact of BRAF codons 594 and 596 mutations , occurring in <1% of CRCs , is completely unknown .
3 The present work aims to describe clinical , pathological and molecular features and prognosis of BRAF codons 594 and 596 mutant mCRCs , compared with BRAF V600E mutant and wild-type ones .
4 PATIENTS AND METHODS :
5 Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014 , with available KRAS and NRAS codon 12 , 13 , 59 , 61 , 117 and 146 and BRAF codon 594 , 596 and 600 mutational status , as detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray , were included .
6 RESULTS :
7 Μ Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542 patients bearing BRAF V600E mutated and BRAF wild-type tumors , respectively .
8 Μ While BRAF V600E mutated tumors were more frequently right-sided , mucinous and with peritoneal spread , BRAF 594 or 596 mutated were more frequently rectal , nonmucinous and with no peritoneal spread .
9 All BRAF 594 or 596 mutated tumors were microsatellite stable .
10 ✓ Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival ( OS ) when compared with BRAF V600E mutated [median OS : 62.0 versus 12.6 months ; hazard ratio : 0.36 ( 95% confidence interval 020-064 ) , P = 0.002] , both at univariate and multivariate analyses . GE-ASS-RO, RO-ASS-GM
11 CONCLUSIONS :
12 BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features , pathological characteristics and clinical outcome .
13 This is consistent with preclinical evidences of a kinase inactivating effect of these mutations .
14 The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596 mutated proteins opens the way to further preclinical investigation .



PMID: 26150735
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Treatment of metastatic colorectal cancer : focus on panitumumab .
1 Molecular classification of colorectal cancer : a dream that can become a reality .



PMID: 26145760
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 Rectal and colon cancer : Not just a different anatomic site .
1 Due to differences in anatomy , primary rectal and colon cancer require different staging procedures , different neo-adjuvant treatment and different surgical approaches .
2 For example , neoadjuvant radiotherapy or chemoradiotherapy is administered solely for rectal cancer .
3 Neoadjuvant therapy and total mesorectal excision for rectal cancer might be responsible in part for the differing effect of adjuvant systemic treatment on overall survival , which is more evident in colon cancer than in rectal cancer .
4 Apart from anatomic divergences , rectal and colon cancer also differ in their embryological origin and metastatic patterns .
5 Moreover , they harbor a different composition of drug targets , such as v-raf murine sarcoma viral oncogene homolog B ( BRAF ) , which is preferentially mutated in proximal colon cancers , and the epidermal growth factor receptor ( EGFR ) , which is prevalently amplified or overexpressed in distal colorectal cancers .
6 Despite their differences in metastatic pattern , composition of drug targets and earlier local treatment , metastatic rectal and colon cancer are , however , commonly regarded as one entity and are treated alike .
7 In this review , we focused on rectal cancer and its biological and clinical differences and similarities relative to colon cancer .
8 These aspects are crucial because they influence the current staging and treatment of these cancers , and might influence the design of future trials with targeted drugs .



PMID: 26137573
(Patient)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Clinical Validation of a Multiplex Kit for RAS Mutations in Colorectal Cancer : Results of the RASKET ( RAS KEy Testing ) Prospective , Multicenter Study .
1 BACKGROUND :
2 RAS ( KRAS and NRAS ) testing is required to predict anti-epidermal growth factor receptor ( EGFR ) treatment efficacy in metastatic colorectal cancer ( CRC ) .
3 Although direct sequencing ( DS ) with manual microdissection ( MMD ) is widely used , a diagnostic kit providing rapid detections of RAS mutations would be clinically beneficial .
4 Μ We evaluated the MEBGEN (TM) RASKET KIT ( RASKET KIT ) , a multiplex assay using PCR-reverse sequence specific oligonucleotide and xMAP ( (R) ) technology to concurrently detect exon 2 , 3 , and 4 RAS mutations in a short turnaround time ( 45 h/96-specimens ) .
5 METHODS :
6 Formalin-fixed paraffin-embedded ( FFPE ) tissues were obtained from 308 consenting patients with histologically-confirmed CRC at six hospitals in Japan .
7 For the RASKET KIT , we used only 50-100 ng DNA from each FFPE specimen not processed by MMD .
8 Μ The primary endpoint was the concordance rate between RAS mutations identified with the RASKET KIT and two reference assays ( DS with MMD and TheraScreen ( (R) ) K-RAS Mutation Kit ) .
9 As the secondary endpoints , we evaluated the concordance rate between DS and the RASKET KIT for RAS mutations in the wild-type KRAS exon 2 population and the genotyping performance of the RASKET KIT compared with DS .
10 FINDINGS :
11 Μ Among 307 analyzable specimens , the reference assays detected 140 ( 456% , 140/307 ) RAS mutations : 111 KRAS exon 2 and 29 other ( minor ) RAS mutations .
12 Μ The RASKET KIT detected 143 ( 466% , 143/307 ) mutations : 114 KRAS exon 2 and 29 minor RAS mutations .
13 The between-method concordance rate was 96.7% ( 297/307 ) ( 95% CI : 94.1-98.4% ) .
14 Μ Minor RAS mutations were detected in 15.7% ( 30/191 ) of the wild-type KRAS exon 2 population ( n = 191 ) ; the concordance rate was 98.4% ( 188/191 ) ( 95% CI : 95.5-99.7% ) .
15 The concordance rate of RAS genotyping was 100% ( 139/139 ) ( 95% CI : 97-100% ) .
16 INTERPRETATION :
17 The RASKET KIT provides rapid and precise detections of RAS mutations and consequently , quicker and more effective anti-EGFR therapy for CRC ( Study ID : UMIN000011784 ) .
18 FUNDING :
19 Medical & ; Biological Laboratories Co. , Ltd. ( MBL ) .
20 MBL had roles in study design , data collection , data analysis , and writing of the report for the study .



PMID: 26136882
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Intra-tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas .
1 BRAF mutations exist in numerous types of cancer , including melanomas , colorectal cancers and lung cancers .
2 The V600E-specific inhibitor vemurafenib has marked clinical activity in patients with BRAF V600E-mutated melanoma .
3 However , there are many cases of resistance to vemurafenib .
4 This may be due to the reported intra-tumor heterogeneity of the BRAF V600E mutation in primary melanomas .
5 Μ BRAF mutations are found in 1-5% of non-small cell carcinomas ( NSCLCs ) , almost exclusively in adenocarcinoma .
6 A few cases have been reported in which vemurafenib was effective against BRAF V600E-mutated lung cancers .
7 Μ In a previous study , five lung adenocarcinomas with BRAF V600E mutation were detected by direct sequencing .
8 Μ The present study analyzed these tumors for the percentage of mutation ( %mutation ) by competitive allele-specific polymerase chain reaction ( CAST-PCR ) assay .
9 In addition , sections of all components of the adenocarcinomas were obtained by laser microdissection and analyzed .
10 The %mutations of BRAF V600E within the macrodissected tumors ( cases 1-5 ) were : Case 1 , 10.0% ; case 2 , 8.0% ; case 3 , 8.9% ; case 4 , 21.5% ; and case 5 , 14.9% .
11 In four cases ( cases 2-5 ) , the %mutations of each adenocarcinoma component were as follows : Case 2 , lepidic growth 6.5-24.5% , papillary 1.3-11.2% and acinar 9.8% ; case 3 , solid 2.5-69.9% , acinar 12.4-27.1% and papillary 3.7-17.4% ; case 4 , acinar 10.0-45.0% and papillary 44.0% ; and case 5 , papillary 3.7-93.4% .
12 Sensitive BRAF mutation detection methods were used and evidence for heterogeneity of the BRAF V600E mutation in these lung adenocarcinoma cases was observed .
13   Targeted therapy with a BRAF V600E inhibitor such as vemurafenib may have potential in the treatment of lung cancer with this mutation ; however , it is necessary to consider how the treatment effect of and drug resistance to BRAF V600E inhibitors are affected by the presence of heterogeneity in future studies .



PMID: 26136684
(Cell)  
Terms: xenograft, in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models .
1 Aurora A kinase and MEK inhibitors induce different , and potentially complementary , effects on the cell cycle of malignant cells , suggesting a rational basis for utilizing these agents in combination .
2 In this work , the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models , with a focus on identifying a subpopulation in which it might be most effective .
3 Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations .
4 Μ Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination , and tumor growth inhibition was observed in double-mutant human tumor xenografts , though effects were variable within this subset .
5   Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer .
6 Overall , in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor .



PMID: 26135109
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Relationship Between 18F-FDG PET/CT Scans and KRAS Mutations in Metastatic Colorectal Cancer .
1 PURPOSE :
2 The secondary T790M mutation in epidermal growth factor receptor ( EGFR ) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors ( EGFR-TKI ) , gefitinib and erlotinib , in lung cancer .
3 Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR .
4 However , it is clear that resistance may also develop to this class of inhibitors .
5 We showed previously that hepatocyte growth factor ( HGF ) induced gefitinib resistance of lung cancer harboring EGFR -activating mutations .
6 Here , we investigated whether HGF induced resistance to the irreversible EGFR-TKI , CL-387,785 , in lung cancer cells ( H1975 ) harboring both L858R activating mutation and T790M secondary mutation in EGFR .
7 EXPERIMENTAL DESIGN :
8 CL-387, 785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors .
9 RESULTS :
10 HGF reduced susceptibility to CL-387,785 in H1975 cells .
11 Western blotting and small interfering RNA analyses indicated that HGF -induced hyposensitivity was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR , ErbB2 , ErbB3 , and ErbB4 .
12 Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts .
13 The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody , HGF antagonist NK4 , or MET-TKI .
14 CONCLUSIONS :
15 We showed HGF -mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs .
16 It will be clinically valuable to investigate the involvement of HGF-MET -mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR .



PMID: 26134512
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic mutations in human rectal cancers detected by targeted sequencing .
1 Role of FDG PET/CT in assessing response to targeted therapy in metastatic lung cancers : Morphological versus metabolic criteria .



PMID: 26132860
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS -dependent sorting of miRNA to exosomes .
1 Mutant KRAS colorectal cancer ( CRC ) cells release protein -laden exosomes that can alter the tumor microenvironment .
2 To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells , and whether mutant KRAS might regulate the composition of secreted microRNAs ( miRNAs ) , we compared small RNAs of cells and matched exosomes from isogenic CRC cell lines differing only in KRAS status .
3 We show that exosomal profiles are distinct from cellular profiles , and mutant exosomes cluster separately from wild-type KRAS exosomes .
4 miR-10b was selectively increased in wild-type exosomes , while miR-100 was increased in mutant exosomes .
5 Neutral sphingomyelinase inhibition caused accumulation of miR-100 only in mutant cells , suggesting KRAS -dependent miRNA export .
6 In Transwell co - culture experiments , mutant donor cells conferred miR-100 -mediated target repression in wild-type-recipient cells .
7 These findings suggest that extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC .



PMID: 26124380
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Cetuximab Might Be Detrimental to Metastatic Colorectal Cancer Patients with KRAS Codon 12 Mutations .
1 BACKGROUND :
2 Anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies benefit patients with wild-type KRAS exon 2 metastatic colorectal cancer ( mCRC ) .
3 However , their effect in KRAS-mutant mCRC remains unclear .
4 PATIENTS AND METHODS :
5 This was a retrospective study enrolling 163 patients with unresectable KRAS-mutant mCRC diagnosed at the National Taiwan University Hospital between 2007 and 2011 .
6 RESULTS :
7 The median overall survival ( mOS ) was 29.5 months in patients who had never used cetuximab and 19.0 months in those who had ( p = 0040 ) .
8 The mOS was 32.0 months in patients with mutant KRAS codon 12 who had never used cetuximab and 17.5 months in those who had ( p = 0017 ) .
9 In patients with mutant KRAS codon 13 , the mOS was not significantly different .
10   Univariate and multivariate Cox proportional hazards analysis revealed that absence of cetuximab treatment was an independent prognostic factor for longer mOS in patients with unresectable KRAS-mutant mCRC .
11 CONCLUSION :
12 Cetuximab usage might be detrimental to patients with mCRC with mutant KRAS codon 12 .



PMID: 26122820
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS and aneusomy of chromosomes 4 , 10 and 12 in colorectal carcinomas .
1 AIMS :
2 KRAS mutation status has predictive significance in EGFR-antibody treatment of colorectal adenocarcinoma .
3 The aim of the study was the evaluation of KRAS mutation status in correlation to KRAS copy numbers and ploidy status .
4 METHODS :
5 Colorectal adenocarcinomas ( n = 52 ) were assembled into a TMA and analyzed by FISH .
6 Probes for centromeres 4 and 10 were applied as surrogate markers for the ploidy status .
7 Μ In addition , a dual color FISH probe set for the centromere of chromosome 12 and the KRAS gene was applied to the TMA to analyze numerical alterations and KRAS gene copy numbers .
8 Further we analyzed DNA sequence profiles of KRAS codons 12 and 13 to assess the allele status of the mutation within the tumor samples .
9 RESULTS :
10 KRAS mutation was confirmed in 24 cases , while 28 cases showed a wild-type KRAS status .
11 The majority of cases showed diploid FISH signals for chromosomes 4 and 10 .
12 Near triploid FISH signals were observed in only 2 cases , 12 cases were hypodiploid , and 8 cases were hyperdiploid .
13 In 6 cases , trisomy 12 could be ascertained .
14 In total , aneuploidy could be detected in 28 cases , including cases with trisomy 12 and hyposomy 10 .
15 Tumors with aneuploid chromosomal content had a worse prognosis compared to euploid tumors , however , without reaching statistical significance ( p = 0231 ) .
16 Hypodiploid carcinomas carried the worst prognosis .
17 Specifically , monosomy 10 was significantly associated with reduced survival ( p = 0039 ) .
18 Increased FISH signals of KRAS did not correlate significantly with relapse ( p = 0916 ) .
19 CONCLUSIONS :
20 FISH analysis can be used as a surrogate marker for the ploidy status .
21 Loss of chromosome 10 may serve as a potential adverse prognostic marker being indicative for tumor progression .



PMID: 26122021
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Germline and somatic genetic predictors of pathological response in neoadjuvant settings of rectal and esophageal cancers : systematic review and meta-analysis .
1 HER2-positive advanced breast cancer : optimizing patient outcomes and opportunities for drug development .



PMID: 26121270
(Patient)  
Terms: Prospective, prospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort .
1 RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients ( mCRC ) , but the knowledge is based on trial patients usually not representative for the general cancer population .
2 Patient characteristics , treatment and efficacy according to KRAS , BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients .
3 The cohort contained many patients with poor performance status ( 39% PS 2-4 ) and elderly ( 37% age>75 ) , groups usually not included in clinical trials .
4 Patients without available tissue micro array ( TMA ) ( 42% ) had worse prognostic factors and inferior survival ( all patients ; 7m versus 11m , chemotherapy-treated ; 12m versus 17m ) .
5 The 92 patients ( 21% ) with BRAF mutation had a poor prognosis regardless of microsatellite instability , but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients .
6 Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS .
7 TMA availability , BRAF mutation and KRAS mutation were all independent prognostic factors for survival .
8 Μ The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC .
9 Μ Screening for BRAF mutations before selection of treatment is relevant for many patients , especially outside clinical trials .
10 A BRAF mutation only partly explained the very poor prognosis of many mCRC patients .
11 Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients .
12 Patients without available TMA had worse prognostic factors and shorter survival , which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases .
13 Lack of available tissue is an important underexposed issue which introduces sample bias , and this should be recognized more clearly when conclusions are made from translational mCRC studies .



PMID: 26118880
(None)  
Terms: this review
Sent# Symbols Sentence Mnemonics
0 [ DNA mismatch repair and BRAF status in colorectal cancer : Interest for the therapeutic management? ] .
1 Colorectal cancer ( CRC ) is the second leading cause of cancer-related mortality in France .
2 Recently , colorectal cancer subtyping consortium ( CRCSC ) identified 4 consensus molecular subtypes ( CMS ) .
3 CMS1 is enriched for CRC with deficient DNA mismatch repair system ( dMMR ) and tumors with mutated BRAF .
4 Intriguingly , CMS1 is characterized by better relapse-free survival but worse survival after relapse , compared with the other subtypes .
5 In this review , we provide a comprehensive overview of prognostic and predictive impacts of MMR and BRAF status .
6   We highlight immune checkpoints inhibitors as potentially future therapeutics for CRC with deficient MMR .
7   We also focus on the management of BRAF mutant metastatic CRC , with a particular interest on targeted therapies .



PMID: 26116215
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A Meta-Regression Method for Studying Etiological Heterogeneity Across Disease Subtypes Classified by Multiple Biomarkers .
1 In interdisciplinary biomedical , epidemiologic , and population research , it is increasingly necessary to consider pathogenesis and inherent heterogeneity of any given health condition and outcome .
2 As the unique disease principle implies , no single biomarker can perfectly define disease subtypes .
3 The complex nature of molecular pathology and biology necessitates biostatistical methodologies to simultaneously analyze multiple biomarkers and subtypes .
4 To analyze and test for heterogeneity hypotheses across subtypes defined by multiple categorical and/or ordinal markers , we developed a meta-regression method that can utilize existing statistical software for mixed - model analysis .
5 This method can be used to assess whether the exposure-subtype associations are different across subtypes defined by 1 marker while controlling for other markers and to evaluate whether the difference in exposure-subtype association across subtypes defined by 1 marker depends on any other markers .
6 To illustrate this method in molecular pathological epidemiology research , we examined the associations between smoking status and colorectal cancer subtypes defined by 3 correlated tumor molecular characteristics ( CpG island methylator phenotype , microsatellite instability , and the B-Raf protooncogene , serine/threonine kinase (BRAF) , mutation ) in the Nurses' Health Study ( 1980-2010 ) and the Health Professionals Follow-up Study ( 1986-2010 ) .
7 This method can be widely useful as molecular diagnostics and genomic technologies become routine in clinical medicine and public health .



PMID: 26114584
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor beta-activated kinase 1 ( TAK1 ) inhibition in KRAS-mutated colon cancer cells .
1 Transforming growth factor beta-activated kinase 1 ( TAK1 ) is critical for survival of many KRAS mutated colorectal cancer cells , and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing .
2 When SW 620 and HCT 116 human colon cancer cells were treated with 5microM 5Z-7-oxozeaenol , cell viability , growth , and clonogenic survival were significantly decreased .
3 Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress , 10mM N-acetylcysteine ( NAC ) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol .
4 In addition , 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione ( GSH ) and glutathione disulfide ( GSSG ) .
5 Interestingly , depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line .
6 In contrast , pre-treatment of cells with auranofin ( Au ) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol -induced growth inhibition and clonogenic cell killing .
7 These results were confirmed in SW 620 murine xenografts , where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth , with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone .
8 These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1 -induced colon cancer cell killing .
9 In addition , these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors .



PMID: 26110974
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Stem vs non-stem cell origin of colorectal cancer .
1 Leptomeningeal metastasis from solid tumors : a single center experience in Chinese patients .



PMID: 26110767
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells .
1 KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer ( CRC ) patients .
2 However , conflicting data exist regarding the variable response to EGFR-targeted therapy .
3 The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations .
4 Cells harboring a single KRASG13D allele showed the most tumorigenic profile , with constitutive activation of the downstream pathway , rendering them EGF-unresponsive .
5 Conversely , KRASA146T cells showed a full EGF-response in terms of signal transduction pathways , cell proliferation , migration or adhesion .
6 Moreover , the global acetylome of CRC cells was also dependent on KRAS mutational status .
7 Several hnRNP family members were identified within the 36 acetylated - proteins .
8 Acetylation status is known to be involved in the modulation of EGF-response .
9 In agreement with results presented herein , hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells , whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells .
10 Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status .
11 Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge .



PMID: 26109816
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Bevacizumab plus XELOX as first - line treatment of metastatic colorectal cancer : The OBELIX study .
1 AIM :
2 To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer ( CRC ) in Italy .
3 METHODS :
4 This multicentric , prospective , open-label study included patients with CRC previously untreated with chemotherapy .
5 Patients were administered bevacizumab in combination with XELOX .
6 The primary efficacy end-point was progression-free survival ( PFS ) .
7 Secondary end-points included time to overall response ( TOR ) , duration of response ( DOR ) , time to treatment failure ( TTF ) and overall survival ( OS ) .
8 The incidence and type of adverse events AEs and severe AEs were evaluated .
9 Also , the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing , and quality of life ( QoL ) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit .
10 RESULTS :
11 The intention-to-treat population included 197 patients ( mean age : 62.3 +/- 9.9 years , 56.4% males ) .
12 Μ At baseline , 16/34 evaluable subjects ( 471% ) harbored a KRAS and/or a BRAF mutation ; the mean QoL index was 80.2 +/- 14.3 .
13   First - line therapy was given for 223.7 +/- 175.9 d , and after a mean follow-up of 387.7 +/- 238.8 d all patients discontinued from the study mainly for disease progression ( PD , 454% ) and AEs ( 254% ) .
14 ✓ Median PFS was 9.7 mo ( 95%CI : 8.4-10.5 ) and the median values for secondary end-points were : TOR = 3.9 mo ( 95%CI : 2.6-4.7 ) , DOR = 8.5 mo ( 95%CI : 7.3-10.3 ) , TTF = 6.7 mo ( 95%CI : 6.0-7.7 ) and OS = 23.2 mo ( 95%CI : 20.1-27.2 ) . GE-ASS-RO
15 ✓ Patients carrying atleast one lesion had a lower overall response rate ( 667% versus 889% ) and a lower probability of achieving complete or partial response than those without mutations , but the difference in relative risk was not statistically significant ( P = 02 ) . RO-ASS-GM
16 Mean EQ-5D-3L raw index score significantly decreased to 74.9 +/- 19.1 at the last visit ( signed-rank test , P = 00076 ) , but in general the evaluation on QoL perceived by patients was good .
17 CONCLUSION :
18 The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed , with acceptable toxicity .



PMID: 26107680
(Patient)  
Terms: Meta-Analysis, in vitro, in vivo
Sent# Symbols Sentence Mnemonics
0 Prognostic Significance of Statin Use in Colorectal Cancer : A Systematic Review and Meta-Analysis .
1 UNLABELLED :
2 EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma ( NSCLC ) , and the clinical success of the anaplastic lymphoma kinase ( ALK ) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy .
3 Here , we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells , leading to greater in vitro potency , superior antitumor efficacy , and prolonged animal survival compared with results obtained with crizotinib .
4 In addition , combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo .
5 Importantly , ganetespib overcame multiple forms of crizotinib resistance , including secondary ALK mutations , consistent with activity seen in a patient with crizotinib-resistant NSCLC .
6 Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure .
7 Taken together , these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC .
8 SIGNIFICANCE :
9 In addition to direct kinase inhibition , pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK .
10 The bioactivity profi le of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC .



PMID: 26106602
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Lack of Association between Membrane-Type 1 Matrix Metalloproteinase Expression and Clinically Relevant Molecular or Morphologic Tumor Characteristics at the Leading Edge of Invasive Colorectal Carcinoma .
1 Colorectal cancer ( CRC ) is one of the leading causes of death from cancer in the western world , but tumor biology and clinical course show great interindividual variation .
2 Molecular and morphologic tumor characteristics , such as KRAS/BRAF mutation status , mismatch repair ( MMR ) protein expression , tumor growth pattern , and tumor cell budding , have been shown to be of key therapeutic and/or prognostic relevance in CRC .
3 Membrane-type 1 matrix metalloproteinase ( MT1-MMP ) is a membrane-anchored zinc-binding endopeptidase that is expressed at the leading edge of various invasive carcinomas and promotes tumor cell invasion through degradation of the extracellular matrix .
4 The aim of this study was to investigate possible associations between MT1-MMP expression and molecular tumor characteristics as well as morphologic features of tumor aggressiveness in a consecutive series of 79 CRC tissue samples .
5 ✓ Μ However , although MT1-MMP was expressed in 41/79 samples ( 52% ) , there was no significant association between MT1-MMP expression and KRAS/BRAF mutation status , MMR protein expression , presence of lymphovascular invasion , tumor growth pattern , tumor-infiltrating lymphocytes , or tumor cell budding in our sample cohort ( P >005 ) . GE-ASS-RO
6 Thus , we conclude that although MT1-MMP may play a role in CRC invasion , it is not of key relevance to the current models of CRC invasion and aggressiveness .



PMID: 26104511
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Epigenetics could explain some Moroccan population colorectal cancers peculiarities : microsatellite instability pathway exploration .
1   Post-operative survival following metastasectomy for patients receiving BRAF inhibitor therapy is associated with duration of pre-operative treatment and elective indication .



PMID: 26104296
(Cell)  
Terms: xenograft, mice
Sent# Symbols Sentence Mnemonics
0 The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts .
1 BACKGROUND :
2 Clinical therapy for metastatic colorectal cancer ( CRC ) remains limited , especially when the tumor harbors a KRAS mutation .
3 This study aimed to identify prognostic biomarkers in CRC that are accessible for therapeutic inhibition .
4 METHODS :
5 Conditioned media from human CRC epithelial cells and myofibroblasts were screened by cytokine arrays for tumorigenic factors .
6 The protein and mRNA expressions of these factors were determined by immunohistochemistry and gene microarrays in human CRC tissues .
7 Prognostic biomarkers were determined by correlation of mRNA expression to overall survival in stage IV CRC patients .
8 Inhibition of CXCL1 was performed with specific neutralizing antibody and lentiviral shRNAs .
9 Malignant growth was assessed by soft agar growth assays and xenograft tumor growth in immunocompromised mice .
10 RESULTS :
11 CXCL1 was highly secreted by KRAS mutant human CRC cells and myofibroblasts in a complementary adaptive response to serum deprivation .
12 Elevated CXCL1 level promoted anchorage -independent growth of murine fibroblasts and human CRC cells .
13 Inhibition of CXCL1 by neutralizing antibody and specific shRNAs decreased CRC tumor growth .
14 ✓ Highly elevated CXCL1 expression significantly correlated with decreased overall survival in stage IV CRC patients ( hazard ratio 028 ; 95% CI 011-072 ) . GE-ASS-RO
15 CONCLUSIONS :
16 ✓ High CXCL1 expression is a poor prognostic biomarker in metastatic CRC . GE-MRK-DS
17 CXCL1 inhibition suppressed tumorigenic growth of KRAS mutant CRC cells .



PMID: 26103891
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Activation of K-RAS by co-mutation of codons 19 and 20 is transforming .
1 With the advent of targeted therapies - drugs that specifically target molecules of tumor-driving signalling pathways-and the availability of biomarkers that predict the response of an individual patient on such a targeted therapy , the analysis of the status of the biomarker became an integral part of the therapy .
2   For metastatic colorectal cancer , anti-EGFR-targeted antibodies ( Cetuximab/Erbitux ( (R) ) , Panitumumab/Vectibix ( (R) ) ) fall into this category of drugs as it was shown in several clinical studies that oncogenic mutations in exons 2-4 of the RAS genes KRAS or NRAS result in therapeutic resistance of the metastatic colorectal cancers against the action of both targeted drugs .
3   Therefore , mutations in the RAS genes exclude patients from this kind of targeted therapy ( negative biomarker ) .
4   Thus the molecular-pathological testing of the mutational status of KRAS and NRAS has become an important cornerstone in planning oncological strategies in the treatment of metastatic colorectal cancer .
5 As the profile of mutations in the RAS genes is characterized by hotspot mutations in only a small number of codons ( 12 , 13 in exon 2-59 , 61 in exon 3-117 , 146 in exon 4 ) .
6 Pyrosequencing ( (R) ) is an ideal and robust tool in the molecular-pathological detection .
7 A detailed protocol for this detection procedure employing Pyrosequencing(R) is given here .



PMID: 26098881
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer .
1 BACKGROUND :
2 Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer ( CRC ) .
3 These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas , followed by in situ malignant transformation and finally invasive carcinoma .
4 The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC .
5 METHODS AND FINDINGS :
6 We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors .
7 In 202 cases with preserved adenoma-adenocarcinoma transition , we identified , in 37.1% of cases , a zone of adenomatous epithelium , located immediately adjacent to the invasive component , that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium .
8 This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor -beta ( TGF-beta ) growth regulator SMAD4 .
9 These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell ( CSC ) markers , including beta-catenin/CTNNB1 , ALDH1 , and CD44 .
10 PTEN was always re-expressed in the invasive tumor in these cases , unlike those with complete loss of PTEN expression .
11 Μ Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones ( 625% ) but not in tumors with downregulated but non-alternating PTEN expression ( 143% ) .
12 There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases .
13 CONCLUSIONS :
14 In conclusion , we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT , TGF-beta/SMAD and Wnt/beta-catenin pathways .
15 This bottleneck-like zone is usually followed by the emergence of invasive tumors with intact PTEN expression but dysregulated TP53 and uniformly high proliferation rates .



PMID: 26097884
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Methylation changes in the TFAP2E promoter region are associated with BRAF mutation and poorer overall & ; disease free survival in colorectal cancer .
1 INTRODUCTION :
2 BRAF mutant colorectal cancer carries a poor prognosis which is thought to be related to poor response to conventional chemotherapy .
3 BRAF mutation is associated with the serrated tumour phenotype .
4 We hypothesised that one of the mechanisms by which BRAF mutant colorectal cancer demonstrate poor outcomes with chemotherapy is abnormal gene methylation .
5 METHODS :
6 Μ The Cancer Genome Atlas ( TCGA ) methylation data was analysed using a linear regression model with BRAF mutation as an independent variable .
7 Expression datasets were also obtained to correlate functional changes .
8 Top differentially methylated probes were taken forward for validation by methylation pyrosequencing .
9 Μ These probes were analysed on a cohort of patients enriched for BRAF mutations taken from the VICTOR and QUASAR2 studies .
10 RESULTS :
11 Μ In an analysis of 91 tumours ( 9 BRAF mutant , 82 wild type ) , the Illumina probe cg11835197 was the probe identified as top differentially methylated ( p = 2.56x10-7 , Bayes Factor ( BF ) =6.54 ) .
12 This probe covered a region -413bp from the promoter region of TFAP2E .
13 We found a complex pattern of CpG specific methylation of this region which was associated with both overall ( p = 0044 ) and disease free ( p = 0046 ) survival .
14 DISCUSSION :
15 BRAF mutant tumours may attain part of their chemoresistance from abnormal TFAP2E methylation , which has not previously been described .



PMID: 26096850
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 EGFR and beta1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion .
1 BACKGROUND AND PURPOSE :
2 Simultaneous targeting of beta1 integrin receptor and epidermal growth factor receptor ( EGFR ) showed higher level of radiosensitization in head and neck cancers than monotherapies .
3 As EGFR inhibition is similarly performed in colorectal cancer ( CRC ) , we investigated the radiosensitizing and anti-invasive potential of beta1-integrin/EGFR inhibition in CRC cell lines grown in more physiological three-dimensional ( 3D ) matrix-based cell cultures .
4 MATERIALS AND METHODS :
5 DLD-1 and HT-29 cells were used for 3D-colony formation , invasion and proliferation assays and Western blotting .
6 beta1 integrin , focal adhesion kinase and EGFR were inhibited by AIIB2 , TAE226 and Cetuximab , respectively .
7 KRAS and BRAF knockdown were accomplished using small-interfering RNA technology .
8 Single doses of X-rays ranged from 2Gy to 6Gy and 5-fluorouracil ( 5-FU ) concentration was 10muM .
9 RESULTS :
10 Neither beta1-integrin/EGFR inhibition nor KRAS or BRAF depletion nor 5-FU significantly modified CRC cell radiosensitivity .
11 Cetuximab , AIIB2 and Cetuximab/AIIB2 differentially modulated MAPK , JNK and AKT phosphorylation .
12 AIIB2 and TAE226 significantly decreased cell invasion .
13 CONCLUSIONS :
14 Our data show inefficiency of Cetuximab and AIIB2 on top of radiochemotherapy .
15 The functions of KRAS and BRAF in therapy resistance remain unanswered and warrant further preclinical molecular-driven investigations .
16 One promising approach might be beta1 integrin targeting for reducing metastatic CRC cell spread .



PMID: 26096739
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability .
1   Cutaneous adverse events in patients treated with BRAF inhibitor -based therapies for metastatic melanoma for longer than 52 weeks .



PMID: 26092596
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Expression of cancer stem cell markers in metastatic colorectal cancer correlates with liver metastasis , but not with metastasis to the central nervous system .
1 Convergent loss of PTEN leads to clinical resistance to a PI(3) Kalpha inhibitor .



PMID: 26091037
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer .
1   KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer .



PMID: 26086204
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms .
1 ✓ Oncogenic mutation of rat KRAS ( Kirsten sarcoma viral oncogene homolog ) in colorectal cancer ( CRC ) confers resistance to both chemotherapy and EGFR ( epidermal growth factor receptor )- targeted therapy .
2 ✓ We uncovered that KRAS mutant ( KRAS ( mut ) ) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 ( rLGALS9 ) , a recently established regulator of epithelial polarity .
3 Upon treatment of CRC cells , rLGALS9 rapidly internalizes via early - and late-endosomes and accumulates in the lysosomal compartment .
4 Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS ( mut ) CRC , but not in CRC with BRAF ( B-Raf proto-oncogene , serine/threonine kinase ) mutations ( BRAF ( mut ) ) .
5 In KRAS ( mut ) CRC , rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion , leading to autophagosome accumulation , excessive lysosomal swelling and cell death .
6 This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS ( mut ) cancer cells .
7 Thus , rLGALS9 has potent antitumor activity toward refractory KRAS ( mut ) CRC cells that may be exploitable for therapeutic use .



PMID: 26084290
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway : a novel strategy for human BRAF-driven colorectal carcinoma .
1 The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination , since BRAF down-regulation , ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition .
2 Since TRAP1 is upregulated in human colorectal carcinomas ( CRCs ) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies , the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated .
3 This study reports that BRAF cytoprotective signaling involves TRAP1 -dependent inhibition of the mitochondrial apoptotic pathway .
4 It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation , a condition associated with resistance to apoptosis .
5 ✓ Consistently , a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug -resistant cells with high TRAP1 levels .
6 In addition , TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells .
7 Thus , TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells .



PMID: 26081767
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The mutation rates of EGFR in non-small cell lung cancer and KRAS in colorectal cancer of Chinese patients as detected by pyrosequencing using a novel dispensation order .
1 AIM :
2 To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer ( mCRC ) .
3 MATERIALS & ; METHODS : We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups : BRAF mutated ; KRAS mutated codons 12-13 only ; any of KRAS codons 61-146 , PIK3CA or NRAS mutations and all wild-type .
4 Point mutations were investigated by pyrosequencing .
5 RESULTS :
6 ✓ BRAF ( 52% ) and KRAS 12-13 ( 319% ) mutations were associated with poorer survival ( HR 28 and 176 , respectively ) . GE-ASS-RO, GM-ASS-RO
7 Presenting with right-sided colon cancer , not resected primary tumor , WBC >10 x 10(9)/l , receiving less chemotherapy or no bevacizumab were all associated with inferior outcome .
8 The all-wild-type subgroup ( 392% ) reported the longest survival .
9 CONCLUSION :
10 Extended mutational profile combined with clinical factors may impact on survival in mCRC .



PMID: 26078581
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Renal cysts - A novel complication of crizotinib treatment for lung cancer ] .
1 AIM :
2 To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer ( mCRC ) with regard to KRAS status .
3 METHODS :
4 PubMed , EMBASE , Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials ( RCTs ) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC .
5 Baseline information such as sex and age was summarized from the included studies .
6 Hazard ratios of progression-free survival ( PFS ) and overall survival ( OS ) as well as objective response based on KRAS status were extracted for analysis .
7 RESULTS :
8 A total of 8 RCTs with 6780 patients were included .
9 The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC .
10   However , in subgroup analysis , the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients , but not in patients with mutant -type KRAS .
11 The addition of cetuximab increased the incidence of adverse events such as diarrhea , rash , skin toxicity/rash , and nausea and vomiting .
12 There was no significant publication bias existing in the included studies .
13 CONCLUSION :
14 The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS .
15 KRAS status could be considered a biomarker of efficacy of cetuximab .



PMID: 26078337
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 .
1 Amino acids , especially leucine and glutamine , are important for tumor cell growth , survival and metabolism .
2 A range of different transporters deliver each specific amino acid into cells , some of which are increased in cancer .
3 These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression .
4 The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids .
5 In this study , we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF (WT) ( C8161 and WM852 ) and BRAF (V600E) mutant ( 1205Lu and 451Lu ) melanoma cell lines .
6 While inhibition of LAT1 by BCH did not suppress melanoma cell growth , the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells , leading to inhibition of mTORC1 signaling .
7 Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture .
8 This included reduced expression of the cell cycle regulators CDK1 and UBE2C .
9 The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown , which inhibited glutamine uptake , mTORC1 signaling and cell proliferation .
10 Taken together , our study demonstrates that ASCT2 -mediated glutamine transport is a potential therapeutic target for both BRAF (WT) and BRAF (V600E) melanoma .



PMID: 26077270
(None)  
Terms: this review, rat
Sent# Symbols Sentence Mnemonics
0 Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer .
1 The discovery of the key role of the epidermal growth factor receptor ( EGFR ) and its downstream signaling effectors in the pathophysiology of colorectal cancer ( CRC ) has ushered in the clinical use of targeted therapies in the treatment of metastatic CRC ( mCRC ) .
2 The anti-EGFR monoclonal antibodies cetuximab and panitumumab improve overall survival when combined with chemotherapy in first - line treatment of rat Kirsten sarcoma viral oncogene homolog ( KRAS ) and neuroblastoma RAS viral oncogene homolog ( NRAS ) wild type mCRC and also improve progression-free survival and response rate in first - line treatment and treatment of refractory mCRC .
3   There are ongoing efforts to discover mechanisms of innate and acquired resistance to anti-EGFR therapies in KRAS wild type mCRC patients and to take therapeutic advantage of this knowledge by using rational combinations of targeted therapies .
4   In this review we will discuss the evidence for current use of anti-EGFR therapies and several recent and ongoing investigations to refine treatment for KRAS wild type mCRC , including more complete inhibition of the EGFR , HER2 inhibition , and MET proto-oncogene , receptor tyrosine kinase ( MET ) inhibition .



PMID: 26077004
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of the prevalence of KRAS-LCS6 polymorphism ( rs61764370 ) within different tumour types ( colorectal , breast , non-small cell lung cancer and brain tumours ) . A study of the Czech population .
1 AIMS :
2 A germline SNP ( rs61764370 ) is located in a let-7 complementary site ( LCS6 ) in the 3'UTR of KRAS oncogene , and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA .
3 The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer ( CRC ) , breast cancer ( BC ) , non-small cell lung cancer ( NSCLC ) and brain tumour patient subgroups from the Czech Republic .
4 The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours .
5 METHODS :
6 DNA of tumour tissues was isolated from 428 colorectal cancer samples , 311 non-small cell lung cancer samples , 195 breast cancer samples and 151 samples with brain tumour .
7 Analysis of SNP ( rs61764370 ) was performed by the PCR+RFLP method and direct sequencing .
8 KRAS , BRAF and EGFR mutation status was assessed using real-time PCR .
9 The status of the HER2 gene was assessed using the FISH method .
10 RESULTS :
11 Μ The KRAS-LCS6 TG genotype has been detected in 16.4% ( 32/195 ) of breast cancer cases ( in HER2 positive breast cancer 33% , in HER2 negative breast cancer 201% ) , in 12.4% ( 53/428 ) of CRC cases ( KRAS/BRAF wild type CRC in 106% , KRAS mutant CRC in 101% , BRAF V600E mutant CRC in 185% ) , in 13.2% ( 41/311 ) of NSCLC samples , ( EGFR mutant NSCLC patients in 8% , EGFR wild type NSCLC in 129% ) , and 17.9% ( 27/151 ) of brain tumour cases .
12 The KRAS-LCS6 TG genotype was not significantly different across the studied tumours .
13 In our study , the GG genotype has not been found among the cancer samples .
14 CONCLUSIONS :
15 Based on the findings , it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer .
16 Μ Furthermore , significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway ( KRAS , BRAF , EGFR ) and the KRAS-LCS6 genotype in colorectal cancer and NSCLC has not been established .



PMID: 26074686
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Significant antitumor effectiveness of imatinib in c- kit negative gastrointestinal stromal tumor - case report .
1 Dysregulation of receptor tyrosine kinases ( RTKs ) contributes to several aspects of oncogenesis including drug resistance .
2 In melanoma , distinct RTKs have been involved in BRAF inhibitors ( BRAFi ) resistance , yet the utility of RTKs expression pattern to identify intrinsically resistant tumors has not been assessed .
3 Transcriptional profiling of RTKs and integration with a previous classification , reveals three robust subtypes in two independent datasets of melanoma cell lines and one cohort of melanoma samples .
4 This classification was validated by Western blot in a panel of patient-derived melanoma cell lines .
5 One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3 , respectively , and included BRAF-mutant tumors all intrinsically resistant to BRAFi PLX4720 , as assessed by analysis of the Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays .
6   Μ High levels of EGFR were detected , even before therapy , in tumor cells of one of three melanoma patients unresponsive to BRAFi .
7 Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype .
8   Our results identify a specific molecular profile of melanomas intrinsically resistant to BRAFi and suggest the PI3K/mTOR pathway as a potential therapeutic target for these tumors .



PMID: 26064730
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Anaplastic lymphoma kinase inhibitors as anticancer therapeutics : a patent review .
1 A 43-year-old women admitted to our hospital for weight loss , anorexia , and abdominal pain was diagnosed with sigmoid neoplasm and multiple bilobar liver metastases .
2 This patient received six cycles of systemic FOLFOX prior to a laparoscopically assisted anterior resection of the rectosigmoid for a poorly differentiated invasive adenocarcinoma T2N2M1 , K-RAS negative ( wild type ) .
3 Hepatic arterial infusion ( HAI ) of LONGTOKEN and cetuximab as adjuvant therapy resulted in a complete metabolic response ( CR ) with CEA normalization .
4 A right hepatectomy extended to segment IV was performed resulting in ( FDG - ) PET negative remission for 7 months .
5 Solitary intrahepatic recurrence was effectively managed by local radiofrequent ablation following 6c FOLFIRI plus cetuximab iv .
6 Multiple lung lesions and recurrence of pulmonary and local lymph node metastases were successfully treated with fractionated stereotactic radiotherapy ( 50 Gy ) and iv LV/5-FU/oxaliplatin (FOLFOX) plus cetuximab finally switched to panitumumab with CR as a result .
7 At present the patient is in persistent complete remission of her stage IV colorectal cancer , more than 5 years after initial diagnosis of the advanced disease .
8   Multidisciplinary treatment with HAI of chemotherapy ( LV/5-FU + CPT-11 ) plus EGFR-inhibitor can achieve CR of complex unresectable LM and can even result in hepatectomy with possible long-term survival .



PMID: 26064214
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Correlation between smoking history and molecular pathways in sporadic colorectal cancer : a meta-analysis .
1 BACKGROUND :
2 Epidemiological studies have shown that smoking increases the risk for colorectal cancer ( CRC ) .
3 Evidence of the guiding significance of smoking history for molecular classification and molecular targeted anti-tumor therapy is not well established .
4 AIMS :
5 To provide indirectly evidence , we conducted a systematic meta-analysis of association between smoking history and different molecular classification .
6 METHODS :
7 We searched in multiple databases up to January 2014 , and identified 27 eligible studies .
8 All studies were divided into seven groups based on different molecular alteration categories , which are MSI , CIMP , and three molecular pathway-associated gene alterations ( APC , KRAS , P53 , BRAF mutation , and APC methylation ) .
9 Crude odds ratios ( ORs ) and their 95% confidence intervals ( CIs ) were calculated to evaluate the association .
10 RESULTS :
11 Μ Smoking showed a significantly positive correlation with P53 mutation ( exons 4 to 8 ) , BRAF ( codon 600 ) mutation , MSI positivity , and CIMP positivity , with ORs of 1.25 ( 95% CI : 1.07-1.45 ) , 1.41 ( 95% CI : 1.18-1.68 ) , 1.28 ( 95% CI : 1.12-1.47 ) , and 1.23 ( 95% CI : 1.01-1.50 ) , respectively .
12 However , smoking was not positively correlated with APC ( mutation cluster region ) and KRAS ( codons 12 and 13 ) mutation in sporadic CRC patients .
13 CONCLUSIONS :
14 These findings suggested smoking history occurred with P53 mutation , BRAF mutation , MSI positivity , and CIMP positivity in sporadic CRCs ; and could guide those specifically therapeutic designs when molecular classification with genetic test was infeasible .
15 More associated studies should be conducted for strengthening and renewing the current result .



PMID: 26063725
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gastrointestinal stromal tumor : analysis of outcome and correlation with c-kit status in Indian population .
1 Inactivation of methylcytosine dioxygenase , ten-eleven translocation ( TET ) is known to be associated with aberrant DNA methylation in cancers .
2 Tumors with a CpG island methylator phenotype ( CIMP ) , a distinct subgroup with extensive DNA methylation , show characteristic features in the case of colorectal cancer .
3 The relationship between TET inactivation and CIMP in colorectal cancers is not well understood .
4 The expression level of TET family genes was compared between CIMP-positive ( CIMP-P ) and CIMP-negative ( CIMP-N ) colorectal cancers .
5 Furthermore , DNA methylation profiling , including assessment of the TET1 gene , was assessed in colorectal cancers , as well as colon polyps .
6 The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines , expression of which was reactivated by demethylating agent .
7 TET1 methylation was more frequent in CIMP-P ( 23/55 , 42% ) than CIMP-N ( 2/113 , 2% , P <00001 ) colorectal cancers .
8 This trend was also observed in colon polyps ( CIMP-P , 16/40 , 40% ; CIMP-N , 2/24 , 8% ; P = 0002 ) , suggesting that TET1 methylation is an early event in CIMP tumorigenesis .
9 TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers .
10 Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation ( P = 0007 and 0045 , respectively ) .
11 Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP -mediated tumorigenesis , which may be incidental to hMLH1 methylation .
12 In addition , our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer .



PMID: 26065050
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The Critical Impact of HIF-1a on Gastric Cancer Biology .
1 Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer .



PMID: 26060408
(None)  
Terms: , orthotopic transplant model
Sent# Symbols Sentence Mnemonics
0 Positive feedback between oncogenic KRAS and HIF-1alpha confers drug resistance in colorectal cancer .
1 Glioma stem-like cells ( GSC ) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma ( GBM ) , the most deadly form of primary brain cancer .
2 In radiation oncology , hyperthermia is known to radiosensitize cells , and it is reemerging as a treatment option for patients with GBM .
3 In this study , we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant .
4 GSCs treated with radiation alone exhibited increased AKT activation , but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation .
5 Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization .
6 Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia .
7 In a preclinical orthotopic transplant model of human GBM , thermoradiotherapy reduced pS6 levels , delayed tumor growth , and extended animal survival .
8 Together , our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment .



PMID: 26059438
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Regulation of ERBB3/HER3 signaling in cancer .
1 Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia .



PMID: 26056087
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Somatic c.34G>T KRAS mutation : a new prescreening test for MUTYH-associated polyposis ?
1 We investigated the somatic c.34G>T KRAS transversion as a marker suggestive of MUTYH-associated polyposis (MAP) .
2 We compared 86 adenomas and 19 colorectal cancers ( CRCs ) of 30 MAP patients to 135 adenomas and five CRCs of 47 familial adenomatous polyposis ( FAP ) patients .
3 The c.34G>T mutation was investigated by DNA sequencing .
4 Secondly , the germline MUTYH gene sequence was analyzed in patients carrying c.34G>T in CRCs diagnosed between 2008 and 2012 .
5 The c.34G>T was present in 39.7% of MAP adenomas versus 1.6% of FAP adenomas ( P <001 ) .
6 Sensitivity and specificity for detecting MAP were 39.7% and 98% , respectively .
7 Sensitivity increased with the number of adenomas tested ( P = 0039 ) .
8 Μ KRAS exon 2 analysis was performed on 2239 CRC and 2.2% harbored the c.34G>T transversion .
9 Μ Among 28 carriers of the c.34G>T mutation , biallelic MUTYH mutations were detected in seven patients ( 25% ) .
10 One patient did not have any polyp or family history and did not fulfill criteria for MUTYH testing .
11 With high specificity , the c.34G>T mutation seems to be a useful and promising test for MAP .
12 For polyposis , it may guide genetic testing toward APC or MUTYH .
13 If routinely performed in CRC patients , it could help to diagnose MUTYH-mutation carriers , even when they don't fulfill genetic testing criteria .



PMID: 26053280
(Patient)  
Terms: phase II study
Sent# Symbols Sentence Mnemonics
0 Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients .
1 Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients , provided that they have no activating KRAS mutation in their tumour .
2 Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS .
3 We hypothesize that the activity of the RAS -induced pathway in patients with a KRAS mutation might be inhibited by simvastatin .
4 This would theoretically result in increased sensitivity to panitumumab , potentially comparable with tumours with wild-type KRAS .
5   A Simon two-stage design single-arm , phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based , oxaliplatin-based and irinotecan-based therapy .
6 The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab , aiming for atleast 40% , which is comparable with , although slightly lower than , that in KRAS wild-type patients in this setting .
7 If this 40% was reached , then the study would continue into the second step up to 46 patients .
8 Explorative correlative analysis for mutations in the KRAS and related pathways was carried out .
9 One of 14 patients was free from progression at the primary endpoint time .
10 The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks .
11 We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic .



PMID: 26050230
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer .
1 Opinion statement : The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer .
2 Epidermal growth factor receptor ( EGFR ) inhibitors have been demonstrated to improve progression-free survival ( PFS ) and overall survival ( OS ) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations .
3 Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry , as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors .
4 Μ However , expanded analyses of first - line metastatic trials reveal that other RAS mutations , such as other KRAS mutations in exons 3 and 4 , along with NRAS mutations , are predictive of poor responses to EGFR inhibitors as well .
5 Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor .
6 Further clinical trials are required to determine the predictive impact of each of these individual mutations .
7 To date , they have been analyzed in the aggregate .
8 The addition of targeted therapy , bevacizumab or an EGFR inhibitor , to a chemotherapy backbone should be considered for all appropriate patients .
9   The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition .
10   The largest trial that compared bevacizumab with an EGFR inhibitor in the first line , CALGB/SWOG 80405 , did not show a statistically significant difference between the two groups , making the use of bevacizumab , cetuximab , or panitumumab reasonable in the first line .



PMID: 26049686
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer ( NSCLC ) .
1 BACKGROUND :
2 Anaplastic lymphoma kinase ( ALK ) immunohistochemical staining on formalin-fixed paraffin-embedded tissue or cell blocks ( CB ) has been reported as an effective alternative to fluorescence hybridization in situ ( FISH ) for the detection of ALK gene rearrangement .
3 However , CB frequently lack adequate cellularity even when the direct smears are cellular .
4 This study aims to assess the utility of ALK immunocytochemical ( ICC ) staining on direct smears using the cell transfer ( CT ) technique for the detection of ALK rearrangement .
5 METHODS :
6 Fine-needle aspiration ( FNA ) cases of lung adenocarcinoma in which the ALK status had been determined by FISH on CB or a concurrent biopsy were identified .
7 ICC staining for ALK was performed on alcohol -fixed Papanicolaou-stained direct smears using the CT technique .
8 ALK immunoreactivity was evaluated using a modified semiquantitative scale .
9 Results were compared with those of FISH .
10 RESULTS :
11 A total of 47 FNA specimens were included .
12 Μ Five of 7 FISH-positive cases showed positive ALK ICC staining ( 714% ) , and 39 of 40 FISH-negative cases were negative on ALK ICC staining ( 975% ) .
13 The overall correlation between ALK ICC and FISH was 93.6% .
14 CONCLUSION :
15 ICC performed on FNA smears using the CT technique is an alternative method for the assessment of ALK rearrangement , especially when CB lack adequate cellularity .



PMID: 26045117
(Patient)  
Terms: retrospective, prospective studies
Sent# Symbols Sentence Mnemonics
0 Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients : a single institution experience .
1 AIMS AND BACKGROUND :
2 Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer ( WT MCRC ) .
3 METHODS :
4 The aim of this study is to assess if panitumumab has some activity in this setting .
5 RESULTS :
6 We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab .
7 All patients had previously received cetuximab and irinotecan ( 20 patients ) or oxaliplatin ( 5 patients ) .
8 We withdrew cetuximab for intolerance in 4 patients ( 16% ) .
9   Twenty-one patients ( 84% ) who had previously responded to cetuximab ( overall response rate [ORR] plus stable disease >/ = 5 months ) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy .
10 The median number of cycles of panitumumab was 7 ( range 1-54 ) .
11 Only 20 patients were evaluable for ORR ( 5 patients received 1-2 cycles and then died ) .
12 We observed 1 ( 5% ) partial response , 5 ( 25% ) stable disease , median duration 9 months .
13 Median progression-free survival ( PFS ) and overall survival ( OS ) were 5 ( 3-28 ) and 8 ( 5-41 ) months , respectively .
14 All patients were evaluable for toxicity .
15 No patients developed anemia or neutropenia .
16 One patient ( 4% ) developed grade 2 thrombocytopenia , 8 patients ( 32% ) grade 2-3 dry skin or rash , and 2 patients ( 8% ) grade 2 nausea-vomiting ( Common Terminology Criteria for Adverse Events version 403 ) .
17 CONCLUSIONS :
18   Our data , with all the limits of a retrospective analysis , show longer PFS and OS as compared to other series in the same setting , demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab .
19 Further confirmatory prospective studies with a larger series of patients are necessary .



PMID: 26045027
(None)  
Terms: clinical trial, This review
Sent# Symbols Sentence Mnemonics
0 Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection , dosing , patient education , prophylaxis , and management of adverse events .
1 There is a consensus that molecular testing of the lung carcinoma should be the standard of care in the clinical management of patients with lung carcinoma .
2 Recent practice guidelines in oncology and pathology recommend that all advanced and metastatic non-small - cell lung carcinoma with adenocarcinoma histology undergo biomarker testing for epidermal growth factor receptor gene ( EGFR ) mutations and anaplastic lymphoma kinase gene ( ALK ) rearrangements .
3 Other types of non-small - cell carcinoma may be considered for such testing if they occur in never-smokers .
4 The landscape of targetable biomarkers in non-small - cell carcinoma is changing rapidly , and demand for clinical testing beyond EGFR mutations and ALK gene rearrangements is increasing .
5 Many patients may test positive for other 'drivers' .
6   As a result , they may be treated with approved biomarker-driven therapies or may be eligible to receive investigational agents in clinical trials .
7 This creates challenges for treating physicians and pathologists such as obtaining sufficient tissue for molecular testing and standardisation of molecular testing in clinical laboratories .
8 This review will focus on the most important lung carcinoma biomarkers predictive of response and will discuss proposed routine molecular testing in clinical practice .



PMID: 26044119
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer .
1 [ Horizon--interpretation of ALK-positive non-small cell lung cancer Chinese story ] .



PMID: 26042813
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distinct Clinicopathological Patterns of Mismatch Repair Status in Colorectal Cancer Stratified by KRAS Mutations .
1 In sporadic colorectal cancer ( CRC ) , the BRAFV600E mutation is associated with deficient mismatch repair ( MMR ) status and inversely associated with to KRAS mutations .
2 In contrast to deficient MMR ( dMMR ) CRC , data on the presence of KRAS oncogenic mutations in proficient MMR ( pMMR ) CRC and their relationship with tumor progression are scarce .
3 We therefore examined the MMR status in combination with KRAS mutations in 913 Chinese patients and correlated the findings obtained with clinical and pathological features .
4 The MMR status was determined based on detection of MLH1 , MSH2 , MSH6 and PMS2 expression .
5 Μ KRAS mutation and dMMR status were detected in 36.9% and 7.5% of cases , respectively .
6 Four subtypes were determined by MMR and KRAS mutation status : KRAS (+) /pMMR ( 340% ) , KRAS (+) /dMMR ( 29% ) , KRAS (-) /pMMR ( 585% ) and KRAS (-) /dMMR ( 46% ) .
7 ✓ A higher percentage of pMMR tumors with KRAS mutation were most likely to be female ( 490% ) , proximal located ( 455% ) , a mucinous histology ( 384% ) , and to have increased lymph node metastasis ( 603% ) , compared with pMMR tumors without BRAFV600E and KRAS mutations ( 360% , 293% , 294% and 507% , respectively ; all P <001 ) . RO-ASS-GM
8 To the contrary , compared with those with KRAS(-)/dMMR tumors , patients with KRAS(+)/dMMR tumors demonstrated no statistically significant differences in gender , tumor location , pT depth of invasion , lymph node metastasis , pTNM stage , and histologic grade .
9 This study revealed that specific epidemiologic and clinicopathologic characteristics are associated with MMR status stratified by KRAS mutation .
10 ✓ Knowledge of MMR and KRAS mutation status may enhance molecular pathologic staging of CRC patients and metastatic progression in CRC can be estimated based on the combination of these biomarkers . GM-REG-RO



PMID: 26038390
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association between body mass index and mortality for colorectal cancer survivors : overall and by tumor molecular phenotype .
1 Pnck overexpression in HER-2 gene -amplified breast cancer causes Trastuzumab resistance through a paradoxical PTEN -mediated process .



PMID: 26035720
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Histogram analysis of iodine maps from dual energy computed tomography for monitoring targeted therapy of melanoma patients .
1 We performed a meta-analysis to assess whether blood can be substituted for tumor tissue in K-ras mutation testing .
2 PubMed , EMBASE , MEDLINE , and BIOSIS databases were searched .
3 Twenty-three studies including 1261 patients were included .
4 The pooled overall sensitivity , specificity , and concordance rate were 0.69 ( 95% CI : 0.59-0.78 ) , 0.96 ( 95% CI : 0.93-0.97 ) , and 0.86 ( 95% CI : 0.82-0.89 ) , respectively .
5 Subgroup analysis indicated that plasma ( sensitivity : 0.74 ; mutation rate : 0.34 ) exhibited superior sensitivity compared with serum ( sensitivity : 0.45 ; mutation rate : 0.24 ) .
6 We conclude that blood is a suitable substitute for tumor tissue in K-ras mutation testing .
7   K-ras mutation positivity in blood can be used to identify patients who should not receive EGFR monoclonal antibody therapy , but the absence of blood positivity does not necessarily imply negativity .



PMID: 26033452
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 .
1 Amino acids , especially leucine and glutamine , are important for tumor cell growth , survival and metabolism .
2 A range of different transporters deliver each specific amino acid into cells , some of which are increased in cancer .
3 These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression .
4 The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids .
5 In this study , we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF (WT) ( C8161 and WM852 ) and BRAF (V600E) mutant ( 1205Lu and 451Lu ) melanoma cell lines .
6 While inhibition of LAT1 by BCH did not suppress melanoma cell growth , the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells , leading to inhibition of mTORC1 signaling .
7 Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture .
8 This included reduced expression of the cell cycle regulators CDK1 and UBE2C .
9 The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown , which inhibited glutamine uptake , mTORC1 signaling and cell proliferation .
10 Taken together , our study demonstrates that ASCT2 -mediated glutamine transport is a potential therapeutic target for both BRAF (WT) and BRAF (V600E) melanoma .



PMID: 26031776
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 KRAS discordance between primary and recurrent tumors after radical resection of colorectal cancers .
1 BACKGROUND :
2 Although KRAS shows high concordance between primary and metastatic colorectal cancers , recent studies have reported discordance and intra-tumoral heterogeneity .
3 To evaluate KRAS concordance between primary colorectal cancers and recurrent tumors after radical resection , we performed this study .
4 METHODS :
5 Between January 2007 and August 2013 , among patients underwent radical resection for primary colorectal cancers and tissue sampling of recurred tumors including resection or biopsy , 74 patients whose both primary and recurred tumor tissues were available for KRAS analysis were enrolled .
6 The clinical and pathologic data were retrospectively revised and KRAS analyses were performed .
7 RESULTS :
8 The patients with initial M1 stage/NN showed significantly higher KRAS discordance rate ( 545% ) .
9 The KRAS concordance rate was 79.7% ( n = 59 ) .
10 Forty-two patients ( 568% ) showed the wild-to-wild type and 17 ( 229% ) showed the mutant-to-mutant type .
11 The discordance rate was 20.3% ( n = 15 ) .
12 Eight patients ( 108% ) showed the wild-to-mutant type , and 7 ( 95% ) showed the mutant-to-wild type .
13 Among 15 discordance cases , intra-tumoral heterogeneity was found in 26.7% ( n = 4 ) .
14 CONCLUSIONS :
15 There is 20.3% KRAS discordance between primary and recurrent tumors , which is higher rate than is generally known .
16 For selection of the effective target agent , KRAS analysis of recurred tumors will be necessary , if it is available .



PMID: 26030242
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular and histologic considerations in the assessment of serrated polyps .
1 UNLABELLED : CONTEXT : Colorectal cancer is a heterogeneous disease resulting from different molecular pathways of carcinogenesis .
2 Recent data evaluating the histologic features and molecular basis of the serrated polyp-carcinoma pathway have significantly contributed to more comprehensive classifications of and treatment recommendations for these tumors .
3 OBJECTIVE :
4 To integrate the most recent molecular findings in the context of histologic classifications of serrated lesions and their implications in diagnostic pathology and colorectal cancer surveillance .
5 DATA SOURCES : Published literature focused on serrated polyps and their association with colorectal cancer .
6 CONCLUSIONS :
7 Three types of serrated polyps are currently recognized : hyperplastic polyps , sessile serrated adenomas/polyps , and traditional serrated adenomas .
8 Μ The BRAF V600E mutation is one of the most frequent molecular abnormalities identified in hyperplastic polyps and sessile serrated adenomas .
9 Μ In contrast , in traditional serrated adenomas , either BRAF V600E or KRAS mutations can be frequently identified .
10 CpG methylation has emerged as a critical molecular mechanism in the sessile serrated pathway .
11 CpG methylation of MLH1 often leads to reduced or lost expression in dysplastic foci and carcinomas arising in sessile serrated adenomas/polyps .



PMID: 26030179
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients .
1 Colorectal cancers ( CRCs ) evolve by a reiterative process of genetic diversification and clonal evolution .
2 The molecular profile of CRC is routinely assessed in surgical or bioptic samples .
3 Genotyping of CRC tissue has inherent limitations ; a tissue sample represents a single snapshot in time , and it is subjected to spatial selection bias owing to tumor heterogeneity .
4 Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy .
5 We exploited circulating tumor DNA ( ctDNA ) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor ( EGFR )- specific antibodies cetuximab or panitumumab .
6 Μ We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes : KRAS , NRAS , MET , ERBB2 , FLT3 , EGFR and MAP2K1 .
7 Mutated KRAS clones , which emerge in blood during EGFR blockade , decline upon withdrawal of EGFR-specific antibodies , indicating that clonal evolution continues beyond clinical progression .
8 Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay , whereas the population regains drug sensitivity .
9 ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS .
10 These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade .



PMID: 26029459
(None)  
Terms: clinical trial, rat
Sent# Symbols Sentence Mnemonics
0 Acute tumour response to the MEK1/2 inhibitor selumetinib ( AZD6244 , ARRY-142886 ) evaluated by non-invasive diffusion-weighted MRI .
1 Mutations of exon 2 of rat Kirsten sarcoma viral oncogene homologue ( KRAS ) ( exon 2 codons 12/13 ) lead to constitutive activation of the EGFR ( epidermal growth factor receptor ) mediated signal transduction pathway and been shown to be a negative predictive biomarker for EGFR -directed monoclonal antibodies among patients with colorectal cancer ( CRC ) .
2 As selection of patients is very important for administration of anti-EGFR therapy , this lone biomarker has proved to be insufficient for selecting the appropriate patients as more patients lacking exon 2 KRAS mutation were resistant to anti-EGFR therapy .
3 The results of various randomized clinical trials have confirmed the presence of other RAS mutation including additional RAS mutations ( KRAS exons 3/4 and NRAS exon 1/2/3/4 ) .
4   Extended RAS analysis should be considered before initiating anti-EGFR therapy to patients of metastatic CRC .
5   This can help in proper selection of patients leading to tailored individualistic treatment , decreasing cost of treatment and the adverse effects related to use of monoclonal antibody therapy .
6   The new evidence is supporting the need to make 'Extended RAS' analysis essential before start of treatment with anti-EGFR monoclonal antibody therapy .
7 Prior to this the Extended RAS testing should be standardized .



PMID: 26029033
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The cost of systemic therapy for metastatic colorectal carcinoma in Slovenia : discrepancy analysis between cost and reimbursement .
1 BACKGROUND :
2 The aim of the study was to estimate the direct medical costs of metastatic colorectal cancer ( mCRC ) treated at the Institute of Oncology Ljubljana and to question the healthcare payment system in Slovenia .
3 METHODS :
4 Using an internal patient database , the costs of mCRC patients were estimated in 2009 by examining (1) mCRC direct medical related costs , and (2) the cost difference between payment received by Slovenian health insurance and actual mCRC costs .
5 Costs were analysed in the treatment phase of the disease by assessing the direct medical costs of hospital treatment with systemic therapy together with hospital treatment of side effects , without assessing radiotherapy or surgical treatment .
6 Follow-up costs , indirect medical costs , and nonmedical costs were not included .
7 RESULTS :
8 A total of 209 mCRC patients met all eligibility criteria .
9   The direct medical costs of mCRC hospitalization with systemic therapy in Slovenia for 2009 were estimated as the cost of medications ( cost of systemic therapy + cost of drugs for premedication ) + labor cost ( the cost of carrying out systemic treatment ) + cost of lab tests + cost of imaging tests + KRAS testing cost + cost of hospital treatment due to side effects of mCRC treatment , and amounted to euro3,914,697 .
10   The difference between the cost paid by health insurance and actual costs , estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 , was euro1,900,757.80 .
11 CONCLUSIONS :
12   The costs paid to the Institute of Oncology Ljubljana by health insurance for treating mCRC with systemic therapy do not match the actual cost of treatment .
13   In fact , the difference between the payment and the actual cost estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 was euro1,900,757.80 .
14 The model Australian Refined Diagnosis Related Groups ( AR-DRG ) for cost assessment in oncology being currently used is probably one of the reasons for the discrepancy between pay-outs and actual costs .
15 We propose new method for more precise cost assessment in oncology .



PMID: 26028667
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogenic KRAS sensitizes premalignant , but not malignant cells , to Noxa -dependent apoptosis through the activation of the MEK/ERK pathway .
1 KRAS is mutated in about 20-25% of all human cancers and especially in pancreatic , lung and colorectal tumors .
2 Oncogenic KRAS stimulates several pro-survival pathways , but it also triggers the trans-activation of pro-apoptotic genes .
3 In our work , we show that G13D mutations of KRAS activate the MAPK pathway , and ERK2 , but not ERK1 , up-regulates Noxa basal levels .
4 Accordingly , premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa -dependent manner .
5 In contrast to these findings , colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression .
6 Μ We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment , especially in presence of oncogenic KRAS .
7 In conclusion , our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene -activated pro-apoptotic stimulation .
8   On the contrary , the combination of chemotherapy to inhibitors of specific pro-survival pathways , such as the one controlled by AKT , could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation .



PMID: 26027741
(Patient)  
Terms: phase I
Sent# Symbols Sentence Mnemonics
0 Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer : Toward targeted personalized therapy .
1 Colorectal cancer ( CRC ) represents one of the most common malignancies and is major cause of cancer-related deaths worldwide .
2 A great improvement in response rate and patient's survival was recently achieved through the introduction of new targeted agents including the anti-EGFR monoclonal antibodies cetuximab and panitumumab , the anti-angiogenic drugs bevacizumab and aflibercept , as well as the multi - kinase inhibitor regorafenib , in combination with standard fluoropyrimidines-based chemotherapeutic regimens .
3 Intrinsic and acquired chemoresistance continue to be a major hindrance toward curative therapy .
4 To overcome the obstacle of the currently unpredictable inter-individual variability in the therapy outcome , concentrated research efforts have been focused on elucidating the contribution of genetic variants predictive of pharmacoresistance in CRC .
5 The occurrence of tumor somatic mutations in the RAS/RAF/MAPK and PI3K/PTEN/AKT pathways remains the main challenge for CRC treatment with the new biological agents .
6 It has been recently proposed to consider a quadruple negative profile for CRC , based on the status of KRAS exon 2 , BRAF-p .
7 V600E , PI3KCA-exon 9 and PTEN , as tumor markers of sensitivity to anti-EGFR treatment .
8 However , in the last years , great efforts have been devoted to address germline genetic profiles of pharmacoresistance .
9 Heritable genetic variants in the ABC and SLC transport pathways ; in the CYP450 , GST , and UGT -mediated phase I and II metabolism ; in the folate metabolic pathway ; as well as in the EGF and VEGF signaling pathways , have been associated with a distinct tumor sensitivity phenotype in CRC patients treated with fluoropyrimidines combined with either irinotecan , oxaliplatin or targeted biological agents .
10 More recently , computation of clinical-pharmacogenetic algorithms , combining multiple host polymorphisms with clinico-demographic features , appeared to be a more reliable strategy to test a complex phenomenon as tumor response to therapy .
11 The final goal of the pharmacogenomics research in the domain of pharmacoresistance in CRC should be the definition of integrated somatic and germline genetic profiles of both intrinsic and acquired resistance .
12 The aim of the present review is to provide a comprehensive update on the most important findings regarding the research of pharmacogenomics markers in the field of CRC treatment that could be integrated in clinical practice in order to accomplish an efficacious personalized treatment .



PMID: 26026309
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Discrepancies between the K-ras mutational status of primary colorectal cancers and corresponding liver metastases are found in codon 13 .
1 K-ras mutation status has remained elusive in the metastatic liver tumors of colorectal cancer ( CRC ) in contrast to the primary CRC tumors .
2 In this study , K-ras mutational status of the primary and corresponding liver metastatic tumors was investigated in the 43 CRC patients .
3 Codons 12 and 13 of K-ras were directly sequenced , and a K-ras mutation was evident in 17 cases ( 395% ) .
4 In 6 cases , the K-ras mutation was evident only in the liver metastasis , but not in the primary CRC , where the mutation was found in codon 13 .
5 This discrepancy between primary and metastatic lesions with regard to codon 13 of the K-ras gene may explain the clinical discrepancy of EGFR antibody therapy .
6 In conclusion , the current data may lead to the development of personalized medicine for recurrent CRC , although further validation study is still required .



PMID: 26024321
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2-b]quinoline Tri-Alkylamine Derivatives .
1 BACKGROUND :
2 A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4) , which has an important role in the regulation of KRAS transcription .
3 We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads .
4 Herein we investigated the anticancer mechanism of action of these compounds , which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression .
5 METHODOLOGY/PRINCIPAL FINDINGS :
6 IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay .
7 Μ Moreover , IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells ( IC50 <269 muM ) , without eliciting cell death in non-malignant HEK293T human embryonic kidney , and human colon fibroblasts CCD18co .
8 IQ3A compounds significantly reduced KRAS mRNA and protein steady-state levels at IC50 concentrations , and increased p53 protein steady-state levels and cell death by apoptosis in HCT116 cells ( mut KRAS , wt p53 ) .
9 Furthermore , KRAS silencing in HCT116 p53 wild-type ( p53(+/+) ) and null ( p53(-/-) ) isogenic cell lines induced a higher level of cell death , and a higher IQ3A -induced cell death in HCT116 p53(+/+) compared to HCT116 p53(-/-) .
10 CONCLUSIONS :
11 Herein we provide evidence that G4 ligands such as IQ3A compounds can target G4 motifs present in KRAS promoter , down-regulate the expression of the mutant KRAS gene through inhibition of transcription and translation , and induce cell death by apoptosis in colon cancer cell lines .
12 Thus , targeting KRAS at the genomic level with G4 ligands may be a new anticancer therapy strategy for colon cancer .



PMID: 26019684
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PIK3CA Amplification Is Common in Left Side-Tubular Adenomas but Uncommon Sessile Serrated Adenomas Exclusively with KRAS Mutation .
1 Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways , from tubular adenomas ( TAs ) and sessile serrated adenomas ( SSAs ) , which are clinically , morphologically , and molecularly different .
2 We examined PIK3CA amplification in colorectal precancerous legions , including TAs and SSAs .
3 DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs .
4 Μ PIK3CA amplification , KRAS mutation , and BRAF mutation were analyzed by real-time PCR and pyrosequencing .
5 Μ PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs , respectively .
6 KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs .
7 In TAs , PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation .
8 These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation .



PMID: 26019172
(Cell)  
Terms: Xenograft, xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models .
1 PURPOSE :
2 The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance .
3 EXPERIMENTAL DESIGN :
4 We have investigated in three models of highly epidermal growth factor receptor ( EGFR )- dependent colorectal cancer xenografts , the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab , after cytotoxic treatment induction with irinotecan plus cetuximab .
5 RESULTS :
6 SW48 , LIM 1215 , and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab .
7 The combined treatment induced a significant reduction of tumor size .
8 A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab , mice were randomly assigned to one of the following treatments : control , cetuximab , regorafenib , a selective PIK3CA inhibitor ( PIK3CAi ) , a selective MEK inhibitor ( MEKi ) , and/or the combination of each inhibitor with cetuximab .
9 The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth .
10 This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival .
11 Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways .
12 Μ Moreover , in the cetuximab plus MEKi-treated SW48 xenograft group , KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group .
13 CONCLUSIONS :
14   A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab .



PMID: 26018692
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic Alterations in Colorectal Cancer Have Different Patterns on 18F-FDG PET/CT .
1 PURPOSE :
2 The aim of this study was to understand the association between various genetic mutation and ( 18 ) F-FDG PET-related parameters in patients with colorectal cancer ( CRC ) .
3 METHODS :
4 One hundred three CRC patients who had undergone preoperative PET/CTs were included in this study .
5 Several PET/CT-related parameters , including SUV ( max ) , and various thresholds of metabolic tumor volume , total lesion glycolysis , and PET/CT-based tumor width ( TW ) were measured .
6 Μ Using high-resolution melting methods for genetic mutation analysis , tumor - and PET/CT-related parameters were correlated with various genetic alterations including TP53 , KRAS , APC , BRAF , and PIK3CA .
7 Mann-Whitney U test and logistic regression analysis were carried out for this analysis .
8 RESULTS :
9 Μ Genetic alterations in TP53 , KRAS , and APC were found in 41 ( 40% ) , 34 ( 33% ) , and 27 ( 26% ) of tumors , respectively .
10 PIK3CA and BRAF were exhibited by 5 and 4 of the patients with CRC .
11 TP53 mutants exhibited higher SUV ( max ) .
12 The odds ratio was 1.28 ( P = 004 ; 95% confidence interval , 101-161 ) .
13 Tumors with a mutated KRAS had an increased accumulation of FDG using a 40% threshold level for maximal uptake of TW ( TW ( 40% ) ) , whereas the odds ratio was 1.15 ( P = 0001 ; 95% confidence interval , 106-124 ) .
14 The accuracy of SUV ( max ) greater than 10 in predicting TP53 mutation was 60% , whereas that for TW ( 40% ) for KRAS was 61% .
15 CONCLUSIONS :
16 Increased SUV ( max ) and TW ( 40% ) were associated in CRC tumors with TP53 and KRAS mutations , respectively .
17 Further studies are required because of the low predictive accuracy .



PMID: 26010451
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Amplicon sequencing of colorectal cancer : variant calling in frozen and formalin-fixed samples .
1 Next generation sequencing ( NGS ) is an emerging technology becoming relevant for genotyping of clinical samples .
2 Here , we assessed the stability of amplicon sequencing from formalin-fixed paraffin-embedded ( FFPE ) and paired frozen samples from colorectal cancer metastases with different analysis pipelines. 212 amplicon regions in 48 cancer related genes were sequenced with Illumina MiSeq using DNA isolated from resection specimens from 17 patients with colorectal cancer liver metastases .
3 From ten of these patients , paired fresh frozen and routinely processed FFPE tissue was available for comparative study .
4 Sample quality of FFPE tissues was determined by the amount of amplifiable DNA using qPCR , sequencing libraries were evaluated using Bioanalyzer .
5 Three bioinformatic pipelines were compared for analysis of amplicon sequencing data .
6 Selected hot spot mutations were reviewed using Sanger sequencing .
7 Μ In the sequenced samples from 16 patients , 29 non-synonymous coding mutations were identified in eleven genes .
8 Most frequent were mutations in TP53 ( 10 ) , APC (7) , PIK3CA (3) and KRAS (2) .
9 Μ A high concordance of FFPE and paired frozen tissue samples was observed in ten matched samples , revealing 21 identical mutation calls and only two mutations differing .
10 Μ Comparison of these results with two other commonly used variant calling tools , however , showed high discrepancies .
11 Μ Hence , amplicon sequencing can potentially be used to identify hot spot mutations in colorectal cancer metastases in frozen and FFPE tissue .
12 However , remarkable differences exist among results of different variant calling tools , which are not only related to DNA sample quality .
13 Our study highlights the need for standardization and benchmarking of variant calling pipelines , which will be required for translational and clinical applications .



PMID: 26005835
(Cell)  
Terms: , mice
Sent# Symbols Sentence Mnemonics
0 RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth .
1 The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited .
2 Here we show that two distinct Ras nucleotide exchange factors , RasGRP1 and SOS1 , lie downstream of EGFR but act in functional opposition .
3 RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth .
4 High RasGRP1 expression in colorectal cancer ( CRC ) patient samples correlates with a better clinical outcome .
5 Μ Biochemically , we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1-Ras signals in CRC cells .
6 Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras-ERK signalling and cell proliferation .
7 The unexpected opposing cell biological effects of EGFR-RasGRP1 and EGFR-SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma .



PMID: 26005817
(Patient)  
Terms: prospective, observational study
Sent# Symbols Sentence Mnemonics
0 [ Molecular analysis of sporadic colon cancer ] .
1 BACKGROUND :
2 In Chile , colorectal cancer ( CRC ) is often diagnosed in late stages .
3 Thus , surgical treatment must be complemented with chemotherapy .
4 Μ KRAS mutations and microsatellite instability have been detected in these tumors .
5 However , the response to treatment in patients without KRAS mutations varies and requires a better understanding .
6 AIM :
7 To determine the frequency and distribution of somatic point mutations in KRAS , BRAF and PIK3CA genes and microsatellite instability status ( MSI ) in patients with colon cancer ( CC ) .
8 MATERIAL AND METHODS :
9 A prospective observational study of patients undergoing surgery for colon cancer .
10 Μ Tumor-derived DNA was analyzed by polymerase chain reaction ( PCR ) for the most frequent mutations of KRAS , BRAF and PIK3CA .
11 PCR was also used to analyze MSI .
12 RESULTS :
13 Μ Fifty-eight patients with sporadic CC were analyzed , 16 showed KRAS mutations ( G12R , G12D , G12V , G13D ) and out of the 42 patients that did not show any mutation , 10 had mutations in BRAF (V600E) and PIK3CA ( E542K , E545D , E545K , Q546E , H1047R ) .
14 Μ BRAF mutations alone or in combination with PIK3CA mutations were observed in 27% of high MSI tumors and in 2% of tumors without instability ( p <0049 ) .
15 Μ A higher percentage of high MSI tumors were located in the right colon ( p <0001 ) , and showed BRAF mutation ( p <0020 ) .
16 CONCLUSIONS :
17 Μ The highest percentage of high MSI and BRAF mutations was observed in the right colon .
18 Therefore , this study suggests the presence of different molecular features between right and left colon tumors that should be considered when defining the therapeutic management .



PMID: 26005530
(None)  
Terms: in vivo, xenograft, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 N- ( 3-Ethynyl-2,4-difluorophenyl ) sulfonamide Derivatives as Selective Raf Inhibitors .
1 A series of N- ( 3-ethynyl-2,4-difluorophenyl ) sulfonamides were identified as new selective Raf inhibitors .
2 The compounds potently inhibit B-Raf ( V600E ) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases .
3 They strongly suppress proliferation of a panel of human cancer cell lines and patient-derived melanoma cells with B-Raf ( V600E ) mutation while being significantly less potent to the cells with B-Raf ( WT ) .
4 The compounds also display favorable pharmacokinetic properties with a preferred example ( 3s ) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-Raf ( V600E ) mutated Colo205 human colorectal cancer cells , supporting it as a promising lead compound for further anticancer drug discovery .



PMID: 26003673
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer .
1 High resolution melting analysis for epidermal growth factor receptor mutations in formalin-fixed paraffin-embedded tissue and plasma free DNA from non-small cell lung cancer patients .



PMID: 26001389
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets .
1 OBJECTIVE :
2 Microsatellite instability ( MSI ) is detected in approximately 15% of all colorectal cancers ( CRC ) and virtually in all cases with Lynch syndrome .
3 The MSI phenotype is caused by dysfunctional mismatch repair ( MMR ) and leads to accumulation of DNA replication errors .
4 Sporadic MSI CRC often harbours BRAF (V600E) ; however , no consistent data exist regarding targeted treatment approaches in BRAF ( wt ) MSI CRC .
5 DESIGN :
6 Μ Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded ( FFPE ) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry .
7 Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors , EGFR -directed antibody cetuximab , HER2 -directed antibody trastuzumab and siRNA -mediated ERBB2/HER2 knockdown .
8 RESULTS :
9 Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy ( area under curve = 09998 ) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms ( p = 0008 ) .
10 Μ Characterisation of BRAF ( wt ) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers , including KRAS ( 387% ) , PIK3CA ( 365% ) , and ERBB2 ( 150% ) .
11 L755S and V842I substitutions in ERBB2 were highly recurrent .
12 Μ Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors .
13 CONCLUSIONS :
14 Μ We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens .
15 We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC .



PMID: 25998052
(Cell)  
Terms: in vitro, in vivo, xenograft, mice
Sent# Symbols Sentence Mnemonics
0 Cetuximab-oxaliplatin-liposomes for epidermal growth factor receptor targeted chemotherapy of colorectal cancer .
1 Oxaliplatin ( L-OH ) , a platinum derivative with good tolerability is currently combined with Cetuximab ( CTX ) , a monoclonal antibody ( mAb ) , for the treatment of certain ( wild-type KRAS ) metastatic colorectal cancer ( CRC ) expressing epidermal growth factor receptor ( EGFR ) .
2 Improvement of L-OH pharmacokinetics ( PK ) can be provided by its encapsulation into liposomes , allowing a more selective accumulation and delivery to the tumor .
3 Here , we aim to associate both agents in a novel liposomal targeted therapy by linking CTX to the drug -loaded liposomes .
4 These EGFR-targeted liposomes potentially combine the therapeutic activity and selectivity of CTX with tumor - cell delivery of L-OH in a single therapeutic approach .
5 L-OH liposomes carrying whole CTX or CTX-Fab' fragments on their surface were designed and characterized .
6 Their functionality was tested in vitro using four human CRC cell lines , expressing different levels of EGFR to investigate the role of CTX-EGFR interactions in the cellular binding and uptake of the nanocarriers and encapsulated drug .
7 Next , those formulations were evaluated in vivo in a colorectal cancer xenograft model with regard to tumor drug accumulation , toxicity and therapeutic activity .
8 In EGFR-overexpressing cell lines , intracellular drug delivery by targeted liposomes increased with receptor density reaching up to 3-fold higher levels than with non-targeted liposomes .
9 Receptor specific uptake was demonstrated by competition with free CTX , which reduced internalization to levels similar to non-targeted liposomes .
10 In a CRC xenograft model , drug delivery was strongly enhanced upon treatment with targeted formulations .
11 Liposomes conjugated with monovalent CTX-Fab' fragments showed superior drug accumulation in tumor tissue ( 29160+/-50784ng/g ) compared to CTX liposomes ( 154602+/-36241ng/g ) or non-targeted liposomes ( 89106+/-1551ng/g ) .
12 Concomitantly , CTX-Fab' targeted L-OH liposomes outperformed CTX-liposomes , which on its turn was still more efficacious than non-targeted liposomes and free drug treatment in CRC bearing mice .
13 These results show that site -directed conjugation of monovalent CTX-Fab' provides targeted L-OH liposomes that display an increased tumor drug delivery and efficacy over a formulation with CTX and non-targeted liposomes .



PMID: 25999741
(None)  
Terms: Phase II
Sent# Symbols Sentence Mnemonics
0 A randomized Phase II clinical study of combining panitumumab and bevacizumab , plus irinotecan , 5-fluorouracil , and leucovorin (FOLFIRI) compared with FOLFIRI alone as second - line treatment for patients with metastatic colorectal cancer and KRAS mutation .
1 [ Prerequisites to the administration and prevention of adverse effects of chemotherapy in colorectal cancer ] .



PMID: 25997687
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS status in Korean patients with stage III and IV colorectal cancer .
1 DNA alterations of microsatellite DNA , p53 , APC and K-ras in Chinese colorectal cancer patients .



PMID: 25994739
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PIK3CA Somatic Mutation Status in Relation to Patient and Tumor Factors in Racial/Ethnic Minorities with Colorectal Cancer .
1 BACKGROUND :
2 Approximately 10% to 20% of colorectal cancers exhibit somatic mutations in the phosphoinositide-3-kinase , catalytic , alpha polypeptide gene (PIK3CA) .
3 We evaluated the relationship of PIK3CA mutation status in colorectal cancer with race/ethnicity , colorectal cancer survival , and other patient and tumor factors .
4 METHODS :
5 This study comprised 377 racial/ethnic minorities with incident invasive colorectal cancer , enrolled in the Colon Cancer Family Registry via population-based cancer registries .
6 Tumor specimens were tested for PIK3CA mutations in exon 9 and 20 hotspots , BRAF p.V600E mutations , and DNA mismatch repair ( MMR ) .
7 In logistic regression models , we evaluated the association between PIK3CA mutation status and race/ethnicity , overall , and by mutation site .
8 Using Cox regression , we evaluated the association between PIK3CA mutation status and survival after colorectal cancer diagnosis .
9 RESULTS :
10 Μ PIK3CA mutations were detected in 42 cases ( 11% ) , with a similar prevalence across racial/ethnic groups .
11 Individuals with PIK3CA-mutated colorectal cancer were significantly more likely than those with PIK3CA-wildtype disease to have proximal colon cancer , MMR-deficient tumors , and a germline MMR mutation ( P
12 There was no evidence for an association between PIK3CA and overall survival ( HR , 077 ; 95% confidence interval , 043-139 ) .
13 CONCLUSIONS :
14 Μ The prevalence of PIK3CA mutation status in colorectal cancer does not differ according to race/ethnicity , but may vary according to other relevant clinicopathologic and etiologic factors , including germline MMR mutation status , tumor MMR status , and tumor site .
15 Μ IMPACT : These findings underscore the importance of PIK3CA mutation status in colorectal cancer epidemiology and provide evidence that the prevalence of such mutations is similar across several racial/ethnic groups .



PMID: 25993166
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Overcoming Resistance to Anti-EGFR Therapy in Colorectal Cancer .
1 Our understanding of the genetic and nongenetic molecular alterations associated with anti-epidermal growth factor receptor ( EGFR ) therapy resistance in colorectal cancer ( CRC ) has markedly expanded in recent years .
2 Mutations in RAS genes ( KRAS/NRAS exons 2 , 3 , or 4 ) predict a lack of clinical benefit when anti-EGFR monoclonal antibodies ( mAbs ) are added to chemotherapy .
3 ✓ Genetic events in additional nodes of the mitogen -activated protein kinase ( MAPK )- phosphoinositide 3-kinase ( PI3K ) pathways that bypass EGFR signaling , such as BRAF or PIK3CA mutations or KRAS , ERBB2 , or MET amplifications , also may confer resistance to cetuximab or panitumumab .
4 Polymorphisms that block antibody binding as a result of EGFR extracellular domain mutations have been reported .
5 Nongenetic mechanisms , including compensatory activation of receptor tyrosine kinases HER3 and MET , together with high expression of the ligands amphiregulin , transforming growth factor alpha heregulin , and hepatocyte growth factor in the tumor microenvironment also are thought to be involved in resistance .
6 Μ In one-third of the samples , more than one genetic event can be found , and nongenetic events most likely coexist with gene alterations .
7 Furthermore , activation of a gene expression signature of epithelial-mesenchymal transition has been associated with reduced cellular dependence on EGFR signaling .
8 Collectively , this body of work provides convincing evidence that the molecular heterogeneity of CRC plays an important role in the context of resistance to anti-EGFR therapy .
9 Herein , we discuss how this knowledge has been translated into drug development strategies to overcome primary and acquired anti-EGFR resistance , with rational combinations of targeted agents in genomically selected populations , second-generation EGFR inhibitors , and other agents expected to boost the immune response at the tumor site .



PMID: 25990448
(None)  
Terms: In vitro, In vivo, mouse models, mouse, transgenic mouse, mice
Sent# Symbols Sentence Mnemonics
0 Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme .
1 Brain metastases are a major cause of mortality in patients with advanced melanoma .
2 Adequate brain distribution of targeted agents for melanoma will be critical for treatment success .
3 Recently , improvement in overall survival led to US Food and Drug Administration ( FDA ) approval of the v-raf murine sarcoma viral oncogene homolog B ( BRAF ) inhibitors , vemurafenib and dabrafenib , and the mitogen-activated protein kinase kinase -1 ( MEK ) -1/2 inhibitor , trametinib .
4 However , brain metastases and emergence of resistance remain a significant problem .
5 MEK-1/2 is downstream of BRAF in the mitogen -activated protein kinase ( MAPK ) signaling pathway , making it an attractive target to combat resistance .
6 The recently approved combination of dabrafenib and trametinib has shown improvement in progression-free survival ; however , adequate brain distribution of both compounds is required to effectively treat brain metastases .
7 In previous studies , we found limited brain distribution of dabrafenib .
8 The purpose of the current study was to investigate factors influencing the brain distribution of trametinib .
9 In vitro studies indicated that trametinib is a substrate for both P-glycoprotein ( P-gp ) and Bcrp , efflux transporters found at the blood-brain barrier .
10 In vivo studies in transgenic mouse models confirmed that P-gp plays an important role in restricting brain distribution of trametinib .
11 The brain-to-plasma partition coefficient ( AUCbrain/AUCplasma ) was approximately 5-fold higher in Mdr1a/b ( (-/-) ) ( P-gp knockout ) and Mdr1a/b ( (-/-) ) Bcrp1 ( (-/-) ) ( triple knockout ) mice when compared with wild-type and Bcrp1 ( (-/-) ) ( Bcrp knockout ) mice .
12 The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice .
13   These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases .



PMID: 25989278
(Patient)  
Terms: Meta-analysis, meta-analysis
Sent# Symbols Sentence Mnemonics
0 ✓ Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer . GM-MRK-RO
1 BACKGROUND :
2 Metastatic colorectal cancer ( mCRC ) that harbours a BRAF V600E mutation ( BRAF MT ) is associated with poorer outcomes .
3 However , whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies ( mAbs ) is uncertain .
4 METHODS :
5 We conducted a systematic review and meta-analysis of randomised controlled trials ( RCTs ) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC .
6 RESULTS :
7 Seven RCTs met the inclusion criteria for assessment of overall survival ( OS ) , whereas eight RCTs met the inclusion criteria for assessment of progression-free survival ( PFS ) .
8 For RAS WT/BRAF MT tumours , the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 ( 95% CI ; 067-141 ) , whereas the hazard ratio was 0.81 ( 95% CI ; 070-095 ) for RAS WT/BRAF WT tumours .
9 However , the test of interaction ( P = 043 ) was not statistically significant , highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone .
10 Regarding PFS benefit with anti-EGFR mAbs , the hazard ratio was 0.86 ( 95% CI ; 061-121 ) for RAS WT/BRAF MT tumours as compared with 0.62 ( 95% CI ; 050-077 ) for RAS WT/BRAF WT tumours ( test of interaction , P = 007 ) .
11 INTERPRETATION : This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals .
12   As such , there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC .



PMID: 25989270
(Patient)  
Terms: Phase I study, phase II
Sent# Symbols Sentence Mnemonics
0 Phase I study of FOLFIRI plus pimasertib as second - line treatment for KRAS-mutated metastatic colorectal cancer .
1 BACKGROUND :
2 The mitogen -activated protein kinase ( MAPK ) pathway has been implicated in the molecular pathogenesis of human cancers , including metastatic colorectal cancer ( mCRC ) .
3 This provides a rationale for the development of MAPK-targeted agents such as pimasertib .
4 METHODS :
5 Patients with KRAS mutant mCRC were treated in the second - line setting with FOLFIRI ( 5-fluorouracil/folinic acid/irinotecan ) plus pimasertib .
6 The primary objective of the safety run-in phase was to determine the maximum-tolerated dose ( MTD ) and the recommended phase II dose of pimasertib combined with FOLFIRI .
7 RESULTS :
8 Sixteen patients were enrolled in the trial .
9 Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI , respectively .
10 The MTD was considered to be 45 mg per day .
11 The most common treatment-emergent adverse events were diarrhoea , nausea , vomiting , asthenia and skin/rash event .
12 Of the 15 patients in the efficacy analysis group , two patients had partial response , nine patients had stable disease , three patients had progressive disease as their best overall response and one patient could not be evaluated .
13 CONCLUSIONS :
14 Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity .
15 At the MTD of 45 mg per day , pimasertib was adequately tolerated in patients with mCRC and no unexpected or new safety signals or concerns were identified .



PMID: 25983749
(Patient)  
Terms: , rabbit, mouse
Sent# Symbols Sentence Mnemonics
0 KRAS and BRAF Mutation Detection : Is Immunohistochemistry a Possible Alternative to Molecular Biology in Colorectal Cancer ?
1 KRAS genotyping is mandatory in metastatic colorectal cancer treatment prior to undertaking antiepidermal growth factor receptor (EGFR) monoclonal antibody therapy .
2 BRAF V600E mutation is often present in colorectal carcinoma with CpG island methylator phenotype and microsatellite instability .
3 Currently , KRAS and BRAF evaluation is based on molecular biology techniques such as SNaPshot or Sanger sequencing .
4 As molecular testing is performed on formalin-fixed paraffin-embedded ( FFPE ) samples , immunodetection would appear to be an attractive alternative for detecting mutations .
5 Thus , our objective was to assess the validity of KRAS and BRAF immunodetection of mutations compared with the genotyping reference method in colorectal adenocarcinoma .
6 KRAS and BRAF genotyping was assessed by SNaPshot .
7 A rabbit human anti-KRAS polyclonal antibody was tested on 33 FFPE colorectal tumor samples with known KRAS status .
8 Additionally , a mouse human anti-BRAF monoclonal antibody was tested on 30 FFPE tumor samples with known BRAF status .
9 Μ KRAS immunostaining demonstrated both poor sensitivity ( 27% ) and specificity ( 64% ) in detecting KRAS mutation .
10 ✓ Μ Conversely , BRAF immunohistochemistry showed perfect sensitivity ( 100% ) and specificity ( 100% ) in detecting V600E mutation . GE-ASS-SR
11 Although molecular biology remains the reference method for detecting KRAS mutation , immunohistochemistry could be an attractive method for detecting BRAF V600E mutation in colorectal cancer .



PMID: 25982297
(Patient)  
Terms: Phase II Study, rat
Sent# Symbols Sentence Mnemonics
0 SPIRITT : A Randomized , Multicenter , Phase II Study of Panitumumab with FOLFIRI and Bevacizumab with FOLFIRI as Second - Line Treatment in Patients with Unresectable Wild Type KRAS Metastatic Colorectal Cancer .
1 BACKGROUND :
2 Second - line treatment with chemotherapy and anti-epidermal growth factor receptor or anti-vascular endothelial growth factor antibodies improves outcomes in patients with wild rat type Kirsten sarcoma viral oncogene homolog ( KRAS ) metastatic colorectal cancer ( mCRC ) .
3 The choice of biological agent in second - line mCRC remains unclear .
4 In this randomized , phase II estimation trial , we compared FOLFIRI ( irinotecan , 5-fluorouracil , and leucovorin ) in combination with panitumumab or bevacizumab in patients with disease progression during oxaliplatin-based chemotherapy and bevacizumab .
5 PATIENTS AND METHODS :
6 One hundred eighty-two patients were randomized to FOLFIRI with panitumumab or bevacizumab .
7 The primary end point was progression-free survival ( PFS ) .
8 Secondary end points included overall survival ( OS ) , objective response rate ( ORR ) , and safety .
9 RESULTS :
10 PFS was similar between arms , with a hazard ratio ( HR ) of 1.01 ( 95% confidence interval [CI] , 0.68-1.50 ; P = .97 ) .
11 Median PFS was 7.7 months ( 95% CI , 57-118 ) in the panitumumab arm and 9.2 months ( 95% CI , 78-106 ) in the bevacizumab arm .
12 OS was also similar between arms , with an HR of 1.06 ( 95% CI , 075-149 ; P = 75 ) .
13 Median OS was 18.0 months ( 95% CI , 135-217 ) in the panitumumab arm and 21.4 months ( 95% CI , 165-246 ) in the bevacizumab arm .
14 ORR was 32% ( 95% CI , 23%-43% ) in the panitumumab arm and 19% ( 95% CI , 11%-29% ) in the bevacizumab arm .
15 Skin disorders , diarrhea , hypomagnesemia , hypokalemia , dehydration , and hypotension were more frequent in the panitumumab arm .
16 Neutropenia was more frequent in the bevacizumab-containing arm .
17 CONCLUSION :
18   Panitumumab or bevacizumab with FOLFIRI as second - line treatment had efficacy similar in patients whose disease progressed during oxaliplatin-based chemotherapy with bevacizumab , with expected toxicities .
19   The development of more accurate biomarkers might help caregivers and patients to better choose between therapies for individual patients .



PMID: 25979833
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Location of colon cancer ( right-sided versus left-sided ) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17 .
1 BACKGROUND :
2 Right - and left-sided colon cancers ( RC , LC ) differ with respect to biology , pathology and epidemiology .
3 Previous data suggest a mortality difference between RC and LC .
4 We examined if primary tumour side also predicts for outcome in chemotherapy refractory , metastatic colon cancer ( MCC ) .
5 We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor ( EGFR ) inhibition with cetuximab .
6 METHODS :
7 Reanalyzing NCIC CO.17 trial ( cetuximab versus best supportive care [BSC] ) , we coded the primary tumour side as RC ( caecum to transverse colon ) or LC ( splenic flexure to rectosigmoid ) .
8 The association between tumour side and baseline characteristics was assessed .
9 Cox regression models determined factors affecting overall survival ( OS ) and progression free survival ( PFS ) .
10 RESULTS :
11 Patients with RC ( 150/399 ) had more poorly differentiated , mutant KRAS , mutated PIK3CA and wild-type BRAF tumours , fewer liver and lung metastases , and shorter interval between diagnosis and study entry .
12 Among BSC patients , tumour side was not prognostic for PFS ( hazard ratios ( HR ) 1.07 [079-144] , p = 0.67 ) or OS ( HR 0.96 [070-131] , p = 0.78 ) .
13   Among wild-type KRAS patients , those with LC had significantly improved PFS when treated with cetuximab compared to BSC ( median 5.4 versus 1.8 months , HR 0.28 [018-045] , p <0.0001 ) , whereas those with RC did not ( median 1.9 versus 1.9 months , HR 0.73 [042-127] , p = 0.26 ) , [interaction p = 0002] .
14 CONCLUSION :
15   In refractory MCC , tumour location within the colon is not prognostic , but is strongly predictive of PFS benefit from cetuximab therapy .
16 Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition .



PMID: 25977643
(Patient)  
Terms: , mouse model, mouse, mice, Syngeneic tumors
Sent# Symbols Sentence Mnemonics
0 MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF .
1 Toll-like receptors ( TLRs ) play a crucial role in the innate and adaptive immune responses against microbial infection , tissue injury and cancer .
2 Ligands of TLR9 have been developed as therapy in non-small-cell lung carcinoma ( NSCLC ) .
3 However , phase III clinical trials in metastatic NSCLC were negative .
4 Our objective was to determine whether TLR9 affects tumor growth .
5 We generated a mouse model of lung adenocarcinoma ( ADC ) mutated for K-ras ( K-ras ( LA1 ) ) , with and without TLR9 inactivation ( K-ras ( LA1 ) TLR9(-/-) and K-ras ( LA1 ) TLR9(+/+) , respectively ) .
6 TLR9 was functionally expressed only in mononuclear cells of K-ras ( LA1 ) TLR9(+/+) mice .
7 These mice had significantly worse survival and a higher tumor burden than K-ras ( LA1 ) TLR9(-/-) mice .
8 Lung tumors were analyzed for 24 cytokines/growth factors using Bio-Plex multiplex bead-based assays .
9 Factor VIII was assessed by immunochemistry .
10 Tumors from K-ras ( LA1 ) TLR9(+/+) mice were characterized by an angiogenic phenotype with higher concentrations of vascular endothelial growth factor ( VEGF ) and higher microvessel density than from K-ras ( LA1 ) TLR9(-/-) mice .
11 LKR13 cells , an ADC cell line derived from K-ras ( LA1 ) mice , were subcutaneously injected into TLR9(-/-) and TLR9(+/+) mice .
12 Syngeneic tumors regressed in TLR9(-/-) but not in TLR9(+/+) mice .
13 Peripheral blood mononuclear cells from TLR9(-/-) mice released less VEGF than those from TLR9(+/+) mice .
14 In 61 patients with early-stage NSCLC , TLR9 was expressed in mononuclear cells that infiltrated tumors , as assessed by immunochemistry , and contributed to worse survival .
15 Our results suggest that TLR9 expression in mononuclear cells was associated with an angiogenic phenotype and promoted lung cancer progression .
16 These findings may aid clinical development of TLR9 ligands to treat cancers .



PMID: 25976417
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prediagnostic Physical Activity and Colorectal Cancer Survival : Overall and Stratified by Tumor Characteristics .
1 BACKGROUND :
2 Physical activity is associated with a lower incidence of colorectal cancer ; however , the relationship of physical activity with colorectal cancer survival is not yet clear .
3 We evaluated the association between prediagnostic physical activity and colorectal cancer survival , overall and accounting for tumor markers associated with colorectal cancer survival : BRAF and KRAS mutation status and microsatellite instability ( MSI ) status .
4 METHODS :
5 Participants were 20 - to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry ( S-CCFR ) .
6 Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week ( MET-h/wk ; n = 1,309 ) .
7 Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients ( n = 1043 ) .
8 Cox regression was used to estimate HRs and 95% confidence intervals ( CI ) for overall and disease-specific survival after adjusting for relevant confounders .
9 Stratified analyses were conducted across categories of BRAF , KRAS , and MSI , as well as tumor stage and site .
10 RESULTS :
11 Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival ( HR for highest vs. lowest category , 070 ; 95% CI , 052-096 ) ; associations were similar for colorectal cancer-specific survival .
12 Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics .
13 CONCLUSION :
14 Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active .
15 IMPACT :
16 Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer .



PMID: 25975986
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PTEN Methylation Dependent Sinonasal Mucosal Melanoma .
1   Changing monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer patients : is efficacy maintained .



PMID: 25975908
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Detection of KRAS , NRAS and BRAF gene mutations in colorectal carcinoma ] .
1 OBJECTIVE :
2 To investigate mutations frequencies of KRAS , NRAS and BRAF genes in colorectal carcinoma .
3 METHODS :
4 Μ Tissue specimens from 200 colorectal cancer patients at diagnosis were collected and subject to KRAS , NRAS and BRAF mutation analyses by PCR-based direct DNA sequencing targeting exons 2 , 3 and 4 of KRAS gene , exons 2 , 3 and 4 of NRAS gene and exon 15 of BRAF gene .
5 RESULTS :
6 Μ Activating mutations were detected in KRAS ( 44% , 88/200 ) , NRAS ( 2% , 4/200 ) and BRAF ( 5% , 10/200 ) in this study cohort .
7 Μ Among KRAS mutations , 64.8% ( 57/88 ) occurred in codon 12 and 12.5% ( 11/88 ) occurred in codon 13 .
8 KRAS gene mutation in exon 3 mainly involved codons 59 and 61 .
9 KRAS gene mutation in exon 4 mainly involved codons 117 and 146 .
10 CONCLUSIONS :
11 Mutations at exon 2 of KRAS gene have the highest frequency in colorectal carcinoma .
12   Expanding the detection sites of KRAS gene combined with NRAS and BRAF genes may help to identify patients who will most likely benefit from targeted therapies .



PMID: 25975014
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of high-resolution melting analysis , Sanger sequencing and ARMS for KRAS mutation detection in metastatic colorectal cancer .
1 BACKGROUND :
2 Μ Treatment of metastatic colon carcinoma with the anti-epidermal growth factor receptor antibody cetuximab/panitumumab is reported to be ineffective in KRAS-mutant tumors ; therefore , it is necessary to perform KRAS mutation analysis before cetuximab or panitumumab treatment is initiated .
3 METHODS :
4 This study was designed to compare and evaluate the efficacy of three different methodologies--high resolution melting ( HRM ) , Sanger sequencing , and Amplification Refractory Mutation System ( ARMS ) --for KRAS mutation detection in a clinical setting .
5 RESULTS :
6 In total , 55 samples from patients with metastatic colorectal cancer were analyzed .
7 Compared to Sanger sequencing , good consistency was found between the results of the ARMS ( Kappa = 0839 ) and HRM ( Kappa = 0839 ) .
8 The sensitivities of the methods were compared after a consensus was reached : if two of the three methodologies showed a similar result , it was considered as the consensus result .
9 Μ The frequency of KRAS mutations in our population was 34.5% , and discordant findings were observed in five samples .
10 No significant difference in sensitivity was found among the three methodologies .
11 CONCLUSIONS :
12 From the results , we can conclude that after careful in-laboratory validation , HRM is a good alternative to the ARMS and Sanger sequencing for KRAS mutation testing .



PMID: 25974029
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era .
1 INTRODUCTION :
2 Fluorescence in situ hybridization ( FISH ) is currently the standard for diagnosing anaplastic lymphoma kinase ( ALK )- rearranged ( ALK+ ) lung cancers for ALK inhibitor therapies .
3 ALK immunohistochemistry ( IHC ) may serve as a screening and alternative diagnostic method .
4 The Canadian ALK ( CALK ) study was initiated to implement a multicenter optimization and standardization of laboratory developed ALK IHC and FISH tests across 14 hospitals .
5 METHODS :
6 Twenty-eight lung adenocarcinomas with known ALK status were used as blinded study samples .
7 Thirteen laboratories performed IHC using locally developed staining protocols for 5A4 , ALK1 , or D5F3 antibodies ; results were assessed by H-score .
8 Twelve centers conducted FISH using protocols based on Vysis' ALK break-apart FISH kit .
9 Initial IHC results were used to optimize local IHC protocols , followed by a repeat IHC study to assess the results of standardization .
10 Three laboratories conducted a prospective parallel IHC and FISH analysis on 411 consecutive clinical samples using post-validation optimized assays .
11 RESULTS :
12 Among study samples , FISH demonstrated 22 consensus ALK+ and six ALK wild type tumors .
13 Preoptimization IHC scores from 12 centers with 5A4 and the percent abnormal cells by FISH from 12 centers showed intraclass correlation coefficients of 0.83 and 0.68 , respectively .
14 IHC optimization improved the intraclass correlation coefficients to 0.94 .
15 Factors affecting FISH scoring and outliers were identified .
16 Post-optimization concurrent IHC/FISH testing in 373 informative cases revealed 100% sensitivity and specificity for IHC versus FISH .
17 CONCLUSIONS :
18 Multicenter standardization study may accelerate the implementation of ALK testing protocols across a country/region .
19 Our data support the use of an appropriately validated IHC assay to screen for ALK+ lung cancers .



PMID: 25974027
(Cell)  
Terms: in-vitro
Sent# Symbols Sentence Mnemonics
0 AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells .
1 Human cutaneous melanoma is an aggressive and chemotherapy-resistant type of cancer .
2 AM251 is a cannabinoid type 1 ( CB1 ) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells .
3 The current study aimed to characterize the in-vitro antimelanoma activity of AM251 .
4 The BRAF V600E mutant melanoma cell line , A375 , was used as an in-vitro model system .
5 Characterization tools included a cell viability assay , nuclear morphology assessment , gene expression , western blot , flow cytometry with Annexin V-FITC/7-AAD double staining , cell cycle analyses , and measurements of changes in intracellular cAMP and calcium concentrations .
6 AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability .
7 AM251 , at a concentration that approximates the IC50 , downregulated genes encoding antiapoptotic proteins ( BCL2 and survivin ) and increased transcription levels of proapoptotic BAX , induced alteration of Annexin V reactivity , DNA fragmentation , chromatin condensation in the cell nuclei , and G2/M phase arrest .
8 AM251 also induced a 40% increase in the basal cAMP levels , but it did not affect intracellular calcium concentrations .
9 The involvement of GPR55 , TRPA1 , and COX-2 in the AM251 mechanism of action was excluded .
10 The combination of AM251 with celecoxib produced a synergistic antitumor activity , although the mechanism underlying this effect remains to be elucidated .
11 This study provides the first evidence of a proapoptotic effect and G2/M cell cycle arrest of AM251 on A375 cells .
12 This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma .



PMID: 25973534
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer .
1 [ Acquired resistance mechanisms to EGFR-TKIs in EGFR mutated lung cancers ] .



PMID: 25973306
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A specific KRAS codon 13 mutation is an independent predictor for colorectal cancer metachronous distant metastases .
1 Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers .



PMID: 25973297
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of ALK expression in non-small - cell lung cancer with ALK gene rearrangements--comparison of multiple immunohistochemical methods .
1 Advanced colorectal cancer is characterized by uncontrolled growth and resistance against anti-cancer agents , including ErbB inhibitors .
2 Recent data suggest that cancer stem cells ( CSC ) are particularly resistant .
3 These cells may reside within a CD133+ fraction of the malignant cells .
4 Using HCT116 cells we explored the role of CD133 and other CSC markers in drug resistance in colon cancer cells .
5 CD133+ cells outnumbered CD133 - cells over time in long-term culture .
6 Both populations displayed the KRAS mutation 38G >A and an almost identical target profile , including EGFR/ErbB1 , ErbB2 , and ErbB4 .
7 Μ Microarray analyses and flow cytometry identified CD26 as additional CSC marker co-expressed on CD133+ cells .
8 However , knock-down of CD133 or CD26 did not affect short-term growth of HCT116 cells , and both cell -populations were equally resistant to various targeted drugs except irreversible ErbB inhibitors , which blocked growth and ERK1/2 phosphorylation in CD133 - cells more efficiently than in CD133+ cells .
9 Moreover , the MEK inhibitor AS703026 was found to overcome resistance against ErbB blockers in CD133+ cells .
10 Together , CD133 and CD26 are markers of long-term growth and resistance to ErbB blockers in HCT116 cells , which may be mediated by constitutive ERK activity .



PMID: 25972331
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Endoscopic ultrasound fine-needle aspiration cytology mutation profiling using targeted next-generation sequencing : personalized care for rectal cancer .
1 BACKGROUND :
2 PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer .
3 We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers .
4 METHODS :
5 Intraoperative image-guided core-needle biopsies ( CNB ) , and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer .
6 Specimens were assessed with reverse-phase protein arrays ( RPPA ) and immunohistochemistry ( IHC ) .
7 RESULTS :
8 There was a moderate or strong correlation between the expression of 149 ( 97% ) of the 154 different RPPA markers in the center and periphery .
9   Correlation was higher for smaller tumors , in patients who did not undergo neoadjuvant therapy , and with shorter cold ischemia time .
10 Of 154 markers , 132 ( 86% ) were not statistically different between the center and periphery , and 97 ( 63% ) were not different between the CNB and the surgical specimen ( average of the central and peripheral specimen ) .
11 pAkt S473 and PTEN had a significant correlation between central and peripheral specimens , and between CNB and surgical specimen .
12 However , pAkt S473 , pS6 S235/236 , and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC .
13 CONCLUSIONS :
14 Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity .
15 However , protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables .
16 PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation , or with cold ischemia of surgical specimens .



PMID: 25970543
(Patient)  
Terms: prospective, retrospective
Sent# Symbols Sentence Mnemonics
0 Immune response gene expression in colorectal cancer carries distinct prognostic implications according to tissue , stage and site : a prospective retrospective translational study in the context of a hellenic cooperative oncology group randomised trial .
1 BACKGROUND :
2 Although host immune response is an emerging prognostic factor for colorectal cancer , there is no consensus on the optimal methodology , surrogate markers or tissue for study .
3 PATIENTS AND METHODS :
4 Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer ( CRC ) treated with adjuvant chemotherapy .
5 Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z , CD8 , CD4 , CXCL9 , CXCL13 , IGHM , FOXP3 , SNAI2 and ESR1 by qRT-qPCR in tissue microarray ( TMA ) cores from the centre of tumour , invasive margin and adjacent normal mucosa .
6 RESULTS :
7 Lymphocytic infiltration , deficient MMR ( 109% ) , KRAS ( 407% ) and BRAF ( 49% ) mutations or single mRNA gene expression were not prognostic .
8 Tumour ESR1 gene expression ( Hazard Ratio [HR] for relapse 2.33 , 95% CI 1.35-4.02 ; HR for death 1.74 , 95% CI 1.02-2.97 ) and absence of necrosis ( HR for relapse 171 , 95% CI 105-271 ; HR for death 198 , 95% CI 114-343 ) were adverse prognostic features .
9 We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score ( mIS ) and proceeded to partitioning analysis in 267 patients , with age , stage , tumour site ( Right versus Left CRC ) , KRAS mutation and tumour mIS as input factors .
10 Only in patients with stage III right-sided colon cancer , a low immune response was associated with inferior disease-free survival ( mIS-low , HR for relapse 228 , 95% CI 105-802 ) .
11 No prognostic significance was seen for tumour mIS in any other stage or site of CRC , or for a similar mIS score derived from adjacent normal mucosa .
12 Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis , tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC .
13 CONCLUSIONS :
14 In localised CRC , mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage , site and tissue -specific prognostic significance , along with ESR1 expression .
15 TRIAL REGISTRATION : ANZCTR .
16 org .
17 au ACTRN12610000509066 .



PMID: 25968046
(None)  
Terms: , genetically engineered mouse, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 CT textural analysis of hepatic metastatic colorectal cancer : pre-treatment tumor heterogeneity correlates with pathology and clinical outcomes .
1 A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma .



PMID: 25965827
(Patient)  
Terms: xenograft, PDX, Xenograft, tumor engraftment in patient-derived xenograft models, mice
Sent# Symbols Sentence Mnemonics
0 Correlation between tumor engraftment in patient-derived xenograft models and clinical outcomes in colorectal cancer patients .
1 Despite numerous studies involving patient-derived xenograft ( PDX ) models , few studies have investigated the relationship between the ability of the tumor to engraft ( tumorigenicity ) and the clinical features of colorectal cancer ( CRC ) .
2 The aim of this study was to determine whether tumorigenicity correlates with clinical outcomes of CRC patients .
3 We included 241 CRC patients who underwent radical surgery from 2010 to 2013 .
4 PDX models were established by implanting tumor fragments obtained from these patients into the subcutaneous layer of immunodeficient mice .
5 Xenografts were successfully established from 62.2% .
6 Successful engraftment was associated with advanced stage ( p <0001 ) and moderate/poor differentiation ( p = 0029 ) .
7 Three-year disease-free survival ( DFS ) rates were lower for patients with tumorigenicity ( p = 0011 ) .
8 In stage III patients , tumorigenicity was an independent predictor of poor DFS ( p = 0034 ) .
9 Μ In addition , mutation of TP53 was most frequently detected in stage III patients with tumorigenicity .
10 ✓ Μ Two models of stage IV disease without KRAS mutations showed high sensitivity to EGFR-targeted agents , while none of the models with KRAS mutations showed high sensitivity . GM-ASS-SR
11 In conclusion , PDX models may provide an effective preclinical tool for predicting cancer progression and could be used to further genomic and pharmacologic research on personalized treatments .



PMID: 25965366
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PD-L1 blockade for cancer treatment : MEDI4736 .
1 BACKGROUND :
2 CMET represents an emerging therapy target for monoclonal antibodies and tyrosine kinase inhibitors in non-small cell lung cancer ( NSCLC ) .
3 METHODS :
4 We investigated CMET gene amplification status by fluorescence in-situ hybridization ( FISH ) and CMET protein expression by immunohistochemistry in a large series of 209 NSCLC brain metastases ( BM ; 165 adenocarcinoma , 20 squamous cell carcinoma , 11 adenosquamous carcinomas , 11 large cell carcinomas and two large cell neuroendocrine carcinomas ) and correlated our results to clinic-pathological parameters and molecular data from previous studies .
5 RESULTS :
6 Μ We found CMET gene amplification in 36/167 ( 216% ) and CMET protein expression in 87/196 ( 444% ) of evaluable BM .
7 There was a strong correlation between the presence of CMET gene amplification and CMET protein expression ( P <0001 , chi-square test ) .
8 Furthermore , presence of CMET amplification correlated positively with presence of ALK amplifications ( P = 0039 , chi-square test ) and high HIF1 alpha index ( P = 0013 , Mann-Whitney U-test ) .
9 ✓ Neither CMET expression nor CMET gene amplification status correlated with patient outcome parameters or known prognostic factors . GE-ASS-RO
10 CONCLUSIONS :
11 Μ CMET overexpression and CMET amplification are commonly found in NSCLC BM and may represent a promising therapeutic target .



PMID: 25963019
(Patient)  
Terms: phase II study, phase II trial, NCT01126112
Sent# Symbols Sentence Mnemonics
0 First - line single-agent panitumumab in frail elderly patients with wild-type KRAS metastatic colorectal cancer and poor prognostic factors : A phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours .
1 BACKGROUND :
2 Frail elderly patients with metastatic colorectal cancer ( mCRC ) are not candidates for chemotherapy .
3 Monotherapy with anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies may be an option for these patients with few systemic toxic effects .
4 PATIENTS AND METHODS :
5 Single-arm , multicentre , phase II trial including patients 70y ears with wild-type ( WT ) KRAS ( exon 2 ) mCRC , Eastern Cooperative Oncology Group ( ECOG ) status 3 , KPC ( Kohne Prognostic Classification ) --defined intermediate or high risk status , frailty and/or ineligibility for chemotherapy .
6 Patients received panitumumab until progression or unacceptable toxicity .
7 The primary end-point was progression free survival ( PFS ) rate at 6 months .
8 RESULTS :
9 The study included 33 patients ( intention-to-treat ( ITT ) population ) .
10 Median age : 81 years ; sex : 66.7% male ; high-risk KPC status : 45.4% .
11 Median treatment duration was 14 weeks and 6-month PFS rate was 36.4% ( 95% confidence interval ( CI ) : 20.0-52.8 ) .
12 The objective response rate : 9.1% ( 95% CI : 0-18.9 ) ( all partial responses ) , and there were 18 stable diseases ( 545% ) .
13 Median PFS was 4.3 months ( 95% CI : 2.8-6.4 ) and median overall survival ( OS ) was 7.1 months ( 95% CI : 5.0-12.3 ) .
14 There were no deaths or grade 4-5 adverse events ( AEs ) related to panitumumab and the most common grade 3-related AE was rash acneiform ( 152% ) .
15 A significant association between clinical response and RAS status was observed ( P = 0037 ) .
16 ✓ In the WT RAS subgroup ( WT exons 2 , 3 , and 4 of KRAS and NRAS , N = 15 ) , 6-month PFS rate was 53.3% ( 95% CI : 30.1-75.2 ) and median PFS and OS were 7.9 and 12.3 months , respectively . GM-ASS-RO
17 CONCLUSIONS :
18   Single-agent panitumumab is active and well tolerated and may be a therapeutic option for high-risk frail elderly patients with WT RAS tumours considered not candidates for chemotherapy ( clinicaltrialsgov identifier NCT01126112 ) .



PMID: 25961376
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells .
1 BACKGROUND :
2 Chemotherapy combinations and addition of cetuximab or bevacizumab to chemotherapy have been shown to improve overall survival of metastatic colorectal cancer ( CRC ) patients .
3 However , the efficacy of cetuximab when administered after bevacizumab failure is still unknown .
4 METHODS :
5 Fifty-eight consecutive patients diagnosed with advanced colorectal cancer between treated with cetuximab following irinotecan failure were included in our analysis .
6 A multivariate Cox model analysis was performed to estimate the effect of previous bevacizumab regimen on survival .
7 RESULTS :
8 Thirteen ( 224% ) were pre-treated with anti-VEGF agents .
9   None of them responded to cetuximab , and this subgroup presented a significantly decreased disease-specific survival as compared to treatment-naive patients ( 91 months vs. 49 months ; p = 0026 ) .
10 This difference remained statistically significant in a multivariate Cox model after adjusting for age , sex , performance status ( PS ) , and K-RAS status ( RR = 2.2 ; 95% CI : 1.1-4.5 , p = 0.03 ) .
11 CONCLUSION :
12 These study results suggest that a previous anti-VEGF therapy decrease cetuximab efficiency .



PMID: 25960722
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Familial breast cancer - targeted therapy in secondary and tertiary prevention .
1 The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment .
2 Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen .
3 The identification of an unaltered gene in tumor tissue in colon cancer ( KRAS ) is a predictor for the patient's response to targeted therapy with a monoclonal antibody ( cetuximab ) .
4 Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014 .
5 This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors ( PARPi ) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and , in particular , BRCA-associated breast cancer .
6 Details of the mechanism of action with information on tumor development are provided , and an outlook for further relevant research is given .
7 The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles .
8   Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi .



PMID: 25956750
(Patient)  
Terms: clinical trial, phase III
Sent# Symbols Sentence Mnemonics
0 Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin ( CAPOX ) with the combination of 5-fluorouracil , leucovorin and oxaliplatin ( modified FOLFOX6 ) as adjuvant therapy in patients with operated high-risk stage II or stage III colorectal cancer .
1 BACKGROUND :
2 The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer ( CRC ) .
3 METHODS :
4 Patients were assigned to oxaliplatin , leucovorin and 5-FU for 12 cycles ( group A , FOLFOX6 ) or oxaliplatin and capecitabine for eight cycles ( group B , CAPOX ) .
5 Primary endpoint was disease-free survival ( DFS ) .
6 Tumors were classified as mismatch repair proficient ( pMMR ) or deficient ( dMMR ) according to MLH1 , PMS2 , MSH2 and MSH6 protein expression .
7 KRAS exon two and BRAF V600E mutational status were also assessed .
8 RESULTS :
9 Between 2005 and 2008 , 441 patients were enrolled , with 408 patients being eligible .
10 After a median follow-up of 74.7 months , 3-year DFS was 79.8 % ( 95 % CI 765-834 ) in the FOLFOX group and 79.5 % ( 95 % CI 759-831 ) in the CAPOX group ( p = 078 ) .
11 Three-year OS was 87.2 % ( 95 % CI 841-911 ) in the FOLFOX and 86.9 % ( 95 % CI 834-899 ) in the CAPOX group ( p = 084 ) .
12 Among 306 available tumors , 11.0 % were dMMR , 34.0 % KRAS mutant and 4.9 % BRAF mutant .
13 Multivariate analysis showed that primary site in the left colon , earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival ( OS ) , while grade one-two tumors were associated with better OS .
14 Finally , a statistically significant interaction was detected between the primary site and MMR status ( p = 0010 ) , while KRAS mutated tumors were associated with shorter DFS .
15 However , the sample was too small for safe conclusions .
16 CONCLUSIONS :
17   No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients , but definitive conclusions cannot be drawn because of the small sample size .
18 TRIAL REGISTRATION :
19 ANZCTR 12610000509066 .
20 Date of Registration : June 21 , 2010 .



PMID: 25956209
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Impact of early tumour shrinkage and resection on outcomes in patients with wild-type RAS metastatic colorectal cancer .
1 The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11 , with consequent activation of the MAPK pathway .
2 Selective MEK inhibitors , such as selumetinib , have shown clinical benefit in uveal melanoma .
3 However , mechanisms of drug resistance limit their efficacy in some patients .
4 Μ Analysis of MEK inhibitor -resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity .
5 This effect was mediated by the RNA helicase DDX43 , which was remarkably overexpressed in these cells .
6 Depletion of DDX43 in MEK inhibitor -resistant cells decreased RAS proteins and inhibited ERK and AKT pathways .
7 On the contrary , ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition .
8 Similar to DDX43 depletion , downregulation of KRAS , HRAS , and NRAS inhibited downstream pathways in the resistant cells , overcoming mutant GNAQ signaling .
9   Μ We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR , and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy .
10 In conclusion , DDX43 induces RAS protein expression and signaling , mediating a novel mechanism of MEK inhibitor resistance .
11   The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease .



PMID: 25956187
(Patient)  
Terms: prospective, rat
Sent# Symbols Sentence Mnemonics
0 Maintenance Therapy With Cetuximab Every Second Week in the First - Line Treatment of Metastatic Colorectal Cancer : The NORDIC-7.5 Study by the Nordic Colorectal Cancer Biomodulation Group .
1 BACKGROUND :
2 In the NORDIC-7.5 trial , how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected rat Kirsten sarcoma viral oncogene homolog wild type ( KRASwt ) metastatic colorectal cancer ( mCRC ) was investigated .
3 Patients were treated in a multicenter phase II trial with cetuximab in combination with the Nordic bolus FLOX ( oxaliplatin , 5-fluorouracil , and folinic acid ) for 4 months followed by maintenance cetuximab .
4 PATIENTS AND METHODS :
5 Patients had KRASwt , nonresectable mCRC , no previous chemotherapy , and Eastern Cooperative Group performance status of 0 to 2 .
6 Patients received 8 courses of Nordic FLOX ( oxaliplatin 85 mg/m(2) over 1 hour on day 1 , and 5-fluorouracil 500 mg/m(2) as a bolus injection , followed 30 minutes later with bolus folinic acid 60 mg/m(2) on days 1 and 2 ) .
7 Cetuximab was administered every 2 weeks at a dose of 500 mg/m(2) for 16 weeks followed by cetuximab as maintenance therapy until disease progression .
8 RESULTS :
9 Between July 2008 and September 2010 , 152 KRASwt patients were included .
10 The response rate was 62% ( 95% confidence interval [CI] , 54%-69% ) , median progression-free survival was 8.0 months ( 95% CI , 75-89 ) and median overall survival was 23.2 ( 95% CI , 181-274 ) months .
11 Twenty-one patients ( 14% ) had later R0-resection of metastasis .
12 FLOX with cetuximab was reintroduced in 47 of 85 patients ( 55% ) .
13 The most common Grade 3/4 nonhematologic adverse events were diarrhea in 14 patients ( 9% ) , skin rash in 13 patients ( 9% ) , infection without neutropenia in 11 patients ( 7% ) , and fatigue in 11 patients ( 7% ) .
14 CONCLUSION :
15 In a prospectively selected KRASwt population , biweekly cetuximab was safely integrated in an intermittent chemotherapy strategy and might have added to a longer chemotherapy-free interval .
16   However , the combination of biweekly cetuximab with chemotherapy needs to be validated in trials using FOLFOX ( oxaliplatin , fluorouracil , and leucovorin ) or FOLFIRI ( irinotecan , fluorouracil , and leucovorin ) .



PMID: 25954997
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing .
1 Microsatellite unstable gastrointestinal neuroendocrine carcinomas : a new clinicopathologic entity .



PMID: 25950441
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detection of K-ras Mutations in Predicting Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase ( EGFR-TK ) Inhibitor in Patients with Metastatic Colorectal Cancer .
1 A RAS renaissance : emerging targeted therapies for KRAS-mutated non-small cell lung cancer .



PMID: 25946211
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of genetic and epigenetic alterations of primary tumors and matched plasma samples in patients with colorectal cancer .
1 BACKGROUND :
2 Although recent advances in circulating DNA analysis allow the prediction of tumor genomes by noninvasive means , some challenges remain , which limit the widespread introduction of cfDNA in cancer diagnostics .
3 We analyzed the status of the two best characterized colorectal cancer ( CRC ) genetic and epigenetic alterations in a cohort of CRC patients , and then compared the degree to which the two patterns move from tissue to plasma in order to improve our understanding of biology modulating the concordance between tissues and plasma methylation and mutation profiles .
4 METHODS :
5 Plasma and tumor tissues were collected from 85 patients ( 69+/-14 years , 56 males ) .
6 KRAS and SEPT9 status was assessed by allele refractory mutation system quantitative PCR and quantitative methylation-specific PCR , respectively .
7 Μ Six of the most common point mutations at codon 12 and 13 were investigated for KRAS analysis .
8 RESULTS :
9 KRAS mutations and SEPT9 promoter methylation were present in 34% ( 29/85 ) and in 82% ( 70/85 ) of primary tumor tissue samples .
10 Μ Both genetic and epigenetic analyses of cfDNA revealed a high overall concordance and specificity compared with tumor - tissue analyses .
11 Μ Patients presenting with both genetic and epigenetic alterations in tissue specimens ( 318% , 27/85 ) were considered for further analyses .
12 The median methylation rates in tumour tissues and plasma samples were 64.5% ( 122-998% ) and 14.5% ( 0-455% ) , respectively .
13 The median KRAS mutation load ( for matched mutations ) was 33.6% ( 18-863% ) in tissues and 2.9% ( 0-173 ) in plasma samples .
14 The plasma/tissue ( p/t ) ratio of SEPT9 methylation rate was significantly higher than the p/t ratio of KRAS mutation load , especially in early stage cancers ( p = 00108 ) .
15 CONCLUSION :
16 The results of this study show a discrepant rate of epigenetic vs.genetic alterations moving from tissue to plasma .
17 Μ Many factors could affect mutation cfDNA analysis , including both presence of tumor clonal heterogeneity and strict compartmentalization of KRAS mutation profile .
18 The present study highlights the importance of considering the nature of the alteration when analyzing tumor-derived cfDNA .



PMID: 25944693
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS testing in metastatic colorectal cancer : excellent reproducibility amongst 17 Dutch pathology centers .
1 A novel antagonist to the inhibitors of apoptosis ( IAPs ) potentiates cell death in EGFR-overexpressing non-small - cell lung cancer cells .



PMID: 25943534
(Patient)  
Terms: In vitro, In vivo, xenograft, clinical trial, mouse
Sent# Symbols Sentence Mnemonics
0 Identification and Characterization of MEDI4736 , an Antagonistic Anti-PD-L1 Monoclonal Antibody .
1 Programmed cell-death 1 ligand 1 ( PD-L1 ) is a member of the B7/CD28 family of proteins that control T - cell activation .
2 Many tumors can upregulate expression of PD-L1 , inhibiting antitumor T - cell responses and avoiding immune surveillance and elimination .
3 Μ We have identified and characterized MEDI4736 , a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody -dependent cell-mediated cytotoxicity .
4 In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function , blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T - cell activation .
5 In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells .
6 This activity is entirely dependent on the presence of transplanted T cells , supporting the immunological mechanism of action for MEDI4736 .
7 To further determine the utility of PD-L1 blockade , an mouse anti-PD-L1 antibody was investigated in immunocompetent mice .
8 Here , mouse anti-PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells .
9 The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin , which resulted in increased release of HMGB1 within CT26 tumors .
10   Taken together , our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models , and suggest it may be a promising therapeutic approach for the treatment of cancer .
11 MEDI4736 is currently in several clinical trials both alone and in combination with other agents , including anti-CTLA-4 , anti-PD-1 , and inhibitors of IDO , MEK , BRAF , and EGFR .



PMID: 25943333
(Patient)  
Terms: Prospective study, prospective
Sent# Symbols Sentence Mnemonics
0 Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab .
1 BACKGROUND :
2 The aim of our study was to evaluate whether a panel of biomarkers , prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone .
3 METHODS :
4 K-RAS ( exons 2 , 3 , 4 ) wild type colorectal cancer patients , candidates to second/third - line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile : favourable ( BRAF and PIK3CA exon 20 wild type , EGFR GCN >/= 26 , HER-3 Rajkumar score
5 After the introduction of N-RAS status ( exons 2 , 3 , 4 ) only RAS wild type patients were considered eligible .
6 Primary aim was response rate ( RR ) .
7 To detect a difference in terms of RR among patients with an unfavourable profile ( estimated around 25% ) and patients with a favourable profile ( estimated around 60% ) , with a probability alpha of 0.05 and beta of 0.05 , required sample size was 46 patients .
8 Secondary endpoints were progression free survival ( PFS ) and overall survival ( OS ) .
9 RESULTS :
10 Forty-six patients were enrolled .
11 Seventeen patients ( 37% ) were allocated to the favourable and 29 patients ( 63% ) to the unfavourable profile .
12 RR in the favourable and unfavourable group was 11/17 ( 65% ) and 2/29 ( 7% ) ( p = 0007 ) respectively .
13 The favourable group also showed an improved PFS ( 8 months vs. 3 months , p <00001 ) and OS ( 15 months vs. 6 months , p <00001 ) .
14 CONCLUSIONS :
15 Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcome .



PMID: 25943321
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 p16 Hypermethylation and KRAS Mutation Are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with Metastatic Colorectal Cancer .
1 PURPOSE :
2 Hypermethylation of the CpG island of p16 ( INK4a ) occurs in a significant proportion of colorectal cancer ( CRC ) .
3 We aimed to investigate its predictive role in CRC patients treated with 5-fluorouracil , leucovorin , irinotecan ( FOLFIRI ) , and cetuximab .
4 MATERIALS AND METHODS :
5 Μ Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 CpG island loci ( p16 , p14 , MINT1 , MINT2 , MINT31 , and hMLH1 ) in DNA extracted from formalin-fixed paraffin-embedded specimens .
6 Logistic regression and Cox regression were performed for analysis of the relation between methylation status of CpG island methylator phenotype ( CIMP ) markers including p16 and clinical outcome .
7 RESULTS :
8 Μ Hypermethylation of the p16 gene was detected in 14 of 49 patients ( 286% ) and showed significant association with KRAS mutation ( Fisher exact , p = 001 ) and CIMP positivity ( Fisher exact , p = 0002 ) .
9 Patients with p16-unmethylated tumors had significantly longer time to progression ( TTP ; median , 90 months vs. 35 months ; log-rank , p = 0001 ) and overall survival ( median , 449 months vs. 164 months ; log-rank , p = 0008 ) than those with p16-methylated tumors .
10 Patients with both KRAS and p16 aberrancy ( n = 6 ) had markedly shortened TTP ( median , 28 months ) compared to those with either KRAS or p16 aberrancy ( n = 11 ; median , 86 months ; p = 0021 ) or those with neither ( n = 32 ; median , 90 months ; p <00001 ) .
11 ✓ Μ In multivariate analysis , KRAS mutation and p16 methylation showed independent association with shorter TTP ( KRAS mutation : hazard ratio [HR] , 3.21 ; p = 0.017 ; p16 methylation : HR , 2.97 ; p = 0.027 ) . GM-ASS-RO
12 CONCLUSION :
13   Hypermethylation of p16 was predictive of clinical outcome in metastatic CRC patients treated with cetuximab and FOLFIRI , irrespective of KRAS mutation .



PMID: 25942399
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MET genetic lesions in non-small - cell lung cancer : pharmacological and clinical implications .
1 Μ Characterization of S628N : a novel KIT mutation found in a metastatic melanoma .



PMID: 25937522
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer .
1 First - line crizotinib versus chemotherapy in ALK-positive lung cancer .



PMID: 25936694
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel approach to detect KRAS/BRAF mutation for colon cancer : Highly sensitive simultaneous detection of mutations and simple pre-treatment without DNA extraction .
1 It has been reported that colon cancer patients with KRAS and BRAF mutations that lie downstream of epidermal growth factor receptor ( EGFR ) acquire resistance against therapy with antiEGFR antibodies , cetuximab and panitumumab .
2 On the other hand , some reports say KRAS codon 13 mutation (pG13D) has lower resistance against anti-EGFR antibodies , thus there is a substantial need for detection of specific KRAS mutations .
3 We have established a state-of-the-art measurement system using QProbe ( QP ) method that allows simultaneous measurement of KRAS codon 12/13 , p.G13D and BRAF mutation , and compared this method against Direct Sequencing ( DS ) using 182 specimens from colon cancer patients .
4 In addition , 32 biopsy specimens were processed with a novel pre-treatment method without DNA purification in order to detect KRAS/BRAF .
5 As a result of KRAS mutation measurement , concordance rate between the QP method and DS method was 81.4% ( 144/177 ) except for the 5 specimens that were undeterminable .
6 Among them , 29 specimens became positive with QP method and negative with DS method .
7 BRAF was measured with QP method only , and the mutation detection rate was 3.9% ( 6/153 ) .
8 KRAS measurement using a simple new pre-treatment method without DNA extraction resulted in 31 good results out of 32 , all of them matching with the DS method .
9 We have established a simple but highly sensitive simultaneous detection system for KRAS/BRAF .
10 Moreover , introduction of the novel pre-treatment technology eliminated the inconvenient DNA extraction process .
11 From this research achievement , we not only anticipate quick and accurate results returned in the clinical field but also contribution in improving the test quality and work efficiency .



PMID: 25934891
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Gefitinib and afatinib treatment in an advanced non-small cell lung cancer ( NSCLC ) patient undergoing hemodialysis .
1   The predictive value of KRAS , NRAS , BRAF , PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer : A systematic review and meta-analysis .



PMID: 25934695
(None)  
Terms: In Vivo, In Vitro, in vivo
Sent# Symbols Sentence Mnemonics
0 Colorectal Carcinogenesis : Connecting K-RAS-Induced Transformation and CREB Activity In Vitro and In Vivo .
1 UNLABELLED :
2 Oncogenic transformation is often associated with an increased expression of the cAMP response element binding ( CREB ) transcription factor controlling the expression of genes involved in cell proliferation , cell cycle , apoptosis , and tumor development , but a link between K-RAS ( V12 )- induced transformation and CREB has not yet been determined .
3 Therefore , the constitutive and/or inhibitor -regulated mRNA and protein expression of CREB and signal transduction components and growth properties of parental fibroblasts , K-RAS (V12)- transformed counterparts , shCREB K-RAS (V12) transfectants and human colon carcinoma cells were determined .
4 Μ Increased CREB transcript and protein levels accompanied by an enhanced CREB activity was detected in K-RAS ( V12 )- transformed murine fibroblasts and K-RAS ( V12 )- mutated human tumor cells , which is dependent on the MAPK/MEK , PI3K , and/or PKC signal transduction .
5 Μ Immunohistochemical ( IHC ) staining of colorectal carcinoma lesions and murine tumors , with known KRAS gene mutation status , using antibodies specific for CREB and phospho-CREB , revealed a mechanistic link between CREB expression and K-RAS ( V12 )- mutated colorectal carcinoma lesions when compared with control tissues .
6 Silencing of CREB by shRNA and/or treatment with a CREB inhibitor (KG-501) reverted the neoplastic phenotype of K-RAS ( V12 ) transformants as demonstrated by a more fibroblast-like morphology , enhanced apoptosis sensitivity , increased doubling time , decreased migration , invasion and anchorage -independent growth , reduced tumorigenesis , and enhanced immunogenicity in vivo .
7 The impaired shCREB -mediated invasion of K-RAS ( V12 ) transformants was accompanied by a transcriptional downregulation of different matrix metalloproteinases ( MMP ) coupled with their reduced enzymatic activity .
8 IMPLICATIONS :
9 CREB plays a key role in the K-RAS ( V12 )- mediated neoplastic phenotype and represents a suitable therapeutic target for murine and human K-RAS ( V12 )- induced tumors .



PMID: 25933688
(None)  
Terms: in vivo, xenograft, mouse, mouse xenograft, mouse xenograft model
Sent# Symbols Sentence Mnemonics
0 Protein tyrosine phosphatase receptor -like genes are frequently hypermethylated in sporadic colorectal cancer .
1 The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials .
2 Similarly to EGFR , MET signals through the RAS-RAF-ERK/MAPK pathway which plays key roles in cell proliferation and survival .
3 Μ Mutations of genes encoding for RAS proteins , particularly in KRAS , are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway .
4 It was shown for EGFR , that KRAS mutations render upstream EGFR inhibition ineffective in EGFR-positive colorectal cancers .
5 Currently , there are no clinical studies evaluating MET inhibition impairment due to RAS mutations .
6 To test the impact of RAS mutations on MET targeting , we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V , G12D , G13D and HRAS G12V variants .
7 We demonstrate that these MAPK -activating RAS mutations differentially interfere with MET -mediated biological effects of MET inhibition .
8 We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition .
9 Consequently , RAS variants counteracted MET inhibition-induced morphological changes as well as anti-proliferative and anchorage -independent growth effects .
10 The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126 .
11 In an in vivo mouse xenograft model , MET-driven tumors harboring mutated RAS displayed resistance to MET inhibition .
12 ✓ Taken together , our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed .



PMID: 25932046
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Wide-field multiplexed imaging of EGFR-targeted cancers using topical application of NIR SERS nanoprobes .
1 AIMS :
2 To assess diagnostic value of Carbohydrate Antigen 19-9 ( CA 19-9 ) , combined CA 19-9 and K-ras mutation in plasma DNA in diagnosing patients with pancreatic carcinoma .
3 MATERIALS AND METHODS :
4 MEDLINE , EMBASE , the Cochrane Library , Sinomed , CNKI and other databases , from established to November , 2013 , were searched for initial studies .
5 All the studies published in English or Chinese relating to the diagnostic value of CA 19-9 and K-ras gene mutation for patients with pancreatic cancer were collected .
6 Methodological quality was assessed .
7 The statistic software called "Meta-disc" ( version 14 ) was used for data analysis .
8 RESULTS :
9 10 studies were included in this meta-analysis .
10 ✓ The pooled sensitivity estimate for CA 19-9 ( 78% ) was significantly higher than K-ras mutation ( 65% ) . SR-ASS-GM
11 While , for the specificity estimate , K-ras mutation ( 93% ) was significantly higher than CA 19-9 ( 77% ) .
12 The pooled DOR estimate for K-ras mutation ( 2182 ) was significantly higher than CA 19-9 ( 1836 ) .
13 SROC curves for K-ras mutation showed better diagnostic accuracy than CA 19-9 .
14 For CA 19-9 measurement , its diagnostic value decreased in differentiating pancreatic cancer for patients with pancreatitis , especially chronic process .
15 CONCLUSION :
16 CA 19-9 was a high sensitive and K-ras was a high specific method in diagnosing patients with pancreatic cancer .
17 These two modalities probably act different roles during different conditions in diagnosing pancreatic carcinoma .



PMID: 25932044
(Patient)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Biology of colorectal cancer .
1 Colorectal cancer is a serious health problem , a challenge for research , and a model for studying the molecular mechanisms involved in its development .
2 According to its incidence , this pathology manifests itself in three forms : family , hereditary , and most commonly sporadic , apparently not associated with any hereditary or familial factor .
3 For the types having inheritance patterns and a family predisposition , the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour .
4 It has been established that environmental and hereditary factors contribute to the development of colorectal cancer , as indicated by the accumulation of mutations in oncogenes , genes which suppress and repair DNA , signaling the existence of various pathways through which the appearance of tumours may occur .
5 In the case of the suppressive and mutating tracks , these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma .
6 ✓ Moreover , alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer . GM-ASS-RO
7 This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer .



PMID: 25929517
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal carcinomas with KRAS codon 12 mutation are associated with more advanced tumor stages .
1 BACKGROUND :
2 KRAS mutation occurs in 35%-40% of colorectal cancer ( CRC ) .
3 The aim of our study was to evaluate the pathological and molecular features of specific KRAS mutated colorectal carcinomas .
4 KRAS and BRAF (V600E) mutation tests were performed in 762 primary tumors from a consecutive cohort study of Chinese CRC patients .
5 METHODS :
6 DNA mismatch repair ( MMR ) status was determined by immunohistochemistry ( IHC ) staining .
7 Assessment of KRAS and BRAF V600E mutational status was performed using a multiplex allele -specific PCR-based assay .
8 RESULTS :
9 Mutations of KRAS ( 348% ) and BRAF (V600E) ( 31% ) were nearly mutually exclusive .
10 Both KRAS - and BRAF - mutated tumors were more likely to be located at proximal colon than wild-type ( WT ) carcinomas .
11 Μ KRAS-mutated carcinomas were more frequently observed in female patients ( 475% versus 371% , p = 0005 ) and mucinous differentiation ( 347% versus 248% , p = 0004 ) , but have no difference between lymph node ( LN ) metastases and among pTNM stages .
12 Μ Whereas , BRAF-mutated carcinomas more frequently demonstrated histologic features such as proximal location ( 609% versus 209% , p = 0001 ) , low-grade histology ( 435% versus 180% , p = 0005 ) , mucinous differentiation ( 696% versus 259% , p = 0001 ) and deficient MMR ( dMMR ) ( 217% versus 76% , p = 003 ) .
13 In particular , KRAS codon 12 mutated carcinomas had increased lymph node metastasis ( odds ratio [OR] = 1.31 ; 95% confidence interval [CI] = 1.04 to 1.65 ; P = 0.02 ) and were more likely in higher disease stage ( III-IV ) than that of WT carcinomas ( OR = 130 ; 95% CI = 103 to 164 ; P = 003 ) .
14 However , there were no significant differences in lymph node metastasis and disease stage between KRAS codon 13 mutated carcinoma and WT carcinoma patients .
15 CONCLUSIONS :
16 ✓ In summary , KRAS codon 12 mutation , but not codon 13 mutation , is associated with lymph node metastasis and higher tumor stages . GM-ASS-RO



PMID: 25928322
(Cell)  
Terms: xenograft, In vitro, mice, mice xenograft
Sent# Symbols Sentence Mnemonics
0 miR-21 and miR-145 cooperation in regulation of colon cancer stem cells .
1 BACKGROUND :
2 Acquired drug resistance is one of the major reasons for failing cancer therapies .
3 Although the reasons are not fully understood , they may be related to the presence of cancer stem cells ( CSCs ) .
4 We have reported that chemo-resistant ( CR ) colon cancer cells , highly enriched in CSCs , exhibit a marked up-regulation of miR-21 and that down-regulation of this miR renders the CR cells more susceptible to therapeutic regimens .
5 However , the underlying molecular mechanism is poorly understood .
6 The aim of this investigation is to unravel this mechanism .
7 METHODS :
8 The levels of miR-145 and miR-21 were manipulated by transfection of mature , antago-miRs or pCMV/miR-145 expression plasmid .
9 Quantitative RT-PCR or/and Western blots were performed to examine the expression of CD44 , beta-catenin , Sox-2 , PDCD4 , CK-20 and k-Ras .
10 Colonosphere formation and SCID mice xenograft studies were performed to evaluate the tumorigenic properties of CSC-enriched colon CR cells .
11 RESULTS :
12 We investigated the role that microRNAs ( miRs ) , specifically miR-21 and miR-145 play in regulating colon CSCs .
13 Μ We found the expression of miR-21 to be greatly increased and miR-145 decreased in CR colon cancer cells that are highly enriched in CSC , indicating a role for these miRNAs in regulating CSCs .
14 Μ In support of this , we found that whereas forced expression of miR-145 in colon cancer cells greatly inhibits CSCs and tumor growth , up-regulation of miR-21 causes an opposite phenomenon .
15 In addition , administration of mature miR-145 or antagomir-21 ( anti-sense miR-21 ) greatly suppresses the growth of colon cancer cell xenografts in SCID mice .
16 This was associated with decreased expression of CD44 , beta-catenin , Sox-2 and induction of CK-20 indicating that administration of miR-145 or antagomir-21 decreases CSC proliferation and induces differentiation .
17 In vitro studies further demonstrate that miR-21 negatively regulates miR-145 and vice versa .
18 k-Ras appears to play critical role in regulation of this process , as evidenced by the fact that the absence of k-Ras in CR colon cancer cells increases miR-145 expression , suppresses miR-21 , and interrupts the negative cooperation between miR-21 and miR-145 .
19 CONCLUSIONS :
20 Our current observations suggest that miR-21 , miR-145 , and their networks play critical roles in regulating CSCs growth and/or differentiation in the colon cancer and progression of chemo-resistance .



PMID: 25928067
(Cell)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Downregulated Long Noncoding RNA BANCR Promotes the Proliferation of Colorectal Cancer Cells via Downregualtion of p21 Expression .
1 BRAF activated non-coding RNA ( BANCR ) , a long non-coding RNA ( lncRNA ) , is crucial for cell migration in melanoma cells and non-small cell lung cancer ( NSCLC ) cells .
2 However , little is known regarding the role of this gene in the proliferation of colorectal cancer .
3 Therefore , we investigated the involvement of BANCR in the proliferation of colorectal cancer cells .
4 In this study , we show that BANCR expression was significantly down-regulated in colorectal cancer tissues compared with normal tissues , and overexpression of BANCR suppressed colorectal cancer cell growth in vitro and in vivo .
5 We also determined that pCDNA-BANCR -mediated colorectal cancer cell proliferation was associated with induction of G0/G1 cell -cycle arrest and apoptosis enhancement through regulation of p21 , and its effects were most likely posttranscriptional .
6 Taken together , our findings suggest that down-regulation of BANCR contributes to the proliferation of colorectal cancer cells , atleast in part , through the regulation of p21 protein .



PMID: 25926745
(Patient)  
Terms: prospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 The significance of combining VEGFA , FLT1 , and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab .
1 Targeting angiogenesis through inhibition of the vascular endothelial growth factor ( VEGF ) pathway has been successful in the treatment of late stage colorectal cancer .
2 However , not all patients benefit from inhibition of VEGF .
3 Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy ; however , an appropriate biomarker for response to anti-VEGF therapy is yet to be identified .
4   VEGF and its receptors , FLT1 and KDR , play a crucial role in colon cancer progression ; individually , these factors have been shown to be prognostic in colon cancer ; however , expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy .
5 Μ In the present study , we analyzed the expression levels of VEGFA , FLT1 , and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis .
6 The observation was further confirmed in another independent colon cancer dataset , wherein high levels of expression of this three - gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status , or mutant p53 status .
7 Most importantly , this signature also predicted tumor response to bevacizumab , an antibody targeting VEGFA , in a cohort of bevacizumab-treated patients .
8   Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer , our results suggest that the three - gene signature approach is valuable in terms of its prognostic value , and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment .



PMID: 25926053
(Cell)  
Terms: , tumour-specific preclinical models
Sent# Symbols Sentence Mnemonics
0 The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets .
1 The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients .
2 Μ Here we describe the mutational and gene expression analyses of 151 colorectal cancer ( CRC ) cell lines .
3 We find that the whole spectrum of CRC molecular and transcriptional subtypes , previously defined in patients , is represented in this cell line compendium .
4 Transcriptional outlier analysis identifies RAS/BRAF wild-type cells , resistant to EGFR blockade , functionally and pharmacologically addicted to kinase genes including ALK , FGFR2 , NTRK1/2 and RET .
5 The same genes are present as expression outliers in CRC patient samples .
6 Genomic rearrangements ( translocations ) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens .
7 The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available .



PMID: 25926041
(None)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Are all RAS mutations the same? Coexisting KRAS and NRAS mutations in a caecal adenocarcinoma and contiguous tubulovillous adenoma .
1 Mutations of the human rat Kirsten sarcoma viral oncogene homologue ( KRAS ) and the highly homologous human neuroblastoma RAS viral oncogene homologue ( NRAS ) are associated with resistance to antiepidermal growth factor receptor therapies in patients with colorectal cancer .
2 In this report , we describe a caecal adenocarcinoma that contains both KRAS c.35G>T ( G12V ) and NRAS c.34G>A ( G12S ) mutations .
3 The adenocarcinoma arises from a contiguous high-grade tubulovillous adenoma , which also carries the identical KRAS and NRAS mutations , supporting their common origin .
4 While KRAS mutations are common in colorectal cancers , NRAS mutations are relatively rare and the coexistence of multiple RAS mutations is not documented , presumably reflecting similar functions of wild-type and mutant forms of RAS .
5 Recent experimental evidence has suggested that KRAS and NRAS may in fact mediate distinct biological processes in the colon , and this unusual case potentially illustrates the hypothesis clinically .
6 Characterisation of the diverse and divergent functions of RAS family members and mutant forms of RAS in the colon form important considerations for the development of RAS-targeting therapeutics .



PMID: 25924988
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Established and Potential Predictive Biomarkers in Gastrointestinal Cancer--c-Kit , Her2 , Ras and Beyond .
1 BACKGROUND :
2 Gastrointestinal cancers are among the leading causes of cancer-related deaths worldwide .
3 In different tumor types , personalized systemic treatment strategies based upon biomarker-selection were established over the last years .
4 Although there is a flood of targeted agents in clinical development , only a few targeted agents with a predictive biomarker could be established for the treatment of patients with gastrointestinal cancer patients so far .
5 SUMMARY :
6 Currently , predictive biomarkers for gastrointestinal cancers include Her2 overexpression or amplification ( gastroesophageal adenocarcinoma ) , c-Kit overexpression ( gastrointestinal stromal tumors ) and RAS wild-type ( colorectal cancer ) .
7 Selection of patients based on these biomarkers allows the efficient use of targeted agents .
8 The presence of a BRAF mutation and/or high microsatellite instability is prognostic and rather a predictive marker in CRC .
9 Promising candidate markers in advanced clinical development are MET amplification in gastroesophageal adenocarcinoma , Met overexpression and high AFP serum levels in hepatocellular carcinoma .
10   KEY MESSAGE : Biomarker-guided systemic treatment is established in a subset of patients with gastrointestinal cancer .
11 Ongoing clinical trials and further advances in high-throughput technologies will hopefully result in more personalized systemic treatment strategies for these patients in the near future .



PMID: 25924923
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer .
1 AIMS :
2 To investigate tumor and patient characteristics of individuals with mismatch repair ( MMR )- deficient colorectal carcinomas .
3 METHODS :
4 We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins ( hMLH1 , hMSH2 , hMSH6 , hPMS2 ) and those with mutations further for microsatellite instability ( MSI ) and BRAF V600E mutations .
5 RESULTS :
6 32/308 ( 104% ) tumors showed MMR deficiency .
7 Seventy five percent ( n = 24 ) had loss of hMLH1 and hPMS2 expression , 3% ( n = 1 ) of hPMS2 alone , 18.8% ( n = 6 ) of hMSH6 and hMSH2 , 3% ( n = 1 ) of hMSH2 alone .
8 Μ All MMR-deficient tumors showed high MSI .
9 These tumors occurred preferably in the right-sided colon , in women and showed specific histological features .
10 We obtained the family history of 18/32 patients ; 2 ( 111% ) met Amsterdam Criteria , 5 ( 278% ) Bethesda Guidelines and 6 ( 333% ) revised Bethesda Guidelines .
11 Μ BRAF V600E mutations were found in 16 ( 67% ) of hMLH1 and none of the hMSH2 deficient tumors .
12 CONCLUSION :
13   We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis , which may be justified as a screening method for MMR deficiency in colorectal cancer , since it identifies patients with possibly hereditary defects and unalike response to chemotherapy .



PMID: 25924068
(None)  
Terms: , mouse, mice
Sent# Symbols Sentence Mnemonics
0 Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer .
1 Crypt stem cells represent the cells of origin for intestinal neoplasia .
2 Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell -niche factors WNT , R-spondin , epidermal growth factor ( EGF ) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable .
3 Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes ( APC , P53 ( also known as TP53 ) , KRAS and SMAD4 ) in cultured human intestinal stem cells .
4 Mutant organoids can be selected by removing individual growth factors from the culture medium .
5 Quadruple mutants grow independently of all stem-cell -niche factors and tolerate the presence of the P53 stabilizer nutlin-3 .
6 Upon xenotransplantation into mice , quadruple mutants grow as tumours with features of invasive carcinoma .
7 Finally , combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy , a hallmark of tumour progression .



PMID: 25920359
(Patient)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Neoadjuvant chemotherapy in locally advanced colon cancer . A phase II trial .
1 BACKGROUND :
2 Neoadjuvant chemotherapy has proven valuable in several tumors , but it has not been elucidated in colon cancer .
3 The present phase II trial addressed the issue in high-risk patients selected by computed tomography ( CT ) scan .
4 MATERIAL AND METHODS :
5 Patients with resectable colon cancer fulfilling the following criteria were offered inclusion ; Histopathological verification of adenocarcinoma , T3 tumor on CT scan with extramural tumor invasion >5 mm or T4 tumor , age >/= 18 years , PS
6 Patients with KRAS , BRAF or PIK3CA mutation or unknown mutational status received three cycles of capecitabine 2000 mg/m(2) days 1-14 q3w and oxaliplatin 130 mg iv day 1 q3w .
7 Wild-type patients received the same chemotherapy supplemented with panitumumab 9 mg/kg iv q3w .
8 After the operation , patients fulfilling the international criteria for adjuvant chemotherapy , i.e.high-risk stage II and III patients , received five cycles of the same chemotherapy without panitumumab .
9 Patients not fulfilling the criteria were offered follow-up only .
10 The primary endpoint was the fraction of patients not fulfilling the criteria for adjuvant chemotherapy ( converted patients ) .
11 Secondary endpoints were recurrence rate , disease-free survival ( DFS ) , and toxicity .
12 RESULTS :
13 The study included 77 patients .
14 The conversion rate was 42% in the wild-type group compared to 51% in patients with a mutation .
15 The cumulative recurrence rate in converted versus unconverted patients was 6% versus 32% ( p = 0005 ) translating into a three-year DFS of 94% versus 63% ( p = 0005 ) .
16 CONCLUSION :
17   Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy .
18 Validation in a randomized trial is warranted .



PMID: 25919696
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS -dependent and -independent mechanisms .
1 Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS , NRAS , or MEK1 .



PMID: 25918287
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Personalizing colon cancer adjuvant therapy : selecting optimal treatments for individual patients .
1 For more than three decades , postoperative chemotherapy-initially fluoropyrimidines and more recently combinations with oxaliplatin-has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer .
2 Although universally recommended for patients with stage III disease , there is no consensus about the survival benefit of postoperative chemotherapy in stage II colon cancer .
3 The most recent adjuvant clinical trials have not shown any value for adding targeted agents , namely bevacizumab and cetuximab , to standard chemotherapies in stage III disease , despite improved outcomes in the metastatic setting .
4 However , biomarker analyses of multiple studies strongly support the feasibility of refining risk stratification in colon cancer by factoring in molecular characteristics with pathologic tumor staging .
5 In stage II disease , for example , microsatellite instability supports observation after surgery .
6 Furthermore , the value of BRAF or KRAS mutations as additional risk factors in stage III disease is greater when microsatellite status and tumor location are taken into account .
7 Validated predictive markers of adjuvant chemotherapy benefit for stage II or III colon cancer are lacking , but intensive research is ongoing .
8   Recent advances in understanding the biologic hallmarks and drivers of early-stage disease as well as the micrometastatic environment are expected to translate into therapeutic strategies tailored to select patients .
9   This review focuses on the pathologic , molecular , and gene expression characterizations of early-stage colon cancer ; new insights into prognostication ; and emerging predictive biomarkers that could ultimately help define the optimal adjuvant treatments for patients in routine clinical practice .



PMID: 25918280
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer .
1 Genetic landscape of esophageal squamous cell carcinoma .



PMID: 25917796
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ UbcH10 expression can predict prognosis and sensitivity to the antineoplastic treatment for colorectal cancer patients . GE-REG-RO
1 Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor -resistant EGFR-mutant lung cancer with and without T790M mutations .



PMID: 25913616
(Cell)  
Terms: phase III study, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma .
1 Pancreatic ductal adenocarcinoma ( PDAC ) is the fourth most common cause of cancer death in North America .
2 Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC , respectively .
3 While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models , their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated .
4 Here , we report that Smad4 represents a barrier in KRAS -mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial ( HPDE ) cell line model .
5 Marked Smad4 downregulation by shRNA in KRAS (G12V) expressing HPDE cells failed to cause tumorigenic transformation .
6 However , KRAS -mediated malignant transformation occurred in a new HPDE-TGF-beta resistant ( TbetaR ) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-beta .
7 This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas .
8 Smad4 restoration re-established TGF-beta sensitivity , markedly increased tumor latency by promoting apoptosis , and decreased metastatic potential .
9 These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells .



PMID: 25913614
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate .
1 PURPOSE :
2 To determine the frequency and clinical significance of epidermal growth factor receptor ( EGFR ) mutations in patients with potentially curable stage III non-small-cell lung cancer ( NSCLC ) who are eligible for definitive chemoradiotherapy ( CRT ) .
3 PATIENTS AND METHODS :
4 Between January 2001 and December 2010 , we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT .
5 The response rate , relapse-free survival , 2-year relapse-free rate , initial relapse sites , and overall survival of the patients were investigated .
6 RESULTS :
7 A total of 528 patients received CRT at our hospital during the study period .
8 Of these , 274 were diagnosed as having nonsquamous NSCLC .
9 Μ Sufficient specimens for mutational analyses could be obtained from 198 of these patients .
10 The proportion of patients with EGFR activating mutations was 17% .
11 Μ In addition to the well-known characteristics of patients carrying EGFR mutations ( female , adenocarcinoma , and never/light smoker ) , the proportion of cases with smaller primary lesions ( T1/2 ) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR .
12 ✓ Patients with EGFR mutations showed similar response rate , relapse-free survival , and 2-year relapse-free rates as compared to patients with wild-type EGFR . GM-ASS-RO, RO-ASS-GM
13 Μ Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation ( 4% versus 21% ; P = 045 ) .
14 ✓ Patients with EGFR mutations showed longer local control ( adjusted hazard ratio 049 ; P = 043 ) . GM-ASS-RO
15 After disease progression , a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors ( 62% ) , and these patients showed longer postprogression survival than those with wild-type EGFR .
16 CONCLUSIONS :
17 Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent .
18 This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC .



PMID: 25911860
(Patient)  
Terms: meta-analysis, case, control, case control
Sent# Symbols Sentence Mnemonics
0 K-Ras mutation and prognosis of colorectal cancer : a meta-analysis .
1 BACKGROUND/AIMS :
2 Colorectal cancer ( CRC ) is one of the most common malignant tumors worldwide .
3 Kirsten ras ( K-ras ) gene is considered to participate in the progression from adenoma to carcinoma of colorectal neoplasms .
4 The correlation between K-ras mutation and the prognosis of CRC is sill controversial .
5 This study aimed at quantitatively summarizing the evidence for such a relationship.METHODOLOGY :
6 The literature search was based on Pub Med .
7 Μ Population-based and hospital-based case-control studies concerning K-ras mutation and prognosis were eligible for analysis .
8 RESULTS :
9 13 literatures were included in the meta-analysis , with 1 multicenter study and 12 case control studies .
10 Totally , 3771 patients were enrolled in the analysis , 1202 of which had K-ras mutation .
11 Μ There were significant difference between the survival of patients with normal and mutated K-ras gene , but no statistic differences were found between either Condon 12 or Condon 13 mutations and prognosis .
12 CONCLUSION :
13 ✓ Μ Current available evidences demonstrated the K-ras mutation is a predictive molecular mark of colorectal cancer patients' survivals , further studies are needed to investigate the race difference and the relationship between certain K-ras mutation and prognosis . GM-ASS-RO



PMID: 25911848
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 High frequency of BRAF proto - oncogene hot spot mutation V600E in cohort of colorectal cancer patients from Ahvaz City , southwest Iran .
1 Colorectal cancer ( CRC ) is one of the most common forms of cancer around the world .
2 Sporadic CRCs are caused by accumulation of mutations in essential genes regulating normal proliferation and differentiation of cells .
3 The proto - oncogene BRAF encoded by the BRAF gene is involved in the RAS/RAF/MAPK pathway of signal transduction during cell growth .
4 Μ Acquired mutations in BRAF have been found at high frequencies in adult patients with papillary thyroid carcinoma and sporadic CRC .
5 One of the predominant hot spot point mutations is T1799A (V600E) mutation among a cohort of CRC patients from Ahvaz city , southwest Iran .
6 The aim of this study was to estimate the frequency of V600E mutation in CRC patients from Ahvaz city , southwest Iran .
7 We analyzed exon 15 of the BRAF gene in isolated DNA from 80 Formalin Fixed Paraffin-embedded ( FFPE ) CRC tumor tissues using PCR-RFLP method .
8 Data were analyzed using SPSS statistical program .
9 According to our results 37 out of 80 cases ( 4625% ) were heterozygous for the mutation while the remaining 43 cases ( 5375% ) had normal homozygous genotype .
10 Μ No homozygous mutant genotype was found .
11 Based on our findings , the frequency of V600E mutation appears to be significantly increased among CRC patients of the studied population but there was no significant relationship between genotypes and age and sex .
12 In conclusion , these findings might prove the effect of V600E mutation on CRC pathogenesis .
13 However , the exact effect of the mutation in CRC progression requires further work .



PMID: 25910169
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 A model -based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients .
1 UNLABELLED :
2 The TNF receptor superfamily member Fn14 ( TNFRSF12A ) is the sole signaling receptor for the proinflammatory cytokine TWEAK (TNFSF12) .
3 TWEAK :
4 Fn14 engagement stimulates multiple signal transduction pathways , including the NF-kappaB pathway , and this triggers important cellular processes ( e.g. , growth , differentiation , migration , and invasion ) .
5 The TWEAK-Fn14 axis is thought to be a major physiologic mediator of tissue repair after acute injury .
6 Various studies have revealed that Fn14 is highly expressed in many solid tumor types , and that Fn14 signaling may play a role in tumor growth and metastasis .
7 Previously , it was shown that Fn14 levels are frequently elevated in non-small cell lung cancer ( NSCLC ) tumors and cell lines that exhibit constitutive EGFR phosphorylation ( activation ) .
8 Furthermore , elevated Fn14 levels increased NSCLC cell invasion in vitro and lung metastatic tumor colonization in vivo .
9 Μ The present study reveals that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src , and that treatment with the Src family kinase ( SFK ) inhibitor dasatinib decreases Fn14 gene expression at both the mRNA and protein levels .
10 Importantly , siRNA -mediated depletion of the SFK member Src in NSCLC cells also decreases Fn14 expression .
11 Finally , expression of the constitutively active v-Src oncoprotein in NIH 3T3 cells induces Fn14 gene expression , and NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity .
12 IMPLICATIONS :
13   These results indicate that oncogenic Src may contribute to Fn14 overexpression in solid tumors , and that Src-mediated cell invasion could potentially be inhibited with Fn14-targeted therapeutics .



PMID: 25905152
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Targeting tumor invasion : the roles of MDA-9/Syntenin .
1 Squamous cell lung cancer ( SQCLC ) is one of the most prevalent subtypes of lung cancer worldwide , about 400,000 persons die from squamous - cell lung cancer around the world , and its pathogenesis is closely linked with tobacco exposure .
2 Unfortunately , squamous - cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor ( EGFR ) inhibitors or anaplastic lymphoma kinase ( ALK ) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 ( EML4 ) -ALK fusions , respectively .
3 Major efforts have been launched to characterize the genomes of squamous - cell lung cancers .
4   Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 ( FGFR1 ) gene , the discoidin domain receptor 2 ( DDR2 ) gene mutation as potential novel targets for the treatment of SQCLCs .
5 Researchers find that there are many specific molecular targeted genes in the genome of squamous - cell lung cancer patients .
6 These changes play a vital role in cell cycle regulation , oxidative stress , cell apoptosis , squamous epithelium differentiation , may be the candidate targeted moleculars in SQCLCs .
7   Here , we provide a review on these discoveries and their implications for clinical trials in squamous - cell lung cancer assessing the value of novel therapeutics addressing these targets .



PMID: 25902072
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutational analysis of circulating tumor cells from colorectal cancer patients and correlation with primary tumor tissue .
1 GIST treatment options after tyrosine kinase inhibitors .



PMID: 25900832
(Cell)  
Terms: xenograft, mice
Sent# Symbols Sentence Mnemonics
0 BRAF -induced tumorigenesis is IKKalpha -dependent but NF-kappaB-independent .
1 KRAS mutations contribute to cell proliferation and survival in numerous cancers , including colorectal cancers ( CRC ) .
2 One pathway through which mutant KRAS acts is an inflammatory pathway that involves the kinase IKK and activates the transcription factor NF-kappaB .
3 BRAF , a kinase that is downstream of KRAS , is mutated in a subset of CRC and is predictive of poor prognosis and therapeutic resistance .
4 We found that , in contrast to mutant KRAS , mutant BRAF (BRAF (V600E)) did not trigger NF-kappaB activation but instead triggered the phosphorylation of a proteolytic fragment of IKKalpha ( p45-IKKalpha ) in CRC cells .
5 BRAF (V600E) CRC cells had a high abundance of phosphorylated p45-IKKalpha , which was decreased by a RAF inhibitor .
6 However , the abundance and DNA binding of NF-kappaB in these cells were unaffected by the RAF inhibitor , and expression of BRAF (V600E) in human embryonic kidney-293T cells did not activate an NF-kappaB reporter .
7 Moreover , BRAF -induced transformation of NIH-3T3 cells and BRAF -dependent transcription required phosphorylation of p45-IKKalpha .
8 The kinase TAK1 , which was associated with the endosomal compartment , phosphorylated p45-IKKalpha .
9 Inhibition of endosomal vacuolar adenosine triphosphatase ( V-ATPase ) with chloroquine or bafilomycin A1 blocked p45-IKKalpha phosphorylation and induced apoptosis in BRAF-mutant CRC cells independent of autophagy .
10 Treating mice with V-ATPase inhibitors reduced the growth and metastasis of BRAF (V600E) xenograft tumors in the cecum of mice .



PMID: 25899481
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ ( 18 ) F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer : a pilot study .
1 OBJECT :
2 This pilot study evaluated the utility of 3'-deoxy-3'[18F]-fluorothymidine ( [ ( 18 ) F]-FLT ) positron emission tomography ( PET ) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers .
3 METHODS :
4 Baseline [ ( 18 ) F]-FLT PET was collected prior to treatment initiation .
5 Follow-up [ ( 18 ) F]-FLT was collected after three weekly infusions of cetuximab , and following a combined regimen of cetuximab , 5-FU , and radiation .
6 Imaging-matched biopsies were collected with each PET study .
7 RESULTS :
8   Diminished [ ( 18 ) F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy .
9 Reduced [ ( 18 ) F]-FLT PET following combination therapy predicted disease-free status at surgery .
10 Overall , [ ( 18 ) F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue , and was predictive of treatment-induced rise in p27 levels .
11 CONCLUSION :
12   These results suggest that [ ( 18 ) F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer .



PMID: 25899003
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Frequent amplification of PTP1B is associated with poor survival of gastric cancer patients .
1 Oncogene -induced senescence ( OIS ) , a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation , is a key barrier in the development of BRAF V600E colon cancer .
2 Μ Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps , as well as through the germline mutations associated with those who develop serrated polyposis .
3 We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene -induced senescence .
4 To identify such autocrine factors , we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts , the Cancer Genome Atlas ( TCGA ; n = 153 ) , and French national Cartes d'Identite des Tumeurs ( CIT ) program ( n = 462 ) , with enhanced gene annotation through natural language processing techniques of the existing medical corpus .
5 We reproducibly associate higher expression of the ligand - receptor axis of TFF2 and CXCR4 with BRAF V600E-mutant colon cancer ( P = 3.0 x 10 ( -3 ) and 0.077 , respectively for TCGA ; P = 3.0 x 10 ( -8 ) and 5.1 x 10 ( -7 ) for CIT ) .
6 Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer , and availability of CXCR4 inhibitors for other clinical indications , this ligand - receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer .



PMID: 25896895
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Cancerous inhibitor of protein phosphatase 2A ( CIP2A ) is an independent prognostic marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy .
1 BACKGROUND :
2 The impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A ( CIP2A ) expression has not yet been explored .
3 We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy .
4 METHODS :
5 We examined CIP2A expression by immunohistochemistry ( IHC ) and used direct sequencing to identify the mutational status of KRAS exon 2 ( codon 12 and 13 ) .
6 The association between CIP2A expression , KRAS genotype , clinicopathological parameters and survival were examined by the Kaplan-Meier method and the Cox proportional hazards model .
7 A combination of immunoblotting and proliferation assays were employed to elucidate the role of CIP2A in signal transduction pathways in wild-type KRAS Caco-2 cells .
8 RESULTS :
9 A total of 220 colorectal cancer patients who had undergone colorectal liver metastasectomy were included in the study .
10 The mutant KRAS genotype was associated with CIP2A overexpression .
11 CIP2A expression was an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy ( relative risk = 1873 , P = 0019 ) .
12 Targeted silencing of CIP2A in Caco-2 cells (wild-type KRAS) led to decreased expression of pERK/ERK and decreased cell proliferation .
13 Overexpression of mutant KRAS G12D in Caco-2 cells led to an increase in CIP2A expression and cell proliferation .
14 In Caco-2 cells with the KRAS G12D , KRAS overexpression preserved the regulation effect of CIP2A in KRAS and abrogated the impact of CIP2A regulation on pERK/ERK and cell proliferation .
15 CIP2A inhibition also increased the efficacy of cetuximab in Caco-2 cells .
16 CONCLUSIONS :
17 CIP2A is an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy .



PMID: 25895463
(Patient)  
Terms: prospective, retrospective, phase III
Sent# Symbols Sentence Mnemonics
0 Panitumumab in Metastatic Colorectal Cancer : The Importance of Tumour RAS Status .
1 Tumour biomarker status is being used more and more frequently to guide treatment decisions in patients with metastatic colorectal cancer ( mCRC ) .
2   Continued cycles of hypothesis generation and biomarker testing in retrospective , prospective-retrospective and prospective analyses from studies of the epidermal growth factor ( EGFR )- targeted monoclonal antibodies ( mAbs ) , panitumumab and cetuximab , have resulted in improved patient selection in mCRC .
3   Initial data suggested EGFR-targeted mAb treatment should be limited to patients with KRAS exon 2 wild-type ( WT ) tumours , but the availability of tumour samples from large phase III studies permitted evaluation of additional potential biomarkers of activity for these agents .
4 Subsequent analyses further refined the target population to those patients whose tumours were WT for KRAS and NRAS exons 2 , 3 and 4 ( i.e. , those with RAS WT status ) .
5   Here , we review key clinical data for panitumumab in mCRC across the lines of treatment , assessing in detail the impact of more comprehensive RAS selection on patient outcomes .
6   Panitumumab data across first - to third - line therapy consistently demonstrate that by testing tumour RAS status , it is possible to select patients more likely to benefit from treatment .



PMID: 25892888
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer : a meta-analysis .
1 Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance .



PMID: 25890236
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Improved survival among colon cancer patients with increased differentially expressed pathways .
1 [6]-shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2 .



PMID: 25889965
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Combined ginger extract & ; Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells .
1 Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint .



PMID: 25889309
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib .
1 BACKGROUND :
2 Regorafenib , a multi - kinase inhibitor , is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy .
3 However , this benefit was limited to 1.4 months improvement in overall survival , with more than half of patients experiencing grade 3 to 4 adverse events .
4 We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit .
5 METHODS :
6 Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study .
7 Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles .
8 Metabolic response was assessed by FDG PET-CT scans ( pre-treatment and day 15 ) ; paired tumour biopsies ( pre-treatment and day 21 post-treatment ) were sampled for immunohistochemistry and proteomic profiling analyses .
9 Plasma circulating cell free DNA was quantified serially before and after treatment .
10 RESULTS :
11 There were 2 ( 6% ) partial responses out of 35 patients , and 8 ( 23% ) patients had stable disease for more than 7 months .
12 Adverse event profile was similar to reported data .
13 Μ Recurrent somatic mutations in K-RAS , PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients ; some mutations were not found in archival tumour .
14 ✓ Total plasma circulating cell free DNA inversely correlated with progression free survival ( PFS ) , and presence of KRAS mutations associated with shorter PFS . GM-ASS-RO
15   Immunohistochemistry of pre - and post - treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2 , podoplanin , phosphorylated-AKT , Ki-67 and upregulation of the MEK-ERK axis , phosphorylated-C-MET , phosphorylated-SRC , phosphorylated-STAT3 and phosphorylated-JUN .
16 Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS .
17 CONCLUSION :
18   Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment .
19 Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit .



PMID: 25888436
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 KRAS testing of patients with metastatic colorectal cancer in a community-based oncology setting : a retrospective database analysis .
1 BACKGROUND :
2 In 2009 , treatment guidelines were updated to recommend KRAS testing at diagnosis for patients with metastatic colorectal cancer ( mCRC ) .
3 We investigated KRAS testing rates over time and compared characteristics of KRAS-tested and not-tested patients in a community-based oncology setting .
4 METHODS :
5 Adult patients with a diagnosis of mCRC from 2008-2011 were selected from the ACORN Data Warehouse ( ACORN Research LLC , Memphis , TN ) .
6 Text mining of physician progress notes and full chart reviews identified KRAS-tested patients , test dates , and test results ( KRAS status ) .
7 The overall proportion of eligible patients KRAS-tested in each calendar year was calculated .
8 Among KRAS-tested patients , the proportion tested at diagnosis ( within 60 days ) was calculated by year .
9 Univariate and multivariate analyses were used to compare patient characteristics at diagnosis between tested and not-tested cohorts , and to identify factors associated with KRAS testing .
10 RESULTS :
11 Among 1,363 mCRC patients seen from 2008-2011 , 648 ( 475% ) were KRAS-tested .
12 Among newly diagnosed mCRC patients , the rate of KRAS testing increased from 5.9% prior to 2008 , to 13.9% in 2008 , and then jumped dramatically to 32.3% in 2009 , after which a modest yearly increase continued .
13 The proportions of KRAS-tested patients who had been diagnosed in previous years but not tested previously increased from 17.7% in 2008 to 27.0% in 2009 , then decreased to 19.0% in 2010 and 17.6% in 2011 .
14 Among patients who were KRAS-tested , the proportions tested at the time of diagnosis increased annually ( to 784% in 2011 ) .
15 Patients more likely to have been tested included those with lung metastases , poor performance status , more comorbidities , and mCRC diagnosis in 2009 or later .
16 CONCLUSIONS :
17   The frequency of KRAS testing increased over time , corresponding to changes in treatment guidelines and epidermal growth factor receptor inhibitor product labels ; however , approximately 50% of eligible patients were untested during the study period .



PMID: 25888291
(Patient)  
Terms: observational study
Sent# Symbols Sentence Mnemonics
0 Efficacy of bevacizumab and chemotherapy in the first - line treatment of metastatic colorectal cancer : broadening KRAS-focused clinical view .
1 BACKGROUND :
2 The aim of the present retrospective study was to analyze clinical outcome and risk factors associated with treatment outcomes according to KRAS status in patient with metastatic colorectal cancer ( mCRC ) treated with bevacizumab ( bev ) plus chemotherapy in the first - line setting .
3 METHODS :
4 We performed observational study on 1622 patients with mCRC treated with bev plus oxaliplatin - or irinotecan-based chemotherapy , and correlated treatment outcomes with KRAS mutation status .
5 The primary endpoint was progression-free survival ( PFS ) and additionally overall survival ( OS ) .
6 Adverse events of bevacizumab and risk factors including location of metastases were evaluated .
7 RESULTS :
8 Mutation in KRAS was present in 40.6% of mCRC cases .
9 The median PFS in patients with wild-type KRAS ( wtKRAS ) versus mutant KRAS was 11.5 versus 11.4 months , respectively .
10 The median OS was 30.7 versus 28.4 months ( p = 0312 ) .
11 Μ Patients with KRAS mutation had lung metastases more frequently than wtKRAS individuals ( 320% versus 238% ; p = 0001 ) .
12 We observed no difference in clinical outcome between hepatic and extrahepatic metastatic disease .
13 CONCLUSION :
14   KRAS mutation does not interfere with clinical benefit from first - line treatment with bevacizumab plus chemotherapy in mCRC patients .



PMID: 25888143
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Russian study of morphological prognostic factors characterization in BRAF-mutant cutaneous melanoma .
1 Melanoma is one of the aggressive cancer types causing the majority of deaths in skin cancer patients .
2 Μ Mutational screening of the tumor revealed a number of driver mutations in oncogenes which enabled melanoma classification into a few molecular subtypes .
3 ✓ BRAF is a key component of mitogen -activated kinase pathway ; its activating mutation leads to accelerated melanoma cells proliferation , invasion and survival . GE-REG-RO
4 Somatic mutations in BRAF were reported in various malignancies , including thyroid cancer , colorectal cancer and melanoma .
5 Specific features of BRAF-positive tumors could have clinical implications as mutational alterations may have an impact on the biological behavior of the tumor and prognosis of the disease .
6 In the present study , the frequency of BRAF V600E mutation was evaluated in Russian patients with melanocytic lesions , of which 41.25% were primary melanoma and 60% were melanocytic nevi .
7 Melanoma patients with trunk localization were of younger age in the BRAF-positive group as compared with BRAF-negative patients .
8 Μ Immunohistochemical evaluations of Ki-67 expression , as well as matrix metalloproteinase-2 , -9 , were found to be equal in BRAF-positive and BRAF-negative tumors .
9 MMP-2/MMP-9 immunoreactivity was observed in stromal and/or melanocytic cells both in melanoma and nevi patients .
10 Μ Besides tumor cells , MMP-9 expression was observed in lymphocytes in 27.2% of BRAF-positive and in 19.1% of BRAF-negative patients .
11 Histopathological prognostic markers ( Breslow thickness , mitotic index , ulceration , tumor infiltrating lymphocytes pattern ) did not show any differences depending on BRAF V600E mutational status .
12 The frequency of BRAF-positive melanomas in Russian cohort is similar to other Caucasian population rates .
13 Μ BRAF V600E mutation harboring tumors are more often observed in younger patients without specific features of morphological prognostic factors .



PMID: 25887718
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Frequency of mitogen -activated protein kinase and phosphoinositide 3 - kinase signaling pathway pathogenic alterations in EUS-FNA sampled malignant lymph nodes in rectal cancer with theranostic potential .
1 BACKGROUND :
2 Targeted next-generation sequencing has the potential to stratify a tumor by molecular subtype and aid the development of a biomarker profile for prognostic risk stratification and theranostic potential .
3 OBJECTIVE :
4 To assess the frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens .
5 DESIGN :
6 Multigene molecular profiling of archived malignant EUS-FNA lymph node cytology specimens using the Ion Ampliseq Cancer Hotspot Panel v2 , which targets atleast 2855 possible mutations within 50 cancer-associated genes .
7 SETTING :
8 Single tertiary referral center .
9 PATIENTS :
10 Sporadic , treatment naive , locally advanced primary rectal cancer by EUS-FNA ( n = 76 ) who subsequently completed neoadjuvant therapy with on - site oncologic surgery .
11 MAIN OUTCOME MEASUREMENTS :
12 The frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens by the mitogen -activated protein kinase ( MAPK ) or phosphoinositide 3-kinase ( PI3K ) signaling pathways , by KRAS or NRAS wild-type lymph node status , by extramesenteric lymph node status , and by a complete pathologic response status .
13 RESULTS :
14 Eleven patients ( 145% ) were 50 - gene panel wild-type .
15 Sixty-five patients had 139 pathogenic alterations ( 2 [1-3] per patient ) in 13 of 50 evaluated genes .
16 Μ The following represent a spectrum of identified alterations : TP53 ( n = 52 ; 684% ) , APC ( n = 36 ; 474% ) , KRAS ( n = 22 ; 289% ) , FBXW7 ( n = 8 ; 105% ) , NRAS ( n = 6 ; 79% ) , PIK3CA ( n = 4 ; 53% ) , SMAD4 ( n = 3 ; 39% ) , and BRAF ( n = 3 ; 39% ) .
17 Μ Pathogenic alterations were identified in the MAPK and PI3K signaling pathways in 41% and 5% of patients , respectively .
18 LIMITATIONS : Findings were limited to a 50 cancer-associated gene analysis .
19 CONCLUSIONS :
20 Μ Molecular EUS lymph node assessments using cancer "hotspot" panels can identify pathogenic alteration frequency and distribution and have theranostic potential for individualized patient care .



PMID: 25886136
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K/AKT signaling .
1 Inoperable c- kit negative gastrointestinal stromal tumor ( GIST ) is commonly considered to be highly resistant to systemic therapy .
2 We present a case of a woman with an abdominal sarcomalike tumor diagnosed at the age of 26 .
3 The patient underwent several surgical procedures and courses of cytostatic therapy without any substantial effect .
4 Later , the tumor was reclassified as c- kit negative GIST harbouring the mutation in exon 12 of PDGFRA gene .
5 Hence , the therapy with imatinib mesylate was initiated , resulting in partial remission of metastatic lesions and further stabilization of the disease for five years to date .
6 Μ We therefore consider imatinib mesylate an appropriate therapy for c- kit negative GIST bearing PDGFRA mutations .



PMID: 25885658
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 HGUE-C-1 is an atypical and novel colon carcinoma cell line .
1 Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis .



PMID: 25884643
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 ( MACC1 ) for survival prognosis of colorectal cancer patients : a retrospective cohort study .
1 Regulation of the cancer cell membrane lipid composition by NaCHOleate : effects on cell signaling and therapeutical relevance in glioma .



PMID: 25884297
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer .
1 BACKGROUND :
2 Molecular alterations are well studied in colon cancer , however there is still need for an improved understanding of their prognostic impact .
3 This study aims to characterize colon cancer with regard to KRAS , BRAF , and PIK3CA mutations , microsatellite instability ( MSI ) , and average DNA copy number , in connection with tumour dissemination and recurrence in patients with colon cancer .
4 METHODS :
5 Disease stage II-IV colon cancer patients ( n = 121 ) were selected .
6 KRAS , BRAF , and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers .
7 Μ Genome -wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis .
8 RESULTS :
9 Μ Patients with mutated KRAS were more likely to experience disease dissemination ( OR 275 ; 95% CI 128-604 ) , whereas the opposite was observed for patients with BRAF mutation ( OR 034 ; 95% 014-081 ) or MSI ( OR 024 ; 95% 009-064 ) .
10 Also in the subset of patients with stage II-III disease , both MSI ( OR 029 ; 95% 010-086 ) and BRAF mutation ( OR 032 ; 95% 016-091 ) were related to lower risk of distant recurrence .
11 However , average DNA copy number and PIK3CA mutations were not associated with disease dissemination .
12 CONCLUSIONS :
13 The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation , whereas the presence of a KRAS mutation increases the likelihood of disseminated disease .



PMID: 25879218
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular subtypes in stage II-III colon cancer defined by genomic instability : early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A .
1 OBJECTIVE :
2 We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer .
3 METHODS :
4 We sought to investigate various molecular subtypes defined by instability at microsatellites ( MSI ) , changes in methylation patterns ( CpG island methylator phenotype , CIMP ) or copy number variation ( CNV ) in 8 genes .
5 Stage II-III colon cancers ( n = 64 ) were investigated by methylation-specific multiplex ligated probe amplification ( MS-MLPA ) .
6 Correlation of CNV , CIMP and MSI , with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni - and multivariate regression .
7 RESULTS :
8 The CIMP phenotype occurred in 34% ( 22/64 ) and MSI in 27% ( 16/60 ) of the tumors , with noted CIMP/MSI overlap.Among the molecular subtypes , a high CNV phenotype had an associated odds ratio ( OR ) for recurrence of 3.2 ( 95% CI 11-93 ; P = 0026 ) .
9 Losses of CACNA1G ( OR of 29 , 95% CI 14-60 ; P = 0001 ) , IGF2 ( OR of 43 , 95% CI 11-158 ; P = 0007 ) , CDKN2A ( p16 ) ( OR of 20 , 95% CI 11-36 ; P = 0024 ) , and RUNX3 ( OR of 34 , 95% CI 13-87 ; P = 0002 ) were associated with early recurrence , while MSI , CIMP , KRAS or or BRAF V600E mutations were not .
10 The CNV was significantly higher in deceased patients ( CNV in 6 of 8 ) compared to survivors ( CNV in 3 of 8 ) .
11 Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk - model for early recurrence .
12 CONCLUSIONS :
13 A high copy number variation phenotype is a strong predictor of early recurrence and death , and may indicate a dose -dependent relationship between genetic instability and outcome .
14 Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation .



PMID: 25877855
(Patient)  
Terms: NCT01183780
Sent# Symbols Sentence Mnemonics
0 Ramucirumab versus placebo in combination with second - line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first - line therapy with bevacizumab , oxaliplatin , and a fluoropyrimidine ( RAISE ) : a randomised , double-blind , multicentre , phase 3 study .
1 BACKGROUND :
2 Angiogenesis is an important therapeutic target in colorectal carcinoma .
3 Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2 .
4 We assessed the efficacy and safety of ramucirumab versus placebo in combination with second - line FOLFIRI ( leucovorin , fluorouracil , and irinotecan ) for metastatic colorectal cancer in patients with disease progression during or after first - line therapy with bevacizumab , oxaliplatin , and a fluoropyrimidine .
5 METHODS :
6 Between Dec 14 , 2010 , and Aug 23 , 2013 , we enrolled patients into the multicentre , randomised , double-blind , phase 3 RAISE trial .
7 Eligible patients had disease progression during or within 6 months of the last dose of first - line therapy .
8 Patients were randomised ( 1 : 1 ) via a centralised , interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression , unacceptable toxic effects , or death .
9 Randomisation was stratified by region , KRAS mutation status , and time to disease progression after starting first - line treatment .
10 The primary endpoint was overall survival in the intention-to-treat population .
11 This study is registered with ClinicalTrials .
12 gov , number NCT01183780 .
13 ld FINDINGS : We enrolled 1072 patients ( 536 in each group ) .
14 Median overall survival was 13.3 months ( 95% CI 124-145 ) for patients in the ramucirumab group versus 11.7 months ( 108-127 ) for the placebo group ( hazard ratio 0844 95% CI 0730-0976 ; log-rank p = 00219 ) .
15 Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI .
16 Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia ( 203 [38%] of 529 patients in the ramucirumab group versus 123 [23%] of 528 in the placebo group , with febrile neutropenia incidence of 18 [3%] versus 13 [2%] ) , hypertension ( 59 [11%] versus 15 [3%] ) , diarrhoea ( 57 [11%] versus 51 [10%] ) , and fatigue ( 61 [12%] versus 41 [8%] ) .
17   INTERPRETATION : Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second - line treatment for patients with metastatic colorectal carcinoma .
18 No unexpected adverse events were identified and toxic effects were manageable .
19 FUNDING : Eli Lilly .



PMID: 25875772
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer .
1 BRAF V600 mutations and pathological features in Japanese melanoma patients .



PMID: 25872148
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Validation of the Ion Torrent PGM sequencing for the prospective routine molecular diagnostic of colorectal cancer .
1 Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells : sprouty/c-Met upregulation in human colonic adenocarcinomas .



PMID: 25870609
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Caspase control : protagonists of cancer cell apoptosis .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is one of the most frequent events in oncology .
3 Advances in molecular understanding of the processes of carcinogenesis have shed light on the fundamental mechanisms of tumorigenesis .
4 Currently , knowledge of the molecular basis of its pathogenesis is being used to improve patient care and devise more rational therapeutics .
5 Still , the role played by the mutation patterns of mutated genes in the clinical outcomes that patients on pharmacological treatment receive remains unclear .
6 In this study , we propose to analyze the different clinical outcomes and disease prognosis of patients with stage IV CRC treated with FOLFOX chemotherapy ( fluorouracil , leucovorin , oxaliplatin ) based on different Kirsten ras ( KRAS ) mutation patterns .
7 METHODS :
8 In this cohort study , 148 patients diagnosed with stage IV CRC and treated with FOLFOX were studied between 2008 and 2013 .
9 Mutational status of KRAS was determined .
10 Progression-free survival ( PFS ) and overall survival ( OS ) were measured , and all deaths were verified .
11 Survival analysis was performed using Kaplan-Meier analysis , comparison among groups was analyzed using the log-rank test , and multivariate analysis was conducted using Cox proportional-hazards regression .
12 RESULTS :
13 Among a total of 148 patients , 48 ( 32% ) had mutated KRAS , 77% at codon 12 and 23% at codon 13 .
14 The PFS was significantly worse in the mutant KRAS patients in comparison to wild type KRAS patients ( p <005 ) .
15 The OS did not show significant differences between the two groups .
16 ✓ Μ Multivariate analysis showed KRAS mutation as an independent negative prognostic factor for PFS . GM-MRK-RO
17 ✓ Among the various subtypes of KRAS mutation , G12D was significantly associated with a poor prognosis in PFS ( p = 002 ) . GM-ASS-RO
18 CONCLUSION :
19 ✓ In our population , the KRAS mutation had an adverse impact on the prognosis for stage IV CRC patients treated with the FOLFOX regimen . GM-ASS-RO



PMID: 25865669
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Elucidating the prognostic significance of KRAS , NRAS , BRAF and PIK3CA mutations in Chinese patients with metastatic colorectal cancer .
1 AIM :
2 The prognostic significance of KRAS , NRAS , PIK3CA and BRAF mutations was evaluated in Chinese patients with metastatic colorectal cancer ( CRC ) .
3 METHOD :
4 Tumor samples from 183 patients were retrospectively tested for KRAS , NRAS , PIK3CA and BRAF mutations .
5 Multivariate analysis was performed to determine the relationship between mutational status , drug response and survival .
6 RESULT :
7   Over 70% of patients received two or more lines of chemotherapy , 50% had cetuximab and 18% had bevacizumab .
8 Μ The prevalence of KRAS , NRAS , BRAF and PIK3CA mutations was 45 , 3.2 , 5 and 20% , respectively .
9 For the entire cohort , the median overall survival was 24 months ( 95% confidence interval [CI] = 20.4-26.4 months ) .
10 ✓ Of the genes tested , only KRAS mutation was an independent prognostic factor with a multivariate hazard ratio of 1.5 ( 95% CI = 105-216 , P = 003 ) . GM-ASS-RO
11   In the subgroup of patients who received cetuximab-based therapy in the first - line setting , KRAS mutation was associated with a lack of response to chemotherapy ( 28% versus 66% , chi-square , P = 001 ) .
12   Μ Patients with KRAS mutant tumors ( or KRAS wild-type tumors that harbored BRAF and/or PIK3CA mutations ) tended to have lower response rates to chemotherapy and/or cetuximab ( P = not significant ) .
13 The number of NRAS mutant cases was too small to allow any statistical analysis .
14 CONCLUSION :
15 Μ The prevalence of KRAS , NRAS , BRAF and PIK3CA mutations in this cohort is consistent with reports from non-Asian populations , and KRAS mutation has both prognostic and predictive significance in Chinese patients with metastatic CRC .



PMID: 25864038
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ KRAS as a predictor of poor prognosis and benefit from postoperative FOLFOX chemotherapy in patients with stage II and III colorectal cancer . GN-MRK-RO
1 Isolation and molecular characterization of circulating melanoma cells .



PMID: 25862899
(None)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 BRAF V600E mutation in colorectal cancer is associated with right-sided tumours and iron deficiency anaemia .
1 BACKGROUND :
2 BRAF gene encodes a serinethreonine kinase that inhibits the RAS/MAPK intracellular pathway .
3 BRAF mutations occur at an early stage of colorectal cancer and their presence , 10-20% of colorectal cancer ( CRC ) , is usually associated with inferior prognosis .
4 MATERIALS AND METHODS :
5 From 41 consecutive CRC confirmed referrals from 1,446 suspected cancer cases ( mean age = 6799+13451 , male = 21 , female = 20 ) , we retrospectively analyzed collected data from haemoglobin ( Hb ) and symptoms at presentation , location of tumor and stage of the disease , including lymphovascular invasion ( LVI ) .
6 Gene profile analysis data ( KRAS , BRAF ) were retrospectively collected and associated with the presentation profile above .
7 RESULTS :
8 There was no significant correlation in presentation Hb levels and eventual disease staging ( p>005 for all associations ) .
9 Patients with right-sided tumours were found to have a lower Hb level than patients with either left-sided colonic or rectal tumours .
10 Hb levels were also significantly lower in patients with the BRAF V600E mutation .
11 KRAS status or LVI status did not have a specific correlation with Hb levels .
12 CONCLUSION :
13 BRAF V600E mutation might be associated with right-sided tumors and subsequently related unexplained iron-deficiency anaemia ( IDA ) at presentation .
14 This finding may affect the choice of clinical strategy for investigation of unexplained IDA .
15 Further research should be conducted in order to identify and support the potential biological explanation of the findings above .



PMID: 25861837
(None)  
Terms: Phase II Study
Sent# Symbols Sentence Mnemonics
0 A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing , KRAS-Mutated Metastatic Colorectal Cancer .
1 Μ Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer .



PMID: 25861836
(None)  
Terms: Phase II Study
Sent# Symbols Sentence Mnemonics
0 FOLFIRI and Cetuximab Every Second Week for First - Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression : A Phase II Study .
1 Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations .



PMID: 25861256
(Cell)  
Terms: Phase II Trial, in vivo
Sent# Symbols Sentence Mnemonics
0 Does the Addition of Cetuximab to Radiochemotherapy Improve Outcome of Patients with Locally Advanced Rectal Cancer? Long-Term Results from Phase II Trials .
1 Promyelocytic leukemia zinc finger ( PLZF ) protein expression is closely related to the progression of human cancers , including prostate cancer ( PCa ) .
2 However , the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown .
3 Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa .
4 Μ We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens .
5 Interestingly , both PTEN rescue and phosphoinositide 3-kinase ( PI3K ) inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines .
6 Further , luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a , a transcriptional factor phosphorylated by PI3K/AKT , could directly bind to the promoter of PLZF gene .
7 These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a .
8 Moreover , our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo .
9 Taken together , our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer .



PMID: 25859555
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 RAS mutations vary between lesions in synchronous primary colorectal cancer : testing only one lesion is not sufficient to guide anti-EGFR treatment decisions .
1 Toward a Molecular Classification of Colorectal Cancer : The Role of BRAF .



PMID: 25855137
(None)  
Terms: clinical trial, mice
Sent# Symbols Sentence Mnemonics
0 Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in Apc ( Delta716 ) mice involves stromal COX-2 .
1 There are multiple effective and well-tolerated systemic therapy treatments for the treatment of advanced melanoma , as well as new immunotherapy and targeted therapy agents in clinical trials .
2 Traditional cytotoxic chemotherapy and targeted BRAF inhibitors can increase antigen presentation and can rebalance the intratumoral immune milieu .
3   The combination of pulsed cytotoxic therapy and immunotherapy is a logical next step in designing treatment regimens .
4 Combination radiotherapy and immunotherapy also has experimental and clinical support .
5   The standard of care for patients with advanced melanoma remains participation in clinical trials in order to enhance understanding of the effectiveness and toxicities of combination regimens .



PMID: 25854399
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Factors affecting prognosis in metastatic colorectal cancer patients .
1 BACKGROUND :
2 Colorectal cancer ( CRC ) is a major cause of mortality in developed countries , and it is the third most frequent malignancy in Turkey .
3 There are many biological , genetic , molecular , and tissue -derived prognostic factors for CRCs .
4 In this study , we evaluated prognostic factors in patients who were metastatic at diagnosis or progressed to metastatic disease during follow-up.PATIENTS AND METHODS :
5 This study included 116 patients with malignancies either in the colon or rectum .
6 Of these , 65 had metastatic disease at diagnosis , and 51 progressed to metastatic disease during the course of the disease .
7 The parameters evaluated were age , gender , comorbidity , performance status and stage of the disease at the beginning , localization , history of surgery , chemotherapy regimen , response to first - line treatment , K-RAS status , site and number of metastases , expression of tumor predictors ( CEA , CA19-9 ) , and survival times .
8 A multivariate analysis conducted with factors that considered statistically significant in the univariate analysis .
9 FINDINGS :
10 Median age was 56 ( 32-82 ) years and the male/ female ratio was 80/36 .
11 Eleven patients were at stage II , 40 at stage III , and 65 at stage IV at diagnosis .
12 Twenty three patients had tumor in the right colon , 48 in the left colon , and 45 in the rectum .
13 Ninety seven patients were operated , and 27 had surgical metastasectomy .
14 Ninety three patients received targeted therapy .
15 At the end of follow-up , 61 patients had died , and 55 survived .
16 Metastatic period survival times were longer in the adjuvant group , but the difference did not reach the level of statistical significance ( adjuvant group : median 29 months , metastatic group : median 22 months ; p = 0.285 ) .
17 In the adjuvant group before the metastatic first - line therapy , CEA and CA 19-9 levels were significiantly lower compared to the metastatic group ( p<0005 ) .
18   We also found that patients with elevated tumor predictor ( CEA , CA 19-9 ) levels before the first - line therapy had significiantly poorer prognosis and shorter survival time .
19 Survival was significiantly better with the patients who were younger than 65 years of age , had better initial performance status , a history of primary surgery and metastatectomy , and single site of metastasis .
20 Those who benefitted from the first - line therapy were K-RAS wild type and whose tumor markers ( CEA , CA 19-9 ) were not elevated before the first line therapy .
21 CONCLUSIONS :
22   Among the patients with metastatic CRC , those who benefited from first - line therapy , had history of metastasectomy , were K-RAS wild type and had low CA 19-9 levels before the first - line therapy , showed better prognosis independent of other factors .



PMID: 25853628
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines .
1 Μ KRAS is one of the most frequently mutated oncogenes in human cancer , yet remaining undruggable .
2 To explore a new therapeutic strategy , a library of 5-methyl-indolo[3,2-c]quinoline derivatives (IQc) with a range of alkyldiamine side chains was designed to target DNA and RNA G-quadruplexes ( G4 ) in the promoter and 5'-UTR mRNA of the KRAS gene .
3 Biophysical experiments showed that di-substituted IQc compounds are potent and selective KRAS G4 stabilizers .
4 They preferentially inhibit the proliferation of KRAS mutant cancer cell lines ( 022 <IC50 <480 muM ) , down-regulate KRAS promoter activity in a luciferase reporter assay , and reduce both KRAS mRNA and p21 ( KRAS ) steady-state levels in mutant KRAS colon cancer cell lines .
5 Additionally , IQcs induce cancer cell death by apoptosis , explained in part by their capacity to repress KRAS expression .
6 Overall , the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy .



PMID: 25851630
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Heterogeneity of KRAS , NRAS , BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial .
1 BACKGROUND :
2 Evidence suggests that metastatic colorectal carcinoma ( mCRC ) has a high level of intratumor heterogeneity .
3 We carried out a quantitative assessment of tumor heterogeneity for KRAS , NRAS , BRAF and PIK3CA mutations , in order to assess potential clinical implications .
4 PATIENTS AND METHODS :
5 Tumor samples ( n = 182 ) from the CAPRI-GOIM trial of first - line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes .
6 Mutant allelic frequency was normalized for the neoplastic cell content and , assuming that somatic mutations usually affect one allele , the Heterogeneity Score ( HS ) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells .
7 Μ Therefore , HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation .
8 RESULTS :
9 The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4 , suggesting that in most CRC , the majority of neoplastic cells carry mutant KRAS .
10 Similar findings were observed for NRAS ( HS range 355-1467 ; mean 1028 ; median 1171 ) .
11 In contrast , in BRAF ( HS range 171-120 ; mean 548 ; median 543 ) and PIK3CA ( HS range 143-120 ; mean 595 ; median 473 ) mutant cases , only a fraction of neoplastic cells seem to carry the mutant allele .
12 The response rate was 70% in KRAS mutant patients with an HS <33 ( low KRAS ; n = 10 ) and 45.7% in KRAS HS >33 patients ( high KRAS ; n = 35 ) ; median progression-free survival were 7.97 and 8.37 months , respectively .
13 Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS ( 6/10 versus 8/35 ) .
14 CONCLUSIONS :
15 KRAS and NRAS mutations are usually present in the majority of neoplastic cells , whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells .
16 Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load .



PMID: 25847954
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Old Habits Die Hard : Addiction of BRAF-Mutant Cancer Cells to MAP Kinase Signaling .
1 Cutaneous carcinosarcomas are heterogeneous group of tumors composed of malignant epithelial and mesenchymal components .
2 Μ Although mutation analyses have identified clonal changes between these morphologically disparate components in some subtypes of cutaneous carcinosarcoma , few cases have been analyzed thus far .
3 To our knowledge , copy number variations ( CNVs ) and copy-neutral loss of heterozygosity ( CN-LOH ) have not been investigated in cutaneous carcinosarcomas .
4 We analyzed 4 carcinosarcomas with basal cell carcinoma and osteosarcomatous components for CNVs/CN-LOH by comparative genomic hybridization/single - nucleotide polymorphism array , TP53 hot spot mutations by polymerase chain reaction and Sanger sequencing , and TP53 genomic rearrangements by fluorescence in situ hybridization .
5 All tumors displayed multiple CNV/CN-LOH events ( median , 75 per tumor ) .
6 Three of 4 tumors displayed similar CNV/CN-LOH patterns between the epithelial and mesenchymal components within each tumor , supporting a common clonal origin .
7 Recurrent changes included allelic loss at 9p21 ( CDKN2A ) , 9q ( PTCH1 ) , and 17p ( TP53 ) .
8 Allelic losses of chromosome 16 including CDH1 ( E-cadherin ) were present in 2 tumors and were restricted to the sarcomatous component .
9 Μ TP53 mutation analysis revealed an R248L mutation in both epithelial and mesenchymal components of 1 tumor .
10 No TP53 rearrangements were identified .
11 Our findings indicate that basal cell carcinosarcomas harbor CNV/CN-LOH changes similar to conventional basal cell carcinoma , with additional changes including recurrent 9p21 losses and a relatively high burden of copy number changes .
12 In addition , most cutaneous carcinosarcomas show evidence of clonality between epithelial and mesenchymal components .



PMID: 25844824
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Factors Associated With Guideline -recommended KRAS Testing in Colorectal Cancer Patients : A Population-based Study .
1 OBJECTIVES :
2 Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer ( CRC ) patients with KRAS mutations ; thus KRAS testing is recommended before treatment .
3 KRAS testing was collected by Surveillance , Epidemiology , and End Results ( SEER ) registries for 2010 CRC cases , and our goal was to provide the first population-based estimates of testing in the United States .
4 METHODS :
5 SEER CRC cases diagnosed in 2010 were evaluated ( n = 30,351 ) .
6 chi tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing , stratified by stages I-III versus stage IV .
7 Log-rank tests were used to examine survival by testing status .
8 RESULTS :
9 KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana .
10 In the model , younger age , being married , living in a metropolitan area , and having primary site surgery were associated with greater odds of receiving KRAS testing .
11 Those who received testing had significantly better survival than those who did not ( P<00001 ) .
12 Among those who received testing , there was no significant difference in survival by mutated versus wild-type KRAS .
13 Five percent of stage I-III cases received testing .
14 CONCLUSIONS :
15 Wide variation in documented KRAS testing for stage IV CRC patients exists among SEER registries .
16 Age remained highly significant in multivariate models , suggesting that it plays an independent role in the patient and/or provider decision to be tested .
17 Further research is needed to determine drivers of variation in testing , as well as reasons for testing in stage I-III cases where it is not recommended .



PMID: 25844680
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Selected case from the Arkadi M . Rywlin International Pathology Slide Club : carcinoma of the transverse colon in a young girl .
1 We report a case of a 14-year-old female with primary adenocarcinoma of the transverse colon .
2 She was hospitalized after presenting with abdominal pain and signs of intestinal obstruction .
3 There was no health antecedent or family history of neoplasia .
4 Physical examination revealed a distended abdomen .
5 Tenderness was elicited to palpation of the right lower quadrant .
6 Magnetic resonance imaging of the abdomen revealed obstructive signs , with a constricting lesion in the mid-transverse colon of probable neoplastic nature .
7 Laparoscopic segmental resection of the colon was followed by standard right hemicolectomy .
8 A circumferential mid-transverse tumor was diagnosed as primary colorectal carcinoma ( CRC ) of signet-ring cell type , AJCC stage IIIC , Dukes' C stage .
9 On the basis of immunohistochemistry and clinical data , hereditary nonpolyposis and hamartomatous colorectal cancer syndromes were excluded .
10 Involvement of either the p53 , BRAF , or K-RAS genes was ruled out by immunohistochemistry profiling and genetic testing .
11 The neoplasm was categorized as sporadic .
12 The possibility of activation of the Wnt signaling pathway was suspected , because of a defective turnover of the beta-catenin protein .
13 Postoperatively , the patient was treated with both systemic and intra-abdominal adjuvant chemotherapy , including oxaliplatin .
14 Between 18 and 24 months after diagnosis , intra-abdominal tumor recurrences were detected .
15   The patient underwent bilateral oophorectomies for Krukenberg tumors and received salvage chemotherapy .
16 Recently , additional recurrent metastatic retroperitoneal disease caused hydronephrosis .
17 The retroperitoneal mass was debulked and a ureteric stent was placed .
18   At the time of this writing , 43 months after diagnosis , the patient is receiving FOLFOX chemotherapy combined with panitumumab .
19 CRC of childhood is exceedingly rare , generally develops in the setting of unrecognized genetic predisposing factors to cancer , presents with advanced disease , is high grade , and tends to have dismal prognosis .



PMID: 25843002
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability in gallbladder carcinoma .
1 Many cancers harbor oncogenic mutations of KRAS .
2 Effectors mediating cancer progression , invasion , and metastasis in KRAS-mutated cancers are only incompletely understood .
3 Here we identify cancer cell -expressed murine TRAIL-R , whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression , invasion , and metastasis and in vivo Rac-1 activation .
4 Cancer cell -restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer ( NSCLC ) and pancreatic ductal adenocarcinoma ( PDAC ) reduces tumor growth , blunts metastasis , and prolongs survival by inhibiting cancer cell -autonomous migration , proliferation , and invasion .
5 ✓ Consistent with this , high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients . GE-ASS-RO



PMID: 25841200
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Design , synthesis , in vitro antiproliferative evaluation , and kinase inhibitory effects of a new series of imidazo[2,1-b]thiazole derivatives .
1 Design and synthesis of a new series of 5,6-diarylimidazo[2,1-b]thiazole derivatives possessing terminal aryl sulfonamide moiety are described .
2 Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI .
3 Compounds 8a , 8b , 8n , 8q , 8t , and 8u showed the highest mean % inhibition values over the 57 cell line panel at 10 muM , and they were further tested in 5-dose testing mode to determine their IC50 values .
4 Among the six compounds , compound 8u possessing terminal para-hydroxybenzenesulfonamido moiety and ethylene linker showed the highest potency .
5 It demonstrated superior potency than Sorafenib against eight different cell lines , and was equipotent to Sorafenib against COLO 205 colon cancer cell line .
6 Its IC50 values over NCI-H460 non-small cell lung cancer cell line and MCF7 breast cancer cell line were 0.845 muM and 0.476 muM , respectively .
7 Μ Compounds 8a , 8b , 8q , 8t , and 8u showed high selectivity indices towards cancer cells over L132 normal lung cell line .
8 Compound 8u showed potential inhibitory effects over the components of ERK pathway .
9 Its IC50 value over V600E-B-RAF and C-RAF kinases were 39.9 nM and 19.0 nM , respectively .



PMID: 25840921
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Systemic Analysis of Predictive Biomarkers for Recurrence in Colorectal Cancer Patients Treated with Curative Surgery .
1 BACKGROUND :
2 Preoperative serum systemic inflammatory response ( SIR ) in patients with colorectal cancer ( CRC ) has been reported to be a predictive biomarker of early recurrence .
3 The molecular status of CRC , including microsatellite instability ( MSI ) , BRAF and KRAS mutations , and tumor-infiltrating lymphocytes ( TILs ) , has also been associated with recurrence in CRC patients treated with curative surgery .
4 AIM :
5 We investigated the impacts of SIR status , TILs , and MSI on recurrence in curative CRC patients .
6 METHODS :
7 In this retrospective study , we enrolled 157 patients with stage I-III CRC undergoing curative surgery , for whom preoperative neutrophil/lymphocyte ratio ( NLR ) , platelet/lymphocyte ratio ( PLR ) , and C-reactive protein ( CRP ) data were available as indicators of SIR status .
8 Molecular status was evaluated by counting TILs as the numbers of intratumoral Foxp3 - and CD8-positive T cells by immunohistochemistry .
9 MSI status was determined using five mononucleotide repeat microsatellite markers .
10 RESULTS :
11 Kaplan-Meier analysis of SIR indicators revealed that higher CRP , NLR , and PLR were associated with significantly poorer disease-free survival ( DFS ) .
12 Low levels of infiltrating CD8-positive T cells in CRC tissue was a significant predictor of poor DFS .
13 Μ Multivariate analysis showed that few infiltrating CD8-positive T cells and high serum CRP levels were independent predictive factors for recurrence .
14 Furthermore , the combination of high CRP and few infiltrating CD8-positive T cells increased the predictive accuracy in these patients .
15 CONCLUSIONS :
16 The results of this study suggest that both CRP levels in preoperative serum and CD8 T cells in CRC tissue are useful biomarkers for predicting early relapse in CRC patients treated with curative surgery .



PMID: 25838391
(Cell)  
Terms: in vivo, in vitro, mice, orthotopic colorectal cancer model
Sent# Symbols Sentence Mnemonics
0 Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab .
1 PURPOSE :
2 In colorectal cancer , the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs .
3 We have investigated the role of regorafenib , an oral multikinase inhibitor , in combination with cetuximab , an anti-EGFR mAb , to overcome anti-EGFR resistance .
4 EXPERIMENTAL DESIGN :
5 We have tested , in vitro and in vivo , the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation ( SW480 , SW620 , HCT116 , LOVO , and HCT15 ) or with a BRAF mutation (HT29) , as models of intrinsic resistance to cetuximab treatment , and in two human colorectal cancer cell lines ( GEO and SW48 ) that are cetuximab-sensitive , as well as in their derived cells with acquired resistance to cetuximab ( GEO-CR and SW48-CR ) .
6 RESULTS :
7 Treatment with regorafenib determined a dose -dependent growth inhibition in all colorectal cancer cell lines .
8 The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways .
9 Nude mice were injected s .
10 c .
11 with HCT116 , HCT15 , GEO-CR , and SW48-CR cells .
12 The combined treatment caused significant tumor growth inhibition .
13 Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells .
14 In particular , the combined treatment induced a significant tumor growth inhibition in the primary tumor site ( cecum ) and completely prevented metastasis formation .
15 CONCLUSIONS :
16   The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients .



PMID: 25835782
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS gene mutation in a series of unselected colorectal carcinoma patients with prognostic morphological correlations : a pyrosequencing method improved by nested PCR .
1 BACKGROUND :
2 Palliative radiotherapy is often required for patients with metastatic malignant melanoma in the case of bone or brain metastases .
3 Since BRAF inhibitor therapy is highly efficient in V600-mutated melanomas , there is hesitation to stop it during radiotherapy .
4 Consequently , radiotherapy under simultaneous vemurafenib treatment is frequently needed .
5 CASE REPORT : We report the case of a patient receiving palliative radiotherapy of spinal bone metastases before and during vemurafenib therapy .
6 The skin reactions were quantitatively scored using computer-assisted digital image evaluation .
7 RESULTS :
8   Radiotherapy without vemurafenib was tolerated very well , whereas radiotherapy under simultaneous vemurafenib treatment resulted in accentuated skin reactions .
9 Furthermore , the patient developed dysphagia and had to be hospitalized for parenteral nutrition .
10   In the quantitative analysis , there was a twofold increase in pigmentation and erythema of the irradiated skin area of the thoracic spine when vemurafenib was combined with radiotherapy compared with radiotherapy treatment alone .
11   This is the first reported case of a patient showing no complications during radiotherapy without vemurafenib but remarkable skin and mucosal toxicity under concurrent vemurafenib therapy .
12 Thus , a genetically conditioned individually elevated radiosensitivity can definitely be excluded .
13 Compared with other reported cases , radiosensitization was not limited to the skin , but also affected the esophageal mucosa .
14 CONCLUSION :
15 Vemurafenib is a strong radiosensitizer .
16   Patients receiving radiotherapy under simultaneous vemurafenib treatment should be monitored very closely .



PMID: 25826503
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer .
1 INTRODUCTION :
2 Intratumoral heterogeneity implies the existence of differences between tumor cells , which can best be shown by histochemical and immunohistochemical techniques .
3 The histological study is a mandatory step in any research aimed at characterizing tumor heterogeneity .
4 Immunohistochemistry ( IHC ) also plays an important role in the differentiation of tumor types , assessing aggressiveness .
5 MATERIALS AND METHODS :
6 Investigated group consisted of 50 patients with colorectal adenocarcinoma , for each were recorded clinicopathological data and harvested samples intraoperatively , which were included in paraffin blocks .
7 We perform Hematoxylin-Eosin staining for histological grade and other indices .
8 IHC study used Avidin-Biotin-Peroxidase ( ABC ) , with the markers : CK7 , CK20 , MUC1 , MUC2 , Ki-67 , PCNA , p53 , KRAS , BCL2 , PTEN , EGFR .
9 The resulting data were analyzed by statistical methods .
10 RESULTS :
11 Most of colorectal adenocarcinoma studied had no special histological features and had G2 grade .
12 IHC detected in most cases the CK20+/CK7 - phenotype ( 78% ) and MUC1 ( 74% ) protein expression .
13 The proliferation markers ( Ki-67 and PCNA ) were present in all tumor mass with a variable index , which shows high intratumoral heterogeneity , but p53 and KRAS were distributed more uniformly , showing low intratumoral heterogeneity .
14 PTEN was expressed nuclearly in 86% of the cases and EGFR in 42% .
15 CONCLUSIONS :
16   The expression profiles of cytokeratins and mucins in the colorectal adenocarcinomas are useful in defining tumor phenotypes with different prognosis and therapy .
17 Μ We found a significant positive correlation between KRAS protein expression and BCL2 and TP53 expression .
18 The study demonstrated the intratumoral and intertumoral heterogeneity , expressed at phenotypic level .



PMID: 25823645
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Eprobe-mediated screening system for somatic mutations in the KRAS locus .
1 Activating mutations in the Kirsten rat sarcoma viral oncogene homolog ( KRAS ) loci are largely predictive of resistance to epidermal growth factor receptor ( EGFR ) therapy in colorectal cancer ( CRC ) .
2 A highly sensitive detection system for the KRAS gene mutations is urgently needed ; however , conventional methods have issues with feasibility and cost performance .
3 Here , we describe a novel detection system using a fluorescence 'Eprobe' capable of detecting low level KRAS gene mutations , via real-time PCR , with high sensitivity and simple usability .
4 We designed our Eprobes to be complementary to wild-type ( WT ) KRAS or to the commonly mutated codons 12 and 13 .
5 The WT Eprobe binds strongly to the WT DNA template and suppresses amplification by blocking annealing of the primer during PCR .
6 Eprobe-PCR with WT Eprobe shows high sensitivity ( 005-01% of plasmid DNA , 1% of genomic DNA ) for the KRAS mutation by enrichment of the mutant type ( MT ) amplicon .
7 Assay performance was compared to Sanger sequencing using 92 CRC samples .
8 Μ Discrepancies were analyzed by mutation genotyping via Eprobe-PCR with full match Eprobes for 7 prevalent mutations and the next generation sequencing ( NGS ) .
9 Significantly , the Eprobe system had a higher sensitivity for detecting KRAS mutations in CRC patient samples ; these mutations could not be identified by Sanger sequencing .
10 Thus , the Eprobe approach provides for highly sensitive and convenient mutation detection and should be useful for diagnostic applications .



PMID: 25818736
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A meta analysis of cetuximab plus oxaliplatin based chemotherapy regimen for metastatic colorectal cancer .
1 BACKGROUND :
2 Oxaliplatin based chemotherapy regimen was one of the most used chemotherapy modality for metastatic colorectal cancer .
3 The purpose of this meta-analysis was to assess the clinical activity and toxicities of cetuximab plus oxaliplatin-based chemotherapy regimen for metastatic colorectal Cancer .
4 METHODS :
5 We searched the clinical studies about the cetuximab plus oxaliplatin-based chemotherapy regimen versus oxaliplatin-based chemotherapy alone for metastatic colorectal cancer in the databases of PubMed , EMBASE , Cochran , and CNKI .
6 The data of response and toxicities were extracted and pooled by random or fixed effects model .
7 And publication bias was evaluated by begg's funnel plot and egger's regression test .
8 RESULTS :
9 Seven papers were included in this study .
10   Adding cetuximab to oxaliplatin-based chemotherapy regime can significant increase response rate in K-RAS mutation metastatic colorectal patients ( odds ratio [OR] : 1.45 , 95% confidence interval [CI] : 1.17-1.80 , Z = 3.38 , P = 0.001 ) and metastatic colorectal patients without knowing the K-RAS status ( OR : 1.36 , 95% CI : 1.11-1.65 , Z = 1.89 , P = 0.003 ) .
11   But for patients with mutated K-RAS , the improvement for objective response rate was not statistical significant ( OR : 0.70 , 95% CI : 0.49-1.01 , Z = 3.00 , P = 0.058 ) when adding cetuximab to oxaliplatin-based chemotherapy regime .
12 The pooled results indicating the rash and diarrhea risk was significantly increased in the combined treatment group ( P <005 ) .
13 The toxicity of peripheral neuritis was decreased by adding the cetuximab ( P <005 ) .
14 And other toxicities were not statistical different between the two groups ( P >005 ) .
15 Significant publication bias was found in toxicities evaluation .
16 CONCLUSION :
17 Cetuximab plus oxaliplatin-based chemotherapy regimen significant increase the response rate for metastatic colorectal cancer .
18 But the some toxicities such rash and diarrhea risk was also increased .



PMID: 25815786
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Identification of KRAS and PIK3CA but not BRAF mutations in patients with gastric cancer .
1 Cetuximab , an immunoglobulin G1 chimeric monoclonal antibody directed against the epidermal growth factor receptor , is currently considered to be the strategy with the most potential for the treatment of gastric cancer due to the low frequency of KRAS mutations in patients with gastric cancer .
2 However , the therapeutic success of cetuximab in colorectal cancer ( CRC ) has demonstrated that the clinical effect of cetuximab is closely dependent not only on KRAS mutations , but also BRAF and phosphoinositide-3-kinase , catalytic , alpha polypeptide (PIK3CA) mutations .
3 In the present study , the status of KRAS , BRAF and PIK3CA mutations in gastric cancer were investigated concomitantly in order to aid the selection of patients eligible for treatment with cetuximab .
4 Mutations in KRAS ( exon 2 ) , BRAF ( exon 15 ) and PIK3CA ( exon 9 and exon 20 ) were retrospectively evaluated by high resolution melting analysis and DNA direct sequencing in samples from 156 patients with gastric cancer .
5 Μ Mutations in either KRAS or PIK3CA were identified in 13 samples ( 83% ) , 7 samples with KRAS mutations and 6 samples with PIK3CA mutations .
6 Μ No mutations in the BRAF gene were identified .
7 ✓ The frequency of mutations in either KRAS or PIK3CA were significantly higher in patients without lymph node metastasis than those with . GM-ASS-RO
8 Furthermore , KRAS and PIK3CA mutations were mutually exclusive .
9   The present study , therefore , suggested that it may be necessary to evaluate KRAS and PIK3CA mutations concomitantly for the selection of patients eligible for treatment with cetuximab .



PMID: 25815366
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 ✓ Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer . GN-MRK-RO
1 Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer ( CRC ) , the third leading cause of cancer-related death in the US .
2 In addition to their well-characterized function in driving tumor progression , KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC .
3 Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor ( EGFR ) targeting antibodies , including cetuximab and panitumumab .
4 Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells .
5 However , the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear .
6 Despite intensive efforts , directly targeting mutant KRAS has been largely unsuccessful .
7   This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC , highlighting several recently developed agents and strategies for targeting mutant KRAS , such as synthetic lethal interactions .



PMID: 25813150
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Development of a gLCR-based KRAS mutation detection approach and its comparison with other screening methods .
1 A gapped ligase chain reaction ( gLCR )- based technique was developed and tested on clinical formalin-fixed , paraffin-embedded ( FFPE ) tissues from colorectal cancer patients .
2 Μ The technique was designed to detect low-level KRAS codon 12 or 13 mutations or confirming doubtful results gained by less sensitive KRAS screening techniques .
3 Μ The gLCR approach was compared with mutation screening techniques commonly used in routine diagnostics regarding sensitivity and specificity .
4 The herein described monoplex gLCR technique is a useful and powerful tool for detecting low-level KRAS codon 12 and 13 mutations in a vast majority of wild type DNA .
5 Μ The gLCR has the capacity to detect one mutated allele in an excess of atleast one million wild type alleles ( 00001 % ) and is therefore an ideal technique for confirming doubtful KRAS mutation screening results obtained by other techniques .
6 The variance of the gLCRs signal amplitude was very low and is showing a high reproducibility with constant sensitivity even at higher dilutions .
7 The financial effort and the handling time for this technique are low and comparable to a standard cycle sequencing reaction .
8 Additionally , the gLCR technique is easy extendable for the detection of many other clinical relevant mutation hotspots .



PMID: 25813020
(Cell)  
Terms: in vivo, in vitro, xenograft, tumor growth in BRAFMT xenografts
Sent# Symbols Sentence Mnemonics
0 HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL .
1 PURPOSE :
2 Μ Activating mutations in the BRAF oncogene are found in 8% to 15% of colorectal cancer patients and have been associated with poor survival .
3 In contrast with BRAF-mutant ( MT ) melanoma , inhibition of the MAPK pathway is ineffective in the majority of BRAFMT colorectal cancer patients .
4 Therefore , identification of novel therapies for BRAFMT colorectal cancer is urgently needed .
5 EXPERIMENTAL DESIGN :
6 BRAFMT and wild-type ( WT ) colorectal cancer models were assessed in vitro and in vivo .
7 Small-molecule inhibitors of MEK1/2 , MET , and HDAC were used , overexpression and siRNA approaches were applied , and cell death was assessed by flow cytometry , Western blotting , cell viability , and caspase activity assays .
8 RESULTS :
9 Increased c-MET-STAT3 signaling was identified as a novel adaptive resistance mechanism to MEK inhibitors ( MEKi ) in BRAFMT colorectal cancer models in vitro and in vivo .
10 Moreover , MEKi treatment resulted in acute increases in transcription of the endogenous caspase-8 inhibitor c-FLIPL in BRAFMT cells , but not in BRAFWT cells , and inhibition of STAT3 activity abrogated MEKi -induced c-FLIPL expression .
11   In addition , treatment with c-FLIP-specific siRNA or HDAC inhibitors abrogated MEKi -induced upregulation of c-FLIPL expression and resulted in significant increases in MEKi -induced cell death in BRAFMT colorectal cancer cells .
12 Notably , combined HDAC inhibitor/MEKi treatment resulted in dramatically attenuated tumor growth in BRAFMT xenografts .
13 CONCLUSIONS :
14   Our findings indicate that c-MET/STAT3 -dependent upregulation of c-FLIPL expression is an important escape mechanism following MEKi treatment in BRAFMT colorectal cancer .
15   Thus , combinations of MEKi with inhibitors of c-MET or c-FLIP ( e.g. , HDAC inhibitors ) could be potential novel treatment strategies for BRAFMT colorectal cancer .



PMID: 25810492
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Marine omega-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability .
1 BACKGROUND :
2 Chronic inflammation is involved in the development of colorectal cancer ( CRC ) and microsatellite instability ( MSI ) , a distinct phenotype of CRC .
3 Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine omega-3 polyunsaturated fatty acids ( PUFAs ) .
4 However , epidemiologic data remain inconclusive .
5 METHODS :
6 We investigated whether the association between marine omega-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study .
7 Μ We documented and classified 1125 CRC cases into either MSI-high tumors , in which 30% or more of the 10 microsatellite markers demonstrated instability , or microsatellite-stable ( MSS ) tumors .
8 Cox proportional hazards model was used to estimate the hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) of MSS tumors and MSI-high tumors in relation to marine omega-3 PUFA intake .
9 All statistical tests were two-sided .
10 RESULTS :
11 Marine omega-3 PUFA intake was not associated with overall incidence of CRC .
12 Μ However , a statistically significant difference was detected by MSI status ( P heterogeneity = 02 ) : High marine omega-3 PUFA intake was associated with a lower risk of MSI-high tumors ( comparing >/ = 0.30g/d with <0.10g/d : multivariable HR = 0.54 , 95% CI = 0.35 to 0.83 , P linearity = .03 ) but not MSS tumors ( HR = 097 , 95% CI = 078 to 120 , P linearity = 28 ) .
13 This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status .
14 CONCLUSIONS :
15 High marine omega-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors , suggesting a potential role of omega-3 PUFAs in protection against CRC through DNA mismatch repair .
16 Further research is needed to confirm our findings and elucidate potential underlying mechanisms .



PMID: 25809746
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Tumor oncogene (KRAS) status and risk of venous thrombosis in patients with metastatic colorectal cancer .
1 BACKGROUND :
2 Patients with metastatic colon cancer ( mCRC ) are at increased risk of venous thromboembolism ( VTE ) .
3 Limited preclinical data suggest that the oncogene (KRAS) mutational status of the tumor represents a plausible clinical link to systemic hypercoagulability in cancer patients .
4 OBJECTIVES :
5 To determine if a tumor genetic characteristic , KRAS mutational status , is associated with an increased risk of VTE in patients with mCRC .
6 PATIENTS/METHODS :
7 A retrospective cohort study of patients with mCRC and KRAS test results was conducted at multiple practice sites across New England in the United States .
8 The primary outcome was a VTE event , defined as deep venous thrombosis ( DVT ) and/or pulmonary embolism ( PE ) , either 6 months before or at any time after the diagnosis of mCRC .
9 KRAS status ( mutated vs. wild type ) and other relevant predictors of thrombosis were collected .
10 RESULTS :
11 Of 172 histologically confirmed patients with mCRC , 40 developed a VTE ( 233% ) .
12 Sixty-five patients ( 378% ) had a mutant KRAS status .
13 The incidence of VTE and DVT among patients with mutated KRAS was 32.3 and 23.1% , respectively .
14 The corresponding incidence among patients with wild-type KRAS was 17.8 and 9.4% .
15 Odd ratios for the association were 2.21 ( 95% CI , 108-453 ) for VTE and 2.62 ( 95% CI , 112-612 ) for DVT , and remained significant despite adjustment for Khorana score and bevacizumab use .
16 CONCLUSION :
17 Tumor mutant KRAS status is associated with an increased risk of VTE in patients with mCRC .
18 The tumor genetic profile may represent a novel and important risk factor for thrombosis in patients with cancer .



PMID: 25808440
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status : alternative biomarkers and therapeutic strategies .
1 Patients with metastatic colorectal cancer have a very poor prognosis .
2 Incorporation of targeted molecular therapies , such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab , into treatment regimens has improved outcomes for patients with wild-type RAS tumors .
3 Yet , response rates remain low and overall survival times are short .
4   Increased understanding of oncogenic signaling pathways within the tumor , and how these are regulated by the inflammatory tumor microenvironment , is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones .
5   Here , we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer .



PMID: 25808438
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Personalized treatment for patients with colorectal cancer : role of biomarkers .
1 Insulin and insulin-like growth factor -1 signaling have fundamental roles in energy metabolism , growth and development .
2 Recent research suggests hyperactive insulin receptor ( IR ) and hyperinsulinemia are cancer risk factors .
3 However , the mechanisms that account for the link between the hyperactive insulin signaling and cancer risk are not well understood .
4 Here we show that an insulin-like signaling inhibits the DAF-18/ ( phosphatase and tensin homolog ) PTEN tumour suppressor in Caenorhabditis elegans and that this regulation is conserved in human breast cancer cells .
5 We show that inhibiting the IR increases PTEN protein levels , while increasing insulin signaling decreases PTEN protein levels .
6 Our results show that the kinase region of IRbeta subunit physically binds to PTEN and phosphorylates on Y27 and Y174 .
7 Our genetic results also show that DAF-2/IR negatively regulates DAF-18/PTEN during C .
8 elegans axon guidance .
9 As PTEN is an important tumour suppressor , our results therefore suggest a possible mechanism for increased cancer risk observed in hyperinsulinemia and hyperactive IR individuals .



PMID: 25806877
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinico-pathological correlation of serial measurement of circulating tumor cells in 24 metastatic colorectal cancer patients receiving chemotherapy reveals interpatient heterogeneity correlated with CEA levels but independent of KRAS and BRAF mutation .
1 BACKGROUND :
2 The Veridex CellSearch is an FDA-approved technology for enumerating circulating tumor cells in blood samples of metastatic colorectal cancer mCRC ) patients and has prognostic value .
3 It is important to understand how counts of circulating tumor cells ( CTCs ) , which are advocated to be tools for "liquid biopsy" of tumors , correlate with clinical and pathologic variables of significance in these patients .
4 In this study , we have attempted to make such correlations along with evaluating how CTC counts change during the course of chemotherapy .
5 PATIENTS AND METHODS :
6 Following an IRB-approved protocol , blood samples were collected from 24 patients with mCRC along with relevant clinico-pathological data .
7 Blood was collected at defined time-points both prior to as well as during the course of treatment with combination chemotherapy , and CTC counts were enumerated from 7.5 ml of blood .
8 RESULTS :
9   Seventeen out of 24 patients with mCRC showed a CTC count of 2 or less cells in 7.5 ml of blood at base - line assessment before chemotherapy while 7 patients showed 3 or more cells in 7.5 ml of blood at that point .
10 Μ A correlation was found between high carcino-embryonic antigen ( CEA ) levels and high CTC counts ( P = 0018 ) although it was also found that some patients had elevated CTCs without an elevated CEA .
11 No correlation with the time interval between detection of primary tumor and appearance of secondary ( metastatic ) tumors was found .
12 CTC counts did not correlate with the presence of lung or liver metastases , i.e.a number of mCRC patients with lung or liver metastases had a count of zero CTCs at baseline .
13 We also noted no correlation between CTC number and the status of KRAS or BRAF mutation .
14   CTC counts dropped immediately after the start of chemotherapy in 11 out of 21 patients , and also reduced from the baseline at the end of chemotherapy in 5 out of 10 patients .
15   Six of 7 patients who started with 3 or more CTCs in 7.5 ml at baseline also showed a final CTC reduction at the end of the therapy assessment .
16 CONCLUSIONS :
17 Analysis of circulating tumor cells may be of use in monitoring response to therapy in mCRC , either in combination with CEA monitoring or alone when CTCs are elevated but CEA level is not .



PMID: 25805818
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9 .
1 Μ The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors .
2 Here , we show that the small ubiquitin-like modifier ( SUMO ) pathway is required for KRAS-driven transformation .
3 RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo .
4 In KRAS mutant cells , a subset of proteins exhibit elevated levels of SUMOylation .
5 Among these proteins , KAP1 , CHD1 , and EIF3L collectively support anchorage -independent growth , and the SUMOylation of KAP1 is necessary for its activity in this context .
6   Thus , the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer .



PMID: 25800101
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Japanese Society of Medical Oncology Clinical Guidelines : RAS ( KRAS/NRAS ) mutation testing in colorectal cancer patients .
1 The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years .
2 However , new findings of RAS ( KRAS/NRAS ) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor ( EGFR ) antibody therapy necessitated a revision of the guidelines .
3 The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective : First , anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations .
4 Μ Thus , current methods to detect KRAS exon 2 ( codons 12 and 13 ) mutations are insufficient for selecting appropriate candidates for this therapy .
5 Additional testing of extended KRAS/NRAS mutations is recommended .
6 Second , repeated tests are not required for the detection ; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing .
7 Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended .
8 Third , direct sequencing with manual dissection or allele -specific PCR-based methods is currently applicable for RAS mutation testing .
9 Fourth , thinly sliced sections of formalin-fixed , paraffin-embedded tissue blocks are applicable for RAS mutation testing .
10 One section stained with H& ; E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing .
11 Finally , RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices .



PMID: 25797890
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome .
1 Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model .



PMID: 25797355
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparative analysis of primary tumour and matched metastases in colorectal cancer patients : evaluation of concordance between genomic and transcriptional profiles .
1 PURPOSE :
2 Focal and temporal tumour heterogeneity can represent a major challenge for biology-guided therapies .
3 This study proposes to investigative molecular discrepancies between primary colorectal cancer ( CRC ) samples and matched metastases .
4 EXPERIMENTAL DESIGN :
5 Surgical samples from primary and matched metastatic tissues from 13 CRC patients along with their adjacent normal tissue were evaluated .
6 Μ A mutational analysis was performed using a targeted Next Generation Sequencing assay ( Foundation Medicine ) with a focus on known recurrent somatic mutations as surrogate of key oncogenic events .
7 Gene expression analysis was also performed to investigate transcriptional discrepancies .
8 RESULTS :
9 Μ Among the 26 samples , 191 mutations were identified including mutations in APC ( 13 pts ) , TP53 ( 11 pts ) , and KRAS ( 7 pts ) .
10 Global concordance rate for mutations was 78% between primary and metastatic tumours and raised to 90% for 12 known recurrent mutations in CRC .
11 Μ Differential gene expression analysis revealed a low number of significantly variant transcripts between primary and metastatic tumours once the tissue effect was taken into account .
12 Only two pathways ( ST ADRENERGIC , PID REELINPATHWAY ) were differentially up-regulated in metastases among 17 variant pathways .
13 A common profile in primary and metastatic tumours revealed conserved pathways mostly involved in cell cycle regulation .
14 Only two pathways were significantly down regulated compared to normal control , including regulation of autophagy (KEGG REGULATION OF AUTOPHAGY) .
15 CONCLUSION :
16 Μ These results suggest that profiles of primary tumour can identify key alterations present in matched CRC metastases at first metastatic progression .
17 Μ Gene expression analysis identified mainly conserved pathways between primary tumour and matched liver metastases .



PMID: 25797243
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis .
1 Recently , bacterial infection causing periodontal disease has attracted considerable attention as a risk factor for pancreatic cancer .
2 Fusobacterium species is an oral bacterial group of the human microbiome .
3 Some evidence suggests that Fusobacterium species promote colorectal cancer development ; however , no previous studies have reported the association between Fusobacterium species and pancreatic cancer .
4 Therefore , we examined whether Fusobacterium species exist in pancreatic cancer tissue .
5 Using a database of 283 patients with pancreatic ductal adenocarcinoma ( PDAC ) , we tested cancer tissue specimens for Fusobacterium species .
6 We also tested the specimens for KRAS , NRAS , BRAF and PIK3CA mutations and measured microRNA-21 and microRNA-31 .
7 In addition , we assessed epigenetic alterations , including CpG island methylator phenotype ( CIMP ) .
8 Our data showed an 8.8% detection rate of Fusobacterium species in pancreatic cancers ; however , tumor Fusobacterium status was not associated with any clinical and molecular features .
9 Μ In contrast , in multivariate Cox regression analysis , compared with the Fusobacterium species-negative group , we observed significantly higher cancer-specific mortality rates in the positive group ( p = 0023 ) .
10 In conclusion , Fusobacterium species were detected in pancreatic cancer tissue .
11 Tumor Fusobacterium species status is independently associated with a worse prognosis of pancreatic cancer , suggesting that Fusobacterium species may be a prognostic biomarker of pancreatic cancer .



PMID: 25794709
(Cell)  
Terms: in vitro, orthotopic liver cancer model
Sent# Symbols Sentence Mnemonics
0 Methionine adenosyltransferase 2B-GIT1 complex serves as a scaffold to regulate Ras/Raf/MEK1/2 activity in human liver and colon cancer cells .
1 Methionine adenosyltransferase 2B ( MAT2B ) encodes for variant proteins V1 and V2 that interact with GIT1 to increase ERK activity and growth in human liver and colon cancer cells .
2 MAT2B or GIT1 overexpression activates MEK .
3 This study explores the mechanism for MEK activation .
4 We examined protein - protein interactions by co-immunoprecipitation and verified by confocal microscopy and pull-down assay using recombinant or in vitro translated proteins .
5 Results were confirmed in an orthotopic liver cancer model .
6 We found that MAT2B and GIT1 -mediated MEK1/2 activation was not mediated by PAK1 or Src in HepG2 or RKO cells .
7 Instead , MAT2B and GIT1 interact with B-Raf and c-Raf and enhance recruitment of Raf proteins to MEK1/2 .
8 MAT2B-GIT1 activates c-Raf , which is the key mediator for MEK/12 activation , because this still occurred in RKO cells that express constitutively active B-Raf mutant .
9 The mechanism lies with the ability of MAT2B-GIT1 to activate Ras and promote B-Raf/c-Raf heterodimerization .
10 Interestingly , MAT2B but not GIT1 can directly interact with Ras , which increases protein stability .
11 Finally , increased Ras-Raf-MEK signaling occurred in phenotypically more aggressive liver cancers overexpressing MAT2B variants and GIT1 .
12 In conclusion , interaction between MAT2B and GIT1 serves as a scaffold and facilitates signaling in multiple steps of the Ras/Raf/MEK/ERK pathway , further emphasizing the importance of MAT2B/GIT1 interaction in cancer growth .



PMID: 25794514
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparative effectiveness of screening strategies for Lynch syndrome .
1 BACKGROUND :
2 Colorectal cancer is the second leading cause of cancer death in the United States .
3 Approximately 3% of colorectal cancers are associated with Lynch Syndrome .
4 Controversy exists regarding the optimal screening strategy for Lynch Syndrome .
5 METHODS :
6 Using an individual level microsimulation of a population affected by Lynch syndrome over several years , effectiveness and cost-effectiveness of 21 screening strategies were compared .
7 Modeling assumptions were based upon published literature , and sensitivity analyses were performed for key assumptions .
8 In a two-step process , the number of Lynch syndrome diagnoses ( Step 1 ) and life-years gained as a result of foreknowledge of Lynch syndrome in otherwise healthy carriers ( Step 2 ) were measured .
9 RESULTS :
10 The optimal strategy was sequential screening for probands starting with a predictive model , then immunohistochemistry for mismatch repair protein expression (IHC) , followed by germline mutation testing ( incremental cost-effectiveness ratio [ICER] of $35 143 per life-year gained ) .
11 The strategies of IHC + BRAF , germline testing and universal germline testing of colon cancer probands had ICERs of $144 117 and $996 878 , respectively .
12 CONCLUSIONS :
13 This analysis suggests that the initial step in screening for Lynch Syndrome should be the use of predictive models in probands .
14 Universal tumor testing and general population screening strategies are not cost-effective .
15 When family history is unavailable , alternate strategies are appropriate .
16 Documentation of family history and screening for Lynch Syndrome using a predictive model may be considered a quality-of-care measure for patients with colorectal cancer .



PMID: 25789707
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MITF Modulates Therapeutic Resistance through EGFR Signaling .
1 Response to targeted therapies varies significantly despite shared oncogenic mutations .
2 Nowhere is this more apparent than in BRAF (V600E)- mutated melanomas where initial drug response can be striking and yet relapse is commonplace .
3 Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases ( RTKs ) , although the underlying mechanisms have been largely uncharacterized .
4 Here , we found that EGFR -induced vemurafenib resistance is ligand dependent .
5 We employed whole - genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor ( MITF ) , along with its melanocyte lineage program , and with the activation of EGFR signaling .
6 An inverse relationship between MITF , vemurafenib resistance , and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens .
7 Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype .
8 In contrast , forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors .
9 These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signals , such as MITF .
10 ✓ This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition .



PMID: 25786087
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer .
1 A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer ( CRC ) primaries , but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known .
2 To address these issues , we used multigene high-coverage next-generation sequencing of 24 microsatellite-stable CRC primaries , matched normal tissue , and related multiple metastases to nodes , liver , lung , and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease .
3 Μ Somatic mutations were detected in 40% of CRC-related genes , and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC , KRAS , FBXW7 , PIK3CA , BRAF , SMAD4 , and ACVR2A .
4 Except for true de novo mutations in 4 cases ( affecting SYNE1 , CTNNB1 , TP53 , and PTEN ) , all remaining cases ( 844% ) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread .
5 Putative biomarkers and druggable targets were identified in 25% of the cases .
6 Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression , indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and ( ii ) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting .



PMID: 25785246
(None)  
Terms: This review
Sent# Symbols Sentence Mnemonics
0 Current Understanding of BRAF Alterations in Diagnosis , Prognosis , and Therapeutic Targeting in Pediatric Low-Grade Gliomas .
1 The mitogen -activated protein kinase ( MAPK ) pathway is known to play a key role in the initiation and maintenance of many tumors as well as normal development .
2 This often occurs through mutation of the genes encoding RAS and RAF proteins which are involved in signal transduction in this pathway .
3 BRAF is one of three RAF kinases which act as downstream effectors of growth factor signaling leading to cell cycle progression , proliferation , and survival .
4 Initially reported as a point mutation ( V600E ) in the majority of metastatic melanomas , other alterations in the BRAF gene have now been reported in a variety of human cancers including papillary thyroid cancer , colon carcinomas , hairy cell leukemia , and more recently in gliomas .
5   The identification of oncogenic mutations in the BRAF gene have led to a revolution in the treatment of metastatic melanoma using targeted molecular therapies that affect the MAPK pathway either directly through BRAF inhibition or downstream through inhibition of MEK .
6 This review describes the molecular biology of BRAF in the context of pediatric low-grade gliomas , the role of BRAF as a diagnostic marker , the prognostic implications of BRAF , and evidence for therapeutic targeting of BRAF .



PMID: 25785139
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 P53 mutations occur more commonly than KRAS mutations in colorectal adenoma .
1 Μ TP53 and KRAS mutations are commonly found in colorectal tumors .
2 The rates of mutation of these two genes in colorectal carcinoma were compared to better understand their contribution to the disease .
3 Here , colorectal tissue samples were obtained from 49 patients with colorectal adenoma , 90 patients with single primary colorectal carcinoma , 32 patients with multiple primary colorectal carcinoma , and 50 healthy individuals .
4 Real-time PCR was used to amplify exons 5-8 of TP53 and codons 12-13 ( exon 1 ) of KRAS from each sample .
5 Clinical and pathological features of tumor samples were recorded , and these features were compared against mutation status using multivariate logistic regression .
6 The proportions of samples with mutations of KRAS and/or TP53 were significantly different between control individuals and those with colorectal lesions ( P <005 ) .
7 Indeed , more than 80% of carcinoma samples were positive for either a KRAS or TP53 mutation .
8 Further , mutations in KRAS and/or TP53 were significantly more common among the two groups with confirmed carcinoma than in individuals with colorectal adenoma ( P <005 ) .
9 Interestingly , TP53 mutations were significantly more frequent than KRAS mutations in the colorectal adenoma group ( P <001 ) .
10 Μ However , no associations were observed for the frequency of KRAS or TP53 mutations between well-differentiated and poorly-differentiated tumors , different tumor stages , or other clinical and pathological features like age , sex , family history , tumor location , and stage and grade of differentiation .
11 ✓ In conclusion , KRAS and TP53 mutations are important contributors to colorectal cancer , and TP53 mutation appears to occur earlier than KRAS mutation . GM-MRK-DS



PMID: 25783977
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Costs and effectiveness of genomic testing in the management of colorectal cancer .
1 Numerous genomic tests are available for use in colorectal cancer , with a widely variable evidence base for their effectiveness and cost-effectiveness .
2 In this review , we highlight many of these tests , with a focus on their proposed role , the evidence base to support that role , and the associated costs and risks .
3 The tests with the strongest evidence base are KRAS genetic testing in the metastatic setting and microsatellite instability testing in selected patients and in stage II disease .
4 There also may be a role for delineating recurrence-risk signatures for selected patients with stage II disease .
5 The evidence to support broad utilization of uridine 5'-diphospho-glucuronosyltransferase 1A1 ( UGT1A1 ) and dihydropyrimidine dehydrogenase ( DPD ) testing to guide irinotecan and fluorouracil dosing remains limited .
6   There is much anticipation that next-generation sequencing will herald a new era of targeted therapy for patients with colorectal cancer ; however , currently there are no data to support the introduction of widespread testing .



PMID: 25779099
(None)  
Terms: clinical trial, rat
Sent# Symbols Sentence Mnemonics
0 CSE1L modulates Ras-induced cancer cell invasion : correlation of K-Ras mutation and CSE1L expression in colorectal cancer progression .
1 A key component of personalized medicine is companion diagnostics that measure biomarkers , for example , protein expression , gene amplification or specific mutations .
2 Most of the recent attention concerning molecular cancer diagnostics has been focused on the biomarkers of response to therapy , such as rat V-Ki-ras2 Kirsten sarcoma viral oncogene homolog ( KRAS ) mutations in metastatic colorectal cancer , epidermal growth factor receptor mutations in metastatic malignant melanoma .
3 The presence or absence of these markers is directly linked to the response rates of particular targeted therapies with small-molecule kinase inhibitors or antibodies .
4 Therefore , testing for these markers has become a critical step in the target therapy of the aforementioned tumors .
5 The core capability of personalized medicine is the companion diagnostic devices' ( CDx ) ability to accurately and precisely stratify patients by their likelihood of benefit ( or harm ) from a particular therapy .
6 There is no reference in the literature discussing the impact of device's measurement performance , for example , analytical accuracy and precision on treatment effects , variances , and sample sizes of clinical trial for the personalized medicine .
7 In this paper , using both analytical and estimation method , we assessed the impact of CDx measurement performance as a function of positive and negative predictive values and imprecision ( standard deviation ) on treatment effects , variances of clinical outcome , and sample sizes for the clinical trials .



PMID: 25778307
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient .
1 PURPOSE :
2 Adding targeted therapies to chemotherapy in metastatic colorectal cancer ( CRC ) improves response rates and survival .
3 KRAS is a predictive indicator for anti-epidermal growth factor receptor ( EGFR ) treatments .
4 Μ The most important reasons for KRAS discordance are intratumoral heterogeneity and incorrect mutation analysis .
5 Evaluating the status of KRAS in primary and metastatic lesions becomes even more crucial to ensure efficient usage of anti-EGFR treatments .
6 METHODS :
7 Patients with metastatic CRC , whose primary disease and liver and/or lung metastases were operated , were retrospectively evaluated , and KRAS assessment was performed on 31 patients who were suitable for DNA analysis .
8 Pyrosequencing with polymerase chain reaction ( PCR ) was used for KRAS analysis .
9 RESULTS :
10 The median age of 31 patients diagnosed with rectal cancer ( N = 13 ) and colon cancer ( N = 18 ) was 63 years ( range 33-73 ) .
11 Metastasectomy locations included the liver ( N = 27 ) , lung ( N = 3 ) , and both lung and liver ( N = 1 ) .
12 KRAS discordance was detected in 22% ( 7/31 ) of the patients .
13 Μ While 3 patients with detected discordance had mutated KRAS in the primary material , wild type KRAS was detected in their liver or lung lesions .
14 On the other hand , while 4 patients had wild type KRAS in the primary material , mutated KRAS was determined in their liver or lung lesions .
15 The McNemar test revealed no significant discordance between primary and metastatic disease ( p = 100 ) .
16 No progression free survival ( PFS ) difference was detected between patients with determined discordance and patients with undetermined discordance ( 106 versus 147 months , p = 0719 ) .
17 CONCLUSION :
18 This is the first study to evaluate KRAS discordance between primary and metastasis in CRC patients , who underwent metastasectomy , together with survival data .
19 In the literature and recent studies with large patient numbers in which modern KRAS tests were used , the KRAS discordance rate varies between 3-12% .
20 In our study , a higher KRAS discordance ( 22% ) was detected , and no survival difference was determined between patients with or without discordance .
21 In recent years , the rising interest in borderline resectable disease may bring forward discussions related to which material the KRAS status should be analyzed .



PMID: 25777075
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Molecular pathology of colorectal cancer ] .
1 In recent years , several predictive and prognostic biomarkers have been established in colorectal cancer ( CRC ) .
2 The RAS-mutation status is widely applied in the daily routine diagnostic as predictive biomarker for treatment with EGFR-inhibitors .
3 A BRAF - mutation has no predictive value in this context .
4 The detection of high-grade microsatellite instability ( MSI-H ) is a predictive biomarker for response to 5-Fluoruracil-monotherapy .
5 Prognostic biomarkers in CRC are the MSI-status and the mutational status of BRAF .
6 According to the current WHO classification poorly and undifferentiated CRC and MSI-associated special morphological subtypes are molecular graded depending on their MSI-status .
7 The detection of a BRAF-mutation in the context of microsatellite stability ( MSS ) is associated with a very poor prognosis and thus represents the most aggressive molecular subtype of CRC .
8 In patients with positive Bethesda criteria a stepwise immunohistochemical and molecular diagnostic scheme is proposed .



PMID: 25774859
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 B-type proto-oncogene -mutated tumors of colon cancer : promising therapeutic approaches .
1 Μ Reliability of K-ras mutational analysis on cytological samples from metastatic colorectal cancer .



PMID: 25773792
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MGMT-B gene promoter hypermethylation in patients with inflammatory bowel disease - a novel finding .
1 Inflammatory bowel disease ( IBD ) is a disease strongly associated with colorectal cancer ( CRC ) as a well-known precancerous condition .
2 Alterations in DNA methylation and mutation in K-ras are believed to play an early etiopathogenic role in CRC and may also an initiating event through deregulation of molecular signaling .
3 Epigenetic silencing of APC and SFRP2 in the WNT signaling pathway may also be involved in IBD-CRC .
4 The role of aberrant DNA methylation in precancerous state of colorectal cancer ( CRC ) is under intensive investigation worldwide .
5 The aim of this study was to investigate the status of promoter methylation of MGMT-B , APC1A and SFRP2 genes , in inflamed and normal colon tissues of patients with IBD compared with control normal tissues .
6 A total of 52 IBD tissues as well as corresponding normal tissues and 30 samples from healthy participants were obtained .
7 We determined promoter methylation status of MGMT-B , SFRP2 and APC1A genes by chemical treatment with sodium bisulfite and subsequent MSP .
8 The most frequently methylated locus was MGMT-B ( 71% ; 34 of 48 ) , followed by SFRP2 ( 666 % ; 32 of 48 ) , and APC1A ( 437% ; 21 of 48 ) .
9 Our study demonstrated for the first time that hypermethylation of the MGMT-B and the SFRP2 gene promoter regions might be involved in IBD development .
10 Methylation of MGMT-B and SFRP2 in IBD patients may provide a method for early detection of IBD-associated neoplasia .



PMID: 25756961
(None)  
Terms: in vivo, in vitro, rat
Sent# Symbols Sentence Mnemonics
0 Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer .
1 KRAS mutations are a major cause of drug resistance to molecular-targeted therapies .
2 Aberrant epidermal growth factor receptor ( EGFR ) signaling may cause dysregulation of microRNA ( miRNA ) and gene regulatory networks , which leads to cancer initiation and progression .
3 To address the functional relevance of miRNAs in mutant KRAS cancers , we transfected exogenous KRAS (G12V) into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes , and we comprehensively profiled the dysregulated miRNAs .
4 The result showed that mature miRNA oligonucleotide ( miR ) -4689 , one of the significantly down-regulated miRNAs in KRAS (G12V) overexpressed cells , was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo .
5 miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa , and it was particularly decreased in mutant KRAS CRC tissues .
6 miR-4689 directly targets v-ki-ras2 rat kirsten sarcoma viral oncogene homolog ( KRAS ) and v-akt murine thymoma viral oncogene homolog 1 ( AKT1 ) , key components of two major branches in EGFR pathway , suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689 .
7 Overall , this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689 , which negatively regulates both RAS/mitogen-activated protein kinase ( MAPK ) and phosphoinositide 3-kinase ( PI3K ) /AKT pathways .
8 These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC .



PMID: 25750328
(None)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Circulating hepatocyte growth factor is correlated with resistance to cetuximab in metastatic colorectal cancer .
1 BACKGROUND :
2 The conventional tests for the diagnosis of early stage pancreatic carcinoma are not acceptable .
3 This meta-analysis is to evaluate the accuracy of K-ras mutation for the diagnosis of pancreatic carcinoma .
4 DATA SOURCES :
5 A systemic search of all relevant literature was performed in Web of Science , EMBASE , Cochrane Database , and MEDLINE ( PubMed as the search engine ) prior to June 1 , 2011 .
6 Thirty-four studies fulfilled the inclusion criteria and data were pooled for analysis .
7 RESULTS :
8 The pooled estimates for K-ras mutation in diagnosis of pancreatic carcinoma were as follows : sensitivity 0.68 ( 95% CI : 0.66-0.71 ) , specificity 0.87 ( 95% CI : 0.85-0.88 ) , positive likelihood ratio 4.54 ( 95% CI : 3.47-5.94 ) , negative likelihood ratio 0.37 ( 95% CI : 0.30-0.44 ) and diagnostic odds ratio 14.90 ( 95% CI : 10.02-22.15 ) .
9 Summary receiver operating characteristic analysis demonstrated that the maximum joint sensitivity and specificity was 0.79 , and the overall area under the curve was 0.86 .
10 CONCLUSIONS :
11 Diagnostic accuracy of K-ras mutation was not superior to that of conventional tests .
12 Μ Therefore , K-ras mutation analysis alone is not recommended for the diagnosis of pancreatic carcinoma .



PMID: 25745621
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathologic Significance of BRAF Mutation and Extracellular Signal Regulated Kinase 1/2 Expression in Patients With a Colorectal Adenocarcinoma .
1 PURPOSE :
2 BRAF mutation and expression of extracellular signal regulated kinase ( ERK ) are linked with colorectal carcinogenesis through the serrated pathway .
3 BRAF and ERK1/2 play important roles in the activation of mitogen -activated protein ( MAP ) kinase signaling pathways .
4 The present study investigated the clinicopathologic outcomes of BRAF mutation and ERK1/2 expression in patients with colorectal cancer ( CRC ) and the possibility of using them as prognostic indicators .
5 METHODS :
6 Μ Dual-priming oligonucleotide -based multiplex polymerase chain reaction for BRAF (V600E) mutation and immunohistochemical analysis of ERK1/2 were performed using 65 formalin-fixed , paraffin-embedded samples from patients with CRC .
7 Μ We analyzed the dependences of the clinicopathologic features on BRAF mutation and ERK1/2 expression .
8 RESULTS :
9 Μ Out of 65 samples from CRC patients , BRAF mutation was detected in 3 ( 46% ) .
10 The 3 patients with BRAF mutation presented with T3 CRC with lymph node metastasis ( stage III ) showing moderately or poorly differentiated histology .
11 ERK1 and ERK2 were positively detected in 73.8% and 15.4% of the patients with CRC , respectively .
12 ✓ ERK1 expression was significantly correlated with lymph node metastasis ( P = 0049 ) . GE-ASS-RO
13 ✓ ERK2 expression was significantly correlated with tumor emboli ( P <005 ) , tumor invasion ( P = 0035 ) , lymph node metastasis ( P = 0017 ) , and stage ( P = 002 ) . GE-ASS-RO
14 CONCLUSION :
15 ✓ BRAF mutation and ERK1/2 expression may be associated with advanced or more aggressive CRC . GM-ASS-DS, GE-ASS-DS
16 These molecular markers might play prognostic roles in CRC developed through the serrated pathway .



PMID: 25742883
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients .
1 BACKGROUND :
2 The metastasis-associated in colon cancer 1 ( MACC1 ) gene has been identified as prognostic biomarker for colorectal cancer ( CRC ) .
3 Μ Here , we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 ( KRAS G12 ) or codon 13 ( KRAS G13 ) , BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I , II and III .
4 FINDINGS :
5 ✓ Μ We showed that only high MACC1 expression ( HR : 6.09 , 95% CI : 2.50-14.85 , P <0.001 ) and KRAS G13 mutation ( HR : 5.19 , 95% CI : 1.06-25.45 , P = 0.042 ) were independent prognostic markers for shorter metastasis-free survival ( MFS ) . GM-MRK-RO, GE-MRK-RO
6 ✓ Μ Accordingly , Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis ( HR : 14.48 , 95% CI : 3.37-62.18 , P <0.001 ) . GM-ASS-RO, GE-ASS-RO
7 Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS ( P = 0003 ) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis .
8 CONCLUSION :
9 According to our results , patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation .
10 Moreover , we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis .
11 This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation .



PMID: 25743147
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A successful multimodality therapy for a case of recurrent rectal cancer with KRAS mutation ] .
1 A man in his 50s underwent high anterior resection for rectosigmoid cancer in January 2010 .
2 The primary tumor was diagnosed as a moderately differentiated adenocarcinoma with KRAS mutation , pStage III a .
3 In May 2011 , the patient had a recurrent lung tumor detected by computed tomography ( CT ) ; the tumor was resected using video-assisted thoracoscopic surgery .
4 However , additional recurrent lung tumors arose , and radiofrequency ablation ( RFA ) was performed to treat these in February 2012 .
5 After RFA therapy , capecitabine was administered as adjuvant chemotherapy .
6 Unfortunately , 10 months later , positron emission tomography ( PET ) /CT suggested a new recurrence in a left lateral lymph node .
7 Although the pelvic lymph node was surgically removed immediately , a new lung recurrence was found on CT three months after the surgery .
8 RFA was again used to treat this lung lesion .
9 After the second RFA , the patient is doing well without any evidence of recurrence .
10   We describe a case of recurrent rectal cancer successfully treated with multimodality therapy .
11   The combination of appropriate local therapy with systemic chemotherapy is an essential strategy to treat advanced colorectal cancer , especially in patients with KRAS mutation when anti-EGFR antibodies are not effective .



PMID: 25743137
(Patient)  
Terms: retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 [ A retrospective analysis of cetuximab or panitumumab monotherapy for KRAS wild-type metastatic colorectal cancer in clinical practice ] .
1 We performed a retrospective study on the use of cetuximab or panitumumab alone in patients with KRAS wild-type metastatic colorectal cancer between November 2008 and February 2012 .
2 Twenty-two patients were analyzed and classified as PS 0/1 ( good PS group ) and PS 2/3/4 ( poor PS group ) with 11 patients in each group .
3 The response rate , disease control rate , median progression-free survival , and median overall survival were 9% , 73% , 5.1 months ( 95% confidence interval[CI] : 1.5-8.7 ) , and 16 months ( 95% CI : 8.8-24 ) , respectively , in the good PS group , and the corresponding values in the poor PS group were 0% , 18% , 0.7 months ( 95% CI : 0.3-1.0 ) , and 1.5 months ( 95% CI : 0.7-2.4 ) .
4 Grade 3 or 4 adverse events were skin toxicities ( 2 patients with grade 3 toxicities ) , panitumumab-related interstitial lung disease ( 1 patient with grade 4 toxicity ) , and cetuximab infusion-related reaction ( 1 patient with grade 4 toxicity ) .
5 No treatment-related deaths were observed .
6   In conclusion , the efficacy and safety of cetuximab or panitumumab monotherapy in patients with a good PS in our study were similar to those reported in previous clinical trials , whereas patients with a poor PS showed poorer outcomes .



PMID: 25742472
(Patient)  
Terms: phase III
Sent# Symbols Sentence Mnemonics
0 Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer .
1 BACKGROUND :
2 Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC .
3 This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab ( +/-mitomycin C ) in the randomised phase III MAX study .
4 METHODS :
5 DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue .
6 Mutation status was determined using pyrosequencing , confirmed with Sanger sequencing ( for equivocal RAS ) and correlated with efficacy outcomes .
7 Predictive analyses were undertaken using a test for interaction involving both C versus CB+CBM .
8 RESULTS :
9 Of the available 280 of the 471 ( 594% ) patients , mutations in KRAS exons 2 , 3 and 4 and NRAS 2 , 3 and 4 were as follows : 32% , 2.9% , 2.2% , 1.4% , 0.7% and 0% ( total RAS MT 39% ) .
10 The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20 .
11 Extended RAS gene mutation status ( WT versus MT ) had no prognostic impact for PFS ( HR 0.91 ( 071-117 ) ) or OS ( HR 0.95 ( 071-125 ) ) .
12 The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS ( HR 0.56 ( 037-085 ) for RAS MT and HR 0.69 ( 05-097 ) for RAS WT ; P for interaction 0.50 ) .
13 The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic .
14 CONCLUSION :
15 Of KRAS exon 2 WT patients , 10% had additional RAS mutations .
16   Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS , or predictive of bevacizumab outcome in patients with advanced CRC .



PMID: 25734426
(None)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Genetic characteristics of mitochondrial DNA was associated with colorectal carcinogenesis and its prognosis .
1 From 1976 to 2010 , only 2 medications were approved for treating metastatic melanoma .
2   Between 2011 and 2013 , 4 agents were approved and other therapies have shown great promise in clinical trials .
3 Fundamental discoveries , such as the identification of oncogenic mutations in most melanomas , the elucidation of the molecular signaling resulting from these mutations , and the revelation that several cell surface molecules serve as regulators of immune activation , have been instrumental in this progress .
4 This article summarizes the molecular pathogenesis of melanoma , describes the current efforts to target oncogene -driven signaling , and presents the rationale for combining immune and molecular targeting .



PMID: 25731451
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic Rearrangements of PTEN in Prostate Cancer .
1 Μ Screening for EGFR and KRAS mutations in patients with lung adenocarcinomas can be used to predict the patient's response to EGFR tyrosine kinase inhibitors , but there is a lack of guidelines for testing in clinical practice .
2 We analyzed the morphological and clinicopathological characteristics , including tumor stage , size , presence of scar , inflammatory response , angiolymphatic and pleural invasion , of 345 surgically treated primary lung adenocarcinomas with respect to their EGFR and KRAS mutational profile and EGFR FISH .
3 Μ EGFR and KRAS mutations were found in 33 ( 10% ) and 78 ( 23% ) of lung adenocarcinomas , respectively , whereas 226 ( 67% ) cases were negative for both mutations .
4 There was a large overlap in the analyzed clinicopathological characteristics among the three study groups .
5 Μ Statistically significant predictors for the presence of EGFR mutations included history of never smoking ( OR 5939 ; 95% Wald confidence limit 1662-21223 , P = 00149 ) , mild lymphocytic host response ( OR 4724 ; 95% Wald confidence limit 133-1776 ; P = 00163 ) , female gender ( OR 2571 ; 95% Wald confidence limit 1015-6511 , P = 00463 ) and absence of solid growth pattern .
6 Μ Statistically significant predictors for the presence of KRAS mutations included older age ( OR 1034 ; 95% Wald confidence limit 1007-1062 , P = 00132 ) , history of smoking ( OR 0617 , 95% Wald confidence limit 0357-1066 , P = 00412 ) and mucinous differentiation .
7 EGFR FISH positivity as defined by the Colorado criteria was a significant predictor of EGFR mutations , with high polysomy as the strongest predictive criteria .
8 Despite statistically significant differences among the study groups and because of the large overlap in the analyzed clinicopathological criteria , none of these could be implemented as the selection criteria for molecular testing in clinical practice .
9 ✓ The cost-effectiveness of lung carcinoma mutational testing would be improved by initial determination of KRAS mutational status as negative predictor of the patient's response to EGFR tyrosine kinase inhibitors , followed by EGFR mutational analysis , if necessary . GE-MRK-RO



PMID: 25731325
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Thyroglossal duct cyst cancer most likely arises from a thyroid gland remnant .
1 A 58-year-old woman was confirmed as having multiple liver metastases after undergoing a high anterior resection for a sigmoid colon tumor .
2 She was administered bevacizumab+FOLFOX as the first regimen and bevacizumab+FOLFIRI and S-1 and irinotecan ( IRIS ) therapy as the second regimen .
3 During this treatment she also underwent hepatectomy 3 times and radiofrequency ablation once .
4 She was administered panitumumab+irinotecan as the third regimen and , due to the presence of multiple pulmonary metastases , was subsequently considered to have had a partial response ( PR ) .
5 Because she subsequently developed progressive disease ( PD ) , she received the fourth regimen as part of a clinical trial ( TAS102 ) in another hospital .
6 Cetuximab+irinotecan was administered as the fifth regimen after PD and the tumor was found to have reduced in size by 23%upon computed tomography ( CT ) 2 months later .
7 Although stable disease ( SD ) was achieved , she was subsequently administered regorafenib for 8 months as a sixth regimen after the disease progressed a second time .
8 In some cases of KRAS wild type metastatic colorectal cancer , re-challenging with an anti-epidermal growth factor receptor ( EGFR ) monoclonal antibody seems to be an effective strategy for reducing tumor mass .



PMID: 25731316
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A case of stage IV rectal cancer successfully resected after chemotherapy ( mFOLFOX6 plus panitumumab ) ] .
1 Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia .



PMID: 25731301
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ A case of postoperative colon cancer with peritoneal dissemination in which a long-term response was achieved using panitumumab maintenance therapy ] .
1 A 66-year-old man underwent a sigmoidectomy for advanced sigmoid colon cancer .
2 The pathological examination revealed that the tumor was T3 , N0 , M0 , and KRAS wild type .
3 Fifteen months after surgery , the patient was hospitalized with stenosis of the anastomosis due to recurrent disease that had disseminated to the peritoneum , and which was unresectable .
4 After transverse colostomy , the patient received 8 courses of mFOLFOX6+panitumumab ( Pmab ) , and 39 courses of infusional 5-fluorouracil ( 5-FU ) + Leucovorin ( LV ) + Pmab .
5 A partial remission ( PR ) was maintained for 27 months .
6 The utility of maintenance therapy with an anti-epidermal growth factor receptor ( EGFR ) antibody -based regime has not previously been demonstrated .
7 In this case , a long PR was achieved using infusional 5-FU+LV+Pmab , suggesting that this is a useful maintenance therapy following mFOLFOX6 + Pmab .
8   However , the side effects resulting from Pmab treatment reduced the patient's quality of life ( QOL ) .
9 We suggest that Pmab maintenance therapy can be established by controlling the side effects of the anti-EGFR antibody .



PMID: 25731256
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ Surgical resection after chemotherapy for advanced rectal cancer - report of a case ] .
1 Herein , we present a case of advanced rectal cancer surgically resected after chemotherapy .
2 A 65-year-old woman presented with anal pain , and rectal cancer extending beyond the anus was diagnosed .
3 The primary tumor was a well-differentiated adenocarcinoma with a KRAS mutation .
4 Computed tomography revealed cancer invasion into the vagina and sacral and coccygeal bones , and cancer metastases to the bilateral inguinal lymph nodes and the left lung .
5 Sigmoid colostomy and subcutaneous venous port insertion were performed .
6 The patient was treated with modified oxaliplatin , leucovorin , and 5 - fluorouracil (FOLFOX6) plus bevacizumab .
7 She showed a partial response according to the Response Evaluation Criteria in Solid Tumors after 13 courses of chemotherapy .
8 The primary tumor was then resected via posterior pelvic exenteration , bilateral inguinal lymphadenectomy , and sacral/coccygeal resection .
9 Histological examination of the resected specimens revealed moderately differentiated adenocarcinoma with vaginal invasion .
10 Metastasis to a right inguinal lymph node was observed .
11 The pathological stage was ypT4bN0M1b , ypStage IV according to the tumor-node-metastasis system of the eighth edition of the Japanese Classification of Colorectal Carcinoma .
12 The pathological response grade of the tumor after chemotherapy was determined to be Grade 1b .



PMID: 25713893
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Impact of KRAS mutation on outcome of patients with metastatic colorectal cancer . GM-ASS-RO
1 BACKGROUND/AIMS :
2 KRAS mutation is present in 30%-50% of colorectal cancers and is associated with the inefficacy of anti-epidermal growth factor receptor therapy , while the impact of KRAS on survival is seldom discussed .
3 The aim of this study was to elucidate the impact of KRAS status on the survival of patients with metastatic colorectal cancer .
4 METHODOLOGY :
5 Two hundred and one patients with metastatic colorectal cancer were enrolled .
6 Amplification and sequencing of the KRAS gene were performed , with the overall survival according to KRAS status analyzed .
7 RESULTS :
8 KRAS mutations were present in 72 ( 358% ) of patients , including 55 ( 273% ) codon 12 mutations and 17 ( 85% ) codon 13 mutations .
9 ✓ Lymphovascular invasion ( hazard ratio 1841 , 95% confidence interval 1043-3247 , p = 0035 ) and KRAS mutation ( hazard ratio 1919 , 95% confidence interval 1104-3333 , p = 0021 ) were independent prognostic factors for overall survival . GM-MRK-RO
10 ✓ The median overall survival for patients with KRAS mutation at codon 12 was 27.3 months , and was similar to those with KRAS mutation at codon 13 ( 204 months , p = 0628 ) . GM-ASS-RO
11 CONCLUSIONS :
12 ✓ KRAS mutation is a poor prognostic factor in patients with metastatic colorectal cancer . GM-MRK-DS
13 ✓ In KRAS mutation metastatic colorectal cancer , mutation at codon 12 or at codon 13 had no relationship with prognosis . GM-ASS-RO



PMID: 25713627
(Patient)  
Terms: Retrospective study
Sent# Symbols Sentence Mnemonics
0 Prognostic significance of KRAS gene mutations in colorectal cancer--preliminary study .
1 OBJECTIVE :
2 The prognostic significance of KRAS gene mutations , evaluated by using two methods in patients with colorectal cancer ( CRC ) .
3 MATERIAL AND METHODS :
4 Retrospective study involving 58 patients diagnosed with CRC and treated between 2003 and 2010 in the General and Esophageal Surgery Clinic of "Sf .
5 Maria" Hospital , Bucharest .
6 The macroscopic and microscopic examination of the resected specimens was also processed for genetic analysis in NIRDPBS , where KRAS status was determined by using two methods : PCR-RFLP and pyrosequencing .
7 RESULTS :
8 The clinical and biological parameters of the patients were assessed for 72 months in average .
9 A relapse in 21 patients and a 5-year survival rate of 79.3% was discovered .
10 Μ The genetic analyses of KRAS gene found mutations in 22 cases ( 453% ) : 17 cases had mutations in codon 12 , 5 cases in codon 13 .
11 Μ The survival rate analyses of patients with wild KRAS gene compared with the patients carrying the mutation on codon 12 /13 revealed a superposition of the survival curve .
12 The statistical analysis based on the TNM stage revealed different survival curves in stage I and II , shorter survival period in patients with KRAS mutation on codon 13 than in those with wild type gene ( stage I--p value = 0015 ; stage II--p value = 0000 ) .
13 CONCLUSIONS :
14 ✓ It was not found that KRAS gene status had any prognostic significance . GE-ASS-RO
15 Μ Nevertheless , for stage I and II patients , the mutation found on codon 13 determined a statistic significant shorter survival rate than for those with wild type .
16 The results obtained by using the pyrosequencing method for the determination of KRAS gene status proved that it represented a reliable and reproducible method .



PMID: 25713610
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetics of colorectal cancer .
1 Protein kinases are mutated or otherwise rendered constitutively active in numerous cancers where they are attractive therapeutic targets with well over a dozen kinase inhibitors now being used in therapy .
2 While fluorescent sensors have capacity to measure changes in kinase activity , surprisingly they have not been utilized for biomarker studies .
3 A first-generation peptide sensor for ERK based on the Sox fluorophore is described .
4 This sensor called ERK-sensor-D1 possesses high activity toward ERK and more than 10-fold discrimination over other MAPKs .
5 The sensor can rapidly quantify ERK activity in cell lysates and monitor ERK pathway engagement by BRAF and MEK inhibitors in cultured melanoma cell lines .
6 The dynamic range of the sensor assay allows ERK activities that have potential for profound clinical consequences to be rapidly distinguished .



PMID: 25713148
(None)  
Terms: prospective, phase III trial, phase III
Sent# Symbols Sentence Mnemonics
0 Primary tumor location as a prognostic factor in metastatic colorectal cancer .
1 BACKGROUND :
2 We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer ( mCRC ) .
3 METHODS :
4 We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first - line chemotherapy +/- bevacizumab in three independent cohorts : a prospective pharmacogenetic study ( PROVETTA ) and two randomized phase III trials , AVF2107g and NO16966 .
5 Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided , respectively .
6 The primary end point was overall survival ( OS ) .
7 Data were analyzed with Cox proportional hazards and logistic regression models .
8 All statistical tests were two-sided .
9 RESULTS :
10 Among evaluable patients in the PROVETTA ( n = 200 ) , AVF2107g ( n = 559 ) , and NO16966 ( n = 1268 ) studies , 72.0% , 63.1% , and 73.7% had left-sided tumors , respectively .
11 In PROVETTA , patients with left-sided tumors had superior OS ( left-sided versus right-sided : hazard ratio [HR] = .44 , 95% confidence interval [CI] = .28 to .70 , P <.001 ) and progression-free survival ( HR = 52 , 95% CI = 36 to 75 , P <001 ) outcomes .
12 Multivariable analyses confirmed right-sided location as a negative prognostic variable , independent of mucinous histology and BRAF mutational status .
13 Data from the AVF2107g ( HR for OS = 55 , 95% CI = 43 to 70 ) and NO16966 trials ( HR for OS = 71 , 95% CI = 62 to 82 both P <001 ) also showed favorable outcomes in patients with left-sided tumors .
14 In both randomized studies , the efficacy of bevacizumab was independent of tumor location .
15 CONCLUSIONS :
16 These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC .
17 Given the consistency across an exploratory set and two confirmatory phase III studies , side of tumor origin should be considered for stratification in randomized trials .



PMID: 25712738
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer .
1 BACKGROUND :
2 Lynch syndrome ( LS ; hereditary nonpolyposis colorectal cancer ) is a common cause of hereditary colorectal cancer ( CRC ) .
3 CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC .
4 There currently are no clear guidelines for the selection criteria for these patients to screen for LS .
5 METHODS :
6 A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction .
7 Μ BRAF mutation screening , high CpG island methylator phenotype , and analysis for germline mutations were performed in 425 CRC samples .
8 These were all high microsatellite instability ( MSI-H ) samples ( 91 cases ) , all low MSI samples ( 143 cases ) , and selected cases from the microsatellite stable group ( 191 cases ) that met revised Bethesda guidelines .
9 RESULTS :
10 Μ Polymerase chain reaction identified 91 MSI-H cases ( 113% ) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only .
11 Of the total of 807 CRC cases , these 8 cases ( 099% ) were MSI-H , met the revised Bethesda guidelines , and did not harbor BRAF mutations .
12 CONCLUSIONS :
13 Μ The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations .
14 This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives .



PMID: 25712343
(None)  
Terms: xenograft, PDX, retrospective, tumor xenografts
Sent# Symbols Sentence Mnemonics
0 Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data .
1 Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations .
2 Here , by studying 52 colorectal patient-derived tumor xenografts ( PDX ) , we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab .
3 PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas .
4 We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways .
5 The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors .
6 We found frequent IGF2 upregulation ( 16% ) , which was mutually exclusive with IRS2 , PIK3CA , PTEN , and INPP4B alterations , supporting IGF2 as a potential drug target .
7 In addition to maintaining the genomic and histologic diversity , correct preclinical models need to reproduce drug response observed in patients .
8 Responses of PDXs to cetuximab recapitulate also clinical data in patients , with partial or complete response in 15% ( 8 of 52 ) of PDXs and response strictly restricted to KRAS wild-type models .
9 The response rate reaches 53% ( 8 of 15 ) when KRAS , BRAF , and NRAS mutations are concomitantly excluded , proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients .
10   Collectively , these results show that , because of their clinical relevance , colorectal PDXs are appropriate tools to identify both new targets , like IGF2 , and predictive biomarkers of response/resistance to targeted therapies .



PMID: 25710585
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 BRAFV600E Gene Mutation in Colonic Adenocarcinomas . Immunohistochemical Detection Using Tissue Microarray and Clinicopathologic Characteristics : An 86 Case Series .
1 The detection of BRAF mutation in colorectal cancer has several clinical applications : enabling the discrimination between sporadic and Lynch syndrome-related colorectal carcinoma , and providing warning of a poorer prognosis .
2 Few immunohistochemical studies using whole - tissue tumor section staining have recently been performed on colorectal cancer .
3 The aim of this study was to evaluate the detection of BRAF mutation by immunohistochemistry ( IHC ) on tissue microarray ( TMA ) .
4 IHC was performed with the BRAF-specific antibody using TMA on a retrospective series of 86 colonic adenocarcinomas with known BRAF status .
5 Μ IHC using BRAF-specific antibody allowed to detect 20/21 BRAF mutated colonic adenocarcinomas and 60/65 BRAF wild-type cases .
6 The staining was equivocal because of equivocal staining in 4 cases and heterogeneity in 3 cases .
7 When compared with TaqMan real-time PCR , the sensitivity and specificity were 95.2% and 92.3% , respectively .
8 Comparison with the whole section immunostaining improved sensitivity to 100% and specificity to 95.4% .
9 Μ Furthermore , in this study we found that BRAF mutated colonic adenocarcinoma were significantly more frequent in women , older patients , and right-sided .
10 Moreover , morphologic features significantly associated with BRAF mutation were : serrated adenocarcinoma subtype , adenocarcinomas with a mucinous component , high histologic grade , pushing margins , stromal inflammation .
11 Μ BRAF-specific antibody can be used on TMA to screen BRAF-mutated colorectal carcinomas .
12 Cases with equivocal or heterogenous staining must be compared with whole section staining .
13 Moreover , BRAF mutated colonic carcinomas have distinct clinical and histopathologic features .



PMID: 25708741
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hyperplastic polyps of the colon and rectum - reclassification , BRAF and KRAS status in index polyps and subsequent colorectal carcinoma .
1 Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B - cell lymphomas of the thyroid--a study of 21 cases .



PMID: 25707609
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer .
1 Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor ( EGFR ) antibody treatment in metastatic colorectal cancer ( mCRC ) .
2 There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients .
3 Between August 2008 and August 2011 , pretreatment serum samples were obtained from KRAS wild-type ( WT ) patients who received anti-EGFR antibody treatment .
4 Serum levels of ligands were measured by ELISA .
5 A total of 103 KRAS WT patients were enrolled in the study .
6 Progression-free survival and overall survival of patients with a high grade ( grade 2-3 ) of skin toxicity were significantly longer than those with a low grade ( grade 0-1 ) of skin toxicity ( median progression-free survival , 64 months versus 24 months , P <0001 ; median overall survival , 146 months versus 71 months , P = 0006 ) .
7 There were significant differences in distribution of serum levels of epiregulin (EREG) , amphiregulin (AREG) , and hepatocyte growth factor ( HGF ) between groups of low/high grade of skin toxicity ( P <0048 , P <0012 , P <0012 , respectively ) .
8 In addition , serum levels of HGF , EREG , and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test ( P = 0019 , P = 0047 , P = 0021 , respectively ) .
9   Our study indicated that serum levels such as HGF , EREG , and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment , which contribute to improvement of the management of skin toxicity and survival time in mCRC patients .



PMID: 25707392
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy .
1 Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors .
2 Vascular endothelial growth factor ( VEGF ) , its receptors and signaling effectors have a central role in tumor-induced angiogenesis .
3 Genetic variation in the VEGF pathway may impact on tumor angiogenesis and , hence , on clinical cancer outcomes .
4 This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer ( mCRC ) patients treated with first - line oxaliplatin/5-fluorouracil chemotherapy .
5 A total of 27 single-nucleotide polymorphisms ( SNPs ) in 16 genes in the VEGF -dependent angionenesis process were genotyped using a dynamic array on the BioMark system .
6 ✓ Μ After assessing the KRAS mutational status , we found that four SNPs located in three genes ( KISS1 , KRAS and VEGFR2 ) were associated with progression-free survival . GM-ASS-RO
7 ✓ Five SNPs in three genes ( ITGAV , KRAS and VEGFR2 ) correlated with overall survival . GM-ASS-RO
8 ✓ The gene - gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes . GM-REG-RO
9   This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy .



PMID: 25706875
(None)  
Terms: in vitro, mice
Sent# Symbols Sentence Mnemonics
0 Modeling colorectal cancer using CRISPR-Cas9 -mediated engineering of human intestinal organoids .
1 Human colorectal tumors bear recurrent mutations in genes encoding proteins operative in the WNT , MAPK , TGF-beta , TP53 and PI3K pathways .
2 Although these pathways influence intestinal stem cell niche signaling , the extent to which mutations in these pathways contribute to human colorectal carcinogenesis remains unclear .
3 Here we use the CRISPR-Cas9 genome -editing system to introduce multiple such mutations into organoids derived from normal human intestinal epithelium .
4 By modulating the culture conditions to mimic that of the intestinal niche , we selected isogenic organoids harboring mutations in the tumor suppressor genes APC , SMAD4 and TP53 , and in the oncogenes KRAS and/or PIK3CA .
5 Organoids engineered to express all five mutations grew independently of niche factors in vitro , and they formed tumors after implantation under the kidney subcapsule in mice .
6 Although they formed micrometastases containing dormant tumor-initiating cells after injection into the spleen of mice , they failed to colonize in the liver .
7 In contrast , engineered organoids derived from chromosome -instable human adenomas formed macrometastatic colonies .
8 These results suggest that 'driver' pathway mutations enable stem cell maintenance in the hostile tumor microenvironment , but that additional molecular lesions are required for invasive behavior .



PMID: 25706807
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS mutation screening by chip-based DNA hybridization--a further step towards personalized oncology .
1 The use of predictive biomarkers can help to improve therapeutic options for the individual cancer patient .
2 For the treatment of colon cancer patients with anti-EGFR-based drugs , the KRAS mutation status has to be determined to pre-select responders that will benefit from this medication .
3 Amongst others , array-based tests have been established for profiling of the KRAS mutation status .
4 Μ Within this article we describe an on-chip hybridization technique to screen therapeutic relevant KRAS codon 12 mutations .
5 The DNA chip-based platform enables the reliable discrimination of selected mutations by allele -specific hybridization .
6 Here , silver deposits represent robust endpoint signals that allow for a simple naked eye rating .
7 With the here presented assay concept a precise identification of heterozygous and homozygous KRAS mutations , even against a background of up to 95% wild-type DNA , was realizable .
8 The applicability of the test was successfully proven for various cancer cell lines as well as clinical tumour samples .
9 Μ Thus , the chip-based DNA hybridization technique seems to be a promising tool for KRAS mutation analysis to further improve personalized cancer treatment .



PMID: 25704501
(Patient)  
Terms: prospective study
Sent# Symbols Sentence Mnemonics
0 Circulating tumor cells as a longitudinal biomarker in patients with advanced chemorefractory , RAS-BRAF wild-type colorectal cancer receiving cetuximab or panitumumab .
1 A still relevant number of patients with RAS-BRAF wild-type colorectal cancer ( CRC ) do not respond to treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab , suggesting that additional biomarkers to guide patient selection are urgently needed .
2 Circulating tumor cells ( CTCs ) may represent such a biomarker .
3 In this prospective study , 38 patients with advanced RAS-BRAF-wild-type CRC received third - line therapy with cetuximab-irinotecan or panitumumab .
4 Peripheral blood samples for CTC status determination were collected at baseline , during treatment at early ( 2-4 weeks ) and at later ( 8-10 weeks ) times .
5 CTC enrichment was done with the AdnaTest ColonCancerSelect kit , whereas CTC detection was done with the AdnaTest ColonCancerDetect kit .
6 CTC status positivity was defined according to the kit manufacturer's thresholds .
7 Fifty percent of patients were defined as CTC positive at baseline and the overall RECIST response rate was 26% .
8 CTC baseline status was not associated with treatment response , whereas early CTC status and CTC status changes during treatment were significantly associated with tumor response .
9 Kaplan-Meier analysis showed a significantly shorter progression-free survival ( median , 20 versus 40 months , p = 0004 ) and overall survival ( 47 versus114 , p = 0039 ) in patients with early CTC + status compared with CTC - ones .
10   In multivariable analysis including classical prognostic factors , the CTC status changes profile during treatment was an independent predictor of both progression-free survival ( p <0001 ) and overall-survival ( p = 0001 ) .
11 CTC status assessed early during treatment with anti-EGFR monoclonal antibodies may predict treatment failure in advance compared to imaging-based tools .



PMID: 25703934
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway .
1 Human gut microbiota is being increasingly recognized as a player in colorectal cancers ( CRCs ) .
2 Evidence suggests that Fusobacterium nucleatum ( F .
3 nucleatum ) may contribute to disease progression and is associated with CpG island methylator phenotype ( CIMP ) and microsatellite instability ( MSI ) in CRCs ; however , to date , there are no reports about the relationship between F .
4 nucleatum and molecular features in the early stage of colorectal tumorigenesis .
5 Therefore , we investigated the presence of F .
6 nucleatum in premalignant colorectal lesions .
7 In total , 465 premalignant lesions ( 343 serrated lesions and 122 non-serrated adenomas ) and 511 CRCs were studied .
8 We determined the presence of F .
9 nucleatum and analyzed its association with molecular features including CIMP , MSI and microRNA-31 status .
10 F .
11 nucleatum was detected in 24% of hyperplastic polyps , 35% of sessile serrated adenomas ( SSAs ) , 30% of traditional serrated adenomas ( TSAs ) and 33% of non-serrated adenomas .
12 F .
13 Μ nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions ( p = 00023 ) .
14 In SSAs , F .
15 nucleatum positivity increased gradually from sigmoid colon to cecum ( p = 0042 ) .
16 F .
17 nucleatum positivity was significantly higher in CRCs ( 56% ) than in premalignant lesions of any histological type ( p <00001 ) .
18 In conclusion , F .
19 Μ nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions .
20 Moreover , F .
21 nucleatum positivity increased according to histological grade , suggesting that it may contribute to the progression of colorectal neoplasia .
22 Our data also indicate that F .
23 nucleatum positivity in SSAs may support the "colorectal continuum" concept .



PMID: 25703078
(Patient)  
Terms: observational study, retrospective
Sent# Symbols Sentence Mnemonics
0 Liver resection rate following downsizing chemotherapy with cetuximab in metastatic colorectal cancer : UK retrospective observational study .
1 AIMS :
2 The high objective response rate to cetuximab along with chemotherapy in patients with colorectal liver metastases makes it an effective downsizing protocol to facilitate surgery in those with initially unresectable disease .
3 Adoption of this strategy has been variable in the UK .
4 A retrospective observational study was conducted in 7 UK specialist liver surgical centres to describe the liver resection rate following a downsizing protocol of cetuximab and chemotherapy and to evaluate the quality and efficiency of processes by which the treatment was provided .
5 METHODS :
6 Data were collected in 2012 by reviewing medical records of patients with colorectal metastases confined to the liver , defined as unresectable without downsizing therapy at first review by a specialist Multi Disciplinary Team ( MDT ) .
7 RESULTS :
8   Sixty patients were included ; 29 ( 48% ) underwent liver resection following cetuximab and chemotherapy .
9 Of the 29 , 17 ( 59% or 28% of all patients ) achieved R0 resection and 7 ( 24% or 12% of all patients ) R1 resection .
10 All treated patients were KRAS wild-type .
11 CONCLUSION :
12   In specialist liver surgical centres , where patients are evaluated for liver resection , optimal management by MDT using KRAS testing , cetuximab and chemotherapy results in a 28% R0 resection rate in patients with initially unresectable colorectal cancer liver metastases .



PMID: 25702261
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 ✓ Role of KRAS mutation as predictor of pathologic response after neoadjuvant chemoradiation therapy for rectal cancer . GM-MRK-RO
1 Individual patient response to neoadjuvant treatment is variable and reproducible biomarkers of response are needed .
2 The role of the rat V-Ki-ras2 Kirsten sarcoma viral oncogene ( KRAS ) in rectal cancer remains equivocal .
3 The aim of the current study was to evaluate the effect of KRAS mutation on outcomes following neoadjuvant chemoradiation therapy ( CRT ) for rectal cancer .
4 A total of 76 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery .
5 In every patient tumor-related features and outcome results were considered for analysis and correlation with KRAS mutations .
6 Forty-four patients ( 58% ) obtained a downstaging after CRT , and in 7 patients ( 9% ) a complete pathological response was found .
7 Μ Twenty-six ( 33% ) mutations of KRAS were found in 26 patients .
8 Nineteen mutations ( 73% ) were located in codon 12 , 6 in codon 13 ( 23% ) and 1 in codon 61 .
9 Μ T-level downsizing and tumor downstaging showed no significant association with KRAS mutation status , except for mutation of codon 13 ( G13D ) .
10 Μ No correlation between cancer-associated mortality following CRT and surgery and KRAS mutation was observed .
11 Μ No correlation between pelvic recurrence and KRAS mutation was observed .
12 ✓ KRAS mutation also failed to correlate with disease-free survival . GM-ASS-RO
13 No patients with a pCR had a local or distant failure .
14 ✓ There appears to be no significant difference in pCR , tumor down-staging , T-downsizing or effects on cancer-associated mortality , overall survival and disease-free survival in patients with KRAS mutations except for patients with KRAS codon 13 mutations that seem to be resistant to neoadjuvant CRT and less likely to achieve a pCR . GM-ASS-RO, RO-ASS-GM



PMID: 25701956
(None)  
Terms: in vivo, this review
Sent# Symbols Sentence Mnemonics
0 Microsatellite instability : an update .
1 Deficient DNA mismatch repair ( MMR ) results in a strong mutator phenotype known as microsatellite instability ( MSI ) , which is a hallmark of Lynch syndrome-associated cancers .
2 MSI is characterized by length alterations within simple repeated sequences that are called microsatellites .
3 Μ Lynch syndrome is primarily caused by mutations in the MMR genes , mainly MLH1 and MSH2 , and less frequently in MSH6 , and rarely PMS2 , and large genomic rearrangements account for 5-20 % of all mutations .
4 Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome .
5 Moreover , germ line 3' deletions of EPCAM gene is involved in MSH2 methylation .
6 MSI is also observed in about 15 % of sporadic colorectal cancer ( CRC ) , gastric cancer ( GC ) , and endometrial cancer ( EC ) , and at lower frequencies in other cancers , often in association with hypermethylation of the MLH1 gene .
7 Trimethylation of is an epigenetic histone mark that was required for DNA MMR in vivo .
8 Thus , mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI .
9 Genetic , epigenetic , and transcriptomic differences have been identified between cancers with and without MSI .
10 Recent comprehensive molecular characterizations of CRC , EC , and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities .
11 The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1 , but is not associated with Lynch syndrome-related CRCs .
12 Accumulating evidence indicates a role of interactions between MSI and microRNA ( miRNA ) in the pathogenesis of MSI-positive ( MSI+ ) cancer .
13 As another new mechanism underlying MSI , overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes .
14 Gene targets of frameshift mutations caused by MSI are involved in various cellular functions , including DNA repair ( MSH3 and MSH6 ) , cell signaling ( TGFBR2 and ACVR2A ) , apoptosis ( BAX ) , epigenetic regulation ( HDAC2 and ARID1A ) , and miRNA processing ( TARBP2 and XPO5 ) , and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype .
15 Moreover , microsatellite repeats in miRNA genes , such as hsa-miR-1273c , may be novel MSI targets for CRC , and mutations in noncoding regulatory regions of MRE11 , BAX ( BaxDelta2 ) , and HSP110 ( HSP110DeltaE9 ) may affect the efficiency of chemotherapy .
16   Μ Thus , analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings , and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions .
17   Μ In this review , we summarize recent advances in the pathogenesis of MSI and focus on genome -wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets .



PMID: 25699356
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Significance of KRAS mutation in patients receiving mFOLFOX6 with or without bevacizumab for metastatic colorectal cancer .
1 BACKGROUND/AIMS :
2 KRAS mutation is an important prognostic factor for patients with metastatic colorectal cancer receiving anti-epidermal growth factor receptor therapy .
3 However , the influence of KRAS mutation on the response to mFOLFOX6 +/- bevacizumab remains unclear .
4 METHODOLOGY :
5 We retrospectively analyzed 49 patients who received modified FOLFOX6 ( mFOLFOX6 ) +/- bevacizumab as first - line therapy .
6 Μ Genetic analysis showed that 30 patients had wild-type ( WT ) KRAS and 19 patients hadKRAS mutations ( MT ) .
7 These two groups were compared with regard to the response rate ( RR ) , progression-free survival ( PFS ) , and overall survival ( OS ) .
8 RESULTS :
9 The RR was not significantly different between the WT and MT groups , but PFS and OS were significantly better in the WT group than the MT group ( PFS : 11.8 months vs. 8.7 months , p<0.01 ; OS : 37.8 months vs. 29.3 months , p<0.0385 ) .
10   A similar analysis of 27 patients who were treated with mFOLFOX6 + bevacizumab showed a better prognosis for WT patients .
11 ✓ Μ Multivariate analysis also revealed that KRAS mutation was an independent factor with a significant relation to PFS . GM-MRK-RO
12 CONCLUSIONS :
13 ✓ These results suggest that KRAS mutation may be a useful prognostic marker for patients with metastatic colorectal cancer receiving mFOLFOX6 +/- bevacizumab therapy , especially for patients treated with mFOLFOX6 + bevacizumab . GM-MRK-DS



PMID: 25699236
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Implications of epithelial-mesenchymal plasticity for heterogeneity in colorectal cancer .
1 Colorectal cancer ( CRC ) is a genetically heterogeneous disease that develops and progresses through several distinct pathways characterized by genomic instability .
2 In recent years , it has emerged that inherent plasticity in some populations of CRC cells can contribute to heterogeneity in differentiation state , metastatic potential , therapeutic response , and disease relapse .
3 Such plasticity is thought to arise through interactions between aberrant signaling events , including persistent activation of the APC/beta-catenin and KRAS/BRAF/ERK pathways , and the tumor microenvironment .
4 Here , we highlight key concepts and evidence relating to the role of epithelial-mesenchymal plasticity as a driver of CRC progression and stratification of the disease into distinct molecular and clinicopathological subsets .



PMID: 25696791
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A modified Lynch syndrome screening algorithm in colon cancer : BRAF immunohistochemistry is efficacious and cost beneficial .
1 Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation .



PMID: 25695537
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A case of heterogeneous sensitivity to panitumumab in cetuximab-refractory colorectal adenocarcinoma metastases .
1 We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung .
2 The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab , followed by surgical resection of the primary tumor and hepatic metastases .
3 His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab .
4 After this regimen failed to arrest his disease progression , treatment with FOLFIRI in combination with another anti-EGFR antibody , panitumumab was started .
5   While on this therapy , the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress .
6 Our case highlights the differences between panitumumab and cetuximab , and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules .



PMID: 25694286
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 [ KRAS gene somatic mutations in Chilean patients with colorectal cancer ] .
1 BACKGROUND :
2 The molecular testing of KRAS mutation status in metastatic colorectal cancer patients is mandatory to identify patients eligible for anti-epidermal growth factor receptor monoclonal antibody therapy .
3 AIM :
4 To report the frequency of KRAS gene mutations in Chilean patients with colorectal cancer ( CRC ) .
5 MATERIAL AND METHODS :
6 A cohort of 262 Chilean patients with CRC aged 26 to 90 years ( 53% males ) , was studied .
7 Μ KRAS mutation status was analyzed by real-time polymerase chain reaction and correlated with clinicopathological data .
8 RESULTS :
9 Ninety-eight patients ( 37% ) were positive for KRAS mutations .
10 G12D was the most common mutation with a frequency of 36.7% , followed by G12V ( 255% ) , G13D ( 173% ) , G12A ( 71% ) , G12C ( 61% ) , G12S ( 51% ) and G12R ( 2% ) .
11 The frequency of the mutation in left , right colon and rectal tumors was 37.8 , 32.6 and 44.9% , respectively .
12 Among tumors with mutations , 86.7% were well or moderately differentiated tumors and the rest were poorly differentiated .
13 Μ No significant associations between KRAS gene mutations and other clinicopathological features of the tumor were observed .
14 CONCLUSIONS :
15 The frequencies of KRAS mutations reported in this study are similar to frequencies reported for European and North-American populations , lower than in a Spanish study and higher than in a Peruvian study .



PMID: 25693079
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Hereditary breast and ovarian cancer susceptibility genes ( review ) .
1 [ Abnormalities of signal transduction molecules in multiple myeloma ] .



PMID: 25688918
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer .
1 BACKGROUND :
2 We evaluated KRAS (mKRAS ( mutant KRAS )) and BRAF (mBRAF ( mutant BRAF )) mutations to determine their prognostic potential in assessing patients with colorectal cancer ( CRC ) for lung metastasectomy .
3 METHODS :
4 Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011 .
5 RESULTS :
6 Molecular analysis revealed mKRAS in 93 patients ( 517% ) , mBRAF in 19 patients ( 106% ) .
7 In univariate analyses , overall survival ( OS ) was influenced by thoracic nodal status ( median OS : 98 months for pN- , 27 months for pN+ , P<0.0001 ) , multiple thoracic metastases ( 75 months versus 101 months , P = 0008 ) or a history of liver metastases ( 94 months versus 101 months , P = 004 ) .
8 mBRAF had a significantly worse OS than mKRAS and wild type ( WT ) ( P<00001 ) .
9 The 5-year OS was 0% for mBRAF , 44% for mKRAS and 100% for WT , with corresponding median OS of 15 , 55 and 98 months , respectively ( P<00001 ) .
10 ✓ In multivariate analysis , WT BRAF ( HR : 0.005 ( 95% CI : 0.001-0.02 ) , P<0.0001 ) and WT KRAS ( HR : 0.04 ( 95% CI : 0.02-0.1 ) , P<0.0001 ) had a significant impact on OS . GE-ASS-RO
11 CONCLUSIONS :
12 mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy .
13 Further studies are necessary .



PMID: 25688736
(None)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer .
1 BACKGROUND :
2 High circulating neutrophil-lymphocyte ratio ( NLR ) appears to be prognostic in metastatic colorectal cancer ( mCRC ) .
3 We investigated the relationship of NLR with circulating cytokines and molecular alterations .
4 METHODS :
5 We performed retrospective analyses on multiple cohorts of CRC patients ( metastatic untreated ( n = 166 ) , refractory metastatic ( n = 161 ) , hepatectomy ( n = 198 ) , stage 2/3 ( n = 274 ) , and molecularly screened ( n = 342 ) ) .
6 High NLR ( ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood ) was defined as NLR>5 .
7 Plasma cytokines were evaluated using multiplex-bead assays .
8 Kaplan-Meier estimates , non-parametric correlation analysis , and hierarchical cluster analyses were used .
9 RESULTS :
10 High NLR was associated with poor prognosis in mCRC ( hazard ratio ( HR ) 1.73 ; 95% confidence interval ( CI ) : 1.03-2.89 ; P = 0.039 ) independent of known prognostic factors and molecular alterations ( KRAS/NRAS/BRAF/PIK3CA/CIMP ) .
11 High NLR correlated with increased expression of interleukin 6 ( IL-6 ) , IL-8 , IL-2Ralpha , hepatocyte growth factor , macrophage-colony stimulating factor , and vascular epidermal growth factor in exploratory ( n = 39 ) and validation ( n = 166 ) cohorts .
12 Fourteen additional cytokines correlated with high NLR in the validation cohort .
13 All 20 cytokines fell into three major clusters : inflammatory cytokines , angiogenic cytokines , and epidermal growth factor ligands .
14 In mCRC , composite stratification based on NLR-cytokine score provided enhanced prognostic information ( HR 2.09 ; 95% CI : 1.59-2.76 ; P<0.001 ) over and above NLR .
15 CONCLUSIONS :
16 High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis .
17 A composite NLR-cytokine stratification has enhanced prognostic value in mCRC .



PMID: 25687873
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Analysis of gene expression profiling in meningioma : deregulated signaling pathways associated with meningioma and EGFL6 overexpression in benign meningioma tissue and serum ?
1 PURPOSE :
2 KRAS mutations have been used widely as prognostic or predictive marker in patients with advanced colorectal cancer ( CRC ) .
3 Μ However , it may be difficult to obtain a tumor tissue for analyzing the status of KRAS mutation in large proportion of patients with advanced disease .
4 MATERIALS AND METHODS :
5 We obtained pairs of tumor and serum samples from 65 patients with advanced CRC , between March 2008 and July 2011 .
6 Μ KRAS mutation status from the tumor samples was analyzed by genomic polymerase chain reaction and direct sequence , and KRAS mutation status from the serum samples was determined by a genomic polymerase chain reaction-restriction fragment length polymorphism assay .
7 RESULTS :
8 Μ KRAS mutations were detected in the serum samples of 26 patients and in the tumor samples of 31 patients .
9 KRAS mutation status in the serum and tumor samples was consistent in 44 of the 65 pairs ( 677% ) .
10 Μ There was a significant correlation between the mutations detected in the serum sample and the mutations detected in the matched tumor sample ( correlation index , 035 ; p <0004 ) .
11   Twenty-two of the 57 patients ( 385% ) received anti-epidermal growth factor receptor therapy as any line therapy .
12 ✓ There was no significant difference in the overall survival ( OS ) in accordance to the status of KRAS mutations in both the serum and tumor samples ( p >005 ) . RO-ASS-GE
13 In a multivariate analysis , liver metastasis and no cytoreductive operation were independent prognostic factors for decreased OS .
14 CONCLUSION :
15 Μ The serum sample might alternatively be used when it is difficult to obtain tumor tissues for analyzing the status of KRAS mutation in patients with advanced CRC .



PMID: 25686118
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Prognostic role of KRAS , NRAS , BRAF and PIK3CA mutations in advanced colorectal cancer . GM-MRK-DS
1 AIM :
2 To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer ( mCRC ) .
3 MATERIALS & ; METHODS : We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups : BRAF mutated ; KRAS mutated codons 12-13 only ; any of KRAS codons 61-146 , PIK3CA or NRAS mutations and all wild-type .
4 Point mutations were investigated by pyrosequencing .
5 RESULTS :
6 ✓ BRAF ( 52% ) and KRAS 12-13 ( 319% ) mutations were associated with poorer survival ( HR 28 and 176 , respectively ) . GM-ASS-RO, GE-ASS-RO
7 Presenting with right-sided colon cancer , not resected primary tumor , WBC >10 x 10(9)/l , receiving less chemotherapy or no bevacizumab were all associated with inferior outcome .
8 The all-wild-type subgroup ( 392% ) reported the longest survival .
9 CONCLUSION :
10 Extended mutational profile combined with clinical factors may impact on survival in mCRC .



PMID: 25685149
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer in iran : molecular epidemiology and screening strategies .
1 Purpose .
2 The increasing incidence of colorectal cancer ( CRC ) in the past three decades in Iran has made it a major public health burden .
3 This study aimed to report its epidemiologic features , molecular genetic aspects , survival , heredity , and screening pattern in Iran .
4 Methods .
5 A comprehensive literature review was conducted to identify the relevant published articles .
6 Μ We used medical subject headings , including colorectal cancer , molecular genetics , KRAS and BRAF mutations , screening , survival , epidemiologic study , and Iran .
7 Results .
8 Age standardized incidence rate of Iranian CRCs was 11.6 and 10.5 for men and women , respectively .
9 Overall five-year survival rate was 41% , and the proportion of CRC among the younger age group was higher than that of western countries .
10 Depending on ethnicity , geographical region , dietary , and genetic predisposition , mutation genes were considerably diverse and distinct among CRCs across Iran .
11 The high occurrence of CRC in records of relatives of CRC patients showed that family history of CRC was more common among young CRCs .
12 Conclusion .
13 Appropriate screening strategies for CRC which is amenable to early detection through screening , especially in relatives of CRCs , should be considered as the first step in CRC screening programs .



PMID: 25680741
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Anticarcinogenic Effect of Corn Tortilla Against 1,2-Dimethylhydrazine ( DMH )- Induced Colon Carcinogenesis in Sprague-Dawley Rats .
1 Mexico has the highest per capita consumption of corn in the world , which is consumed mainly as tortilla .
2 However , only a few in vivo studies have demonstrated the anticarcinogenic potential of some maize components against colon cancer , but not as a whole food product .
3 Therefore , our objective was to evaluate the protective effect of corn tortillas against the development of colon cancer .
4 First , blue , red , yellow and white corn grains were lime-cooked and processed to elaborate tortillas .
5 Then , tortillas were administered into the diet ( 27% w/w ) to male Sprague-Dawley rats induced with the colon carcinogen 1,2-dimethylhydrazine ( DMH ) .
6 Our results indicated that consumption of tortillas , particularly from white and blue corns , significantly decreased adenocarcinoma incidence ( up to 775% ) and mean number compared to DMH-treated animals .
7 In addition , an inhibition of beta- glucuronidase activity , and induction of detoxifying enzymes in liver and colon , as well as a decrease in the expression of the two most important proliferative proteins ( K-ras and beta-catenin ) involved in colon carcinogenesis , were also observed .
8 These results highlight some of the molecular mechanisms related to the chemopreventive effect of tortillas , thus indicating that corn products retain their biological properties even after nixtamalization and tortilla processing .



PMID: 25680623
(Patient)  
Terms: Phase II Trial, phase II trial, phase III
Sent# Symbols Sentence Mnemonics
0 Circulating Tumor Cell Enumeration in a Phase II Trial of a Four - Drug Regimen in Advanced Colorectal Cancer .
1 BACKGROUND :
2 Multidrug regimens are active against advanced colorectal cancer ( ACRC ) .
3 However , the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit .
4 We assessed circulating tumor cells ( CTCs ) as a prognostic biomarker in patients treated with a 4 - drug regimen .
5 PATIENTS AND METHODS :
6 A single-arm phase II trial ( Erbitux Study of CPT11 , Oxaliplatin , UFToral Targeted-therapy [eSCOUT] ) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan , oxaliplatin , and tegafur-uracil with leucovorin and cetuximab .
7 Baseline CTCs were enumerated using CellSearch .
8 The endpoints were an objective response rate ( ORR ) and overall survival ( OS ) .
9 We modeled our results and compared them with those modeled for the capecitabine , oxaliplatin , bevacizumab +/- cetuximab ( CAIRO2 ) trial , stratifying patients a priori into low ( <3 ) and high ( >/= 3 ) CTC groups .
10 RESULTS :
11 For 48 eligible patients , the best ORR from the 4 - drug regimen was 71% , with a disease control rate of 98% .
12 The median OS for patients with a high and low CTC count was 18.7 and 22.3 months ( log-rank test , P = 038 ) , respectively .
13 Μ In our modeled data , for patients with a low CTC count , no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial ( 222 vs. 220 months ) .
14 However , for the high CTC group , a clinically relevant improvement was seen in median OS ( eSCOUT vs . CAIRO2 , 187 vs. 137 months ; P = 001 ) .
15 CONCLUSION :
16 These data are hypothesis generating-for patients with ACRC , stratification by CTC count can identify those who might benefit the most from an intensive 4 - drug regimen , avoiding high-toxicity regimens in low CTC groups .
17 This hypothesis warrants validation in a phase III biomarker-driven trial .



PMID: 25675084
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Direct correlation between double K-RAS mutation and mucinous carcinoma . A case report .
1 Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway : emerging therapeutic opportunities .



PMID: 25674493
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer .
1 A comprehensive investigation of molecular features and prognosis of lung adenocarcinoma with micropapillary component .



PMID: 25673644
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations .
1 UNLABELLED : BRAF mutations occur in approximately 10% of colorectal cancers .
2 Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma , response rates in BRAF-mutant colorectal cancer are poor .
3 Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy , but patients ultimately develop resistance .
4 Μ To identify molecular alterations driving clinical acquired resistance , we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations .
5 Μ We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors , including KRAS amplification , BRAF amplification , and a MEK1 mutation .
6 ✓ These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity , but an ERK inhibitor could suppress MAPK activity and overcome resistance .
7   Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance .
8 SIGNIFICANCE : RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer .
9 Μ Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling , highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance .



PMID: 25673558
(Patient)  
Terms: meta-analysis, phase III trial, phase II trial
Sent# Symbols Sentence Mnemonics
0 Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab : a meta-analysis .
1 BACKGROUND :
2 Wild type RAS ( RAS-wt ) status is predictive of the activities of the anti-epidermal growth factor receptor ( EGFR ) monoclonal antibodies cetuximab (C) and panitumumab (P) .
3 We examined the impact of C and P on progression-free survival ( PFS ) , overall survival ( OS ) and overall response rate ( ORR ) in advanced colorectal cancer ( CRC ) patients who have RAS-wt/BRAF-mutant ( BRAF-mut ) status .
4 METHODS :
5 Randomised trials that compared C or P plus chemotherapy ( or C or P monotherapy ) with standard therapy or best supportive care ( BSC ) were included .
6 We used published hazard ratios ( HRs ) if they were available , or we derived treatment estimates from other survival data .
7 Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method .
8 All statistical tests were two-sided .
9 RESULTS :
10   Nine phase III trials and one phase II trial ( six first - line and two second - line trials , plus two trials involving chemorefractory patients ) , that included 463 RAS-wt/BRAF-mut CRC patients , were analysed .
11 Overall , the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS ( HR , 0.88 ; 95% confidence interval ( CI ) , 0.67-1.14 ; p = 0.33 ) , OS ( HR , 091 ; 95% CI , 062-134 ; p = 063 ) and ORR ( relative risk , 131 ; 95% CI 083-208 , p = 025 ) compared with control regimens .
12 CONCLUSIONS :
13   C- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients .
14 These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies .



PMID: 25666296
(None)  
Terms: meta-analysis, clinical trial, phase II/III
Sent# Symbols Sentence Mnemonics
0 Role of first - line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer : a meta-analysis of randomized clinical trials .
1 BACKGROUND :
2 Monoclonal antibodies targeting epidermal growth factor receptor ( EGFR ) or vascular endothelial growth factor ( VEGF ) have demonstrated efficacy in combination with chemotherapy in the first - line therapy of advanced colorectal cancer ( CRC ) .
3 Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting , and their comparative efficacy remains unclear .
4 We aimed to evaluate the impact of these targeted therapies on patient outcomes by combining the data from randomized clinical trials .
5 MATERIALS AND METHODS :
6 MEDLINE , PubMed , EMBASE , and meeting proceedings within the past 12 months were searched to identify relevant studies .
7 All randomized phase II/III clinical trials of advanced CRC comparing an anti-EGFR therapy with an anti-VEGF agent in the first - line setting were included .
8 Data were extracted on sample size , objective response rate ( ORR ) , progression-free survival ( PFS ) , and overall survival ( OS ) .
9 RESULTS :
10 Three randomized studies comprising 2014 participants were included in the meta-analysis .
11   For patients with KRAS wild type ( KRAS-WT ) CRC , the ORR was superior in patients who received first - line anti-EGFR therapy compared with those who received anti-VEGF therapy ( odds ratio [OR] , 1.31 ; 95% confidence interval [CI] , 1.09-1.58 ; P = .004 ) .
12 This effect was even stronger for all RAS-WT patients ( OR , 146 ; 95% CI , 113-190 ; P = 004 ) .
13 There was no difference in PFS overall irrespective of the KRAS-WT ( HR , 103 ; 95% CI , 093-113 ; P = 61 ) or all RAS-WT ( HR , 092 ; 95% CI , 071-118 ; P = 50 ) status .
14   The OS was significantly longer in the patients who received first - line anti-EGFR therapy compared with those who received anti-VEGF therapy ( KRAS-WT : HR , 0.79 ; 95% CI , 0.65-0.97 ; P = .026 ; all RAS-WT : HR , 0.77 ; 95% CI , 0.63-0.95 ; P = .016 ) .
15 CONCLUSION :
16   The results of our research show superior ORR and OS with first - line anti-EGFR therapy compared with anti-VEGF therapy in both KRAS-WT and all RAS-WT patients with advanced CRC .
17   These results suggest that anti-EGFR monoclonal antibodies may be a real alternative to anti-VEGF therapy as initial treatment of advanced CRC .



PMID: 25666295
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status : Updated Analysis of the CECOG/CORE 1.2.002 Study .
1   CA19-9 level as a prognostic and predictive factor of bevacizumab efficacy in metastatic colorectal cancer patients undergoing oxaliplatin-based chemotherapy .



PMID: 25664394
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab .
1 Circulating forms of the urokinase plasminogen activator receptor ( uPAR ) are associated with prognosis in patients with colorectal cancer .
2 Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor ( EGFR ) in a ligand -independent manner .
3 The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR ( I-III ) + ( II-III ) levels could identify a subpopulation of patients with metastatic colorectal cancer ( mCRC ) where treatment with cetuximab would have a beneficial effect .
4 Plasma samples were available from 453 patients treated in the NORDIC VII study .
5 Patients were randomized between FLOX and FLOX + cetuximab .
6 The levels of uPAR ( I-III ) + ( II-III ) were determined by time-resolved fluorescence immunoassay .
7 We demonstrated that higher baseline plasma uPAR ( I-III ) + ( II-III ) levels were significantly associated with shorter progression-free survival ( PFS ) ( HR = 130 , 114-148 , p = 00001 ) and overall survival ( OS ) ( HR = 175 , 152-202 , p <00001 ) .
8 Multivariate Cox analysis showed that plasma uPAR ( I-III ) + ( II-III ) was an independent biomarker of short OS ( HR = 145 , 120-175 , p = 00001 ) .
9 ✓ There were no significant interactions between plasma uPAR ( I-III ) + ( II-III ) levels , KRAS mutational status and treatment either PFS ( p = 043 ) or OS ( p = 0095 ) . GE-ASS-RO
10   However , further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR .
11 These results thus support the preclinical findings and should be further tested in an independent clinical data set .



PMID: 25663927
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab .
1 Approximately 5-10% of breast cancers may be inheritable , up to 90% of which are due to mutations in BRCA1 and BRCA2 .
2 A substantial minority are caused by non-BRCA mutations , such as TP53 , PTEN , STK11 , CHEK2 , ATM , BRIP1 , and PALB2 mutations .
3 This review highlights translational research advances with regard to the development of probabilistic models for hereditary breast cancer syndromes , the identification of specific genetic mutations responsible for these syndromes , as well as their testing and interpretations .



PMID: 25663768
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MiR-21/RASA1 axis affects malignancy of colon cancer cells via RAS pathways .
1 A 50 - gene signature is a novel scoring system for tumor-infiltrating immune cells with strong correlation with clinical outcome of stage I/II non-small cell lung cancer .



PMID: 25663765
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients . GE-ASS-RO
1 AIM :
2 To investigate the clinicopathologic characteristics and prognostic implications associated with loss of CDX2 expression in colorectal cancers ( CRCs ) .
3 METHODS :
4 We immunohistochemically evaluated CDX2 expression in 713 CRCs and paired our findings to clinicopathologic and molecular characteristics of each individual .
5 Endpoints included cytokeratin 7 and CK20 expression , microsatellite instability , CpG island methylator phenotype , and KRAS and BRAF mutation statuses .
6 Univariate and multivariate survival analysis was performed to reveal the prognostic value of CDX2 downregulation .
7 RESULTS :
8 CDX2 expression was lost in 42 ( 59% ) patients .
9 Moreover , loss of CDX2 expression was associated with proximal location , infiltrative growth , advanced T , N , M and overall stage .
10 On microscopic examination , loss of CDX2 expression was associated with poor differentiation , increased number of tumor-infiltrating lymphocytes , luminal serration and mucin production .
11 Loss of CDX2 expression was also associated with increased CK7 expression , decreased CK20 expression , CpG island methylator phenotype , microsatellite instability and BRAF mutation .
12 ✓ In a univariate survival analysis , patients with loss of CDX2 expression showed worse overall survival ( P <0001 ) and progression-free survival ( P <0001 ) . GM-ASS-RO
13 ✓ In a multivariate survival analysis , loss of CDX2 expression was an independent poor prognostic factor of overall survival [hazard ratio ( HR ) = 1.72 , 95%CI : 1.04-2.85 , P = 0.034] and progression-free survival ( HR = 1.94 , 95%CI : 1.22-3.07 , P = 0.005 ) . GE-MRK-RO, GE-ASS-RO
14 CONCLUSION :
15 ✓ Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs . GE-MRK-DS



PMID: 25663616
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular markers predictive of chemotherapy response in colorectal cancer .
1 A series of novel 2 - ( 1,3-diaryl - 4,5-dihydro-1H-pyrazol-5-yl ) phenol derivatives ( C1-C24 ) have been synthesized .
2 The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested .
3 Compound C6 displayed the most potent biological activity against B-RafV600E ( IC50 = 015 microM ) and WM266.4 human melanoma cell line ( GI50 = 175 microM ) , being comparable with the positive control ( Vemurafenib and Erlotinib ) and more potent than our previous best compounds .
4 The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions .
5 This work aimed at seeking more potent inhibitors as well as discussing some previous findings .
6 As a result , the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful .



PMID: 25657200
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 External quality assessment unravels interlaboratory differences in quality of RAS testing for anti-EGFR therapy in colorectal cancer .
1 BACKGROUND :
2 Regulations for the selection of patients with metastatic colorectal cancer for anti-EGFR treatment changed at the end of 2013 .
3 The set of mutations to be tested extended from KRAS codons 12 and 13 to KRAS and NRAS exons 2 , 3 , and 4 .
4 A European external quality assessment scheme monitored the performance of laboratories and evaluated the implementation of the new regulations .
5 MATERIALS AND METHODS :
6 The 131 participating laboratories received 10 samples of formalin-fixed paraffin-embedded material , including RAS ( exon 2 , 3 , 4 ) and BRAF mutations .
7 Mock clinical data were provided for three cases .
8 Using their routine methods , laboratories determined the genotypes and submitted three written reports .
9 Assessors scored the results according to predefined evaluation criteria .
10 RESULTS :
11 Half of the participants ( 493% ) had completely implemented the new test requirements ( codons 12 , 13 , 59 , 61 , 117 , and 146 of KRAS and NRAS ) , and 96 laboratories ( 733% ) made no genotype mistakes .
12 Correct nomenclature , according to the Human Genome Variation Society , was used by 82 laboratories ( 626% ) .
13 CONCLUSION :
14 Although regulations were effective for several months , many laboratories were not ready for full RAS testing in the context of anti-EGFR therapy .
15 Nevertheless , in each participating country , there are laboratories that provide complete and correct testing .
16 External quality assessments can be used to monitor implementation of new test regulations and to stimulate the laboratories to improve their testing procedures .
17 Because the results of this program are available on the website of the European Society of Pathology , patients and clinicians can refer test samples to a reliable laboratory .



PMID: 25655305
(Patient)  
Terms: , rat
Sent# Symbols Sentence Mnemonics
0 Whole genome amplification induced bias in the detection of KRAS-mutated cell populations during colorectal carcinoma tissue testing .
1 Whole genome amplification replicates the entire DNA content of a sample and can thus help to circumvent material limitations when insufficient DNA is available for planned genetic analyses .
2 However , there are conflicting data in the literature whether whole genome amplification introduces bias or reflects precisely the spectrum of starting DNA .
3 We analyzed the origins of discrepancies in KRAS ( Kirsten rat sarcoma viral oncogene homolog gene ) mutation detection in six of ten samples amplified using the GenomePlex(R) Tissue Whole Genome Amplification kit 5 ( WGA5 ; Sigma-Aldrich , St Louis , MO , USA ) and KRAS StripAssay(R) ( KRAS SA ; ViennaLab Diagnostics , Vienna , Austria ) .
4 We undertook reextraction , reamplification , retyping , authentication , reanalysis , and reinterpretation to determine whether the discrepancies originated during the preanalytical , analytical , and/or interpretative phase of genotyping .
5 We conclude that a combination of glass slide/sample heterogeneity and biased amplification due to stochastic effects in the early phases of whole genome amplification ( WGA ) may have adversely affected the results obtained .
6 Our findings are relevant for both forensic genetics testing and massively parallel sequencing using preamplification .



PMID: 25648497
(Patient)  
Terms: xenograft, in vivo, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 Potentiating effects of GHRH analogs on the response to chemotherapy .
1 Growth hormone releasing hormone ( GHRH ) from hypothalamus nominatively stimulates growth hormone release from adenohypophysis .
2 GHRH is also produced by cancers , acting as an autocrine/paracrine growth factor .
3 This growth factor function is seen in lymphoma , melanoma , colorectal , liver , lung , breast , prostate , kidney , bladder cancers .
4 Μ Pituitary type GHRH receptors and their splice variants are also expressed in these malignancies .
5 Synthetic antagonists of the GHRH receptor inhibit proliferation of cancers .
6 Besides direct inhibitory effects on tumors , GHRH antagonists also enhance cytotoxic chemotherapy .
7 GHRH antagonists potentiate docetaxel effects on growth of H460 non-small cell lung cancer ( NSCLC ) and MX-1 breast cancer plus suppressive action of doxorubicin on MX-1 and HCC1806 breast cancer .
8 We investigated mechanisms of antagonists on tumor growth , inflammatory signaling , doxorubicin response , expression of drug resistance genes , and efflux pump function .
9 Triple negative breast cancer cell xenografted into nude mice were treated with GHRH antagonist , doxorubicin , or their combination .
10 The combination reduced tumor growth , inflammatory gene expression , drug -resistance gene expression , cancer stem - cell marker expression , and efflux-pump function .
11 Thus , antagonists increased the efficacy of doxorubicin in HCC1806 and MX-1 tumors .
12 Growth inhibition of H460 NSCLC by GHRH antagonists induced marked downregulation in expression of prosurvival proteins K-Ras , COX-2 , and pAKT .
13 In HT-29 , HCT-116 and HCT-15 colorectal cancer lines , GHRH antagonist treatment caused cellular arrest in S-phase of cell cycle , potentiated inhibition of in vitro proliferation and in vivo growth produced by S-phase specific cytotoxic agents , 5-FU , irinotecan and cisplatin .
14 This enhancement of cytotoxic therapy by GHRH antagonists should have clinical applications .



PMID: 25647260
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population .
1 Several studies from developing countries have shown human papillomavirus to be associated with colorectal cancers , but the molecular characteristics of such cancers are poorly known .
2 We studied the various genetic variations like microsatellite instability ( MSI ) , oncogenic mutations and epigenetic deregulations like CpG island methylation in HPV associated and nonassociated colorectal cancer patients from Indian population .
3 HPV DNA was detected by PCR using My09/My11 and Gp5+/Gp6+ consensus primers and typed using HPV16 and HPV18 specific primers .
4 Μ MSI was detected using BAT 25 and BAT 26 markers , and mutation of KRAS , TP53 and BRAF V600E were detected by direct sequencing .
5 Methyl specific polymerase chain reaction ( MSP ) was used to determine promoter methylation of the classical CIMP panel markers ( P16 , hMLH1 , MINT1 , MINT2 and MINT31 ) and other tumour-related genes ( DAPK , RASSF1 , BRCA1 and GSTP1 ) .
6 HPV DNA was detected in 34/93 ( 365 % ) colorectal tumour tissues , HPV 18 being the predominant high-risk type .
7 Μ MSI was detected in 7.5 % cases ; KRAS codon 12 , 13 , BRAF V600E and TP53 mutations were detected in 36.5 , 3.2 and 37.6 % of the cases , respectively .
8 Μ CIMP-high was observed in 44.08 % cases .
9 HPV presence was not associated with age , stage or grade of tumours , MSI or mutations in KRAS , TP53 or BRAF genes .
10 Μ Higher methylation frequencies of all genes/loci under study except RASSF1 , as well as significantly higher CIMP-high characteristics were observed in HPV positive tumours as compared to negative cases .
11 HPV in association with genetic and epigenetic features might be a potent risk factor for colorectal cancer in Indian population .



PMID: 25639985
(Patient)  
Terms: meta-analysis
Sent# Symbols Sentence Mnemonics
0 Concordant analysis of KRAS , BRAF , PIK3CA mutations , and PTEN expression between primary colorectal cancer and matched metastases .
1 Current data on the concordance of KRAS , BRAF , PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer ( CRC ) are conflicting .
2 We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients .
3 The biomarker status in primary tumors was used as the reference standard .
4 Concordance data for KRAS , BRAF , PIK3CA and PTEN were provided by 43 , 16 , 9 and 7 studies , respectively .
5 The pooled concordance rate was 92.0% ( 95% CI : 89.7%-93.9% ) for KRAS , 96.8% ( 95% CI : 94.8%-98.0% ) for BRAF , 93.9% ( 95% CI : 89.7%-96.5% ) for PIK3CA and 71.7% ( 95% CI : 57.6%-82.5% ) for PTEN .
6 The pooled false positive and false negative rates for KRAS were 9.0% ( 95% CI : 6.5%-12.4% ) and 11.3% ( 95% CI : 8.0%-15.8% ) , respectively .
7 KRAS , BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC , but PTEN loss is not .
8   Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases , while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases .
9   These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment .



PMID: 25638164
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Methylation of MGMT and ADAMTS14 in normal colon mucosa : biomarkers of a field defect for cancerization preferentially targeting elder African-Americans .
1 Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene ( MGMT ) was previously associated with G >A transition mutations in KRAS and TP53 in colorectal cancer ( CRC ) .
2 We tested the association of MGMT methylation with G >A mutations in KRAS and TP53 in 261 CRCs .
3 Sixteen cases , with and without MGMT hypermethylation , were further analyzed by exome sequencing .
4 Μ No significant association of MGMT methylation with G >A mutations in KRAS , TP53 or in the whole exome was found ( p >05 in all comparisons ) .
5 The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas ( TCGA ) consortium dataset .
6 Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic .
7 We also found a significant clustering ( p = 0001 ) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients .
8 This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci , including MGMT or ADAMTS14 , that may lead to predictive biomarkers for CRC .
9 Methylation of these loci in normal mucosa was more frequent in elder ( p = 0001 ) patients , and particularly in African Americans ( p = 1 x 10-5 ) , thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America .



PMID: 25637165
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Biomarker-driven phase 2 study of MK-2206 and selumetinib ( AZD6244 , ARRY-142886 ) in patients with colorectal cancer .
1 PURPOSE :
2 PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer ( CRC ) .
3 We conducted a biomarker-driven trial of the combination of MK-2206 , an allosteric AKT 1/2/3 inhibitor , and selumetinib , a MEK 1/2 inhibitor , in patients with CRC to evaluate inhibition of phosphorylated ERK ( pERK ) and AKT ( pAKT ) in paired tumor biopsies .
4 PATIENTS AND METHODS :
5 Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status .
6 Initially , 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles .
7 Following an interim analysis , the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily , respectively .
8 Paired tumor biopsies were evaluated for target modulation .
9 RESULTS :
10 Common toxicities were gastrointestinal , hepatic , dermatologic , and hematologic .
11 Of 21 patients enrolled , there were no objective responses .
12 Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies .
13 CONCLUSION :
14 Despite strong scientific rationale and preclinical data , clinical activity was not observed .
15 The desired level of target inhibition was not achieved .
16 Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity , highlighting the challenges in developing optimal combinations of targeted agents .



PMID: 25637035
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Development of a semi-conductor sequencing-based panel for genotyping of colon and lung cancer by the Onconetwork consortium .
1 BACKGROUND :
2 The number of predictive biomarkers that will be necessary to assess in clinical practice will increase with the availability of drugs that target specific molecular alterations .
3 Therefore , diagnostic laboratories are confronted with new challenges : costs , turn-around-time and the amount of material required for testing will increase with the number of tests performed on a sample .
4 Our consortium of European clinical research laboratories set out to test if semi-conductor sequencing provides a solution for these challenges .
5 METHODS :
6 We designed a multiplex PCR targeting 87 hotspot regions in 22 genes that are of clinical interest for lung and/or colorectal cancer .
7 The gene -panel was tested by 7 different labs in their own clinical setting using ion-semiconductor sequencing .
8 RESULTS :
9 Μ We analyzed 155 samples containing 112 previously identified mutations in the KRAS , EGFR en BRAF genes .
10 Only 1 sample failed analysis due to poor quality of the DNA .
11 Μ All other samples were correctly genotyped for the known mutations , even as low as 2% , but also revealed other mutations .
12 Optimization of the primers used in the multiplex PCR resulted in a uniform coverage distribution over the amplicons that allows for efficient pooling of samples in a sequencing run .
13 CONCLUSIONS :
14 We show that a semi-conductor based sequencing approach to stratify colon and lung cancer patients is feasible in a clinical setting .



PMID: 25636897
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma - a report of a case . GM-MRK-RO
1 BACKGROUND :
2 The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients .
3 Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E , which has analogous molecular functions to those of the conventional BRAF mutation V600E , and may have potential as a prognostic marker for colorectal cancer ( CRC ) .
4 CASE PRESENTATION :
5 The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma ( stage II by AJCC TNM staging 7th edition ) 14 months after surgery and was treated with modified FOLFOX6 ( fluorouracil , leucovorin , and oxaliplatin ) , radiation , and FOLFIRI ( fluorouracil , leucovorin , and irinotecan ) .
6 The tumor progressed before further treatment could be initiated , resulting in death after 15 months .
7 This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab .
8 CONCLUSIONS :
9   Thus , the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities .



PMID: 25632919
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Clinicopathological and molecular characteristics of serrated lesions in Japanese elderly patients .
1 BACKGROUND :
2 The population in Japan is aging more rapidly than in any other country .
3 However , no studies have determined the characteristics of the large population of elderly patients with colorectal tumors .
4 Therefore , we examined the clinicopathological and molecular features of these tumors in elderly patients .
5 METHODS :
6 In total , 1,627 colorectal tumors ( 393 serrated lesions , 277 non-serrated adenomas and 957 colorectal cancers ) were acquired from patients .
7 Μ Tumor specimens were analyzed for BRAF and KRAS mutations , CpG island methylator phenotype-specific promoters ( CACNA1G , CDKN2A , IGF2 and RUNX3 ) , IGFBP7 , MGMT , MLH1 and RASSF2 methylation , microsatellite instability ( MSI ) and microRNA - 31 ( miR-31 ) .
8 RESULTS :
9 The frequency of elderly patients ( aged >/ = 75 years ) with sessile serrated adenomas ( SSAs ) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas ( p <00001 ) .
10 In elderly patients , all SSAs were located in the proximal colon ( particularly the cecum to ascending colon ) .
11 Μ High miR-31 expression , MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients .
12 Μ In contrast , no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations .
13 CONCLUSION :
14 In elderly patients , all SSAs were located in the proximal colon .
15 Μ Furthermore , cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients .
16 Thus , careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential .



PMID: 25632202
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer .
1 AIM :
2 To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability ( MSI ) status in Japanese colorectal cancer ( CRC ) population .
3 METHODS :
4 We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected , stage I-III CRC and examined associations of these mutations with disease-free survival ( DFS ) and overall survival ( OS ) using uni - and multivariate Cox proportional hazards models .
5 RESULTS :
6 Μ KRAS and BRAF mutations were detected in 312 ( 38% ) of 812 and 40 ( 5% ) of 811 tumors , respectively .
7 Μ KRAS mutations occurred more frequently in females than in males ( P = 002 ) , while the presence of BRAF mutations was significantly associated with the female gender ( P = 0006 ) , proximal tumor location ( P<0001 ) , mucinous or poorly differentiated histology ( P<0001 ) , and MSI-high tumors ( P<0001 ) .
8 ✓ After adjusting for relevant variables , including MSI status , KRAS mutations were associated with poorer DFS ( HR = 1.35 ; 95%CI : 1.03-1.75 ) and OS ( HR = 1.46 ; 95%CI : 1.09-1.97 ) . GM-ASS-RO
9 ✓ BRAF mutations were poor prognostic factors for DFS ( HR = 2.20 ; 95%CI : 1.19-4.06 ) and OS ( HR = 2.30 ; 95%CI : 1.15-4.71 ) . GM-MRK-RO
10 Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS .
11 CONCLUSION :
12 ✓ KRAS and BRAF mutations are associated with inferior survival , independent of MSI status , in Japanese patients with curatively resected CRC . GE-ASS-RO, GM-ASS-RO



PMID: 25628921
(Cell)  
Terms: in vitro, In vivo, xenograft, in vivo
Sent# Symbols Sentence Mnemonics
0 Dovitinib ( TKI258 ) , a multi-target angiokinase inhibitor , is effective regardless of KRAS or BRAF mutation status in colorectal cancer .
1 INTRODUCTION :
2 We aimed to determine whether KRAS and BRAF mutant colorectal cancer ( CRC ) cells exhibit distinct sensitivities to the multi-target angiokinase inhibitor , TKI258 ( dovitinib ) .
3 MATERIALS AND METHODS :
4 We screened 10 CRC cell lines by using receptor tyrosine kinase ( RTK ) array to identify activated RTKs .
5 MTT assays , anchorage -independent colony-formation assays , and immunoblotting assays were performed to evaluate the in vitro anti-tumor effects of TKI258 .
6 In vivo efficacy study followed by pharmacodynamic evaluation was done .
7 RESULTS :
8 Fibroblast Growth Factor Receptor 1 ( FGFR1 ) and FGFR3 were among the most highly activated RTKs in CRC cell lines .
9 In in vitro assays , the BRAF mutant HT-29 cells were more resistant to the TKI258 than the KRAS mutant LoVo cells .
10 However , in xenograft assays , TKI258 equally delayed the growth of tumors induced by both cell lines .
11 TUNEL assays showed that the apoptotic index was unchanged following TKI258 treatment , but staining for Ki-67 and CD31 was substantially reduced in both xenografts , implying an anti-angiogenic effect of the drug .
12   TKI258 treatment was effective in delaying CRC tumor growth in vivo regardless of the KRAS and BRAF mutation status .
13 CONCLUSIONS :
14   Our results identify FGFRs as potential targets in CRC treatment and suggest that combined targeting of multiple RTKs with TKI258 might serve as a novel approach to improve outcome of patients with CRC .



PMID: 25628445
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment .
1 INTRODUCTION :
2 KRAS and EGFR ectodomain -acquired mutations in patients with metastatic colorectal cancer ( mCRC ) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies ( mAbs ) .
3 We investigated the frequency , co-occurrence , and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA ( ctDNA ) .
4 PATIENTS AND METHODS :
5 Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS ( wt ) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12 , 13 , 61 , and 146 and EGFR 492 mutations .
6 RESULTS :
7 Μ Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8% ; 95% confidence interval ( CI ) 0.02-0.18] and 27/62 ( 44% ; 95% CI 03-056 ) samples , respectively .
8 KRAS codon 61 and 146 mutations were predominant ( 33% and 11% , respectively ) , and multiple EGFR and/or KRAS mutations were detected in 11/27 ( 41% ) cases .
9 The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs ( P = 0038 ) .
10 ✓ In the matching archival tissue , these mutations were detectable as low-allele -frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival ( PFS ) compared with the cases with no new mutations ( 30 versus 80 months , P = 00004 ) . GM-ASS-RO
11 CONCLUSION :
12   Μ Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare , pre-existing clones in the primary tumors .
13   These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment .
14   Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time .
15   Μ Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients .



PMID: 25627125
(None)  
Terms: clinical trial, phase III
Sent# Symbols Sentence Mnemonics
0 Evaluation of a novel tissue stabilization gel to facilitate clinical sampling for translational research in surgical trials .
1 Therapy of patients with advanced NSCLC has lately changed due to the algorithm based on the presence or absence of oncogenic mutations .
2 There is an agreement nowadays that in the presence of activating EGFR mutations , the administration of EGFR TKI ( gefitinib , erlotinib , afatinib ) is the most efficacious initial treatment .
3 Unlike the first-generation TKIs , afatinib is a new , irreversible ErbB blocker , selectively and effectively blocking signals from the ErbB family receptors .
4 Afatinib's marketing authorization is based on a large , randomized , phase III clinical trial , LUX-Lung 3 , where patients in the control arm were treated with the best available chemotherapy ( pemetrexed/cisplatin combination ) .
5 Primary endpoint was progression-free survival ( PFS ) .
6 ✓ Patients with common EGFR mutations showed a PFS of 13.6 months when treated with afatinib , while treatment in the control arm resulted in a PFS of 6.9 months . GM-ASS-RO
7 Overall survival ( OS ) was 31.6 and 28.2 months , respectively .
8   LUX-Lung 3 has been followed by the LUX-Lung 6 trial , comparing afatinib treatment to traditional chemotherapy ( gemcitabine/cisplatin ) in Asian patients with NSCLC harboring EGFR mutations .
9 This clinical trial has also proved benefit of afatinib : PFS was 11.0 months in the afatinib arm and 5.6 months in the control arm by independent reviewer , while OS was 23.6 months and 23.5 months , respectively .
10 Similarity of the OS values in both trials is explained by the cross-over treatment .
11 When further analyzing OS data , a statistically significant difference between the afatinib and the control arm was seen in the EGFR exon 19 del subgroup ( LUX-Lung 3 : 33.3 vs. 21.1 months , LUX-Lung 6 : 31.4 vs. 18.4 months , respectively ) .



PMID: 25624727
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Deficient DNA mismatch repair is associated with favorable prognosis in Thai patients with sporadic colorectal cancer .
1 Oncogenic KRAS mutation is the signature genetic event in the progression and growth of pancreatic ductal adenocarcinoma ( PDAC ) , an almost universally fatal disease .
2 Although it has been appreciated for some time that nearly 95% of PDAC harbor mutationally activated KRAS , to date no effective treatments that target this mutant protein have reached the clinic .
3 A number of studies have shown that oncogenic KRAS plays a central role in controlling tumor metabolism by orchestrating multiple metabolic changes including stimulation of glucose uptake , differential channeling of glucose intermediates , reprogrammed glutamine metabolism , increased autophagy , and macropinocytosis .
4 We review these recent findings and address how they may be applied to develop new PDAC treatments .



PMID: 25623536
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Inter - and intra-tumor profiling of multi-regional colon cancer and metastasis .
1 Intra - and inter-tumor heterogeneity may hinder personalized molecular-target treatment that depends on the somatic mutation profiles .
2 We performed mutation profiling of formalin-fixed paraffin embedded tumors of multi-regional colon cancer and characterized the consequences of intra - and inter-tumor heterogeneity and metastasis using targeted re-sequencing .
3 We performed targeted re-sequencing on multiple spatially separated samples obtained from multi-regional primary colon carcinoma and associated metastatic sites in two patients using next-generation sequencing .
4 Μ In Patient 1 with four primary tumors ( P1-1 , P1-2 , P1-3 , and P1-4 ) and one liver metastasis ( H1 ) , mutually exclusive pattern of mutations was observed in four primary tumors .
5 Μ Mutations in primary tumors were identified in three regions ; KARS (G13D) and APC ( R876* ) in P1-2 , TP53 (A161S) in P1-3 , and KRAS (G12D) , PIK3CA (Q546R) , and ERBB4 ( T272A ) in P1-4 .
6 Μ Similar combinatorial mutations were observed between P1-4 and H1 .
7 Μ The ERBB4 ( T272A ) mutation observed in P1-4 , however , disappeared in H1 .
8 Μ In Patient 2 with two primary tumors ( P2-1 and P2-2 ) and one liver metastasis ( H2 ) , mutually exclusive pattern of mutations were observed in two primary tumors .
9 Μ We identified mutations ; KRAS (G12V) , SMAD4 ( N129K , R445* , and G508D ) , TP53 (R175H) , and FGFR3 (R805W) in P2-1 , and NRAS (Q61K) and FBXW7 (R425C) in P2-2 .
10 Μ Similar combinatorial mutations were observed between P2-1 and H2 .
11 Μ The SMAD4 ( N129K and G508D ) mutations observed in P2-1 , however , were nor detected in H2 .
12 These results suggested that different clones existed in primary tumors and metastatic tumor in Patient 1 and 2 likely originated from P1-4 and P2-1 , respectively .
13 In conclusion , we detected the muti-clonalities between intra - and inter-tumors based on mutational profiling in multi-regional colon cancer using next-generation sequencing .
14 Primary region from which metastasis originated could be speculated by mutation profile .
15 Characterization of inter - and inter-tumor heterogeneity can lead to underestimation of the tumor genomics landscape and treatment strategy of personal medicine .



PMID: 25623215
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer .
1 We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung , responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel .
2 The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor , a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer ( NSCLC ) such as epidermal growth factor receptor mutation .
3 Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered , particularly in the absence of alternative therpateutic options .



PMID: 25620379
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B .
1 Fascin-1 is a filamentous actin-binding protein that crosslinks actin microfilaments into tight , parallel bundles .
2 These bundles are important for the extension of microspikes , filopodia and invadopodia from cell surfaces and for the functionality of these protrusions in cell migration and/or dynamic sensing of the local microenvironment .
3 Fascin-1 is absent in normal colonic epithelium , but its upregulation in colorectal adenomas and adenocarcinomas and its correlation with an aggressive clinical course has piqued the interest of many laboratories with research interests in cancer metastasis .
4 This report summarizes current knowledge of the molecular interactions of fascin-1 in relation to its activities and mechanisms of upregulation in colorectal carcinoma cells .
5 The status and key questions surrounding investigations of fascin-1 as a novel , early prognostic biomarker in colorectal cancer are discussed .
6 Ongoing pre-clinical research into new migration inhibitory and anti-metastatic compounds that alter the actin cytoskeleton , and the goal of targeting fascin-1 , is also discussed .



PMID: 25617745
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas .
1 Μ Previous genetic studies on colorectal carcinomas ( CRC ) have identified multiple somatic mutations in four candidate pathways ( TGF-beta , Wnt , P53 and RTK-RAS pathways ) on populations of European ancestry .
2 However , it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes .
3 In this study , to evaluate the mutational spectrum of novel somatic mutations , we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC , including 29 colon carcinomas and 12 rectal carcinomas .
4 We designed Illumina Custom Amplicon panel to target 43 genes , including genes in the four candidate pathways , as well as several known oncogenes for other cancers .
5 Candidate mutations were validated by Sanger sequencing , and we further used SIFT and PolyPhen-2 to assess potentially functional mutations .
6 We discovered 3 new somatic mutations in gene APC , TCF7L2 , and PIK3CA that had never been reported in the COSMIC or NCI-60 databases .
7 Additionally , we confirmed 6 known somatic mutations in gene SMAD4 , APC , FBXW7 , BRAF and PTEN in Chinese CRC patients .
8 While most were previously reported in CRC , one mutation in PTEN was reported only in malignant endometrium cancer .
9 Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients .
10 We also discovered a number of novel somatic mutations in these pathways , which may have implications for the pathogenesis of CRC .



PMID: 25613750
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Methylation and expression of the tumour suppressor , PRDM5 , in colorectal cancer and polyp subgroups .
1 BACKGROUND :
2 PRDM5 is an epigenetic regulator that has been recognized as an important tumour suppressor gene .
3 Silencing of PRDM5 by promoter hypermethylation has been demonstrated in several cancer types and PRDM5 loss results in upregulation of the Wnt pathway and increased cellular proliferation .
4 PRDM5 has not been extensively investigated in specific subtypes of colorectal cancers .
5 We hypothesized it would be more commonly methylated and inactivated in serrated pathway colorectal cancers that are hallmarked by a BRAF V600E mutation and a methylator phenotype , compared to traditional pathway cancers that are BRAF wild type .
6 METHODS :
7 Cancer ( 214 BRAF mutant , 122 BRAF wild type ) and polyp ( 59 serrated polyps , 40 conventional adenomas ) cohorts were analysed for PRDM5 promoter methylation using MethyLight technology .
8 PRDM5 protein expression was assessed by immunohistochemistry in cancers and polyps .
9 Μ Mutation of PRDM5 was analysed using cBioPortal 's publicly available database .
10 RESULTS :
11 BRAF mutant cancers had significantly more frequent PRDM5 promoter methylation than BRAF wild type cancers ( 77/214,36% versus 4/122,3% ; p<00001 ) .
12 Serrated type polyps had a lower methylation rate than cancers but were more commonly methylated than conventional adenomas ( 6/59,10% versus 0/40,0% ) .
13 PRDM5 methylation was associated with advanced stages of presentation ( p<005 ) and the methylator phenotype ( p = 003 ) .
14 PRDM5 protein expression was substantially down-regulated in both BRAF mutant and wild type cancer cohorts ( 92/97,95% and 39/44,89% ) .
15 The polyp subgroups showed less silencing than the cancers , but similar rates were found between the serrated and conventional polyp cohorts ( 29/59 , 49% ; 23/40 , 58% respectively ) .
16 Of 295 colorectal cancers , PRDM5 was mutated in only 6 ( 2% ) cancers which were all BRAF wild type .
17 CONCLUSIONS :
18 Serrated pathway colorectal cancers demonstrated early and progressive PRDM5 methylation with advancing disease .
19 Interestingly , PRDM5 protein expression was substantially reduced in all polyp types and more so in cancers which also indicates early and increasing PRDM5 down-regulation with disease progression .
20 Methylation may be contributing to gene silencing in a proportion of BRAF mutant cancers , but the large extent of absent protein expression indicates other mechanisms are also responsible for this .
21 These data suggest that PRDM5 is a relevant tumour suppressor gene that is frequently targeted in colorectal tumourigenesis .



PMID: 25611103
(Patient)  
Terms: retrospective, prospective
Sent# Symbols Sentence Mnemonics
0 Challenges posed to pathologists in the detection of KRAS mutations in colorectal cancers .
1 CONTEXT :
2 Detection of KRAS mutation is mandatory to predict response to anti-epidermal growth factor receptor monoclonal antibodies in patients with metastatic colorectal cancers .
3 OBJECTIVE :
4 To demonstrate challenges posed to pathologists in the clinical detection of KRAS mutations in colorectal cancers .
5 DESIGN :
6 In this retrospective analysis for quality assessment of the pyrosequencing assay , we survey the characteristics of 463 formalin-fixed , paraffin-embedded neoplastic tissues submitted for KRAS mutation detection during a 26-month period .
7 RESULTS :
8 Μ The KRAS mutation was detected in 39.2% of tumors .
9 This included 2 tumors with complex pyrograms ( GGT>GAG at codon 12 and GGC>GTT at codon 13 , as resolved by a Pyromaker software program ) and 3 tumors with an indeterminate percentage of mutant alleles ( defined as 4% to 5% and confirmed by a next-generation sequencing platform ) .
10 Among the 25 specimens ( 55% ) with fewer than 20% tumor cells , 22 were resected after chemotherapy/radiation .
11 Significant depletion of tumor cells was observed in rectal cancers resected after neoadjuvant therapy ( 310% ) versus those without previous treatment ( 0% ) ( P = 01 ) .
12 Μ We also explore other specimens with low tumor cellularity and potential causes of discrepancy between the estimated tumor cell percentage and detected mutant allele frequency , such as intratumor heterogeneity of KRAS mutation .
13 CONCLUSIONS :
14 Neoadjuvant therapy may deplete tumor cells and confound the molecular diagnosis of KRAS mutations .
15 Accurate detection of specimens with poor tumor cellularity requires the appropriate selection of neoplastic tissues , evaluation of tumor cellularity , use of assays with high sensitivity , and prospective quality assessment .



PMID: 25609577
(Patient)  
Terms: In vitro
Sent# Symbols Sentence Mnemonics
0 KRAS mutant allele -specific imbalance ( MASI ) assessment in routine samples of patients with metastatic colorectal cancer .
1 AIMS :
2 Patients with colorectal cancer harbouring KRAS mutations do not respond to antiepidermal growth factor receptor ( anti-EGFR ) therapy .
3 Μ Community screening for KRAS mutation selects patients for treatment .
4 Μ When a KRAS mutation is identified by direct sequencing , mutant and wild type alleles are seen on the sequencing electropherograms .
5 KRAS mutant allele -specific imbalance ( MASI ) occurs when the mutant allele peak is higher than the wild type one .
6 The aims of this study were to verify the rate and tissue distribution of KRAS MASI as well as its clinical relevance .
7 METHODS :
8 A total of 437 sequencing electropherograms showing KRAS exon 2 mutation was reviewed and in 30 cases next generation sequencing ( NGS ) was also carried out .
9 Five primary tumours were extensively laser capture microdissected to investigated KRAS MASI tissue spatial distribution .
10 KRAS MASI influence on the overall survival was evaluated in 58 patients .
11 In vitro response to anti-EGFR therapy in relation to different G13D KRAS MASI status was also evaluated .
12 RESULTS :
13 Μ On the overall , KRAS MASI occurred in 58/436 cases ( 128% ) , being more frequently associated with G13D mutation ( p = 005 ) and having a heterogeneous tissue distribution .
14 KRAS MASI detection by Sanger Sequencing and NGS showed 94% ( 28/30 ) concordance .
15 The longer overall survival of KRAS MASI negative patients did not reach statistical significance ( p = 008 ) .
16 ✓ In cell line model G13D KRAS MASI conferred resistance to cetuximab treatment .
17 CONCLUSIONS :
18 KRAS MASI is a significant event in colorectal cancer , specifically associated with G13D mutation , and featuring a heterogeneous spatial distribution , that may have a role to predict the response to EGFR inhibitors .
19 The foreseen implementation of NGS in community KRAS testing may help to define KRAS MASI prognostic and predictive significance .



PMID: 25609485
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Functional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer .
1 BACKGROUND :
2 Survival of metastatic colon cancer ( mCC ) patients has considerably improved with optimization of new drugs regimen .
3 Μ Inactivation of TP53 pathway by TP53 mutations is observed in nearly half of colorectal tumors .
4 The impact of such mutations has been poorly studied in the metastatic setting .
5 METHODS :
6 The files of 254 mCC treated in a single institution at Saint-Louis hospital between January 1999 and April 2011 were retrospectively reviewed .
7 Tissue samples for analysis of TP53 mutations were available for 68 patients , performed using FASAY .
8 The prognostic value of TP53 status was evaluated by comparing progression free survival ( PFS ) and overall survival ( OS ) in the group of TP53-mutated and wild type patients .
9 RESULTS :
10 PFS was 6.9 months and OS 21.7 months in the whole population .
11 There was no statistical difference in TP53-mutated and wild type groups in term of PFS ( HR = 104 ; IC 95% = 06-179 ) and OS ( HR = 099 ; IC 95% = 053-155 ) whatever the chemotherapy regimen ( oxaliplatin - or irinotecan-based ) .
12 Μ Only BRAF V600 mutation was demonstrated to be a poor prognostic factor for PFS and OS , and CEA level for OS .
13 CONCLUSIONS :
14 Routine determination of TP53 mutations , even with a highly sensitive method , cannot be recommended to predict chemotherapy response in mCC .



PMID: 25608838
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 TIMP-1 and CEA as biomarkers in third - line treatment with irinotecan and cetuximab for metastatic colorectal cancer .
1 KRAS wild-type ( wt ) status determines indication for treatment with combination therapy , including epidermal growth factor receptor ( EGFR ) inhibitors , but still , the overall response rate in KRAS wt patients is less than 40 % .
2 Consequently , the majority of patients will suffer from substantial side effects and no apparent benefit .
3 Tissue inhibitor of metalloproteinases-1 is a glycoprotein , which regulates metalloproteinases and may consequently imply a central role in tumour progression .
4 Furthermore , it is closely related to the EGFR regulation and has shown promising potential as a biomarker in colorectal cancer ( CRC ) .
5 The aim of the present study was to investigate the clinical value of TIMP-1 in patients with metastatic colorectal cancer ( mCRC ) treated with cetuximab and irinotecan .
6 Patients with chemotherapy-resistant mCRC referred to third - line treatment with cetuximab ( initial 400 mg/m(2) followed by weekly 250 mg/m(2) )/irinotecan ( 350 mg/m(2) q3w ) were prospectively included in the biomarker study , as previously published .
7 Pre-treatment blood samples were collected , and plasma TIMP-1 was measured by a validated in-house ELISA assay .
8 In addition , carcinoembryonic antigen ( CEA ) measurement was performed with a standardised method .
9 A total of 107 patients were included in the biomarker study .
10 The median baseline plasma TIMP-1 level was 271.1 ng/ml ( range 659-1432 ng/ml ) with no significant associations with baseline clinical characteristics .
11 ✓ Median baseline plasma TIMP-1 levels were significantly higher in patients with early progression compared to patients who achieved disease control , 349 ng/ml ( 233-398 95 % confidence interval ( CI ) ) and 215 ng/ml ( 155-289 95 % CI ) , respectively , p = 0.03 , suggesting some association with treatment efficacy . GE-ASS-RO
12 When dividing patients according to TIMP-1 tertiles , the median progression-free survival ( PFS ) in patients with a high level of TIMP-1 was 2.4 months ( 95 % CI 21-41 ) compared to 3.3 months ( 95 % CI 21-62 ) and 4.7 months ( 95 % 32-76 ) in patients with intermediate or low levels , respectively .
13 Analysis of TIMP-1 as a continuous variable revealed a shorter PFS associated with increasing levels of TIMP-1 (hazard ratio ( HR ) 1.36) .
14 These results translated into a significantly lower overall survival ( OS ) in patients with a high baseline TIMP-1 level ( 4.5 months ( 95 % CI 34-54 ) ) , compared to those with intermediate or low TIMP-1 levels ( 7.8 months ( 95 % CI 44-137 ) and 12.0 months ( 95 % CI 101-143 ) , respectively , p <0.0001 ) .
15 An 83 % higher hazard for death was revealed ( HR = 183 ) with each twofold increase in the TIMP-1 level .
16 Pre-treatment levels of CEA were not associated with any of the baseline characteristics ( except primary tumour localisation ) or to differences in PFS or OS .
17 The rank correlation between CEA and TIMP-1 was r = 0.50 , and a test for interaction between TIMP-1 and CEA ( dichotomised at 5 ng/ml ) in survival analysis was not significant ( p = 018 ) .
18 A multivariate analysis for PFS and OS resulted in a model with significant contributions from TIMP-1 , KRAS , and the number of metastatic sites .
19   We have confirmed the potential prognostic value of TIMP-1 measurement prior to palliative chemotherapy for mCRC .
20 However , validation in randomised trials will be essential with the perspective of establishing a potential predictive role of plasma TIMP-1 in this setting .



PMID: AACR_2013-3381
(Cell)  
Terms: in vitro, PDX, xenograft, tumor xenografts
Sent# Symbols Sentence Mnemonics
0 Overcoming resistance to BRAF inhibitors in colon cancer and melanoma cell lines. .
1 Mutations in the B-raf oncogene constitutively activate the RAF-MEK-ERK signaling pathway , a key regulator of cell proliferation and survival .
2 The most common BRAF mutation (V600E) occurs in approximately 70% of primary melanomas and 10% of colorectal cancers .
3 Μ Melanoma patients carrying the BRAF (V600) mutation respond with frequency of 80% to the BRAF inhibitor vemurafenib , while colon cancer patients respond at a rate of 5% only , indicative of intrinsic resistance .
4 Moreover , clinical benefit is further limited by the rapid emergence of acquired resistance among vemurafenib responders .
5 Combination therapy targeting both BRAF (V600E) and possible escape pathways appears to be a promising approach to reverse resistance to BRAF inhibitors .
6 Here , we present the molecular characterization and in vitro chemosensitivity profiles of 20 melanoma and 20 human colorectal cancer cell lines .
7 Four of the colon and 11 of the melanoma cell lines were established at Oncotest from patient-derived tumor xenografts ( PDX ) .
8 Molecular profiles include the mutation status of BRAF , PIK3CA , KRAS , and NRAS ( exon sequencing ) and protein levels for components of the MAPK , EGFR and PI3K/AKT pathways ( Western blot analysis ) .
9 Sensitivity profiles for inhibitors of BRAF , MEK , EGFR and PI3K were determined in vitro using a fluorescence-based survival and proliferation assay .
10 Overcoming resistance to BRAF inhibitors was investigated by combination of vemurafenib with other inhibitors of the RAF-MEK-ERK pathway or inhibitors of potential escape pathways like EGFR , PI3K/AKT or c-MET and evaluated by combination index according to Chou-Talalay .
11 Μ In line with the clinical situation , the BRAF V600E substitution was found in 13/20 ( 65% ) of the melanoma and only in 4/20 ( 20% ) of the colon cancer cell lines .
12 BRAF and NRAS mutations were mutually exclusive in melanoma cell lines and KRAS mutations did not occur at all .
13 Among the colon cancer cell lines , in addition to the BRAF ( v600E ) mutation , alteration in KRAS ( 10/20 cell lines ) , PIK3CA ( 6/20 ) and NRAS ( 1/20 ) were detected .
14 ✓ Chemosensitivity profiling revealed intrinsic resistance to BRAF inhibitors for 3/13 ( 23% ) BRAF ( V600E ) melanoma cell lines and for 3/4 ( 75% ) BRAF ( V600E ) colon cancer cell lines .
15 Reversal of the resistance of BRAF inhibitor -insensitive melanoma cell lines was recorded as synergism between vemurafenib and inhibitors of vasious kinases ( c-MET , AKT , PI3K , MEK , or EGFR .
16 A particularly strong synergistic interaction was found for vemurafenib and the c-MET inhibitor SU11274 , irrespective of BRAF status .
17 For colon cancer cell lines , the strongest synergisms were detected for the combinations of vemurafenib with inhibitors of c-MET , EGFR , PI3K , AKT and MEK .
18 Displaying similar mutation and chemosensitivity profiles as melanomas and colon cancers in the clinic , the present cell line panels represent valuable tools to investigate the reversal of resistance towards BRAF inhibitors .



PMID: ASCO_43481-74
(Patient)  
Terms: NCT00004150, retrospective
Sent# Symbols Sentence Mnemonics
0 Lessons from PETACC 2 : No prognostic impact of KRAS-/BRAF-status in stage III colon cancer treated with adjuvant 5-FU monotherapy. .
1 Background : KRAS and possibly BRAF mutations are negative predictors for anti-EGFR therapy in colorectal cancer .
2 The prognostic impact of these mutations is less clear .
3 This study aimed to assess the correlation of KRAS/BRAF status with morphological characteristics and its prognostic impact for long-term outcome in UICC stage III colon cancer ( CC ) .
4 Methods : FFPE material from 493 patients treated with adjuvant 5-FU/FA in the PETACC2 trial ( ClinicalTrialsgov NCT00004150 ) was collected retrospectively .
5 Μ KRAS mutations were detected by direct sequencing ( ABI Prism 310 ) , BRAF mutations by pyrosequencing ( Pyromark Q24 ) .
6 Statistical analysis was done using Fisher exact test and Kaplan Meier survival analyses ( level of significance : 005 ) .
7 Results : Neither KRAS nor BRAF mutations were associated with patient age or patient sex .
8 KRAS mutations did also not correlate with any pathological parameters .
9 BRAF mutations , however , were significantly more frequent in mucinous ( n = 12/45 ; 267% ) than in nonmucinous carcinomas ( n = 36/408 ; 88% , p = 0001 ) .
10 Μ BRAF mutations were also associated with higher pT stage ( p = 0016 ) : while pT1 and pT2 tumors showed BRAF mutations in 0 ( n = 0/13 ) and 5.1% ( n = 2/39 ) , pT3 and pT4 tumors showed them in 9.2% ( n = 32/347 ) and 20.2% ( n = 17/84 ) .
11 BRAF-mutation frequency increased with decreasing histologic differentiation ( p = 0002 ) : only 1.9% of grade 1 ( n = 1/35 ) and 8.2% of grade 2 ( n = 26/316 ) whereas 18.8% of the grade 3 tumors ( n = 24/128 ) had a BRAF mutation .
12 Μ Location in the right-sided colon was correlated with BRAF mutation ( p = 0034 ) : 15.4% of the right-sided tumors ( n = 23/149 ) showed a mutation as opposed to 8.4% of the left sided tumors ( n = 25/298 ) .
13 ✓ Neither KRAS nor BRAF status showed any impact on disease-free and overall survival in univariate analyses . GE-ASS-RO
14 After 3 years , 63% of the patients with KRAS mutation , 68% with KRAS/BRAF wildtype (HR 089) and 65% with BRAF mutation (HR 108) were still alive .
15   Conclusions : KRAS/BRAF status has no prognostic impact in stage III CC treated with adjuvant 5-FU/FA therapy .
16 While BRAF mutations are associated with tumor location , histological type , differentiation and pT stage , KRAS mutations are not .



PMID: ASCO_94963-114
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer. .
1 Background : Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer .
2 To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western , we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment .
3 Methods : We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009 .
4 Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing .
5 Microsatellite instability ( MSI ) status was determined by genotyping in the 5 loci .
6 Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated .
7 Μ Results : KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients , respectively .
8 ✓ KRAS mutation was correlated with poor recurrence free survival ( RFS ) ( p = 003 ) , especially in stage II patients ( p = 0007 ) . GM-ASS-RO
9 BRAF mutation was significantly correlated with the anatomical site of tumor ( p < 0001 ) , tumor grade ( p = 0001 ) and high frequency of microsatellite instability ( p < 0001 ) .
10 ✓ BRAF mutation was also correlated with poor overall survival in all cases of patients ( p = 0009 ) . GM-ASS-RO
11 Overall , the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese .
12 However , KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC .
13 ✓ Conclusions : Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer . GM-INV-RO, GE-INV-RO
14   These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy .



PMID: ASCO_32298-65
(None)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 EGFR gene copy number , KRAS and BRAF status , PTEN and AKT expression analysis in patients with metastatic colon cancer treated with anti-EGFR monoclonal antibodies chemotherapy. .
1 Background : Cetuximab and panitumumab have proven to be effective in metastatic colon cancer ( mCRC ) .
2 Μ KRAS mutation has been demonstrated to be a biomarker of resistance to both monoclonal antibodies .
3 However the status and expression of other biomarkers of the RAS-RAF-MAPK signalling pathway can have a crucial role in sensitivity to anti-EGFR monoclonal antibodies .
4 Methods : We have retrospectively analyzed tumor tissue biomarkers including EGFR gene copy number ( GCN ) by FISH , KRAS and BRAF status by PCR-based sequencing , PTEN and AKT expression by IHC in patients with mCRC treated with cetuximab and panitumumab chemotherapy .
5 Response to treatment , TTP and OS were evaluated .
6 Results : Sixty-three patients ( pts ) have been analyzed .
7 Median age was 59 years ( 34-80 ) ; 53 pts had received cetuximab and 10 pts panitunumab .
8 Concomitatnt chemotherapy was FOLFIRI , CPT-11 , FOLFOX4 and Xeliri in 35 , 13 , 6 and 4 pts respectively .
9 Five pts had received monoclonal antibodies only .
10 Twenty - one pts were treated in 1st-2nd line and 42 pts in 3rd-4th line .
11 So far EGFR GCN is available on 55 pts , KRAS and BRAF on 63 pts , PTEN in primary tumor ( PT ) on 36 pts and in metastatic ( MTS ) site on 24 pts , AKT on 19 pts .
12 EGFR/nuclei ratio was > 2.9 in 31 % of the pts , KRAS and BRAF were mutated in 36.5 % and 3 % of the pts respectively ; PTEN was positive in 42 % and 79 % in PT and MTS respectively .
13 Moreover 21.8 % of the pts had EGFR/nuclei > 2.9 and CEP7 Polisomy > 50 % .
14 Four pts achieved a partial remission ( 63 % ) .
15 Partial response rate was 17 % vs. 2.6 % in pts with high and low EGFR GCN respectively ( p : 0.007 ) and 13 % vs. 2.5 % in pts with WT and mutated KRAS respectively ( p : 0.048 ) .
16 Median TTP was 3 months ( 083-329 ) .
17 It was 4.2 vs. 2.3 mos in pts with WT and mutated KRAS respectively ( p : 0.001 ) .
18 Median OS was 9.7 mos ( 203-490 ) and no statistically significant differences were observed according to the biomarkers status .
19 However a trend was observed for pts with KRAS WT 10.6 vs. 7.8 mos and for PTEN positive in PT : 9.0 vs. 5.67 mos .
20 Conclusions : Our data confirm the predictive role of EGFR gene copy number and KRAS status on the response and survival .
21 Complete biomarker characterization is ongoing and an analysis for interaction will be performed .



PMID: ASCO_80710-102
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Influence of KRAS and BRAF mutational status and rash on disease-free survival ( DFS ) in patients with resected stage III colon cancer receiving cetuximab ( Cmab ) : Results from NCCTG N0147. .
1 Background : Mutation ( mut ) of KRAS and BRAF negatively influence response to Cmab in metastatic colorectal cancer with the possible exception of KRAS Gly13Asp ( JAMA 304 : 1812 ) .
2 Incidence of rash has served as a biomarker of a positive response to Cmab .
3 N0147 assessed FOLFOX alone ( arm A ) or with Cmab ( arm D ) in resected stage III colon cancer .
4 Impact of KRAS and BRAF mut status , and rash , on 3 yr DFS was assessed individually and jointly .
5 Methods : Tissue from patients ( pts ) enrolled in N0147 was evaluated for mut in KRAS using the DxS mutation test kit KR-03/04 assessing for 7 different potential mut in codons 12 and 13 .
6 The V600E BRAF mut was assessed using an automated sequence technique .
7 CTCAE v3.0 was used to classify and grade skin rash .
8 Results : 2,580 pts were evaluable for KRAS analysis ; 2516 for BRAF .
9 See table for DFS based on KRAS and BRAF status .
10 Pts with wtKRAS and wtBRAF had a DFS of 76% and 72% in arms A and D , respectively. 9% of pts treated with Cmab had Gr 3+ rash , with a nonsignificant trend toward increased DFS with rash in wtKRAS and wtBRAF groups ( 3 yr DFS in pts with rash 76% versus no rash 69% , p = 026 ) .
11 Conclusions : Pts with wtKRAS and wtBRAF did not benefit from Cmab added to FOLFOX .
12 None of the different KRAS mut predicted improved DFS with Cmab .
13 DFS for pts with mutBRAF was similar to that for mutKRAS .
14 Gr3+ rash was associated with some trend toward improved DFS with Cmab .
15 Supported by NIH Grant CA25224 , Bristol-Myers Squibb , ImClone , Sanofi-Aventis , and Pfizer .



PMID: AACR_2013-5586
(Patient)  
Terms: ex vivo
Sent# Symbols Sentence Mnemonics
0 Interpatient differences in colon tumors reflected in kinase activity and inhibition profiles related to KRAS and BRAF mutation status. .
1 Background .
2 Due to the biological heterogeneity , response to systemic therapy is variable in colon cancer .
3 Chemotherapy improves median survival from 6-12 months to 18-24 months .
4 Epidermal growth factor receptor ( EGFR ) antibodies have shown to improve survival , although modest , even further .
5 Μ KRAS mutations were identified as negative predictive markers for EGFR directed therapy .
6 The response rate to EGFR targeted therapy remains low .
7 Therefore there is an urgent need to find additional therapeutic options and accompanying biomarkers .
8 The analysis of kinase activity in colon tumors may yield tumor-specific information on aberrant cell signaling pathways and may be usefull in a better patient stratification .
9 Aim of this study is to generate overall kinase activity profiles from colon cancer tissues to explore if subtypes of this cancer show distinct kinase activity profiles .
10 This can help to find new therapeutic options or predictive markers for response to therapy .
11 Methods .
12 Normal and tumorous colon tissue from patients who had given informed consent was fresh frozen after surgical resection .
13 Μ All tumor specimens were analyzed for BRAF and KRAS mutation status .
14 Tissue cryosections were lysed in buffer with phosphatase and protease inhibitors .
15 Tyrosine kinase (PTK) and serine/threonine kinase ( STK ) activity profiles of normal and tumor tissue were generated on PamChip peptide microarrays comprising peptide sequences derived from known human phosphorylation sites .
16 The ex vivo effect of kinase inhibitors on these kinase activity profiles was also determined .
17 Peptide phosphorylation was monitored using fluorescently labeled antibodies .
18 Data were analysed with Bionavigator software .
19 Results .
20 Tumor tissue has a higher PTK activity than normal tissue , whereas STK activity was equal to or lower than in normal tissue .
21 STK activity profiles of 23 colon tumors could not be grouped according to mutation status , percentage of tumor tissue , differentiation grade or TNM classification .
22 The STK activity profiles showed that within the group of wild type KRAS tumors , clearly different clusters were found .
23 In the group with KRAS mutations ( G12V , G12D , G12C , G12R ) the STK activity profiles differed between the tumors .
24 A subset of tumors , ( two KRAS mutants , a BRAF mutant and a WT tumor ) were tested ex vivo with a selection of 11 kinase inhibitors and showed different sensitivity to these inhibitors .
25 Conclusions .
26 Kinase activity and the response to inhibitors can be measured ex vivo in colon tumor tissue to capture the diversity in kinase activity and response to inhibitors between patients .
27 The differences in kinase activity profiles of colon cancer samples could not be explained by subtypes according to mutation ( KRAS , BRAF ) status .
28 Interesting subclusters could be identified using the kinase activity profiling providing a higher granularity than KRAS mutation scoring allows .



PMID: ASCO_126870-144
(Patient)  
Terms: clinical trial
Sent# Symbols Sentence Mnemonics
0 Prognostic value of KRAS exon 2 gene mutations in stage III colon cancer : Post hoc analyses of the PETACC8 trial. .
1 Background : Prognostic value of KRAS mutations in resected colon adenocarcinoma remains debated .
2 We examined the prognostic impact of KRAS exon 2 mutations in stage III patients receiving adjuvant FOLFOX + /- cetuximab patients from the PETACC8 Phase III trial .
3 Methods : KRAS exon 2 mutations in codon 12 ( pG12V , pG12R , pG12S , pG12A , pG12C , pG12D ) and codon 13 ( pG13D ) were examined in all patients with available material and signed translational research informed consent enrolled in the PETACC8 trial .
4 Analyses were restricted to BRAF wild type tumors , since the prognostic impact of BRAFV600E in this population has already been described .
5 Because no benefit or deleterious effect from adjuvant cetuximab was reported in this trial , tumors from both study arms were pooled for analysis .
6 Association between time to recurrence ( TTR ) and disease-free survival ( DFS ) and type of KRAS mutation was evaluated using Cox proportional hazard model .
7 Μ Results : KRAS mutations were found in 638/1657 tumors , including 502 codon 12 and 136 codon 13 alterations .
8 KRAS mutations in codon 12 ( HR : 1.67 ; 95% confidence interval [CI] [135-204] ; P < 0.001 ) but not in codon 13 ( HR : 1.23 ; 95% confidence interval [CI] [085-179] ; P = 0.26 ) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors , independently of other covariates .
9 Similar results were found for DFS .
10 Μ When anatomic sites were taken into account , the impact of KRAS mutations on TTR was only found for distal tumors ( n = 1043 ) with an increased risk of relapse ( HR : 1.96 ; 95% confidence interval [CI] [151-256] ; P < 0.0001 ) for KRAScodon 12 mutated tumors and a trend for codon 13 ( HR : 1.59 ; 95% confidence interval [CI] [100-256] ; P = 0.051 ) , as compared to KRAS/BRAFwild type patients .
11 Similar results were found for DFS .
12 ✓ Conclusions : KRAS exon 2 mutations are independent predictors of TTR or DFS for patients with stage III distal colon cancer receiving adjuvant therapy . GM-MRK-RO
13 Future clinical trials in the adjuvant setting should consider tumor location and type of KRAS mutation as important stratification factors .



PMID: AACR_2014-2820
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Clinical significance of low frequency KRAS and BRAF subclones for advanced colon cancer management .
1 Alongside conventional chemotherapies , targeted treatments have significantly improved the survival of patients with metastatic colorectal cancer ( mCRC ) from 6 months with best supportive care treatment , to 24 months with a combination of conventional and targeted chemotherapies .
2 However , patients with KRAS mutated tumors have little or no benefit from these anti-EGFR antibodies based therapies ( Panitumumab , Cetuximab ) as single agents or combined with chemotherapy .
3 These findings led to an amendment of the Marketing Authorization of these drugs that are now restricted to patients with KRAS wild-type tumor .
4 However , the response of these patients ranged from 40 to 60% .
5 Recent works have demonstrated that secondary resistance to such therapies was associated with emergence of KRAS mutated subclones in KRAS wild-type patients at the diagnosis time .
6 To understand the importance of KRAS mutant subclones at the diagnosis time and to evaluate the consequence of their presence in terms of management of mCRC patients , a highly sensitive and quantitative procedure is required .
7 Droplet-based digital PCR has recently emerged as a highly sensitive and quantitative approach for rare sequence detection .
8 A retrospective study was set up where tumor samples from 177 mCRC patients were analyzed using a multiplex highly sensitive droplet-based procedures and ultra-deep sequencing using a new droplet-based target enrichment .
9 Results are compared with data obtained by conventional qPCR .
10 Sixty-two patients were classified as responders according to RECIST criteria .
11 Μ All tumors ( 41 ) detected as positive using conventional procedures were also positive with our procedure .
12 Μ Among the samples detected as negative with conventional procedures , 23 presented a KRAS or a BRAF mutation only detected by droplet-based procedures and 6 presented additional subclones .
13 Μ For 20 patients , additional biopsy samples were available and presented comparable results. 167 samples were also submitted to deep sequencing and , for alleles detected at fractions superior to 1% , the mutational status of the sample were in agreement for 94% of the samples ( 157/167 ) and we observed a correlation with the observed fraction of mutant alleles with the two procedures ( R2= 07 ) .
14 Μ We observed an inverse correlation between the proportion of mutated DNA and the frequency of anti-EGFR responses ( P< 00001 ) .
15 The mean percentage of mutated DNA was 0.45% and 12.7% for responders and non-responders respectively .
16 ✓ Progression Free Survival of patients was significantly different depending on the percentage of KRAS mutated allele within the tumor . RO-ASS-GM
17 The Progression Free Survival of patients with tumor presenting less than 5% of mutated KRAS was comparable to the one of non-mutated patients .
18 HRs were of 1.07 ( CI95% 06-2 , NS ) , 2.9 ( CI95% 17-49 , P < 0001 ) , 3.6 ( CI95% 22-58 , P < 0001 ) for patients with tumor containing less than 5% , between 5 and 25% or more than 25% of mutated DNA respectively .



PMID: AACR_2014-1502
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A rapid and fully automated multiplex assay for KRAS-BRAF mutations with high mutation sensitivity using novel selective amplification and detection technologies .
1 IntroductionThe MAPK/ERK pathway is a complex signaling cascade involved in many cancer types .
2 KRAS and BRAF gene mutations are present in a number of cancers , including colon , lung and pancreas , and identification of mutations in these genes is of great importance in clinical diagnostics .
3 Moreover , there is a growing demand for performing multiple tests simultaneously on a single sample and there is an increased need to provide these answers to oncologists in a short timeframe .
4 MethodsIdyllaTM is a fully integrated and automated molecular diagnostics platform (1) that combines speed and ease of use with high sensitivity and high multiplexing capabilities .
5 Moreover , it overcomes the current time-consuming step of processing formalin-fixed paraffin-embedded tissue ( FFPE ) samples .
6 After insertion of a single FFPE slice into the cartridge , the complete process of sample preparation , real-time PCR and reporting is fully automated and takes less than 2 hours .
7 We present here a KRAS-BRAF mutations prototype assay that allows the sensitive detection of 13 KRAS mutations and 5 BRAF mutations in one single assay .
8 The assay discriminates the individual mutations at codons 12 , 13 and 61 of KRAS and codon 600 of BRAF using novel Primer Assisted Sequence Switching ( PASS ) primers along with Multi-component Nucleic Acid enzyme ( MNAzyme ) detection .
9 Μ These technologies confer advantages for multiplex mutation analysis ; PASS primers selectively amplify the target sequences of interest resulting in enhanced specificity between wild type ( WT ) and mutant , and between mutants , and MNAzymes allow for efficient detection and discrimination of multiple mutations simultaneously .
10 ResultsSeveral performance characteristics of the IdyllaTM KRAS-BRAF prototype assay were examined : specificity , cross-reactivity , sensitivity and performance on clinical samples .
11 Specificity of mutant versus WT as well as cross-reactivity between individual mutations at each codon was evaluated .
12 Results demonstrated excellent specificity and cross-reactivity for all individual targets , with delta Cq values of >7 between mutants and >12 between mutant and WT .
13 Sensitivity was assessed using cell lines embedded in FFPE containing defined ratios of mutants and dilutions of these in FFPE WT background .
14 The results indicated sensitivities of <1% of mutant allele .
15 The performance of the IdyllaTM KRAS-BRAF prototype assay was evaluated on a set of colon cancer and melanoma FFPE samples characterized by Sequenom MassARRAY , Illumina MiSeq , or Biocartis IdyllaTM BRAF-only assay which demonstrated a >96 % concordance .



PMID: AACR_2012-1151
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 cMYC amplification in colon cancer : A novel association with BRAF V600E and proficient DNA mismatch repair .
1 Background : Colon cancer is categorized by the acquisition of a number of molecular alterations in both oncogenes and in tumor suppressor genes .
2 Although cMYC alterations have been reported in colon cancer cell lines , little other information exists in primary colon tumors .
3 We sought to determine the frequency of cMYC amplification in primary colon cancer and its relationship to other well defined colon tumor alterations .
4 Methods : An initial set of 392 tumors were evaluated .
5 All samples were tested for the BRAF V600E mutation and all were classified as proficient mismatch repair ( pMMR ) based on both IHC and microsatellite analysis of tumor tissue .
6 A second set of 522 tumors was selected to replicate associations identified in the first set of samples .
7 Similar to the initial cohort , both the BRAF V600E and the mismatch repair status of the tumors were assessed .
8 The second cohort , however , included tumors that were both pMMR and dMMR .
9 In both sets of samples , fluorescent in situ hybridization was used to evaluate cMYC gene amplification .
10 Μ Results : In cohort 1 , cMYC amplification was observed in 15 of the 362 ( 4% ) pMMR tumors successfully analyzed ( Table 1 ) .
11 Μ cMYC amplification was detected in 10 of 323 ( 3% ) tumors with normal BRAF status vs. 5 of 39 ( 13% ) tumors with altered BRAF status ( p = 0015 ) .
12 Μ In the second cohort , cMYC amplification was found in 20 of the 522 ( 4% ) tumors .
13 Only 1 of the 152 ( <1% ) dMMR tumors had cMYC amplification vs. 19 of the 370 ( 5% ) pMMR tumors ( p = 0012 ) .
14 Μ Of the pMMR tumors , cMYC amplification was detected in 13 of 333 ( 4% ) tumors with normal BRAF status vs. 6 of 37 ( 16% ) tumors with altered BRAF status ( p = 0007 ) , nearly identical to the first group .
15 Conclusion : cMYC amplification in colon cancer is an infrequent event .
16 However , when present , cMYC amplification occurs almost exclusively in tumors that are pMMR .
17 Additionally , among pMMR tumors , cMYC amplification is associated with the presence of the BRAF V600E mutation .



PMID: ASCO_34539-65
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 KRAS mutation , cancer recurrence , and patient survival in stage III colon cancer : Findings from CALGB 89803. .
1 ✓ Purpose : KRAS mutation in stage IV colorectal cancer predicts resistance to anti-EGFR targeted treatment ( cetuximab or panitumumab ) .
2 However , whether the presence of KRAS mutation independently predicts the survival of colon cancer patients remains uncertain .



PMID: AACR_2015-3188
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MEK and TAK1 signaling interactions coordinately regulate inflammation and apoptosis in KRAS dependent colon cancer cells .
1 The KRAS protooncogene is mutated in 40 to 50% of colon cancers .
2 In an effort to identify strategies to treat KRAS mutant colon cancers , we previously implicated the TGF - activated kinase ( TAK1 ) as a candidate therapeutic target that promotes the survival of KRAS dependent cancers .
3 In follow-up studies , we have explored and investigated the detailed mechanistic basis for TAK1 mediated survival signaling in KRAS dependent cancer cells .
4 Using proteomic and transcriptomic analyses of proinflammatory signaling mediators , we have uncovered complex autocrine/paracrine signaling loops that are constitutively activated in KRAS dependent colon cancer cells .
5 A central mediator of these signaling loops is the BMP7-BMP receptor ( BMPR1A ) pathway , which functions coordinately with oncogenic KRAS to drive TAK1 and NF-B mediated transcriptional upregulation of proinflammatory cytokines such as GM-CSF , CCL5/RANTES and IL-8 .
6 Conversely , a number of cytokines and cytokine regulators are negatively regulated by KRAS-BMPR signaling interactions , including CXCL9/MIG and IL1RN .
7 We previously showed that TAK1 inhibition with a small molecule agent , 5Z-7-oxozeaenol promotes apoptosis in colon cancer cells .
8 We have now determined that 5Z-7-oxozeaenol , in addition to irreversibly inhibiting TAK1 kinase activity , also transiently inhibits the MEK kinase .
9 Therefore , combined TAK1/MEK inhibition explains the potent killing effects that we have observed in KRAS dependent colon cancer cells .
10 To test this empirically , we have used 2 selective kinase inhibitors targeting each respective kinase , AZ-TAK1 and AZD6244 to show either single agent can induce apoptotic cell selectively in KRAS dependent cells , with TAK1 inhibition resulting in stronger killing effects .
11   Importantly , treatment of KRAS dependent colon cancer cells with combinations of AZ-TAK1 and AZD6244 results in additive killing effects , revealing a potential therapeutic strategy for KRAS dependent cancers in the clinic .
12 Mechanistically , MEK and TAK1 converge on the control of NF-B and canonical Wnt -dependent transcriptional activities .
13 Surprisingly , we find that NF-B and Wnt signaling mutually antagonize each other in terms of cytokine expression to create a finely-tuned balance between pro-death and pro-survival signals .
14 We hypothesize that , as a consequence , these balanced signals allow for both efficient maintenance of tumor cell survival and as well as for communication with stromal components in the tumor microenvironment .
15 Thus , KRAS , MEK or TAK1 blockade results in a tipping of the balance to favor pro-death signals .



PMID: AACR_2014-2602
(None)  
Terms: in vivo, in vitro, xenograft
Sent# Symbols Sentence Mnemonics
0 KRAS G12D and G12V specific alkylating agent ( KR12 ) inhibits growth of colon cancer with those KRAS mutations in vitro as well as in vivo .
1 Despite extensive efforts to develop chemotherapeutic drugs targeting mutated RAS , the successful drug discovery , especially targeting KRAS codon 12 mutation , has never been made .
2 Μ We have found that Pyrrole-Imidazole polyamide seco-CBI conjugate ( KR12 ) selectively recognized mutated KRAS sequence (ACGCCT-A/T-CA) at codon 12 and significantly suppressed tumor growth specifically in human colon cancer cells with G12D or G12V mutation .
3 KRAS expression suppressed preferentially at mutated allele and active KRAS were markedly reduced .
4 Μ G2/M arrest , senescence and subsequent apoptosis by activating the p53 pathway were observed in KR12-exposed LS180 cells with G12D heterozygous mutation .
5   In LS180 and SW480 ( G12V homozygous mutation ) xenograft colon cancer models , KR12 treatment induced massive tumor growth suppression with low host toxicity .
6 Collectively , our current results strongly suggest that KR12 is a specific alkylating agent against KRAS codon 12 mutations , and could become a powerful candidate compound for the unmet need of KRAS-mutant tumor treatment .



PMID: AACR_2013-5459
(Cell)  
Terms: Phase II, clinical trial
Sent# Symbols Sentence Mnemonics
0 Molecular mechanisms of dysregulated GLI activation in Hedgehog ( HH )- dependent survival in human colon cancer. .
1 In normal cellular processes the canonical Hedgehog ( HH ) pathway signals via the transmembrane receptor PTCH , intermediary molecule SMO , and activates the proteins GLI1 and GLI2 , which transcriptionally regulate HH target genes .
2 In colon cancer , HH signaling is aberrantly regulated , driving cell survival and genomic instability in oncogenesis , progression and metastasis .
3 Oncogene -driven signaling pathways , specifically KRAS/BRAF in colon cancer , circumvent the HH/SMO axis to converge on and activate GLI .
4 Using a small molecule inhibitor of GLI1/GLI2 transcription , GANT61 , we have demonstrated : 1 ) inhibition of HH signaling at the level of GLI1 and GLI2 by GANT61 induces extensive cell death in human colon carcinoma cell lines in contrast to targeting SMO ; 2 ) cells with acquired resistance to SMO inhibitors remain highly sensitive to GANT61 ; 3 ) oncogenic KRAS/BRAF signaling activates GLI transcription , inhibited by GANT61 .
5 These findings thus delineate GLI as a critical target in colon cancer .
6 HT29 (BRAFV600E mutant) , SW480 ( KRASG12V mutant ) and HCT116 ( KRASG13D mutant ) cells are sensitive to the MEK inhibitor , AZD6244 , a novel , selective , ATP-uncompetitive inhibitor of MEK1/2 currently in Phase II clinical trial .
7 Μ AZD6244 inhibited transcription of GLI2 , but not GLI1 ( mRNA expressed at low level ) , suggesting integration of oncogenic KRAS/BRAF signals at the level of GLI2 transcription .
8 In experiments with the protein synthesis inhibitor cycloheximide , MG132 ( proteasome inhibitor ) , and AZD6244 , stabilization of GLI1 and GLI2 was determined not to be a mechanism of MEK/ERK -dependent GLI activation in HT29 cells .
9 The ZIC2 transcription factor effects translocation of GLI proteins to the nucleus and regulates GLI transcriptional activity .
10 GLI1 and GLI2 proteins co-immunoprecipitated with ZIC2 in HT29 cells .
11 Further , ZIC2 was extensively bound to the promoters of GLI1 and GLI2 , and binding was significantly reduced by AZD6244 ( ChIP analysis ) .
12 ZIC2 -dependent transcriptional regulation requires phosphorylation ( p-ZIC2 ) by DNA-dependent protein kinase catalytic subunit ( DNA-PKcs ) .
13 The DNA-PKcs inhibitor , NU7441 , inhibited GLI2-luciferase reporter activity .
14 How GLI activation is regulated in cancer cells remains poorly understood , yet GLI marks an important target in cancer biology .
15 We propose a model in which oncogenic KRAS/BRAF regulates GLI2 transcription involving ZIC2 , which is phosphorylated by DNA-PKcs and regulated by ERK .
16 Using drugs that inhibit GLI1/GLI2 transcription and studies of GLI activation in oncogenesis , these findings will provide new insights into critical targets that determine HH -dependent survival , and for the translation of drugs that target dysregulated HH signaling in cancer .



PMID: AACR_2017-3066
(Cell)  
Terms: xenograft
Sent# Symbols Sentence Mnemonics
0 Inhibition of hsp90 by auy922 preferentially kills mutant KRAS colon cancer cells by activating Bim through ER stress. .
1 Colon cancer is one of the most common and deadly malignancies (1) .
2 Despite recent advances in early diagnosis and the development of molecularly targeted therapy , the overall survival of patients with metastatic colon cancers remains disappointing (1) .
3 This is often associated with resistance of colon cancer cells to systemic therapies resulting from oncogenic mutations of KRAS that drive activation of multiple downstream signalling pathways important for cell survival and proliferation .
4 Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the heat shock protein 90 ( HSP90 ) inhibitor AUY922 than those carrying wild-type KRAS .
5 Although AUY922 inhibited HSP90 activity with the comparable potency in colon cancer cells irrespective of their KRAS mutational statuses , those with activating mutations of KRAS were markedly more sensitive to AUY922 -induced apoptosis .
6 This was associated with upregulation of the BH3 only proteins Bim , Bik , and PUMA .
7 However , only Bim appeared essential , in that knockdown of Bim abolished , whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922 .
8 Mechanistic investigations revealed that endoplasmic reticulum ( ER ) stress was responsible for AUY922 -induced upregulation of Bim , which was inhibited by a chemical chaperone or overexpression of GRP78 .
9 Conversely , siRNA knockdown of GRP78 or XBP-1 enhanced AUY922 -induced apoptosis .
10 In addition , AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress .
11   Taken together , these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers , and that agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy .



PMID: ASCO_170068-176
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of right-sided colon cancer with poor efficacy of cetuximab in patients with RAS wild-type metastatic colorectal cancer. .
1 Background : Right-sided colon cancer ( RC ) is distinct from left-sided colorectal cancer ( LC ) in terms of embryology , pathology and genetics .
2 Previous reports have shown that RC have more KRAS and BRAF mutations and poorer clinical outcomes than LC .
3 We investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type ( WT ) metastatic colon cancer determined by extended RAS genotyping .
4 Methods : Extended RAS analysis by SequenomMassARRAY technology platform ( OncoMap ) targeting KRAS ( exon 2 , 3 , 4 ) , NRAS ( exon 2 , 3 , 4 ) , PIK3CA and BRAF ( exon 15 ) was performed in tumors from 307 patients treated with cetuximab as salvage treatment .
5 Tumors with mutated RAS ( n = 127 ) and synchronous primary tumors ( n = 10 ) were excluded .
6 The border of right-sided colon and left-sided colon was defined as splenic flexure .
7 Results : A total of 170 patients were included ( RC versus LC , 23 and 147 ) .
8 More mutant BRAF ( 391% vs. 54% ) , poorly differentiated ( 174% vs. 34% ) and mutant PIK3CA ( 13% vs. 14% ) tumor and peritoneal involvement ( 261% vs. 88% ) were observed in RC .
9 Progression-free survival ( PFS ) was significantly shorter in RC ( 20 versus 49 months , P = 0004 ) .
10 Overall survival ( OS ) was 4.1 months in RC and 13.0 months in LC ( P = 0002 ) .
11 ✓ In multivariate analysis , BRAF mutations , RC , poorly differentiated histology and peritoneal involvement were associated with shorter overall survival ( adjusted hazard ratios , 296 , 163 , 297 and 212 , respectively ) . GM-ASS-RO
12 Conclusions : In RAS WT colon cancer treated with cetuximab as salvage treatment , right-sided colon cancer had a poor survival .
13 Further investigation is required to verify the difference in cetuximab efficacy according to primary site of metastatic colorectal cancer .



PMID: AACR_2014-2232
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Next generation sequencing of the EGFR signaling pathway in colon cancer tumors from Chilean patients .
1 Introduction : The Epidermal Growth Factor Receptor ( EGFR ) signaling pathway regulates key cell functions like proliferation and survival .
2 This pathway presents two signaling cascades , RAS/RAF/MAPK and PIK3/PTEN/AKT/mTOR .
3 Mutations in different components of the EGFR pathway have been described in different cancers .
4 This pathway is a therapeutic target for monoclonal antibodies and tyrosine kinase inhibitors based therapies .
5 Additionally , in advanced colorectal cancer patients , somatic KRAS mutations are response predictors for biological therapy with anti-EGFR antibody .
6 The sensitivity of the mutations detection methods is key to a proper application of personalized therapeutic strategies .
7 Μ Traditionally , somatic mutations are detected by Sanger sequencing and real-time PCR .
8 We determined the presence of mutations in specific genes of the EGFR pathway in colon cancer tumors from Chilean patients .
9 Methods : DNA was extracted from twenty-eight fresh frozen tumor samples .
10 DNA libraries were created using SureSelect ( Agilent ) designed for the analysis of EGFR , KRAS , BRAF , MAP2K1 , PIK3CA , PIK3R1 and PTEN genes .
11 Next generation sequencing was performed in MiSeq sequencer ( Illumina ) at Sistemas Genmicos ( Spain ) .
12 Results : Sequencing coverage varied between 100 and 250 readings between tumors , which assures the real presence of the changes .
13 This technique allows detecting mutations that are present in a smaller percentage of tumoral cells , as low as 20% in the sample .
14 Μ Pathogenic mutations were identified in 19 out of the 28 tumors .
15 Μ Mutations were found in KRAS ( pGly12Asp , pGly12Arg , pGly12Val and pGly12Cys ) , BRAF ( pVal600Glu and pGly606Glu ) , PIK3CA ( pGlu542Lys , pGlu545Lys , pGlu545Gln , pAla1035Val , pAsp1045Val and pHis1047Arg ) and PTEN (pLys267ArgfsX9) .
16 Five tumors presented mutations in both branches of the EGFR signaling pathway ( KRAS-PIK3CA , BRAF-PIK3CA and BRAF-PTEN ) .
17 Μ Three allelic variants were identified in MAP2K1 and PIK3R1 .
18 Μ Mutations that were identified in KRAS , BRAF and PIK3CA genes corresponded to gain of function mutations while a change found in PTEN gene corresponded to a loss of function mutation .
19 Finally , mutations in PIK3CA and KRAS of 6 tumors were not previously detected by Sanger sequencing .
20 Μ Discussion : Mutations were found in 68% of analyzed tumors .
21 Eighteen percent of the tumors presented mutations in two genes .
22 Μ Forty-six percent of mutations were identified in KRAS gene .
23 Μ Three allelic variants of unknown significance were detected which have not been described in cancer mutations nor in SPNs databases .
24 Therefore , it is necessary to perform functional studies to determine the effect on protein function .
25 Μ Next generation sequencing allowed us to obtain more reliable and reproducible results , and was able to detect mutations present in a low percentage of tumoral cells in the sample , maybe due to tumoral heterogeneity or contamination with normal cells .



PMID: ASCO_176793-195
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Correlation between total lesion glycolysis in 18F-FDG PET/CT and KRAS mutation and clinical features in patients with resectable colon cancer. .
1 Background : Recently , novel metabolic parameters in 18F-FDG PET/CT such as total lesion glycolysis ( TLG ) and metabolic tumor volume ( MTV ) as well as maximum standardized uptake value ( SUVmax ) have been reported to be prognostic and be related with genomic aberration .
2 We evaluated the prognostic role of these metabolic parameters and the correlation with clinical features in resected colon cancer .
3 Methods : This study included 212 colon cancer patients who underwent surgical resection of stage II and III disease and conducted pre-treatment 18F-FDG PET/CT between February 2009 and December 2013 .
4 Μ TLG , MTV of the primary tumors as well as SUVmax were analyzed according to clinical features including KRAS mutation , pre-treatment carcinoembryonic antigen ( CEA ) and recurrence free survival ( RFS ) .
5 Results : TLG was significantly higher in patients with right colon cancer than those with left colon cancer ( P = 0015 ) and in patients with elevated CEA than those with normal range of CEA ( P = 0034 ) , while MTV and SUVmax were not correlated with cancer location and CEA level .
6 Μ KRAS mutation analysis using peptide nucleic acid -mediated real-time polymerase chain reaction clamping was conducted in 94 patients and forty-one ( 436% ) patients showed KRAS mutation in tumor tissues .
7 TLG was significantly higher in patients with mutated KRAS compared with in those with wild KRAS ( P = 0021 ) .
8 CEA was significantly higher in patients with mutated KRAS than those with wild KRAS ( P-value = 0024 ) .
9 CEA and TLG could predict KRAS mutation showing odds ratio 1.07 and 1.02 in the multivariate logistic analysis ( P-value = 0024 , 0048 ) .
10 There was no difference of RFS between in patients with high TLG and in those with low TLG .
11 Conclusions : Based on the result that TLG had a predictive role for KRAS mutation and was related with tumor location and CEA value , we suggested that TLG might reflect genomic alteration and other clinical features as well as tumor burden .
12 It could be useful for differentiating different population of colon cancer and further study is clinically warranted .



PMID: ASCO_169385-176
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular subtyping of colon cancer ( CC ) based on mutational status of RAS , BRAF , and DNA mismatch repair ( MMR ) proteins . Prognostic value. .
1 Background : CC is a heterogeneuous disease with clinical , pathological and biological variability .
2 Molecular classification could indentify prognostic subtypes .
3 Methods : 105 patients with stage I-III were included in the study .
4 Μ KRAS , NRAS ( Exons 2,3,4 ) and BRAFV600E mutations were analyzed by a PCR-based assay .
5 MMR ( MLH1 and MSH2 ) proteins expression were analyzed by immunohistochemistry ; loss of expression of any indicated deficient ( dMMR ) versus proficient MMR ( pMMR ) .
6 CC was categorized into 5 subtypes : Traditional (T) ( pMMR ; wt BRAF and RAS ) ; Alternate (A) ( pMMR ; wt BRAF and mutant RAS ) ; Serrated (S) ( pMMR ; mutant BRAF and wt RAS ) ; Serrated dMMR ( Sd ) ( dMMR ; mutant BRAF and wt RAS ) and Familial (F) ( dMMR ; wt BRAF , any RAS ) .
7 Non-parametric tests were used for correlation with clinico-pathological variables and Cox models for association with Disease Free Survival ( DFS ) .
8 Results : Mutational status : 41% KRAS , 5% NRAS and 11% BRAF mutations .
9 MMR status : dMMR 19% ; pMMR 81% .
10 Molecular subtypes : T 35% , A 39% , S 7% , Sd 5% and F 14% .
11 Right-sided CC 46% ; high grade ( HG ) CC 12% .
12 Μ Right-sided and dMMR CC showed higher rate of BRAF mutations ( 21% versus 4% p = 011 and 25% versus 8% p = 034 ) .
13 Μ Stage II and III CC showed higher rate of BRAF mutations versus stage I ( 14% and 21% versus 0% , respectively ; p < 005 ) .
14 dMMR CC was more often right-sided ( 85% versus 37% , p < 001 ) and had more HG histology ( 31% versus 8% , p = 006 ) .
15 T subtype versus others was more likely left-sided ( 78% versus A 55% versus S 28% versus Sd 0% versus F 20% ; p < 0005 ) .
16 S dMMR and F versus A were more likely right-sided ( 100% and 80 % versus 45 % ; p < 05 ) .
17 F versus T and versus A CC had more HG ( 33% versus 8% , p = 039 ; versus 7% , p = 026 ) .
18 Risk of progression is higher in mutated KRAS CC ( Odds ratio ( OR ) 3,36 ; CI : 1,19-9,47 p = .017 ) .
19 RAS mutated CC showed higher risk of death ( OR 5,11 ; CI : 1,00-25,43 p = .040 ) .
20 ✓ Wt KRAS and wt RAS CC showed better DFS ( HR 0,31 CI 012-079 p = 015 and HR 0,39 CI 0,151,00 p = 051 ) . GE-ASS-RO
21 T versus S showed better DFS ( HR 0,21 IC 0,04 0,95 p = 044 ) .
22 S and A together compared to T , showed a tendency to a worse DFS ( HR 2,86 IC 0,930,78 p = 066 ) .
23 Conclusions : This molecular classification identifies prognostic groups with different clinical and pathological features in early-stage CC .



PMID: ASCO_30841-65
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Stage-specific prognostic value of molecular markers in colon cancer : Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. .
1 Background : We compared the incidence of molecular markers in stage II ( SII ) and III ( SIII ) colon cancer and tested their prognostic value per stage , using PETACC 3 , an adjuvant trial with 3,278 patients .
2 We included expression of P53 , SMAD4 , thymidylate synthetase ( TS ) and hTERT , mutations of KRAS and BRAF , microsatellite instability ( MSI ) and 18qLOH .
3 Methods : 1,564 formalin fixed paraffin embedded tissue blocks were prospectively collected and DNA from normal and tumor tissue was extracted after macrodissection .
4 High P53 , TS and hTERT expression and SMAD4 loss were assessed by immunohistochemistry .
5 MSI was studied with 10 markers .
6 Μ KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs .
7 Prognostic value of the markers was analysed per stage by Cox regression for Relapse Free Survival ( RFS ) .
8 Results : marker frequencies and stage specific p-values in prognostic models in 420 SII and 984 SIII patients are listed in the table .
9 Significant differences in frequency per stage were found for all markers except KRAS and BRAF .
10 An interaction test for differences between marker prognostic value for SII and SIII was significant for MSI ( p = 004 ) and 18qLOH ( p = 004 ) in SII .
11 Multivariate analysis including markers , T stage , N stage ( for SIII ) , Tu grade , age <60 , sex , treatment arm , and Tu site found T stage ( p = 00001 ) and MSI ( p = 002 ) as independently significant clinical predictors in SII ; N stage ( p < 00001 ) , T stage ( p < 00001 ) , SMAD4 ( p < 00001 ) and P53 ( p = 001 ) in SIII .
12 Conclusions : Molecular markers in colon cancer have a stage specific prognostic value .
13 The possibility that the stages represent different diseases , rather than sequential steps in the evolution of a single disease , needs to be considered .
14 Marker alteration frequency ( % ) Prognostic value* S IIS IIIp valueS IIS III MSI-H2212 < 0.00010.0040.06 P5330370.0090.990.02 TS4329 < 0.00010.020.03 SMAD49130.020.73 < 0.0001 18qLOH63700.040.030.91 hTERT40480.060.320.006 KRAS3637n .
15 s.0.790.69 BRAF88n .



PMID: ASCO_81682-102
(Patient)  
Terms: Prospective, clinical trial, prospective
Sent# Symbols Sentence Mnemonics
0 Prospective analysis of KRAS , BRAF , and PIK3CA mutational status and EGFR copy number in patients ( pts ) with locally advanced rectal cancer : A translational substudy of a clinical trial ( SAKK 41/07 ) evaluating the effect of neoadjuvant chemoradiation ( CRT ) with or without panitumumab. .
1 Background : The prevalence of possible prognostic and predictive markers is of great importance for future study designs and essential for the interpretation of clinical trials incorporating an EGFR-inhibitor .
2 KRAS , BRAF and PIK3CA mutational status has not been prospectively assessed in rectal cancer patients .
3 Methods : Macrodissection was performed on pretreatment formalin fixed paraffin embedded biopsy sections to increase the proportion of tumor cells .
4 DNA was extracted with the Maxwell 16 FFPE Tissue LEV DNA purification kit .
5 Μ After PCR amplification , mutations were identified by pyrosequencing analysis .
6 We prospectively analysed pretreatment biopsy material from 127 rectal cancer patients biopsies for KRAS ( exon 2 codon 12 [2-12] and 13 [2-13] , exon 3 codon 59 [3-5] ) and 61 [3-61] , codon 4 codon 117 [4-117] and 146 [4-146] ) .
7 68 patients ( KRASwt exon 2 , 3 only ) were further analysed regarding BRAF ( exon 15 codon 600 ) and PIC3CA ( exon 20 codon 1043 [20-1043] and 1047 [20-1047] ) mutations and EGFR copy number , which was measured by qPCR .
8 To normalize the quantification of the EGFR copy number , we used KRAS copy number as a reference .
9 The calculation was done on the basis of the two standard curves relative quantification method .
10 Results : KRAS mutations : 29 pts ( 23% ) with exon 2-12 , 8 pts ( 6% ) with exon 2-13 , 1 pts ( 1% ) with exon 3-59 , 4 pts ( 3% ) with exon 3-61 , 4 pts ( 3% ) with exon 4-117 , 9 pts ( 7% ) with exon 4-146 .
11 Μ KRAS mutational rate ( for all analysed exons/codons ) 43% .
12 Μ One patient ( 15% ) showed a BRAF mutation. 5 patients ( 74% ) had a PIK3CA mutation ( 1 x Exon 20-1043 , 4 x Exon 20-1047 ) .
13 The median EGFR copy number was 1.1 .
14 Conclusions : KRAS mutations appear equally common in rectal and in colon cancer .
15 BRAF and PIK3CA mutations are rare in KRASwt rectal cancer patients .
16 In KRASwt patients the EGFR copy number is not increased .
17 Correlation analyses between molecular results and response data from neoadjuvant therapy trial is ongoing and will be presented at the meeting .



PMID: AACR_2016-1012
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Systems analysis of colon cancer cell metabolism rewired by p53 and KRAS mutations .
1 Introduction .
2 Somatic mutations in proto-oncogenes and tumour-suppressor genes contribute to rewire the already deregulated metabolic network in cancer cells , resulting in uncontrolled proliferation and oncogenesis .
3 In this study , we set out to establish a dynamic mathematical model of bioenergetics and to exploit it to explore the multifaceted cross-talk between bioenergetics , somatic gene mutations in KRAS and p53 , and cell proliferation and survival .
4 Model Development .
5 We have developed an ordinary differential equations-based model of central carbon metabolism in cancer cells which includes glycolysis , pentose phosphate pathway , citric acid cycle and respiratory chain , based on our previous work and published models .
6 The model describes how nutrients ( glucose , glutamine , lactate , pyruvate , serine and glycine ) from the extracellular micro-environment affect bioenergetics parameters .
7 The resulting model predictions are linked to cell proliferation via a heuristic function .
8 Enzymatic activities regulated by p53 and KRAS mutations were obtained by mining publically available datasets and their regulation by the mutational status was modelled by adapting the corresponding kinetic parameters .
9 To estimate the kinetic parameters , model simulation outputs were fitted to a portfolio of experimental data both generated de novo in house and gathered from the literature in HCT-116 colon cancer cells .
10 Experiments were performed on parental HCT-116 ( p53 competent ; harbouring a KRAS mutation on exon 2 of codon G13 ) and three derived mutant cell lines covering all four combinations of p53 and KRAS mutational status to isolate their relative and joint effect on bioenergetics signatures .
11 HCT-116-derived cell lines included : p53 proficient cells with the KRAS allelic mutation silenced by homologous recombination in the presence or absence of p53 knockout by lentiviral shRNA .
12 Results .
13 The model was calibrated against ATP concentrations measured via single - cell microscopy ( ATeam probe and TMRM dye ) following pharmacological inhibition of respiratory chain complexes ( rotenone , sodium azide and oligomycin ) as a function of nutrients availability ( glucose , lactate , pyruvate ) .
14 Μ Modelling results revealed that p53 and KRAS mutations drive a shift in metabolic signatures and L-lactate emerged as a pivotal metabolite to stratify the different phenotypes .
15 Μ Systems analysis revealed that in KRAS mutated cells p53 deficiency leads to an increase in glucose uptake and flux through the pentose phosphate pathway and a decrease in lactate production .
16 Indeed , p53 deficient HCT-116 cells showed a decrease in extracellular lactate with respect to p53 proficient cells in validation experiments .
17 Conclusions .
18 The computational model developed can be used to benchmark mechanistic hypotheses by which tumour suppressors and/or oncogenic mutations rewire metabolism and to identify putative targets for therapeutic intervention .



PMID: AACR_2012-4548
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic value of occult metastases detected by cytokeratin 20 and mucin 2 mRNA quantification in sentinel lymph nodes from colon cancer patients .
1 RAF signaling and SHOC2 mediate mutant NRAS acquired resistance to RAF inhibitors in melanoma .



PMID: ASCO_182555-199
(Patient)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 ✓ Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status. . RO-ASS-GE
1 Background : Recent data suggest that the anatomic site of colon primary tumor may be an important factor in the interpretation of molecular markers with clinical outcome in metastatic colon cancer ( CC ) patients ( pts ) .
2 We assessed here the prognostic value of primary location in fully resected stage III CC pts and its relationship to MSI , RAS and BRAF mutational status .
3 Methods : Pts enrolled in the PETACC-8 trial were analyzed .
4 We categorized tumor site as located proximal ( left-sided ) or distal ( right-sided ) to the splenic flexure .
5 The association between tumor location and disease free survival ( DFS ) , survival after relapse ( SAR ) and overall survival ( OS ) were assessed by Cox models and adjusted for clinical and pathological features , MSI , BRAF and RASmutation status .
6 The outcome of pts receiving FOLFOX or FOLFOX and cetuximab in the adjuvant setting were also determined according to tumor site .
7 Results : Among the 1869 pts with full molecular data available , 755 ( 40% ) had a right-sided tumor , 164 ( 10% ) were MSI , 942 ( 50% ) were mutated for RAS and 212 ( 11% ) were mutated for BRAF .
8 Right-sided tumor was not prognostic for DFS in the whole population but was associated to a shorter SAR ( HR : 1.54 [123 - 193] , p = 0.001 ) and OS ( HR : 1.25 [102 - 154] , p = 0.03 ) .
9 Same results were observed for MSS and for MSI pts .
10 However , when looking at pts mutated for RAS or BRAF (MUT) and those double wild type ( DWT ) for those mutations , we found that right-sided tumors , when compared to left-sided tumors , was associated with a worst DFS in DWT patients ( HR : 1.39[1.01-1.92] , p = 0.04 ) and a better DFS in MUT patients ( HR : 0.77[0.63-0.95] , p = 0.01 ) .
11   These results were found independently of the treatment received and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors .
12 Conclusions : In the whole study population of stage III CC pts , though right-sided tumor location influences OS as previously reported , it does not seem to influence DFS but only SAR , when disease becomes metastatic .
13 Interestingly , sidedness seems to influence DFS when splitting the population in MUT or DWT for RAS and BRAF , with a worst DFS for right-sided tumors in DWT and a worst DFS for left-sided tumors in RAS or BRAF mutants .
14 Clinical trial information : 2005-003463-23 .



PMID: AACR_2015-2577
(Cell)  
Terms: in vivo
Sent# Symbols Sentence Mnemonics
0 Aurora kinase inhibitors require PUMA to induce apoptosis and preferentially kill KRAS-mutant colon cancer cells .
1 Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells .
2 Inhibition of aurora kinases results in mitotic arrest and death of cancer cells , and has been explored as an anti-cancer strategy .
3 However , how aurora inhibition kills cancer cells is poorly understood .
4 In this study , we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53-upregulated modulator of apoptosis ( PUMA ) , a BH3-only BCL-2 family protein , in colorectal cancer cells irrespective of p53 status .
5 Deficiency in PUMA increased polyploidy and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors .
6 In response to aurora kinase inhibition , PUMA was directly activated by p65 through the canonical NF-kB pathway following AKT inhibition .
7 Interestingly , aurora kinase inhibitors were found to preferentially kill KRAS-mutant colon cancer cells , which is associated with enhanced induction of PUMA and another BH3-only protein NOXA .
8 Furthermore , PUMA was necessary for the chemo-sensitization and in vivo anti-tumor effects of aurora kinase inhibitors in colon cancer cells .
9 These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition , and may be a useful indicator for the anti-cancer activity of aurora kinase inhibitors .



PMID: AACR_2012-3851
(Cell)  
Terms: in vivo, mice
Sent# Symbols Sentence Mnemonics
0 Killing of Kras mutant colon cancer cells by the GBP cytokine , a physiological PI3K inhibitor therapeutically effective in vivo .
1 Activating Kras mutations are the most frequent oncogenic mutations in human cancer .
2 Numerous downstream pathways responsible for cell proliferation and cell survival have been shown to be deregulated by oncogenic Kras but there are no effective targeted therapies to date for Kras driven oncogenesis .
3 Mutant -activated Kras defines a subset of patients for whom prognosis is poor and therapeutic options are limited .
4 We demonstrate that GBP , a cytokine produced by CD4+ and CD8+ activated T cells , which operates by inhibiting class IA and class IB PI3K , is a potent activator of apoptosis in Kras-mutant colorectal cancer cells , even when co-harboring mutant -activated PIK3CA .
5 Mechanics initiate with inhibition of PI3K activity and Rac -independent actin reorganisation assignable to phosphoinositide changes at the plasma membrane .
6 Cyclin E deregulation , arrest of DNA synthesis and Chk2 activation underscore events critical to the activation of intrinsic apoptosis .
7 Clustering of CD95/Fas death receptors underscores events critical to the activation of extrinsic apoptosis .
8 In nude mice we present the first evidence that tumor development is strongly inhibited .
9 This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-GBP may be therapeutically effective against other cancers harbouring activating Ras mutations .
10 Wells , V .
11 and Mallucci , L. ( 2009 ) .
12 Phosphoinositide 3 - kinase targeting by the -galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death .
13 Breast Cancer Research 11 , R2 , 1-10 .
14 Wells , V. , Downward , D .
15 and Mallucci , L. ( 2007 ) .
16 Functional inhibition of PI3K by the GBP molecule suppresses Ras-MAPK signalling to block cell proliferation .
17 Oncogene 26 , 7709-7714 .
18 Mallucci , L .
19 and Wells , V. ( 2007 ) .
20 Alternative use of signaling by the GBP cytokine in cell growth modulation and cancer control .
21 From surveillance to therapy .
22 In : Apoptosis , Cell Signaling and Human Diseases .
23 Ed .
24 R .
25 Srivastava .
26 The Humana Press Inc .
27 Vol .
28 I , 203-216 .



PMID: ASCO_143325-156
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Role of LINE-1 methylation status of adjacent normal colonic mucus in the survival of Chinese patients with colon cancer. .
1 Background : As a global epigenetic change , LINE-1 hypomethylation in normal mucosa were reported to have a key role in forming a field defect in colorectal carcinogenesis .
2 We aimed to study its influence on the survival of Chinese colon cancer patients .
3 Methods : Tissue samples of tumor or normal mucosa were utilized to detect certain genetic and epigenetic modifications .
4 Prognostic variables for the patients survivals were determined and the influence of LINE-1 methylation rate ( LMR ) level was further analyzed by survival studies .
5 Results : Overall , 127 patients , 83 males and 44 females , completed a median follow-up of 65 ( 3-85 ) months .
6 Μ It was revealed 14 ( 1102% ) and 5 ( 394% ) cases mutated in KRAS and BRAF gene , respectively .
7 Sixteen ( 1260% ) were confirmed as MSI-H , and 76 ( 5984% ) were found to have a loss of heterozygosity ( LOH ) at 18q .
8 There were 26 ( 2047% ) cases defined as hypermethylation at hMLH1 gene promoter .
9 A mean of 64.42 ( 945-8693 ) % of LMRs were determined by pyrosequencing and further sub-grouped into high or low level by X-tile program .
10 Cox multivariate analysis confirmed that the LMR level ( high vs. low , HR = 0.396 , 95% CI : 0.194-0.805 , p = 0.011 ) , MSI status ( MSI-H vs . MSS or MSI-L , HR = 0.082 , 95% CI : 0.011-0.629 , p = 0.016 ) , and distant metastases ( M1 vs . M0 , HR = 28.006 , 95% CI : 11.380-68.920 , p = 0.000 ) were the independent prognostic factors for colon cancer specific survival .
11 Sub-layer analysis revealed that patient with lower LMR level had a significantly worse survival in the subgroups of M0 , right-sized colon , size 5 cm , Stage I-III , MSI-L or MSS , serum CEA at normal level , age > 60 years , 18q LOH , BRAF gene wild-types , KRAS gene mutation , etc. ( all with p < 005 ) .
12 Conclusions : Genetic and epigenetic alterations can concurrently exist in the complex mechanisms of colonic tumorigenicity .
13 Hypomethylation of LINE-1 at adjacent normal mucosa might be associated with worse outcome in certain Chinese patients with colon cancer .
14 Acknowledgements : This work was supported by the National Natural Science Foundation of China ( No 81372646 to Cai SJ , No 81472222 to Li DW , and No 51377024 to Li XX ) .



PMID: AACR_2012-4900
(Cell)  
Terms: phase i
Sent# Symbols Sentence Mnemonics
0 Bortezomib induces G2-M arrest through ROS-inducible phosphorylation of ATM independent on genotypes of KRAS in human colon cancer cells .
1 The use of cetuximab ( CET ) as an inhibitor of EGFR for treatment of colorectal cancer ( CRC ) has revolutionized .
2 However , a number of CRC patients exhibits resistance to CET .
3 In this report , we suggest the possibility of using bortezomib as a proteasome inhibitor in human colon cancer cells .
4 Although bortezomib has been known to induce apoptosis and cell cycle arrest in various human cancer cells , the inhibitory mechanism of it was not clear .
5 First , bortezomib induced G2-M arrest independent on genotype of KRAS in all of tested human colon cancer cells .
6 Its treatment causes an increase of intracellular ROS levels and activation of ATM-CHK1 pathway , but not ATR .
7 Also , activation of that pathway led to inactivation of cdc2 .
8 Moreover , treatment with NAC , Reactive Oxygen Species ( ROS ) scavenger , inhibited phosphorylation of ATM and subsequent to decrease of cell number at G2-M phase in response to bortezomib indicating that the increased level of ROS after exposure to bortezomib is a result of ATM phosphorylation .
9 In addition , knockdown of endogenous ATM by RNA interference induced the decreased sensitivity to bortezomib .
10   Therefore , these results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and responses to colon cancer cells independent on genotype of KRAS , implying a potential possibility of it in the treatment of CRC patients .



PMID: ASCO_133664-144
(Patient)  
Terms: phase II trial, NCT01918527, Clinical trial
Sent# Symbols Sentence Mnemonics
0 A marker-driven phase II trial of neoadjuvant chemotherapy in locally advanced colon cancer. .
1 Background : The treatment of locally advanced colon cancer faces many challenges and new approaches are needed .
2 Neoadjuvant chemotherapy has proven valuable in several tumors , but it has not been elucidated in colon cancer .
3 One major reason has been the lack of validated methods for selection , but recent improvement in CT scanning has allowed for identification of high-risk patients in need of adjuvant chemotherapy .
4 Methods : Patients with resectable colon cancer fulfilling the following criteria were offered inclusion ; Histopathological verification of adenocarcinoma , T3 tumor on CT scan with extramural tumor invasion > 5 mm or T4 tumor , age 18 years , PS 2 , adequate hematology , and informed consent .
5 Patients with KRAS , BRAF , or PIK3CA mutation or unknown mutational status received 3 cycles of capecitabine 2000 mg/m2days 1-14 q3w and oxaliplatin 130 mg iv day 1 q3w .
6 Wildtype patients received the same chemotherapy supplemented with panitumumab 9 mg/kg iv q3w .
7 After the operation , patients fulfilling the international criteria for adjuvant chemotherapy received 5 cycles of the same chemotherapy without panitumumab .
8 Patients not fulfilling the criteria ( converted patients ) were offered follow-up only .
9 The primary endpoint was the fraction of converted patients .
10 Secondary endpoints were 2-year disease free survival ( DFS ) and toxicity .
11 The study was approved by the Regional Scientific Ethical Committee ( S-20100014 ) and registered at ClinicalTrials .
12 gov ( NCT01918527 ) .
13 Results : The study included 77 patients .
14 The conversion rate was 42% in the wildtype group compared to 51% in patients with a mutation .
15 The objective response rate by CT scan was 45% .
16 Three patients had complete pathological remission .
17 The cumulative recurrence rate in converted vs.non-converted patients was 3% vs. 27% ( p = 0003 ) translating into a 2-year DFS of 96% vs. 54% ( p = 0004 ) .
18 Toxicity was manageable and 90% received two cycles of the three planned cycles of neoadjuvant chemotherapy .
19   Conclusions : Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy .
20 A randomized trial is warranted .
21 Clinical trial information : NCT01918527 .



PMID: ASCO_166685-176
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Dynamics of mutant BRAF V600E in free circulating DNA ( fcDNA ) of non-melanoma cancer patients ( pts ) in response to treatment with BRAF and MEK/EGFR inhibitors. .
1 Functional and molecular characteristics of 20 novel patient-derived xenografts of Asian gastric cancer. .



PMID: AACR_2014-2172
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Association of right-sided colon cancer with poor efficacy of cetuximab in patients with RAS wild-type metastatic colorectal cancer. .
1 BackgroundPrevious studies have suggested that physical activity is associated with a reduced risk of colon cancer .
2 The association of physical activity with colorectal cancer ( CRC ) survival , however , is less clear .
3 Studies evaluating the association between post-diagnostic physical activity and CRC survival suggest a favorable survival among those who engage in regular physical activity after diagnosis .
4 However , such studies are limited by the possibility of reverse causality since individuals engaging in regular physical activity after diagnosis may have had a better prognosis to begin with .
5 MethodsWe evaluated the association between pre-diagnostic physical activity and survival , both overall and CRC-specific , within the Seattle Colon Cancer Family Registry ( SCCFR ) , a prospective cohort of persons diagnosed with CRC between 1997 and 2002 .
6 All cases completed a risk - factor questionnaire including information on medical history , demographic and lifestyle factors , such as obesity and decade-specific recreational physical activity .
7 Vital status and cause of death was determined through linkage to a regional cancer registry and National Death Index .
8 Tumor markers ( BRAF and KRAS mutation status ) were evaluated for a subset of cases .
9 Physical activity was summarized as average weekly metabolic equivalent-task hours ( MET-h/week ) .
10 Adjusted hazard ratios ( HR ) and 95% confidence limits ( 95%CI ) were estimated using Cox regression .
11 ResultsPrimary analyses included 1171 persons who self-reported their physical activity status , of whom 471 died ( 292 deaths attributable to CRC ; median follow-up 63 years ) .
12 After adjusting for age at diagnosis , sex , body mass index and smoking status , those who engaged in physical activity had a significantly lower risk of dying from any cause compared to those who did not engage in any physical activity ( HR 072 , 95%CI 051-099 ; HR 062 , 95%CI 044-087 ; and HR 060 , 95%CI 043-085 for >0-64 , 64-192 , and >192 MET-h/wk , respectively ; P for trend = 0035 ) .
13 Results for CRC-specific survival were similar and suggested improved survival among physically active individuals compared to those that were inactive , although no trend was evident ( HR 081 , 95%CI 051-128 ; HR 072 , 95%CI 045-115 ; and HR 072 , 95% CI 044-114 for >0-64 , 64-192 , >192 MET-h/wk respectively ; P for trend= 052 ) .
14 Further adjustment for stage at diagnosis or BRAF and KRAS mutation status did not alter the results .
15 ConclusionOur results suggest that individuals who are physically active prior to CRC diagnosis experience more favorable survival than those who are inactive .
16 Increased physical activity was also associated with better CRC-specific survival , but this trend was not statistically significant .
17 Continued follow-up of this and other larger cohorts is needed to further clarify the role of physical activity in CRC prognosis .



PMID: ASCO_52270-74
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 ALK chromosomal alterations in colon cancer patients. .
1 Μ Background : The identification of oncogenic chromosomal alterations in anaplastic lymphoma kinase ( ALK ) in lung cancer and neuroblastoma has revealed ALK as a potential candidate for anticancer targeted therapy .
2 Thus , ongoing clinical trials with ALK inhibitors are showing promising results .
3 ALK chromosomal alterations in other solid tumors are controversial .
4 The aim of this study was to analyze ALK translocations and gene copy number status in a series of colorectal cancer patients and correlate these findings with tumor pathological features including TNM staging , KRAS and BRAF mutations as well as clinical outcome .
5 Μ Methods : ALK status was retrospectively evaluated by fluorescence in situ hybridization ( FISH ) with a break-apart ALK probe and centromeric probe of chromosome 2 in biopsies from colorectal cancer primary tumors , as were KRAS and BRAF by mutational analysis .
6 Survival was analyzed by Kaplan-Meier method .
7 Immunohistochemistry to assess ALK expression is ongoing .
8 Results : Ninety-eight colorectal cancer patients were evaluated .
9 Normal colon mucosa from 10 patients was used as negative control .
10 Thirty-seven per cent of the patients had an increase in ALK gene copy number ( 3-5 copies ) with the percentage of cells with ALK copy gain within a tumor ranging between 6%-46% ( mean 22% ) .
11 There was no correlation between ALK gene amplification and KRAS mutational status .
12 Μ BRAF mutations were observed in five patients and interestingly all these patients had ALK normal copy number .
13 ALK translocations were not observed .
14 ALK amplification was correlated with nodal status .
15 Forty-three per cent of patients with positive nodal status had an increase in ALK copy number , while only 15% of patients with negative lymph nodes had ALK amplification ( p = 005 ) .
16 ✓ ALK amplification was not correlated with overall survival . GM-ASS-RO
17   Conclusions : The identification of ALK gene amplification in colorectal cancer patients reveals a potential new therapeutic target for this tumor .
18 Moreover , the correlation between ALK amplification and nodal status suggests that ALK amplified tumors have a more aggressive phenotype .
19 Further evaluation of the biological meaning of ALK amplification in colorectal cancer is ongoing .



PMID: AACR_2013-42
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of BRAF (V600E) mutation by immunohistochemical staining with anti-BRAF V600E ( VE1 ) antibody : A comparison with Sanger sequencing. .
1 Background : The most common of all activating BRAF mutations ( T1799A point mutation ) leads to a substitution of valine (V) to glutamic acid (E) at the position 600 of the amino acid sequence .
2 This oncogenic mutation in the BRAF gene constitutively activates the MAPK signaling pathway and results in increased proliferation and inhibition of apoptosis .
3 BRAF V600E mutation was described in approximately 8% of all solid tumors ( 43% melanomas , 39-67% papillary thyroid carcinomas and 12% colorectal adenocarcinomas ) .
4 Μ However , it is challenging to identify patients with this mutation .
5 Currently , the gold standard is sequencing of the tumor DNA , but this method is not practical for routine practice .
6 In contrast , immunohistochemistry ( IHC ) is a relatively easy diagnostic tool to detect proteins in paraffin-embedded tissues .
7 The major goal of this study was to compare detection of BRAF V600E by sequencing and IHC using anti-BRAF V600E ( VE1 ) antibody .
8 This clone is mutation specific and can distinguish the V600E mutation in BRAF from the wild type BRAF protein .
9 Methods : Tissues from sixty-nine patients with colon cancer ( N = 40 ) and thyroid cancer ( N = 29 ) were evaluated for the BRAF V600E mutation .
10 Genomic DNA was extracted from 20 m tissue sections and analyzed by PCR amplification followed by Sanger sequencing .
11 Primers were designed to cover the BRAF coding sequences at mutation site and a few nucleotides in the intron on both ends ( BRAF-ex15F-TGCTTGCTCTGATAGGAAAATG ; BRAF-ex15R-AGCATCTCAGGGCCAAAAAT ) .
12 Both forward and reverse strands were sequenced on an Applied Biosystem's 3730xl DNA Analyzer .
13 Immunohistochemical staining using anti-BRAF V600E ( VE1 ) antibody was done on VENTANA BenchMark XT platform with OptiView DAB IHC Detection Kit .
14 Results : All cases ( 22/22 , 100% ) that were negative for BRAF V600E mutation by IHC were confirmed to be BRAF V600E negative by sequencing .
15 Out of 47 cases staining positive for BRAF V600E ( VE1 ) 43 cases were confirmed by sequencing .
16 Of the four discordant cases , one case was weakly positive by IHC ( score 1 ) , two cases that were negative by sequencing showed stronger BRAF V600E ( VE1 ) staining ( score 2 ) and one case contained a different mutation at codon 600 ( V600K ) .
17 Overall , there was high concordance between IHC and DNA sequencing .
18 Using the sequencing as the reference standard , negative predictive value was 100% , positive predictive value was 91% with a sensitivity of 100% and specificity of 85% .
19 Overall percentage agreement across all cases was 94% ( 65/69 cases ) .
20 Next-generation sequencing will be used to evaluate discordant cases for BRAF V600 mutation status .
21 Conclusion : Detection of the BRAF V600E mutation is emerging as an important biomarker with diagnostic , prognostic , and predictive potential .
22 Importantly , our data suggests that there is high concordance between sequencing and IHC using anti-BRAF V600E ( VE1 ) antibody .



PMID: AACR_2012-5601
(Cell)  
Terms: clinical trial, in vitro, in vivo, xenograft
Sent# Symbols Sentence Mnemonics
0 Overcoming acquired resistance to BRAF inhibitors in melanoma with the HSP90 inhibitor ganetespib .
1 Activating BRAF (V600E) kinase mutations occur in 50% of melanoma , 45% of papillary thyroid cancer and 10% of colon cancer .
2 BRAF inhibitors have elicited significant clinical response in melanomas but acquired resistance frequently develops after initial responses .
3 Therefore , consideration of new treatment strategies to block activity of mutant BRAF and deter therapeutic resistance is warranted .
4 Heat shock protein 90 ( HSP90 ) is a molecular chaperone required for the stability of hundreds of client proteins , including the RAF family of kinases , and has emerged as a highly relevant anticancer target .
5 Ganetespib is a second generation , small molecule HSP90 inhibitor currently being evaluated in multiple clinical trials .
6 To investigate the potential for ganetespib in the treatment of melanoma we evaluated its preclinical activity as monotherapy , and in combination with targeted agents , in cells sensitive or resistant to BRAF inhibitors .
7 Ganetespib displayed potent anticancer activity in a large panel of BRAF (V600E) mutant melanoma , thyroid and colon cancer cell lines , with IC50 between 4 and 40 nM .
8 Further analysis showed that ganetespib disrupted oncogenic signaling by inducing the destabilization of mutant BRAF and subsequent inactivation of MEK and ERK .
9 ✓ Levels of wild-type BRAF were only slightly reduced in response to ganetespib treatment , implying that the stability of activated BRAF is more reliant on HSP90 and that ganetespib may selectively deplete oncogenic forms of BRAF . GM-REG-RO
10   Notably , ganetespib treatment also led to depletion of CRAF , which is implicated in driving therapeutic resistance to BRAF inhibitors .
11 In an effort to maximize antitumor activity , we combined low levels of ganetespib with BRAF or MEK inhibitors in vitro and observed increased cytotoxicity compared to single agent treatment .
12 Both the BRAF and MEK inhibitors were cytostatic on their own , which may be due to continued PI3K/mTOR signaling .
13 We subsequently assayed the combination of ganetespib with a PI3K/mTOR inhibitor and observed synergistic increases in cell death .
14 Importantly , ganetespib was capable of blocking the feedback activation on MAPKK induced by a MEK inhibitor as well as the activation of ERK by PI3K/mTOR inhibitors .
15 To determine if these results translated in vivo , similar combinations were performed in BRAF mutant human melanoma xenografts .
16 Co-administration of ganetespib with either a BRAF or PI3K/mTOR inhibitor suppressed in vivo tumor growth to a greater extent compared to monotherapy .
17 ✓ Finally , we show that ganetespib effectively blocked MAPK signaling and killed RPMI-7951 melanoma cells ( IC50 = 4 nM ) , which are resistant to BRAF and MEK inhibitors due to the overexpression of COT .
18 In conclusion , targeting HSP90 with ganetespib represents a promising approach for the treatment of BRAF (V600E)- driven cancers and may be especially relevant in the context of acquired resistance to BRAF inhibitors .



PMID: ASCO_116614-132
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Prognostic biomarkers in a series of stage II colon cancer. .
1 Background : Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer ( CC ) that may benefit of adjuvant treatment .
2 Moreover , several molecular markers , such as microsatellite instability ( MSI ) and BRAF , have been widely investigated as prognostic factors .
3 Recently a high stroma component ( EMT+ subtypes ) has also been associated with poor outcome .
4 The aim of the study is to analyze the prognostic value of MSI , BRAF and tumor-stroma ratio in a prospective series of stage II CC patients .
5 Methods : FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge ( 1996 - 2006 ) were included in the study .
6 MSI status was assessed by the analysis of 5 mononucleotide repeat markers ( BAT-25 , BAT-26 , NR-21 , NR-24 and MONO-27 ) .
7 Μ BRAF V600E mutation was analyzed by single strand conformation polymorphism technique .
8 Tumor-stroma ratio was analyzed by immunohistochemistry .
9 Associations between molecular factors and clinical features were assessed by Chi-Squared ( X2 ) tests .
10 A Cox regression model was used to evaluate the Relapse Free ( RFS ) and the Colon Cancer specific Survival .
11 Results : MSI status could be determined in 350 patients. 48 ( 14% ) had MSI high ( MSI-H ) tumor .
12 BRAF status could be assessed in 380 cases. 58 ( 15% ) cases were BRAF mutated .
13 Tumor-stroma ratio was analyzed in 407 tumor samples. 176 ( 43% ) tumors had more than 50% intra-tumor stroma and were classified as stroma-high .
14 MSI-H tumors were significantly located in right colon ( X2 p-value = 103e-5 ) , were poorly differentiated ( X2 p-value = 0003 ) and had more than 12 lymph nodes resected ( X2 p-value = 0037 ) .
15 MSI-H tumors were associated with BRAF mutation ( X2 p-value = 002 ) and stroma-low ( X2 p-value = 00005 ) .
16 When a molecular prognostic risk classification was performed , patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high , microsatellite stable ( MSS ) /stroma-low and MSS/stroma-high patients ( HR = 315 ; 95 CI , 076 131 , p-value = 00602 ) .
17 Conclusions : MSI-H tumors have BRAF mutation as well as low intra-tumor stroma .
18 Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors .



PMID: ASCO_32653-65
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effect of panitumumab on autophagy in colon cancer. .
1 Background : Panitumumab , a human monoclonal antibody raised against EGFR , has been approved by the Food and Drug Administration ( FDA ) and the European Medicines Agency ( EMEA ) for the treatment of patients with EGFR-expressing mCRC and wild type kras .
2 The ratio of reduced/oxidised form of glutathione (GSH/GSSG) is an indicator of the redox status in cells .
3 The aim of the current study was to investigate the effect of panitumumab on the redox status of colon cancer cell lines Caco-2 , DLD-1 and HT-29 regarding proliferation , apoptosis , necrosis , cell cycle arrest and autophagy .
4 Methods : Cell proliferation was measured by MTT assay .
5 Apoptosis and necrosis were detected by annexin v/propidium iodide assay .
6 Cell cycle arrest was estimated by propidium iodide assay .
7 Autophagy was detected by immunobloting and GSH levels were measured by spectrophotometrical analysis .
8 Μ kras mutations were detected by sequencing analysis .
9 Results : Caco-2 , DLD-1 and HT-29 cell lines differ in the expression levels of EGFR and HER-2 .
10 Μ Kras mutation analysis in previous studies and in the current study showed that DLD-1 cells express mutated kras while Caco-2 and HT-29 cells express wild type of kras .
11 Panitumumab decreased proliferation only in DLD-1 cells 48 h after its application besides the mutated kras .
12 However , panitumumab did not affect DLD-1 cell apoptosis , necrosis or cell cycle progression 24 and 48 h after cells treatment .
13 Interestingly , panitumumab increased protein levels of beclin 1 , an indicator of autophagy , 24 h after its addition in cells .
14 Moreover , an increase in GSH levels was noted 48 h after cells treatment with panitumumab .
15 Conclusions : This is the first study to show that panitumumab , an EGFR inhibitor , affects colon cancer cell proliferation independently of kras mutations and EGFR protein levels through the induction of autophagy .
16 The inhibition in cell proliferation was followed by an increase in GSH levels reflecting an imbalance on the redox status of cells .



PMID: ASCO_150501-156
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Influence of molecular alterations on site -specific ( ss ) time to recurrence ( TTR ) following adjuvant therapy in resected colon cancer ( CC ) ( Alliance Trial N0147 ) . .
1 Background : Influence of tumor molecular alterations on ssTTR after resection of stage 3 CC has not been well studied .
2 Phase 3 trial N0147 ( adjuvant FOLFOX +/- cetuximab ) provided an opportunity to assess possible correlations .
3 Methods : 3098 stage 3 CC pts were enrolled and sites of all recurrences were reviewed centrally : liver , lung , peritoneal , local ( < 5 cm of anastomosis ) , regional , and other metastatic .
4 Genetic markers include MMR , mutations ( mut ) in KRAS exon 2 ( codons 12 , 13 ) , BRAF V600E exon 15 .
5 Cumulative incidence rate ( CIR ) was estimated for ss recurrences .
6 Associations between biomarkers and TTR across sites ( interaction ) were assessed by a frailty Cox model .
7 Association between biomarker and ssTTR were evaluated by multivariable Cox model when the site -biomarker interaction effect presents , adjusting for age , T/N stage , type of surgery , tumor sidedness , and treatment .
8 Results : Most common recur sites were liver , regional , peritoneal , and lung , with 3 yr CIR of 8.4% , 8.3% , 5.5% and 5.4% , respectively , with no difference between treatment arms ( p = 09 ) .
9 Interactions between sites of recurrence and BRAF ( p = 006 ) or MMR ( p = 018 ) status were significant and marginal for combined KRAS/BRAF ( p = .10 ) .
10 Compared to wild type ( wt ) pts , BRAF mut pts had shorter TTR for peritoneal HR2.14 ; 95% CI , 1.36-3.37 ; padj= .001] and metastatic sites [HR , 119 ; 95 CI , 107-342 ; padj= 033] , but not for liver or lung .
11 KRAS mut/BRAF wt pts had shorter TTR for liver ( HR , 155 ; 95% CI , 119-203 ) and lung ( HR , 181 , 95% CI , 132-250 ) , and KRAS wt/BRAF mut pts had shorter TTR for peritoneal ( HR , 214 ; 95% CI , 136-337 ) compared to double wt pts .
12 dMMR pts had longer TTR for liver ( HR , 044 ; 95% CI , 025-078 ; padj= 002 ) and peritoneal ( HR , 046 ; 95% CI , 025-082 ; padj= 004 ) compared to pMMR pts .
13 Conclusions : Status of MMR and BRAF , but not KRAS ( alone ) , influences site of recurrence and TTR .
14   Accordingly , these biomarkers may assist in treatment and follow-up approaches .



PMID: AACR_2017-4856
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Next-generation sequencing-based molecular characterization of primary urinary bladder adenocarcinoma .
1 MAPK pathway dysregulation via mutations in proteins such as BRAFV600E and NRASQ61 is a key feature in melanomas , leading to constitutive ERK signaling .
2 Currently , there are no FDA-approved targeted therapies effective in vemurafenib-resistant BRAFV600E mutant , NRAS mutant , or wild-type melanoma .
3 THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
4 Among BRAFV600E mutants with in vitro acquired resistance to vemurafenib , those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH722984 .
5 Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines , resulting in up to 10-fold decrease in the 50% inhibitory concentration ( IC50 ) and with combination indices ( CI ) below 1 .
6 SCH722984 inhibited phosphorylation of RSK , an ERK downstream target .
7   Finally , long term cultures of two BRAFV600E-mutant cell lines sensitive to SCH722984 showed that treatment with SCH722984 alone or in combination with vemurafenib was more potent than vemurafenib alone and resulted in a significant delay in developing acquired resistance .
8 SCH722984 may therefore be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance , alone or in combination with BRAF inhibitors .



PMID: AACR_2016-4082
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Epithelial-stromal interactions are altered at the earliest stages of colon cancer development .
1 Μ While progression of nonmalignant colonic cells carrying somatic mutations to early malignancy is dependent upon interactions between mutated epithelium and surrounding stroma , the nature of these interactions is poorly understood .
2 Here we report the development of an ultra-sensitive laser capture microdissection/RNA-seq approach for profiling the epithelial and stromal compartments of mutated aberrant crypt foci ( ACF ) .
3 Μ ACF are the earliest detectable pre-neoplastic lesion found in human colon and were identified using high-definition endoscopy with contrast dye-spray .
4 Μ We focused on epithelial and stromal cells of ACF carrying somatic mutations to either KRAS , BRAF or APC , and compared these to control samples from each patient .
5 Μ By comparing the gene expression from each group , we identified an increase in a number of pro-inflammatory NF-B target genes that are specific to ACF epithelium ( including TIMP1 , RELA and RELB ) .
6 We confirmed distinct transcriptional changes associated with each somatic mutation and demonstrate that a subset of ACF display a BRAFV600E -mediated senescence-associated transcriptome , characterized by increased expression of CDKN2A ( p16 ) .
7 Furthermore , ACF-associated stroma is transcriptionally distinct from adjacent normal stroma and genes related to immune cell infiltration and activation of fibroblasts are up-regulated .
8 Immunofluorescence analysis confirms the abundance of activated fibroblasts in ACF stroma regardless of mutational status .
9 These results provide new insight into the cellular interplay that occurs at the very early stages of colon cancer development , highlighting the role of activated stromal fibroblasts and inflammation .



PMID: ASCO_150052-156
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Turkish National Colon Cancer Registry. .
1 Background : Colorectal cancers ( CRC ) have become the 3rd most common cancer in Turkey with increasing incidence over the years .
2 Studies investigating the clinical and biologic features of CRC Turkey are small retrospective case series providing limited information .
3 We initiated a Turkish National CRC Registry program in October 2012 to define clinical and pathological variables of CRC .
4 Methods : Pts presenting to medical oncology clinics were prospectively registered in 28 centers nationwide .
5 Pt demographics and clinicopathological characteristics were recorded .
6 Results : 6143 pts ( mean age 582123 ) were analyzed ( 57% males ) .
7 Mean ages of males were higher ( 59 versus 57 yrs , p = 0001 ) .
8 Adenocarcinoma was the most common histology ( 978% ) .
9 Initial stages at diagnosis : I ( 54% ) , II ( 296% ) , III ( 338% ) and IV ( 202% ) , unknown ( 98% ) .
10 Pts from Eastern Turkey were younger ( 56 versus 59 , p < 0001 ) with a more advanced stage ( metastatic pts , 265% versus 184% ) .
11 T stage was unknown in 22% , and T3 ( 46% ) and T4 ( 20% ) tumors were most commonly observed .
12 Median number of examined and involved lymph nodes were 14 ( 1-148 ) and 1 , respectively .
13 Lymphovascular and perineural invasion were present in 27.7% and 21.2% .
14 Most common tumor sites were rectum ( 35% ) , and sigmoid ( 24% ) .
15 Surgery was done in 85.4% : hemi/partial colectomy ( 35% ) , LAR ( 34% ) , APR ( 46% ) , total colectomy ( 36% ) .
16 Metastasectomy was done in 16.9% with R0 resection in 15.9% .
17   Adjuvant chemo was given to 66.3% of nonmetastatic patients with fluoropyrimidines and oxaliplatin-based regimens. 10.8% pts received neoadjuvant chemoradiotherapy. 33% pts had metastasis ( at diagnosis or recurrent disease ) : liver ( 62% ) , lung ( 26% ) and others .
18 Metastatic pts received chemo in combination with bevacizumab in 53.5% .
19 KRAS was available in 41% and BRAF in 3% of metastatic pts .
20 Of these , 61% were KRAS wild-type and 20% BRAF mutant .
21 Cetuximab in first - line was rare ( 37% total , 16% of KRAS wild-type ) .
22 Conclusions : This study is the first comprehensive CRC registry in Turkey .
23 Pt demographics were similar to Western countries including molecular studies .
24 However , molecular testing was not readily available in most of the metastatic cases .
25 A low rate of biologicals use in combination therapies in metastatic pts may result in inferior pt outcome overall .



PMID: ASCO_146390-156
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Analysis of DNA mismatch repair ( MMR ) and clinical outcome in stage III colon cancers from patients ( pts ) treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials. .
1 Background : The prognostic impact of deficient (d) MMR , including sporadic and familial types , in stage III colon cancer pts receiving standard adjuvant FOLFOX therapy remains unknown .
2 We examined the association of MMR status with clinical outcome in two phase III clinical trials of adjuvant FOLFOX +/- cetuximab .
3 Μ Methods : Prospectively collected tumors from both studies were separately analyzed for MMR protein ( MLH1 , MSH2 , MSH6 ) expression and mutations in BRAF (V600E) .
4 Loss of any MMR protein indicated dMMR .
5 Methylation of the MLH1 gene promoter was studied in tumors with loss of MLH1 and wild-type ( WT ) BRAF .
6 Associations of MMR status with time-to-recurrence ( TTR ) , disease-free survival ( DFS ) and overall survival ( OS ) were analyzed using a stratified Cox proportional hazards model .
7 Multivariate models were adjusted for treatment and covariates ( age , sex , tumor grade , T/N stage , tumor location , ECOG PS , BRAF/KRAS ) .
8 Results : The frequency of dMMR in the overall cohort was 10.7% ( 499/ 4674 ) .
9 3-year ( yr ) DFS for dMMR versus proficient (p) MMR pts was 75% versus 74% ( HR = 087 ; 95% CI , 071-107 ; padustedj = 196 ) .
10 Among pts with complete biomarker data ( N = 4339 ) , there were 405 dMMR tumors of which 265 ( 654% ) were categorized as sporadic ( BRAF mutation or WT with MLH1 methylation ) and 140 ( 346% ) as familial ( BRAF WT and unmethylated MLH1 or loss of MSH2 or MSH6 ) .
11 DFS rates of pts with sporadic and familial dMMR tumors were similar ( HR , 115 ; 95% CI , 073-181 ; padjusted = 54 ) .
12 Pts with dMMR tumors had similar DFS rates as did pts with pMMR tumors without BRAF or KRAS mutations ( Table ) .
13 Consistent results were found for biomarkers and TTR and OS .
14   Conclusions : In this large cohort of stage III colon cancer pts enrolled in two adjuvant trials testing FOLFOX +/- cetuximab , MMR status was not prognostic .
15 Similar outcomes were found for sporadic and familial dMMR cases , and when each of these dMMR subtypes was compared to pMMR tumors WT for both BRAF and KRAS genes .



PMID: AACR_2017-5393
(None)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 BRAF mutant allele fraction in circulating tumor DNA as marker of treatment response in BRAF mutated non malignant melanoma cancers identified in the Copenhagen Prospective Personalized Oncology study. .
1 Colorectal cancer ( CRC ) is characterized by genome -wide alterations to DNA methylation that influence gene expression and genomic stability .
2 Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development .
3 In this study , we have combined laser-capture microdissection with reduced representation bisulfite sequencing to identify cancer-associated DNA methylation changes in human aberrant crypt foci ( ACF ) , the earliest putative precursor to CRC .
4 Using this approach , methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation , as well as matched samples of normal mucosa .
5 Of 811 differentially methylated regions ( DMRs ) identified in ACF , 537 ( 66% ) were hypermethylated and 274 ( 34% ) were hypomethylated .
6 DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated .
7 Furthermore , gene ontology analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development , including homeobox genes and targets of the Polycomb repressive complex 2 .
8 Consistent with their role in the earliest stages of colonic neoplasia , 75% of the loci harboring methylation changes in ACF were also altered in CRC samples , though the magnitude of change at these sites was lesser in ACF .
9 Although aberrant promoter methylation was associated with altered gene expression in CRC , this was not the case in ACF , suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia .
10 Altogether , these data demonstrate that DNA methylation changes , including significant hypermethylation , occur more frequently in early colonic neoplasia than previously believed , and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk .
11 Oncogene advance online publication , 1 May 2017 ; doi : 10.1038/onc.2017.130 .



PMID: AACR_2015-4691
(Cell)  
Terms: xenograft, in vivo, in vitro, In vivo, mouse model, mouse, mice
Sent# Symbols Sentence Mnemonics
0 KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts .
1 Μ Constitutive active mutations of KRAS are detected in 35-40% of human colon cancers , and almost all of them are the constitutive active missense mutations at codon 12 ( 80% ) or codon 13 ( 20% ) .
2 Consistent with these observations , the presence of KRAS mutations has been shown to be associated with malignant properties of tumors as well as a poor clinical outcome of the patients bearing these tumors .
3 Unfortunately , yet no effective anti-cancer drugs specifically targeting KRAS mutations have been developed .
4 Hence , we synthesized an alkylating agent conjugated with the Pyrrole-Imidazole polyamide ( KR12 : PI-polyamide-seco-CBI ) , which recognized KRAS G12D or G12V mutations at codon12 .
5 We have previously found that KR12 has anti-tumor effects in vitro and in vivo .
6 However , it still remains elusive whether KR12 exerts its selective toxicity towards colon cancer cells by penetrating into the tumor tissues and inhibiting the expression of mutant KRAS gene in mouse model of human cancer .
7 To address this issue , we decided to examine the distribution of KR12 using FITC labeled PI polyamide .
8 In vivo imaging of tumor-bearing mice after single intravenous administration demonstrated that the highest fluorescence intensity was seen in the tumor sites 24 hours after injection with showing nuclear localization .
9 Μ Quantitative RT-PCR revealed that KR12 decreased the mutated KRAS expression in tumor tissues obtained from KRAS-heterozygous-mutated-LS180-xenografted mice ( G12D heterozygous mutation ) .
10 Since KR12 showed long lasting accumulation in xenografts we compared the effect of single and multiple administration of KR12 .
11 Once a week injection for five to eight weeks resulted in significant suppression of tumor growth in homozygous mutant SW480 ( G12V homozygous mutation ) xenografts .
12 Surprisingly , both single and multiple treatments of KR12 induced massive tumor volume reduction without affecting body weight gain .
13 These data suggest that KR12 accumulation in colon xenograft tumor tissues may emphasize drug local effect and minimize systemic adverse effect .



PMID: AACR_2014-3136
(Patient)  
Terms: clinical trial, PDX, tumor models, mouse
Sent# Symbols Sentence Mnemonics
0 XMAN isogenic DualXenoTM models with KRAS mutation predicts the effect of anti-EGFR agents .
1 Μ We have previously reported using cell lines generated with Horizon Discovery's rAAV-based GENESIS gene editing platform to establish a comprehensive list of isogenic cancer models for in vivo compound screening , with mutations in a wide variety of genes including KRAS , PIK3CA , PTEN , IDH1 and IDH2 , and p53 .
2 These isogenic tumor models comprise pairs of cell lines which share the same genetic background , differing only by the mutation of interest , and therefore allow definitive studies of specific genetic variances to be performed .
3 In the current study we developed a DualXenoTM method where isogenic pairs of a colorectal cell line , one of each pair with a KRAS mutation , were inoculated simultaneously in the two flanks of the same mouse .
4 The tumors were then treated with EGFR targeted therapeutics to address the question of resistant phenotypes elicited by different KRAS mutations .
5 This design allows direct comparison of wild type and mutant isogenic pairs for treatment responses that are associated with the defined genetic variations .
6 ✓ Μ Our results demonstrated that tumors harboring the G12V mutation were resistant to both Cetuximab and Erlotinib treatment , while tumors harboring the G13D mutation remained sensitive to both agents .
7 This is in consistent with clinical findings ( De Roock , et al .
8   JAMA 2010 , 304 ( 16 ) , pp 1812 ) , and our own findings with PDX mouse clinical trials in colon cancer , suggesting that the KRAS G13D mutation may establish a different signaling network to other KRAS mutations , and that colon cancer patients with the mutation should not be excluded from the EGFR targeted therapies .



PMID: ASCO_110568-132
(None)  
Terms: phase III trial, Clinical trial, NCT00265811
Sent# Symbols Sentence Mnemonics
0 Subgroup analyses results of the PETACC8 phase III trial comparing adjuvant FOLFOX4 with or without cetuximab ( CTX ) in resected stage III colon cancer ( CC ) . .
1 Background : Potential benefit of adding CTX to the current standard treatment for stage III CC , was assessed .
2 Subgroup analyses of demographic , clinical and molecular data may improve our understanding of this patient population .
3 Methods : Patients ( pts ) were randomized 28-56 days following resection .
4 They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1 , with leucovorin 200 mg/m2 , 5-FU 400 mg/m2 bolus IV , followed by 5-FU 600 mg/m2 22-hr IV on d1-2 ( FOLFOX4 ) , without ( arm A ) or with weekly CTX ( arm B ) 250 mg/m2 ( initial dose 400 mg/m2 ) .
5 Primary endpoint was disease free survival time ( DFS ) .
6 Secondary endpoints included overall survival ( OS ) , treatment compliance and safety .
7 Enrolment was restricted to KRAS wt pts in 06/2008 .
8 Planned accrual of 1,407 KRAS wild-type ( wt ) pts provided 90% power to detect a hazard ratio ( HR ) of 0.75 with 2-sided =0.05 , with interim analyses after 65% of planned events .
9 Preplanned subgroup analyses were performed .
10 Results : 1,602 KRAS wt pts ( 811 arm A , 791 arm B ) and 742 mutated (m) KRAS ( prior to the amendment ) , were randomized .
11 BRAF status was determined in 1134 ( 71% ) KRAS wt pts .
12 Median follow-up was 40 months .
13 This interim analysis showed no difference between arms for DFS ( HR 105 , 95% CI 085-129 ; p = 066 ) or OS ( HR 109 , 95% CI 081-147 ; p = 055 ) in KRAS wt pts or for DFS ( HR 099 , 95% CI 075-128 ; p = 091 ) or OS ( HR 098 , 95% CI 067-144 ; p = 092 ) in KRAS/BRAF wt pts ( n = 984 ) .
14 Similar results were seen in KRAS mutant ( mt ) pts without any detrimental effect .
15 In KRAS wt pts worse outcomes were seen with CTX in pts >70 years ( n = 149 , DFS : HR 1.97 , 95% CI 0.99-3.93 ; p = 0.05 ) , in females ( n = 666 , HR 145 , 95% CI 103-203 ; p = 003 ) and in pts with right-sided CC ( n = 570 , HR 140 , 95% CI 101-194 ; p = 004 ) .
16 Conversely , a better outcome was seen in pts with pT4pN2 CC ( n = 146 , HR 055 , 95% CI 035-089 ; p = 001 ) .
17 Conclusions : Adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt , KRAS/BRAF wt and KRAS mt CC .
18 Subgroup analyses suggest that KRAS wt pts with pT4pN2 tumors may derive benefit from CTX .
19 MSI status determination is ongoing to explore its potential interaction with poor outcome in female and/or with right-sided tumors pts .
20 Clinical trial information : NCT00265811 .



PMID: AACR_2015-4687
(None)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 A novel alkylating pyrrol-imidazole polyamide , KR12 , specifically recognizes mutant KRAS genes and potently induces cell death .
1 Μ RAS mutations are found in around 30% of all human cancers , with KRAS being the most frequently activated RAS family of oncogenes .
2 Although extensive efforts to develop attractive chemotherapeutic drugs targeting KRAS mutations with clinical benefit have been made , these experimental trials have often resulted in unsuccessful .
3 Recently , we have successfully produced for the first time a novel alkylating agent ( termed KR12 ) conjugated with the sequence -specific Pyrrole-Imidazole polyamide (PI polyamide) , which was expected to have an ability to bind to base sequences of KRAS mutations at codon 12 ( G12D and G12V ) .
4 Μ According to our results , KR12-treated colon cancer-derived LS180 cells carrying a KRAS G12D heterozygous mutation underwent remarkable G2/M cell cycle arrest , cellular senescence and subsequent p53 -dependent apoptotic cell death in association with a massive down-regulation of mutant KRAS expression as examined by quantitative real-time RT-PCR and immunoblotting .
5 In the present study , we have further assessed the sequence -specificity of KR12 in detail by using an in vitro gel mobility shift assay , binding affinity assays with surface plasmon resonance ( Biacore system ) and also determined IC50 of KR12 in a variety of colon cancer-derived cells with the distinct KRAS status .
6 Μ Gel mobility shift assay demonstrated that the mobility of the oligonucleotide containing KRAS mutation was significantly retarded in the presence of KR12 but not in the absence of KR12 .
7 In agreement , KR12 specifically bound to the oligonucleotide containing KRAS mutation with high affinity as examined by Biacore system in vitro .
8 Notably , ligation-mediated PCR analysis ( LM-PCR ) revealed that KR12 indeed alkylate the adenine residue next to KRAS at codon G12D in LS180 cells .
9 These observations imply that KR12 is capable to bind to and alkylate the expected KRAS sequence in vitro and in cells .
10 Next , we have investigated the sensitivity to KR12 in a variety of colon cancer-derived cells .
11 ✓ Μ Based on our standard WST cell survival assay demonstrated that KRAS mutation-bearing SW480 (G12V) , SW620 (G12V) , and LS180 (G12D) cells exhibited a significantly higher sensitivity to KR12 as compared with HT-29 (WT) , Caco-2 (WT) , DLD-1 (G13D) and SW1463 (G12C) cells . GM-ASS-SR
12   Μ Taken together , our present results strongly suggest that KR12 is a novel sequence -specific alkylating agent targeting KRAS G12D as well as G12V mutation , and thus might be a promising anti-cancer drug for the treatment of patients bearing malignant cancers with KRAS mutations .



PMID: ASCO_123338-143
(Patient)  
Terms: retrospective study
Sent# Symbols Sentence Mnemonics
0 Molecular and clinical prognostic factors in metastatic colorectal cancer ( CRC ) patients ( pts ) : A retrospective study. .
1 Background : Strong evidence is emerging about the usefulness of mutational profiling for CRC pts .
2 This study aimed to evaluate the overall survival in three molecular groups , taking as reference the all-wild type category : (1) BRAF mutated ; (2) KRAS mutated codons 12-13 only ; (3) any of KRAS codons 61-146 , PIK3CA exon 9-20 or NRAS cod 12-13-61 mutations .
3 Also clinical variables were investigated as potential prognostic factors .
4 Methods : Data of 194 consecutive pts treated for metastatic colorectal cancer ( mCRC ) at our University Hospital in Udine , Italy , between Jan 2004 and Jan 2013 were reviewed .
5 Μ Point mutations were detected by pyrosequencing platform PyroMark Q96 ID instrument for KRAS/NRAS codons 12 , 13 , 61 , and 146 , BRAF exon 15 , and PIK3CA exons 9 and 20 .
6 Clinical and molecular prognostic factors were identified using the Cox proportional hazards model .
7 Results : The all wild-type population consisted of 76 pts ( 39% ) .
8 Μ 62 cases ( 32% ) harboured mutations in KRAS codons 12-13 .
9 Μ BRAF V600E mutation was found in 10 ( 52% ) samples .
10 Μ Mutations in KRAS 61-146 , PIK3CA and NRAS codons were detected in 9 ( 46% ) , 32 ( 165% ) and 6 ( 31% ) pts , respectively .
11 All factors significant in univariate analysis were subjected to multivariate analysis ( see Table ) .
12 The all-wild type category had the longest survival ( 277 months ) .
13 Μ Patients carrying BRAF mutations reported an overall survival of 7.6 months and those with KRAS 12-13 mutation 16.7 months .
14 Conclusions : This study reinforces the prognostic value of a full mutational molecular profile and points out some prognostic clinical factors in CRC .
15 The influence of clinical variables such as right colon cancer , primary tumour not resected , exposure to bevacizumab and lines of chemotherapy need further investigation .



PMID: AACR_2015-4689
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting constitutive GLI activation in colon carcinomas and cancers with oncogenic KRAS signaling .
1 The GLI genes , GLI1 and GLI2 , encode transcription factors that regulate target genes at the distal end of the canonical Hedgehog signaling ( HH ) pathway ( SHH - > PTCH - > SMO - > GLI ) , tightly regulated in embryonic development , tissue patterning and differentiation .
2 In cancers , both GLI1 and GLI2 are oncogenes , aberrantly and constitutively activated .
3 Oncogene -driven signaling pathways , in particular KRAS/BRAF in colon cancer , circumvent the HH-GLI axis to further drive GLI activation , which serves as a nodal channel for oncogenic signals , and provides a pivotal role for GLI in cell survival .
4 GANT61 , a small molecule inhibitor of GLI -dependent transcription , terminates oncogenic HH-GLI and KRAS/BRAF-GLI signaling , inducing DNA damage and extensive cell death in seven human colon carcinoma cell line models examined .
5 The overall goal is to understand how GANT61 induces cell death by inhibiting GLI -dependent transcription mechanisms .
6 We have demonstrated that GANT61 is : a ) specific for binding to GLI , and does not bind to DNA or to other transcription factors ; b ) selective for cancer cells versus normal cells that lack constitutive GLI activation .
7 Inhibition of GLI1 and GLI2 by GANT61 rapidly reduces GLI binding to consensus sequences in target gene promoters and inhibits GLI -dependent transcription .
8 Stalling of Pol II occurs adjacent to GLI binding regions at target gene promoters ( FOXM1 , BCL-2 ) , associated with inhibition of GLI binding , enrichment of Pol II , and modification of promoter -bound pause ( DSIF , NELF ) or pause-release ( P-TEFb ) factors within a 300bp region of the FOXM1 promoter .
9 Single-stranded DNA and RNA : DNA hybrids determining R-loop formation ( distributed throughout the nucleoplasm ) occur at sites of stalled Pol II , inhibited by RNAseH .
10 Consistent with transcriptional inhibition , GANT61 induced DNA damage (H2AX foci) in S-phase and non-S-phase cells , recognized at the initiation of S-phase ( G1/S ) , prior to the onset of cell death .
11 This may be due to one of two mechanisms : 1 ) The GLI1 target gene FOXM1 , and its transcriptional target CDC6 , downregulated in GANT61-treated cells , regulate Pre-Replication Complex assembly at G1/S thereby inhibiting the initiation of DNA replication ; this controls outcome of the GANT61 response , dependent on GLI ; 2 ) Transcriptional R-loop formation can conflict with DNA replication in GANT61-treated cells .
12 These events inhibit initiation of DNA replication from unfired origins at early replicons and inhibit further progression through S-phase .
13 GLI1 and/or GLI2 are constitutively activated in epithelial cancers of the GI tract , brain tumors , melanoma , pediatric solid tumors , liver , lung , breast , pancreatic and prostate cancers .
14 Further , KRAS is mutated in one third of all human cancers and in 50% of colon carcinomas .
15   Targeting GLI therefore has the potential for high impact in therapeutics , and is anticipated to lead to new approaches and therapeutic strategies for treating cancer .



PMID: ASCO_167714-176
(None)  
Terms: clinical trial, prospective
Sent# Symbols Sentence Mnemonics
0 Prognostication using molecular ( mol ) markers and clinicopathological ( clpath ) features in high-risk stage II/III colon cancer ( CC ) . .
1 Background : AJCC v.7 staging and clpath covariates do not accurately predict outcome of CC patients ( pts ) eligible for adjuvant chemotherapy ( adjCh ) .
2 Mol markers , microsatellite instability ( MSI ) and mutations ( mut ) in BRAF and KRAS , may further improve prognostication in high-risk CC .
3 Methods : Data from 4,796 stage II/III pts accrued to phase 3 trials PETACC3 and N0147 ( train set ) were used to construct Cox models for overall survival ( OS ) .
4 Variables included stage ( pT , pN ) ; clpath ( #/# lymph nodes [LNs] positive , #/# LNs assessed , tumor grade , primary site , age , gender , adjCh ) ; and mol ( MSI , BRAF and KRAS mut ) .
5 Final models ( 1 TNM ; 2 TNM + mol ; 3 TNM + clpath ; 4 TNM + clpath + mol ) were internally ( train set ) and externally ( test set ) validated on 597 stage II/III treated pts from non-clinical trial cohorts .
6 Results : All examined traits were statistically significant for OS prediction ( Table 1 ) .
7 We found significant interaction between site and MSI ( p = 03 ) in multivariate models , with worse OS for MSI versus MSS left CC (HR 122) and better OS for right CC (HR 070) .
8 Models 1 to 4 associated with C-indices of 0.65 , 0.68 , 0.70 , 0.72 , respectively , in train set ; and 0.68 , 0.71 , 0.73 , 0.74 in test set .
9 Corresponding time -dependent AUCs ( 5 years summary ) were 0.54 , 0.66 , 0.73 , 0.74 in train set ; and 0.55 , 0.68 , 0.72 , 0.73 in test set .
10 Conclusions : Incorporation of mol markers ( MSI , BRAF and KRAS mut ) improves prognostic estimation in stage II/III CC pts treated with adjCh .
11 We propose their prospective assessment in larger clinical cohorts , including untreated pts , and development of online calculators that could aid in prognostication ( model -based staging ) and patient/physician communication .
12 Multivariable OS Cox model in train set .



PMID: ASCO_189653-199
(Patient)  
Terms: observational studies, prospective, observational study
Sent# Symbols Sentence Mnemonics
0 Nut consumption and survival in stage III colon cancer patients : Results from CALGB 89803 ( Alliance ) . .
1 Background : Recent prospective cohort studies suggest states of energy excess and hyperinsulinemia , including type 2 diabetes ( T2D ) , obesity , sedentary lifestyle , Western pattern diet , increased dietary glycemic load , high intake of sugar-sweetened beverages , and elevated plasma C - peptide are each associated with an increased risk of colon cancer ( CC ) recurrence and mortality .
2 Conversely , observational studies indicate that increasing nut intake is associated with lower risk of T2D , metabolic syndrome and insulin resistance .
3 However , the effect of nut intake on CC recurrence and survival is unknown .
4   Methods : We conducted a prospective , observational study of 826 patients with stage III CC who reported dietary intake with food frequency questionnaires while enrolled in a randomized adjuvant chemotherapy trial .
5 Using Cox proportional hazards regression , we assessed associations of nut intake with cancer recurrence and mortality .
6   The primary endpoint was disease-free survival ( DFS ) defined as time from completion of dietary questionnaire following adjuvant therapy to cancer recurrence , death or last follow-up.Results : Compared to patients who abstained from nuts , those who consumed 2 servings of nuts per week had an adjusted hazard ratio ( HR ) of 0.58 ( 95% CI , 037 to 092 ; Ptrend = 003 ) for DFS and 0.43 ( 95% CI , 025 to 074 ; Ptrend = 001 ) for overall survival ( OS ) .
7 On subgroup analysis , the significant association was confined to tree-nut intake : HR = 0.54 ( 95% CI , 034 to 085 ; Ptrend = 004 ) for DFS and HR = 0.47 ( 95% CI , 027 to 082 ; Ptrend= 004 ) for OS .
8 There was no significant association between intake of peanut or peanut butter and patient outcome .
9 Association of total nut intake with improved outcomes was maintained across other known or suspected predictors of recurrence and mortality , including across common genomic alterations ( microsatellite instability , KRAS mutation , BRAF mutation , and PIK3CA mutation ) .
10 Conclusions : Higher consumption of nuts may be associated with significantly reduced cancer recurrence and death in patients with stage III CC .
11 Support : U10CA180821 , U10CA180882 , Pfizer .



PMID: AACR_2015-3984
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Increasing microRNA-378 to enhance sensitivity of EGFR inhibitor in colorectal cancer .
1 Μ Colorectal cancer ( CRC ) is the fourth most frequently diagnosed cancer , more then 40% of patients with CRC have KRAS mutations are resistant to anti-EGFR therapy .
2 Lower expression of microRNA-378 ( miR-378 ) was reported to be associated with CRC contain with KRAS or BRAF mutation when compared with wild type of CRC cells .
3 As known that miR-378 is derived from the 3-UTR of PGC-1 ( Peroxisome proliferator activated receptor gamma coactivator-1 ) gene , and expressed abundantly could be stimulated by lauric acid .
4 Therefore , we hypothesized once increase the expression level of miR-378 might restore the sensitivity to anti-EGFR sensitizing of cetuximab in KRAS or BRAF mutated colon cancer cells .
5 Herein , we firstly enhanced expression level of miR-378 in mutants via transfection method , and further treated with cetuximab , hopefully , the mutants re-sensitizing to previously failed therapies could be demonstrated .
6 Seven colon cancer cell lines with confirmed KRAS and BRAF statuses were used in current study .
7 Untreated original cells , cells treated with cetuximab , cells transfected with miR-378 , and miR-378 transfected cells combined with cetuximab treatment were included .
8 Cell viabilities were then measured for all , and compared to each other group .
9 Our results showed , after transfected miR-378 , although most all of KRAS mutants increased cell viabilities except the BRAF mutated CRC cells ; nevertheless , the mutants significantly responsed to cetuximab treatment could be observed when compared to the cells treated with cetuximab only .
10 The results indicated that increased the level of miR-378 combined anti-EGFR drug treatment could lead cell viabilities significantly decreased in either BRAF mutants or 50% of KRAS mutated cells .
11 Obviously , re-sensitized to anti-EGFR drug was coming off following transfected with miR-378 in mutated cells .
12 Based on above findings , we then further tried to use lauric acid ( C12 : 0 ) to enhance the expression level of miR-378 in the cancer cells , and hopefully it would benefit to those CRC cases who ever failed to anti-EGFR antibody treatment .
13 Μ The similar results showed once enhancing the expression level of miR-378 , and then treated with anti-EGFR antibody , consequentially lower cell survival could be observed .
14 Μ Lower protein expression of ERK 1/2 has been also been observed in lauric acid treated CRC cells .
15 All the results tend to disclose lauric acid might be an element , which could trigger KRAS cells restored sensitivity to anti-EGFR based drug .
16 In conclusion , elevating miR-378 expression level in mutated CRC cells by lauric acid , which could be easily derived from olive oil , would allow drug re-sensitization in both BRAF and 50% of KRAS mutated cells , the cells were all significantly suppressed by cetuximab .
17   The role of miR-378 in modulating anti-EGFR sensitivity is obvious ; therefore , it was strongly suggested to be a potentially new strategy for the clinical CRC patients who have failed anti-EGFR drug treatment .
18 Note : This abstract was not presented at the meeting .



PMID: AACR_2015-5424
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Therapeutic targeting of KRAS mutation-driven tumor progression in colorectal cancer .
1 Μ KRAS is the most frequently altered gene in colorectal cancer ( CRC ) , with mutations occurring in 30-40% of colorectal cancer .
2 Although KRAS mutation is associated with poor prognosis and resistance to anti-epidermal growth factor receptor therapy , the mechanism by which it promotes tumor metastasis remains undefined .
3 Our study explored a new hypothesis that targeting the Y-box binding protein-1 ( YB-1 )- insulin-like growth factor-I receptor ( IGF-IR ) signaling axis which is downstream of KRAS , with a novel integrin-linked kinase inhibitor , T315 , represents a therapeutically relevant strategy to block KRAS mutation-driven tumor progression .
4 Μ In liver metastases from CRC patients , we observed that there was a preponderance ( 79/108 ) of over-expression in both YB-1 and IGF-1R by immunohistochemistry .
5 In colon cancer cell lines HCT-116 and SW480 , knockdown and over-expression of KRAS affected the protein and mRNA levels of IGF-1R in a dose -dependent manner .
6 But KRAS only affected the protein level and not mRNA of YB-1 , thus suggesting that KRAS regulated YB-1 expression at the post-transcriptional level .
7 Manipulation of YB-1 via plasmid overexpression and siRNA affected IGF-1R protein and mRNA levels in a dose -dependent manner , and YB-1 and IGF-1R promoter binding was confirmed via ChIP assay .
8 There was a dose -dependent decrease in YB-1 and IGF-1R protein levels with MEK162 , a MEK inhibitor , but not with LY294002m a PI3K inhibitor .
9 This demonstrated that the KRAS regulation of the YB-1 - IGFR-1R signaling axis to be via the MEK signaling pathway and not PI3K/Akt .
10 Our novel drug T315 targets YB-1 , and was shown to inhibit cell viability and cell migration in a dose -dependent manner .
11 T315 treatment of the colon cancer cells also decreased protein levels of YB-1 and IGF-1R and affected epidermal mesenchymal transition markers such as E-cadherin , vimentin , and snail .
12   These results suggest that a combination of a MEK inhibitor and T315 may be an effective therapeutic strategy to target KRAS mutation driven CRC .



PMID: AACR_2013-5468
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 RET proto - oncogene point mutations in sporadic neuroendocrine tumors .
1 The epidermal growth factor receptor ( EGFR ) is overexpressed in many tumours and is a target for cancer therapy .
2 Cetuximab is a monoclonal antibody targeting EGFR .
3 It is used for the treatment of metastatic colorectal cancer ( mCRC ) as monotherapy and in combination with oxaliplatin or irinotecan-based chemotherapy .
4 Μ Several clinical studies have shown no benefit when cetuximab is combined with oxaliplatin as opposed to the positive effects observed with irinotecan .
5 The aim of this study is to investigate these interactions in cellular models of colon cancer .
6 The antitumour effects of cetuximab in vitro in combination with oxaliplatin or irinotecan were determined in the SW 48 colon cancer cell line and the isogenic KRAS mutant G12A cell line .
7 Combination indices ( CI ) describing the interaction of a fixed concentration of cetuximab and a range of concentrations of oxaliplatin or irinotecan were determined .
8 Combination of cetuximab ( 100g/ml ) with oxaliplatin ( 1M ) indicated antagonism in both cell lines tested ( CI = 47 in the KRAS wild type cell line and CI = 199 in the KRAS G12A cell line ) .
9 In contrast , the combination of cetuximab ( 100g/ml ) with irinotecan ( 01M ) showed synergistic effects ( CI = 028 in the KRAS wild type cell line and CI = 014 in the KRAS G12A cell line ) .
10 Preclinical studies have suggested that the cytotoxic efficacy of oxaliplatin may depend partially on the production of Reactive Oxygen Species ( ROS ) .
11 The combination of cetuximab with oxaliplatin resulted in a reduction of ROS levels by 30% 2.9 in the KRAS WT and by 40% 10 in the KRAS G12A cell line compared to those produced by oxaliplatin alone .
12 Additionally , levels of oxaliplatin-induced apoptosis measured by caspase 3/7 cleavage , were reduced by 70% 5.4 in the KRAS WT and by 50% 2.7 in the KRAS G12A cell line with the antioxidant N-acetyl-cysteine ( NAC ) , suggesting that oxaliplatin induces apoptosis through the production of ROS .
13 To elucidate the mechanism of the modulation of ROS by cetuximab and oxaliplatin , RT-PCR arrays analyzing 84 genes involved in oxidative stress response were performed following cetuximab , oxaliplatin and their combination treatment .
14 Experiments to determine the contribution of these genes to the antagonism between oxaliplatin and cetuximab are under investigation .
15 Our results show that alteration of ROS levels by cetuximab affects efficacy of oxaliplatin and suggests a key role for ROS in the observed antagonism between the two drugs .



PMID: AACR_2015-823
(Cell)  
Terms: , mice, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 Gene expression profiling for oncogenic Kras mutation in mice and human colorectal cancer .
1 Μ Purpose : Oncogenic KRAS mutations are found in 40-50% of human colorectal cancers .
2 However , specific therapeutics has not been yet available .
3 We aimed to search new therapeutic molecular targets or biomarkers in KRAS mutated colorectal cancers .
4 Experimental design : We generated Apcflox/flox ; CDX2P9.5-G22Cre and LSL-KrasG12D ; Apcflox/flox ; CDX2P9.5-G22Cre mice , that had been considered as sporadic colon cancer mouse model with Kras wild and mutant , respectively .
5 We observed the carcinogenesis at the age of 3-4 weeks by necropsy , and harvested the tumors for gene expression profiling .
6 We compared the gene expression by Microarray ( GeneChip , Affymetrix ) between each 3 tumors from these mice strains .
7 Genes with >5 fold changes between the two groups were selected as candidate genes , and subsequently narrow these down by bibliographic search for further analyses in human colorectal cancers .
8 Result : In macroscopic findings , extensive polyps were generated in cecum and proximal colon , but not in other site of gastrointestinal tract .
9 Tumors occurred in the both strains were considered as well differentiated adenocarcinomas in hematoxylin-eosin staining .
10 It was confirmed that tumors generated in Apcflox/flox ; CDX2P9.5-G22Cre mice had Cre-targeted Apc 580D alleles and wild-type Kras , and that tumors generated in LSL-KrasG12D ; Apcflox/flox ; CDX2P9.5-G22Cre mice had both Cre-targeted Apc 580D alleles and activated oncogenic KrasG12D .
11 Μ In the subsequent gene expression profiling , we identified 31 genes with >5 fold change in Microarray analyses .
12 Μ Of these , we focused on some genes that showed lower expression in Kras mutant tumor than in Kras wild type tumor .
13 We confirmed the lower expressions of these genes in murine tumors by quantitative RT-PCR , and the lower expression in early-staged human colorectal cancers with oncogenic KRAS mutant by immunohistochemistry staining .
14 To analyze the functions , the retroviral vectors that lead overexpression of these genes were constructed and infected to SW480 and RKO CRC cell lines .
15 Proliferation and migration is being analyzed using these cell lines .
16 Μ Conclusion : We identified novel genes associated with oncogenic KRAS mutation , using the analyses of gene expression in colon cancer mouse model .



PMID: ASCO_184370-199
(Patient)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 Association of microsatellite instability with distinct clinical and molecular characteristics in resected colon cancer : Analysis of a platform trial of the AIO colorectal study groupColopredict Plus. .
1 Background : High microsatellite instability ( MSI-H ) is a prognostic marker in resected colon cancer ( CC ) identified in post-hoc analysis of multiple trials .
2 However , validation in real-life cohorts and its association with clinical and molecular markers is lacking .
3 Methods : In Sep 2013 we started a platform trial in 49 German cancer centers recruiting patients with UICC stage II and III CC diagnosed between 2008 to 2016 .
4 MSI was tested by immunohistochemistry ( IHC ) of mismatch repair proteins MLH1 , MSH2 , MSH6 and PMS2 .
5 In case of any loss of protein expression ( IHC neg ) , fragment length analysis ( FLA ) was performed , defining MSI high tumors ( MSI-H ) and MS stable tumors ( MSS ) .
6 Besides , mutations in known prognostic factors for CC such as RAS , BRAF , PI3K and others were determined by next generation sequencing ( NGS ) .
7 Results : By end of 2016 , 1249 patients have been recruited into the trial : median age 73yrs. , stage II/III : 686/563 pts .
8 So far , tissue was analysed in 512 pts .
9 Of these , 182 pts .
10 were IHC neg with 116 pts .
11 tested MSI-H upon FLA ( 227% ) .
12 Median age was 73yrs. , female/male : 260/252 pts. , stageII/III : 292/220 pts .
13 Association of MS status with clinical factors is shown in Table 1 .
14 Μ Upon NGS analysis we found 16.3% BRAF mutations , 39% KRAS mutations , 2.8% NRAS mutations and 22.6% PI3K mutations .
15 MSI-H status was significantly associated with BRAF mutation and wildtype status of RAS .
16 Conclusions : We found a higher percentage of MSI-H cancers in our registry compared to reported data from randomised trials , possibly related to a higher median age in this real-life cohort .
17 MSI-H was associated with female sex , primary tumor site , and distinct molecular markers and should therefore be considered a heterogeneous subgroup of CC .
18 Updated analysis including NGS data and survival will be presented at the meeting .
19 Clinical trial information : AIO - KRK-0413 , DKRS : 00004305 .
20 Numbers of MSI-H and MSS by FLA in CC subpopulations .



PMID: AACR_2015-4147
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Synergistic effect of combined EGFR and Src inhibitor in colon cancer cell migration .
1 EGFR signaling plays the important role in cancer cell proliferation and cell migration .
2 Cetuximab which is the antibody against EGFR was approved for colon cancer treatment .
3 Recently , Src inhibitor , dasatinib has been demonstrated to improve drug sensitivity to cetuximab in KRAS mutant colorectal cancer cell growth .
4 Src is a non - receptor tyrosine kinase which is necessary for full activation of EGFR and also functions in focal adhesion kinase activity in cell migration , therefore , the combination of cetuximab and dasatinib may has effect on colon cell migration .
5 In this study , cetuximab and dasatinib were applied to SW480 colon cell which is KRAS mutant cell line .
6 Cell viability and cell migration were analyzed , localization of Src and focal adhesion kinase ( FAK ) were observed by confocal microscopy .
7 In the result , Combination of 5M cetuximab and 40 nM dasatinib treatment resulted in synergistic effect on cell viability .
8 However , when cetuximab combined with 25nM dasatinib was applied in trans-well migration assay , the synergistic inhibition on cell migration was observed .
9 The immunofluorescence confocal microscopic image demonstrated cetuximab treatment induced phospho-Src accumulation on the cell membrane and colocalized with phospho-FAK .
10 When the combination of 5M cetuximab and 25 uM dasatinib were applied in the cell , the membrane accumulation of phospho-Src and Phospho-FAK were decreased .
11 Taken together , cetuximab combined with dasatinib has synergistic efficacy in colon cancer cell proliferation , however , cetuximab combined with lower concentration of dasatinib ( 25nM ) suppressed cell migration by inhibited FAK membrane localization through Src inactivation .



PMID: AACR_2017-2173
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeting CDK1 and MEK/ERK overcome mutant BRAF -mediated apoptosis resistance in human colorectal cancer cells. .
1 BRAFV600E mutation occurs in ~10% of human colorectal cancers ( CRC ) where it is associated with treatment resistance and poor prognosis .
2 Data from TCGA and a clinical trial cohort identified a distinct subset of BRAF mutant colon cancers with deregulation of the cell cycle and overexpression of CDK1 ( Barras D , et al , Clin Cancer Res 2016 ) .
3 We tested the hypothesis that CDK1 inhibition can enhance apoptosis in BRAFV600E CRC cells .
4 Since BRAF mutant cells show p-ERK activation , combined inhibition of CDK1 and MEK/ERK was evaluated .
5 Using isogenic colon cancer cells , BRAF mutant alleles were shown to confer resistance to the CDK1 inhibitor , R0-3306 , in a gene dose -dependent manner that was associated with reduced cleavage of caspase-3 and downstream PARP , and decreased pH2AX ( DNA fragmentation marker ) .
6 Ectopic BRAFV600E or constitutively active MEK mutant also conferred resistance to R0-3306 .
7 CDK1 siRNA was shown to increase cobimetinib-induced apoptosis , including annexin V labeling , and increased pH2AX .
8 Furthermore , ERK siRNA or cobimetinib treatment attenuated CDK1 protein expression and increased R0-3306 -induced pH2Ax .
9   Moreover , treatment with R0-3306 plus cobimetinib significantly enhanced a caspase -dependent apoptosis and markedly reduced colony formation versus either drug alone in two CRC cell lines .
10 Caspase-3 cleavage by R0-3306 + cobimetinib was dependent upon caspase-8 .
11 Mechanistically , CDK1 inhibition by R0-3306 suppressed the phosphorylation of procaspase-8 at Ser-387 shown by R0-3306 withdrawal which restored p-C8-S387 coincident with expression of the mitotic marker , pH3S10 .
12 In conclusion , inhibition of CDK1 can significantly augment apoptosis induction by MEK/ERK inhibition in BRAFV600E CRC cells , suggesting a novel therapeutic strategy to overcome mutant BRAF -mediated resistance .



PMID: AACR_2016-2115
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 ✓ MEK/ERK and MCL-1 inhibition synergistically reverse apoptosis resistance in colon cancer cells with BRAF (V600E)- mediated MCL-1-upregulation .
1 Background .
2 Oncogenic BRAFV600E mutations in colorectal cancer ( CRC ) are associated with poor prognosis and treatment resistance .
3 BRAF mutations activate MAP kinase signaling and may confer apoptosis resistance by upregulating anti-apoptotic BCL-2/BCL-XL/MCL-1 proteins .
4 Results .
5 Ectopic expression of mutant BRAFV600E was shown to potently activate MEK/ ERK that mediated the phosphorylation ( T163 ) and upregulation of MCL-1 , but not BCL-2 or BCL-XL .
6 MEK/ERK -mediated phosphorylation of MCL-1 (T163) increased its protein stability , shown by an MCL-1 phospho-mimic mutant .
7 In human colon cancers , mutant versus wild-type BRAF was associated with increased MCL-1 expression by IHC .
8 MEK/ERK inhibition by cobimetinib induced pro-apoptotic BIM in BRAF mutant CRC cell lines ( HT-29 , RKO ) , and suppressed phospho-MCL-1/MCL-1 proteins as did ERK siRNA .
9 Suppression of MCL-1 by shRNA or using a small molecule MCL-1 inhibitor ( A-1210477 ) synergistically enhanced cobimetinib-induced apoptosis ( Table ) that was associated with BAK/BAX activation .
10 A-1210477 antagonized MCL-1 by disrupting its interaction with BAK and BIM proteins , shown by immunoprecipitation .
11 Conclusion .
12 BRAF/MEK/ERK induces upregulation of MCL-1 via phosphorylation/stabilization to confer apoptosis resistance that can be overcome by combined ERK and MCL-1 inhibition , suggesting a novel therapeutic strategy against BRAF mutant CRCs .



PMID: AACR_2012-2773
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 HSP90 inhibitors target KRAS mutant human tumors through degradation of STK33 .
1 Mutations in the KRAS proto-oncogene occur in 30% of human cancers and are particularly prevalent in adenocarcinomas of the pancreas , lung , and colon .
2 Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS have not met with success .
3 We have recently shown that cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation , supporting STK33 as a context -dependent therapeutic target .
4 However , specific strategies for interfering with the critical functions of STK33 , which remain to be elucidated , are not yet available .
5 Using a mass spectrometry-based screen for STK33 protein interaction partners , we report that the HSP9037 chaperone complex and BAG2 , a member of the BAG family of molecular chaperone regulators , bind to and stabilize STK33 in human cancer cells .
6 Pharmacologic inhibition of HSP90 , using structurally divergent small molecules currently in clinical development , induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo , and triggered apoptosis preferentially in KRAS mutant cells in an STK33 -dependent manner .
7 Furthermore , HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon cancer-initiating cells harboring mutant KRAS .
8 Similar to HSP90 inhibition , short hairpin RNA -mediated suppression of BAG2 depleted STK33 , whereas BAG2 overexpression rescued STK33 protein levels in the presence of HSP90 inhibitors , resulting in diminished apoptosis in KRAS mutant cancer cells .
9   These findings (1) provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells , (2) indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors , (3) identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential , and (4) point to BAG2 as a candidate cancer drug target .



PMID: ASCO_176416-195
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The clinical significance of KRAS monitoring in tumor tissues and blood of patients with pancreatic tumor. .
1 Background : Monitoring of gene alterations in blood to track circulating tumor DNAs has been attempted for a clinical application .
2 For example , KRAS monitoring in colorectal cancer provides a valuable biomarker for diagnosis and prediction of treatment outcome .
3 While half of of colon cancer has RAS mutation , 90% of pancreatic cancer shows KRAS mutation , suggesting that most of pancreatic cancer is a good candidate for KRAS monitoring .
4 In this study , we elucidated the clinical significance of KRASmonitoring in patients with pancreatic tumor during treatments .
5 Methods : KRAS mutation in tumor tissues was determined by Scorpion ARMS or RASKET methods in 39 patients with pancreatic tumors .
6 KRASmutation in blood ( G12D , G12V , G12C , G12A , G12S , G12R , G13D , Q61L , Q61H ) were investigated by using droplet digital polymerase chain reaction ( ddPCR ) in 24 patients treated with chemotherapy .
7 Μ Results : KRAS assessment in tumor tissues showed 33 patients with mutation and 6 patients without mutation .
8 ✓ Thirty-three patients with mutation showed significantly poor prognosis of 49% in three years overall survival ( OS ) as compared with 100% in 6 patients with mutation ( p = 002 ) . GM-ASS-RO, RO-ASS-GM
9 Μ KRAS assessment in blood revealed that KRAS mutation was detected in 14 patients , but no detection was seen in 10 patients .
10 ✓ Patients harboring KRAS mutation in blood exhibited significantly poor treatment outcome , including 12 patients with progressive disease , as compared with 10 patients without detection of mutation , including 6 patients with any treatment responses ( stable disease in 4 patients and partial response in 2 patients , p = 003 ) . GM-ASS-RO
11 Fourteen patients with mutation in blood displayed poor prognosis of 20% in three years overall survival ( OS ) , comparing to 69% in 10 patients without mutation in blood ( p = 006 ) .
12 ✓ Conclusions : KRAS status in tumor tissues was involved in prognosis ; in addition , KRAS status in blood was implicated in treatment response of chemotherapy in patients with pancreatic tumor . GE-INV-RO
13   KRAS monitoring in tumor tissues and blood provides useful information for the treatment strategy including chemotherapy in patients with pancreatic tumor .



PMID: AACR_2014-533
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MicroRNA486-5p is a KRas target involved in promoting cell proliferation in lung cancer .
1 Point mutations of ras genes ( K - , H - , and N-ras ) at codons 12 , 13 , and 61 and of the Gi2 alpha gene at codons 179 and 205 , were studied in 56 primary adrenal cortical tumors and 6 adrenal cortical hyperplasias .
2 Of 56 tumors , 24 were carcinomas and 32 were benign .
3 The 24 carcinomas and 20 of the benign tumors were from American patients ; the 12 remaining adenomas were from Japanese patients .
4 Of the benign tumors 12 were cortisol-producing adenomas , 15 were aldosterone-producing adenomas , 3 were nonfunctioning adenomas , and 2 were adenomas that produced a virilizing syndrome .
5 Μ Tumor DNA obtained from archival formalin-fixed , paraffin-embedded tissue or fresh frozen tissue was amplified by polymerase chain reaction ; and point mutations were detected by sequence -specific oligonucleotide hybridization .
6 Μ Activating ras mutations were found in 7 of 56 ( 125% ) of all tumors : 3 of 24 ( 125% ) carcinomas and 4 of 32 ( 125% ) adenomas .
7 Of adenomas from an American population , 4 of 20 ( 20% ) exhibited positive ras mutations , whereas none was present in the Japanese tumors .
8 Μ All mutations detected were adenine to guanine transitions at the second position of N-ras codon 61 , resulting in a conversion from glutamine to arginine .
9 Μ No mutations were found in K-ras or H-ras genes .
10 Μ Furthermore , no mutations of the Gi2 alpha gene were identified .
11 These findings demonstrate that N-ras mutations at codon 61 may contribute to the genesis of both benign and malignant human adrenal cortical tumors .
12 Μ Finally , no mutations of the ras or Gi2 alpha genes were identified in hyperplastic adrenocortical tissues .



PMID: AACR_2013-4162
(Patient)  
Terms: In vitro, in vitro
Sent# Symbols Sentence Mnemonics
0 Four human ras homologs differ in their abilities to activate Raf-1 , induce transformation , and stimulate cell motility .
1 Purpose : The microRNA-34 family ( miR-34a , -34b and -34c ) have been reported to be tumor suppressor microRNAs ( miRNAs ) that are regulated by the TP53 and DNA hypermethylation .
2 However , the expression , regulation , and prognostic value of the miR-34 family have not been systematically studied in colon cancer .
3 The aim of this study is to elucidate the roles of miR-34 family in colon carcinogenesis .
4 Methods : MiR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR .
5 We examined associations between miR-34a/b/c expression with TNM staging , cancer-specific mortality , TP53 mutation status , KRAS mutation status , promoter methylation andAffymetrix microarray data .
6 Μ Ingenuity Pathway Analysis ( IPA ) identified transcriptional regulators that were involved with miR-34 expression .
7 In vitro experiments were performed to identify the target gene of miR-34 family .
8 Results : All miR-34 family members were significantly increased in colon tumors , counter to the proposed tumor suppressor role for these miRNAs .
9 Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality .
10 While the expression of miR-34 family was not associated with TP53 mutation status , TP53 transcriptional activity was associated with miR-34a/b/c expression which is consistent with the proposed regulation of miR-34a/b/c by TP53 .
11 KRAS mutation status was associated with increased miR-34a expression .
12 Hypermethylation of miR-34a and miR-34b/c was found in tumors .
13 Μ IPA found that the activity of the tumor suppressor gene Peroxisome Proliferator-Activated Receptor ( PPARG ) was negatively associated with miR-34 expression , and in vitro experiments identified PPARG as a direct target of miR-34 family .
14 Conclusion : miR-34 family may have important roles in colon carcinogenesis as oncogenic miRNAs by targeting PPARG .



PMID: AACR_2013-1040
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 The effect of Irinotecan in k-Ras wild and mutant type colon cancer cell lines. .
1 Irinotecan ( IRI ) prevents DNA from unwinding by inhibition of topoisomerase1 .
2 Its main use is in colon cancer , in particular , in combination with other chemotherapy agents .
3 Recent studies , those withIrinotecan treatment has a synergistic effect appears .
4 However , there is no study on the effect of the Irinotecan mono-treatment .
5 In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor , especially kras wild and mutant type colon cancer , are not yet known .
6 Bax protein is a key mediator of apoptosis and might be related to chemosensitivity .
7 In this work , we evaluated the anti-tumorigenic action of these Irinotecan anti-cancer agent with especially k-ras wild and mutant type colon cancer cell lines , and investigated their apoptosis-inducing effects as the potential mechanism in this process .
8 The results show that the growth inhibitory effects of 5-fuorouracil ( 5-FU ) , Oxaliplatin ( OX ) produced a dose - and time dependent fashion in k-ras wild ( HT29 , Colo205 ) and mutant type ( HCT116 , DLD-1 ) colon cancer cell lines .
9 Otherwise , Irinotecan ( IRI ) produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines .
10 Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase , compared to untreated cells .
11 Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V - positive and PI-negative cells .
12 The results by multiple in vitro experimental model , showed that IRI induce these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria , the activation of caspase9 , the cleavage of PARP .
13 But Bax protein was inactivation in k-ras wild type colon cancer cell lines .
14 Importantly , inhibition of ERK kinase activity demonstrated that IRI -induced apoptotic pathway was regulated by the ERK signaling cascade .
15 These data indicate that Anti-cancer agent , Irinotecan , promotes Bax mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9 .



PMID: ASCO_52258-74
(None)  
Terms: phase II study, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 FOxTROT : Randomized phase II study of neoadjuvant chemotherapy with or without an anti-EGFR monoclonal antibody for locally advanced , operable colon cancer. .
1 Investigation of the signaling factors involved in Ras/MAPK-promoted metastasis in the PTEN/TP53/ mouse model. .



PMID: AACR_2015-3575
(Cell)  
Terms: xenograft, in vitro, mouse models, mouse
Sent# Symbols Sentence Mnemonics
0 Novel targets and monoclonal antibodies for antibody - drug conjugate therapy .
1 The study focuses on two novel potential therapeutic targets identified by an immune-histochemistry ( IHC ) screening with a large collection of polyclonal antibodies ( approximately 1600 ) raised against marginally characterized human proteins .
2 Here we describe the molecular characterization of two surface-exposed proteins ( EXN91 and EXN36 ) associated to different cancer types .
3 EXN91 is an adhesion molecule and it acts as a signaling receptor , cell communication and motility .
4 Μ Prevalence studies showed that the protein is mainly detected in colon cancer ( CRC ) with high frequency ( approximately 90% ) , both in early and advanced colon cancer stages , with a statistical association for early cancer stages .
5 Moreover , the protein is clearly surface exposed in liver metastasis from colon .
6 Experiments are ongoing to assess whether EXN91 is also expressed in precancerous conditions of colon and rectum that have the potential to develop into cancer .
7 Μ Interestingly , EXN91 is over-expressed in KRAS and BRAF mutant CRC with high frequency .
8 Moreover , an expanded IHC analysis revealed that it is also over-expressed and surface exposed in a number of other cancers , including HCC , RCC , bladder and endometrium cancer .
9 Preliminary data showed that EXN91 behaves as an auto-antigen being able to induce specific autoantibodies in CRC patients .
10 Μ EXN36 is mainly over-expressed in ovary and breast cancers ( frequency of approximately 30-40% ) , including triple negative breast cancer .
11 EXN36 prevalence studies in different cancer entities are ongoing .
12 Moreover , EXN36 is involved in cell proliferation , migration and invasiveness .
13 Murine monoclonal antibodies ( mAb ) able to recognize EXN91 and EXN36 on the surface of cancer cells show potential for specific therapeutic indications .
14 In particular , a murine mAb recognizes EXN91 on the surface of colon cancer cells , including KRAS and BRAF mutant CRC .
15 This antibody inhibits growth of colon cancer in xenograft mouse models .
16 Concerning anti-EXN36 antibodies , they are able to bind the surface of different breast and ovary cancer cells .
17 EXN36 and EXN91 mAbs show a high number of binding sites on the cell surface .
18 The mAb specificity has been confirmed in different immunoassays by gene silencing and peptide competition assays .
19 Moreover , they show limited IHC reactivity in normal tissues .
20 The anti-EXN36 and antiEXN91 antibodies are efficiently internalized by cancer cells , suggesting that they can be exploited for the development of Antibody-Drug -Conjugate ( ADC ) .
21 Initial results from in vitro studies show that these antibodies , when tested in drug screening assays with Protein G conjugated to commercially available drugs show significant anti-tumor activity with a specific conjugation chemistry .
22 Overall , the results indicate that EXN36 , EXN91 and their mAbs could be developed for the targeted therapy of different cancer indications at high medical need .



PMID: AACR_2013-5386
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Investigating the role of N-terminal protein methylation in colon cancer progression. .
1 We have recently identified the first mammalian N-terminal methyltransferase , NRMT .
2 NRMT is a highly conserved , ubiquitously expressed nuclear enzyme that is predicted to methylate more than 300 target proteins , including the proven targets Retinoblastoma Protein ( RB ) , DDB2 , and the oncoprotein SET .
3 N-terminal methylation has been shown to regulate protein -DNA interactions and has also been implicated in regulating protein stability .
4 Multiple microarray analyses have shown that NRMT is overexpressed in human colon cancer , and our preliminary data indicate the more aggressive the cancer , the higher the NRMT expression .
5 However , there are currently no commercially available inhibitors specific for this enzyme and very little is known about the downstream signaling consequences of NRMT misregulation .
6 We have used in silico screening of the ZINC small molecule library to identify potential NRMT-specific inhibitors .
7 Screening of the top 100 candidates produced 10 compounds that could inhibit NRMT methyltransferase activity in vitro .
8 The top compound of these 10 can also inhibit NRMT methyltransferase activity in cell culture and specifically stops the growth of colon cancer cell lines that have high NRMT expression .
9 We are currently working to optimize this small molecule inhibitor for stability and solubility , understand its downstream signaling consequences , and test its efficacy in a murine model system .
10   We are especially interested in the potential of NRMT inhibitors as a treatment for patients with mutant kRAS .
11   These patients are often insensitive to anti-EGFR therapy , but oncogenic RAS seems to require functional RB .
12 Therefore , impairment of NRMT activity could also impair oncogenic RAS signaling through destabilization of RB .
13 Data from this study will enhance our understanding of how colon cancer develops and could lead to novel treatments for the disease .



PMID: ASCO_176792-195
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Effect of colon cancer sidedness compared to tumor biology on stage-specific survival. .
1 Background : Recent studies have reported a survival difference between right colon cancer ( RCC ) and left colon cancer ( LCC ) but were limited by lack of data on surgical therapy and underlying tumor biology including microsatellite instability ( MSI ) status .
2 Our objective was to examine the influence of tumor sidedness on stage-specific survival after adjustment for those factors using a large national database .
3 Methods : Adult patients with primary invasive colon cancer were identified from the National Cancer Data Base ( NCDB ) between 2009 and 2012 .
4 Cecum , ascending colon , hepatic flexure , and transverse colon were classified as RCC and sigmoid , descending colon , and splenic flexure were classified as LCC .
5 Differences in 3-year overall survival ( OS ) between RCC versus LCC , stratified by stage , were obtained .
6 Results : Of 24,092 patients , 9,095 ( 3775% ) presented with a LCC and 14,997 ( 6225% ) with a RCC .
7   After adjustment for confounding factors , including demographics , MSI , KRAS , nodal retrieval and treatment , patients with RCC stage I , III , or IV had a 31-35% decreased OS compared to those with a LCC .
8 However , in patients with stage II disease , RCC had a 15% improvement in OS compared to LCC ( Table 1 ) .
9 MSI positivity was not significantly different in RCC versus LCC stage for stage nor did it contribute to decreased OS for either side .
10   Conclusions : Colon cancer sidedness is an independent risk factor for decreased survival after adjusting for potential confounders including tumor biology and treatment characteristics .
11 For patients with stage I , II , and IV disease , RCC portends a decreased survival compared to LCC , whereas the opposite is true for patients with stage II disease .
12 Further research is needed to elucidate the exact the role of sidedness in risk-profiling and staging for colon cancer patients .
13 Overall survival outcome by stage among patients with RCC versus LCC .



PMID: AACR_2014-5128
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Different effect of irinotecan induced apoptosis in k-Ras wild and mutant type colon cancer cell lines .
1 Irinotecan ( IRI ) prevents DNA from unwinding by inhibition of topoisomerase I .
2 Its main use is in colon cancer , in particular , in combination with other chemotherapy agents .
3 Recent studies , those withIrinotecan treatment has a synergistic effect appears .
4 However , there is no study on the effect of the Irinotecan mono-treatment .
5 In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor , especially kras wild and mutant type colon cancer , are not yet known .
6 Bax protein is a key mediator of apoptosis and might be related to chemosensitivity .
7 In this work , we evaluated the anti-tumorigenic action of these Irinotecan anti-cancer agent with especially k-ras wild and mutant type colon cancer cell lines , and investigated their apoptosis-inducing effects as the potential mechanism in this process .
8 The results show that the growth inhibitory effects of 5-fuorouracil ( 5-FU ) , Oxaliplatin ( OX ) produced a dose - and time dependent fashion in k-ras wild ( HT29 , Colo205 ) and mutant type ( HCT116 , DLD-1 ) colon cancer cell lines .
9 Otherwise , Irinotecan ( IRI ) produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines .
10 Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase , compared to untreated cells .
11 Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V - positive and PI-negative cells .
12 The results by multiple in vitro experimental model , showed that IRI induce these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria , the activation of caspase9 , the cleavage of PARP .
13 But Bax protein was inactivation in k-ras wild type colon cancer cell lines .
14 Importantly , inhibition of ERK kinase activity demonstrated that IRI -induced apoptotic pathway was regulated by the ERK signaling cascade .
15 These data indicate that Anti-cancer agent , Irinotecan , promotesBax-mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9 .



PMID: ASCO_88257-115
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 PKM2 mRNA expression to predict disease recurrence in patients with stage II or III colon cancer treated with oxaliplatin in combination with fluoropyrimidines. .
1 Background : Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase ( PKM2 ) , which is a key enzyme that regulates aerobic glycolysis in tumor cells .
2 Use of RNA interfering ( RNAi ) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models .
3 We evaluated the predictive significance of PKM2 in patients with high risk stage II or stage III colon cancer treated with oxaliplatin-fluoropyrimidines chemotherapy adjuvant treatment .
4 Methods : FFPE primary tumours from 261 patients with stage II or III colon cancer with colon cancer were analyzed for PKM2 mRNA expression by RT-qPCR .
5 All patients had received adjuvant treatment with an oxaliplatin and fluoropyrimidine combination .
6 Also , match normal mucosas from 50 of these patients have been analyzed .
7 Finally , 50 polyps ( 20 with low grade dysplasia , 20 high grade dysplasia and 10 serrated adenomas ) from non-colon cancer patients were included in the for PKM2 mRNA expression by RT-qPCR .
8 The analysis was performed with a set of primers and probes which amplify only the M2 isoform .
9 Results : PKM2 mRNA expression was significantly higher in tumor areas in comparison with normal mucosa ( p = 0001 ) and low-grade adenomas ( p = 0001 ) as well as in tumors with BRAF mutations ( p = 0001 ) .
10 Adenomas with high-grade dysplasia ( p = 0002 ) and serrated adenomas ( p = 0001 ) presented significantly higher PKM2 mRNA expression .
11 Overexpression of PKM2 was associated with significantly lower Disease Free ( p = 0018 ) and Overall Survival ( p = 0031 ) .
12 ✓ Μ Multivariate analysis revealed PKM2 high mRNA expression as independent prognostic factors for decreased DFS ( HR : 2.1 , p = 0.003 ) and OS ( HR : 1.8 , p = 0.019 ) . GE-MRK-RO
13 Conclusions : These results provide evidence that the PKM2 mRNA expression could be used as prognostic/predictive marker for disease recurrence in patients with operable colon cancer .
14   Analysis of the PKM2 mRNA expression in patients treated with non-oxaliplatin containing adjuvant treatment is currently performed .



PMID: AACR_2017-4386
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Identification of clinically relevant colon cancer genes predictve of improved relapse free survival. .
1 Colorectal cancer ( CRC ) is the third most common cancer worldwide , affecting over 15,000 individuals in Australia each year .
2 While CRC is often detected at a stage where resection of the primary tumour is possible , approximately 50% will relapse and die from metastatic disease .
3 Prognostication is mainly determined by tumour depth (T) , lymph node stage (N) and the extent of cancer spread (M) .
4 However , clinical outcomes of patients with the same TNM stage can be heterogeneous .
5   Therefore , there is a need to identify markers to better predict prognosis and stratify patients for treatment regimes .



PMID: ASCO_191488-199
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Comparison of BEAMing assays and competitive approaches in the detection of main alteration of RAS in circulating DNA of non small-cell lung cancer ( NSCLC ) and metastatic colon cancer . Manuscript 2016. .
1 ✓ Background : A number of RAS mutations confer resistance to anti-EGFR therapies routinely used in the treatment of colon cancer .
2 The objective of this study was to evaluate the pertinence of analyzing circulating-free plasma DNA ( cfDNA ) as an indicator of the mutational status of a tumor , in order to use liquid biopsies instead of invasive and painful tumor biopsies during tumor progression .
3 Methods : A cohort of 24 lung and 25 colon cancer patients was constituted in the Hospices Civils of Lyon .
4 Liquid biopsy plasma samples were collected at diagnosis ( colon cancer ) and during tumor progression ( lung cancer ) for the purpose of the current study .
5 KRAS and NRAS somatic alterations were quantified using three different technologies : the Droplet Digital polymerase chain reaction ( ddPCR ) from BioRad , the BEAMing Digital PCR from Sysmex Inostics , and the NGS NextSeq 500 by Illumina with the Accel-Amplicon 56G Oncology Panel from SWIFT BIOSCIENCES .
6 Μ Results : We observed a high level of sensitivity and specificity with the BEAMing technology , which provided us with excellent matches , around 96% and 73% , between solid and liquid biopsies taken at diagnosis ( colon cancer ) or during tumor progression ( lung cancer ) , respectively .
7 Indeed , when examining cfDNA from patients displaying one of the KRAS or NRAS mutations , 11 of the 13 mutations were confirmed using this technology , whereas only 5-6 matched the initial NGS status , using the two other technologies .
8 The detection threshold was estimated at 1% for samples containing atleast 0.8 ngctDNA/L for the multiplex screening ddPCR from BioRad and for the 56G Oncology Panel from SWIFT BIOSCIENCES .
9 The threshold was lower , at 0.03% , in samples containing only 0.25 ng ctDNA/L for the BEAMing technology , which includes a PCR pre-amplification step.Conclusions : The advantage of the Illumina NGS technology is the larger coverage of longer gene regions , and thus the detection of more genetic mutations .
10 Finally , the BEAMing technology enabled us to follow the appearance and disappearance of somatic alterations , with a very high level of sensitivity .



PMID: AACR_2014-1515
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Simultaneous detection of KRAS and TP53 mutations in human cancer cell lines using multiplex qPCR .
1 Genetic alterations in KRAS and TP53 genes are common in many cancers and the understanding of their role in progression of cancer is vital for the design of successful treatment approaches .
2 Studies suggest that mutations in KRAS and TP53 genes independently hindered the use of EGFR inhibiting drugs like Cetuximab ( Erbitux ) for the treatment of colorectal cancer (1) .
3 The genetic alterations in these genes are now routinely checked before starting any expensive treatments .
4 Μ Here , we successfully demonstrated use of duplex mutli-color SNP genotyping assays to detect KRAS and TP53 mutation in human colon cancer cell lines .
5 This method can be potentially used to analyze samples with limited quantity and get as much information as possible from a single sample .
6 To study the impact of these mutations , we generated gene expression profiles of 672 genes related to signaling pathways by using the Human signal transduction medium-throughput OpenArray Panel .
7 Selected cancer genes like BRAC1 , BAX , CFLAR , MYC and others were evaluated using multiplexed single-tube PCR simultaneously detecting four different targets in the same sample .
8 These results demonstrate that duplex SNP genotyping and multiplexed gene expression profiling from a single sample increases research capacity in situations when sample is limited .
9 Reference : 1 .
10 A Oden-Gangloff , F Di Fiore , F Bibeau , A Lamy , G Bougeard , F Charbonnier , F Blanchard , D Tougeron , M Ychou , F Boissire , F Le Pessot , J-C Sabourin , J-J Tuech , P Michel and T Frebourg .
11 ✓ TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy . GM-REG-RO



PMID: AACR_2016-672
(None)  
Terms: , mouse model, mouse, genetically engineered mouse, mice
Sent# Symbols Sentence Mnemonics
0 ✓ Differential effects of p53 mutations on cancer invasion and metastasis in a mouse model of colon cancer . GM-INV-RO
1 Inactivation of the APC ( adenomatous polyposis coli ) tumor suppressor gene plays an important role in initiating most adenomas and colorectal cancers ( CRCs ) .
2 Somatic mutations in the TP53 tumor suppressor gene and KRAS oncogene are found in roughly 60% and 40% of CRCs , respectively , and contribute to tumor progression .
3 In the vast majority of human CRCs , TP53 missense mutations lead to high levels of mutant p53 protein expression and the loss of the other wild type TP53 allele .
4 To evaluate the role of TP53 missense mutations in CRC progression , we generated a genetically engineered mouse model of colorectal carcinoma , via combined targeting of Apc , Kras , and Trp53 alleles in mouse colon epithelium , focusing on comparing phenotypic effects of the murine equivalent of the human R273H mutation ( i.e. , murine R270H mutation ) or a large deletion mutation of mouse Trp53 .
5 Inactivation of one allele Apc and activation of an oncogenic Kras allele in colon epithelium generated serrated and hyperplastic morphologic epithelium and adenomas .
6 The addition of either the R270H missense mutation or the Trp53 null mutation to the Apc and Kras mutations led to markedly shortened survival of the mice , due to the development of multiple colon tumors in each mouse ranging from adenomas to late stage adenocarcinomas .
7 Μ Evidence of invasion into the smooth muscle and serosa area was found in both compound mice with missense or deletion mutations in Trp53 , with the Trp53R270H mutant mice displaying an increased prevalence of deeply invasive tumors relative to the mice with deletion of Trp53 .
8 Μ Furthermore , we found that the missense mutant Trp53R270H allele in combination with Apc and Kras mutations , but not the null-mutant Trp53 allele , was strongly linked to metastases to lymph nodes and lung .
9 We have developed a useful mouse model of metastatic colon cancer that recapitulates the role of TP53 mutations in cooperating with APC and KRAS mutations in human CRC development and progression .
10 ✓ In addition , our findings strongly suggest a powerful role for missense mutant p53 proteins compared to TP53 null mutations in promoting invasion and metastasis in CRC progression . GM-REG-RO



PMID: ASCO_103629-127
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 DNA mismatch repair deficiency and benefit from adjuvant bevacizumab in NSABP C-08 : Molecular profiling results. .
1 Background : The purpose of this study was to identify biomarkers that define a subset of patients who received benefit from bevacizumab ( bev ) in NSABP trial C-08 , even though bev did not improve outcomes over standard adjuvant chemotherapy ( CT ) in the treatment of stage II and III colon cancer .
2 Methods : A randomly selected cohort of C-08 cases ( N = 500 ) were profiled for whole genome expression ( N = 445 ) and for mutations ( N = 463 ) in KRAS , NRAS , PIK3CA , and MET .
3 BRAF mutations and mismatch repair ( MMR ) status were profiled on the available cases ( N = 1,764 and 1,993 , respectively ) .
4 Cox proportional hazard models were used to assess prognosis and prediction for the value of bev using overall survival ( 0S ) and time to recurrence ( TTR ) as end points .
5 Results : The effect of bev was different for MMR deficient ( MMR-d ) and proficient tumors for OS ( interaction p = 035 ) but not TTR ( interaction p = 08 ) .
6 Patients with MMR-d ( N = 252 ) tumors showed a significant benefit from the addition of bev to CT for OS ( hazard ratio =0.52 ( 95% CI : 0.29-0.94 , p = 0.028 ) .
7 KRAS , NRAS , PIK3CA , and MET were not significant for interaction with bev in the discovery cohort .
8 ✓ BRAF mutations were associated with MMR status ( p < 0001 ) and the prognostic value of MMR depended on BRAF for TTR ( interaction p = 027 ) but not OS ( interaction p = 31 ) . GM-ASS-RO
9 The effect of bev was independent of BRAF ( interaction p = 28 TTR and 37 OS ) .
10 Three - factor interaction tests for bev , MMR , and BRAF were not significant for either endpoint .
11 Μ Gene expression analysis with BRB array tools identified 5 BioCarta pathways ( p < 005 ) which differentially expressed in 4 statistical tests ; 4 of these pathways were directly or indirectly involved in T cell activation and one was involved in the activation of VEGF .
12   Conclusions : Patients in C-08 with MMR-d tumors received benefit from bev treatment but these results need to be validated in a separate study .
13 Μ Gene expression data suggest that T - cells may be differentially expressed based on MMR status .
14 Activation of VEGF has been shown to suppress T - cell development ( Ohm et al Blood 2003 : 10 ; 4878 ) .
15 A speculative possibility for the benefit of bev in MMR-d tumors may be due to blocking of VEGF , releasing T cells from VEGF suppression .



PMID: ASCO_169815-176
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular markers and survival after recurrence in stage III colon cancers from NCCTG N0147 and NSABP C-08 adjuvant chemotherapy trials. .
1 Response to therapy of papillary thyroid cancer of known BRAF status .



PMID: AACR_2012-1902
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sorafenib overcome irinotecan resistance in colorectal cancer .
1 Prognostic significance of HER-2/neu overexpression in stage I adenocarcinoma of lung .



PMID: ASCO_97048-114
(None)  
Terms: retrospective, prospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 Molecular predictors of treatment response in colon and gastric cancer. .
1 Background : With the exception of KRAS mutational status , there is limited use of tumor-derived biomarkers in the clinical management of GI malignancies .
2 High ERCC1 expression is associated with inferior outcomes in platinum-exposed patients with non-small cell lung , esophageal , and head and neck cancers .
3 Previous studies have concluded ERCC-1 gene expression levels may identify patients unlikely to benefit from oxaliplatin-based chemotherapy in metastatic colon cancer and in the adjuvant therapy of esophageal/gastric cancer .
4 Methods : Biomarkers were obtained from formalin fixed paraffin embedded tumor samples from 69 colorectal and 22 gastric cancer subjects .
5 Each tumor was dissected using laser-captured microdissection and analyzed mRNA expression using a quantitative RT-PCR .
6 A retrospective chart review was performed to evaluate clinical response .
7 The primary objective was todetermine the prevalence of select tumor biomarkers including ERCC1 , TS , VEGFR2a , Her2 , KRAS , BRAF , and EGFR mutation status and and correlate these with overall survival .
8 ✓ Results : Colon : Subjects with high ERCC1 expression had significantly worse OS survival compared to those with lower ERCC1 expression ( 260 versus 711 mo , p = 00077 ) . GE-ASS-RO, RO-ASS-GE
9 There was a trend towards decreased OS with high TS expression , but this was not statistically significant ( 71 versus 56 mo , p = 049 ) .
10 ✓ Subjects with the V600E BRAF mutation had significantly worse OS compared to wild-type tumors ( 485 versus 613 mo , p = 003 ) . GM-ASS-RO, RO-ASS-GM
11 Gastric : Median OS was not reached due to a limited number of gastric subjects and only 9 of 22 had died at time of analysis .
12 Updated analysis is planned .
13 Conclusions : Even in this small population it is possible to detect survival differences using biomarker analysis of biopsy and resection specimens .
14 Virtually all tumor samples yielded sufficient material for analyses .
15 We suspect that the decreased OS in high ERCC1 expressing tumors is a result of platinum resistance .
16   These results suggest that the use of biomarkers may identify patients unlikely to respond to conventional therapy , and warrant further investigation in a prospective clinical trial .



PMID: AACR_2014-5102
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Telomeres and survival in stage III colon cancers : Findings from NCCTG N0147 ( Alliance ) study .
1 Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 ( CNKSR1 ) is correlated with clinical outcome in pancreatic cancer .



PMID: ASCO_185007-199
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Distribution and pathogenicity of nsSNPs in receptor tyrosine kinases ( RTKs ) in patients with colorectal cancer. .
1 Background : Non-synonymous single nucleotide polymorphisms ( nsSNPs ) occur along the entire sequence of RTKs and can promote oncogenic activity .
2 As prior hot-spot testing was limited to the tyrosine kinase domain ( TKD ) , next-generation sequencing ( NGS ) allows the discovery of novel extra-TKD variants .
3 Methods : We analyzed all nsSNPs in 29 RTKs of colon cancer patients ( pts ) who received tumor profiling ( 2013-2015 ) with Caris NGS .
4 Mutations were classified by location including the TKD , extracellular domain ( ECD ) , transmembrane domain ( TM ) , juxtamembrane domain ( JM ) and carboxy-terminal ( CT ) regions .
5 nsSNPs underwent in silico analysis using PolyPhen-2 ( Harvard ) to predict if damaging ( pnsSNP ) .
6 Results : 110 pts were identified with a median age of 58 years ( range 37-86 ) ; 55% male ; 57% white , 41% black. 51 were KRAS+ , 12 BRAF+ , 5 NRAS+ and 5 were microsatellite unstable ( MSI-H ) ; 67 were left-sided , 31 right-sided , 10 transverse and 2 unknown .
7 Μ A total of 171 nsSNPs and 7 pathogenic mutations ( Pmut ) were detected : ERBB2 ( ECD S310F , TKD V777L and TKD V842I ) , ERBB3 ( ECD A232V and TKD Q809R ) , FGFR2 (ECD S252L) and RET (TKD L790F) .
8 83/110 ( 76% ) pts had 1 RTK mutation ( median 1 ; range 0-9 ) .
9 Μ 72/171 ( 42% ) variants were pnsSNPs and found in 50 ( 45% ) pts ; 14% of pts had 2 .
10 All 29 RTKs had nsSNPs with median 6 ( range 2-12 ) ; 24/29 RTKs had a Pmut or pnsSNP ( median 2 ; range 0-8 ) .
11 RTKs with the most nsSNPs were EPHA5 ( 8/10 were pnsSNPs ) , PDGFA ( 7/8 ) , ALK ( 6/8 ) , ERBB4 ( 5/8 ) , NTRK3 ( 5/6 ) , cKIT ( 4/9 ) , ROS1 ( 3/12 ) , PDGFRB ( 3/6 ) and FGFR1 ( 3/6 ) .
12 nsSNPs were distributed across all RTK domains : 50% were ECD ( 30/86 pnsSNPs ) , 27% TKD ( 28/46 ) , 13% CT ( 7/22 ) , 5% JM ( 6/9 ) and 5% TM ( 1/8 ) .
13 No significant difference was seen between pnsSNP incidence and sidedness or KRAS/BRAF/NRAS status .
14 In MSI-H pts , 13/22 variants were pnsSNPs ( median 2 ; 1-5 ) ; 4/5 MSI-H were right-sided ( Fishers exact p < 001 ) .
15 Conclusions : > 70% colon cancer pts had 1 mutation in 29 RTKs with > 70% outside the TKD , and > 40% pnsSNPs .
16 MSI-H had a higher incidence of pnsSNPs ; further study is warranted to determine their significance and actionability .



PMID: ASCO_47556-74
(None)  
Terms: Phase III Trial, prospective
Sent# Symbols Sentence Mnemonics
0 Adjuvant mFOLFOX6 plus or minus cetuximab ( Cmab ) in patients ( pts ) with KRAS mutant (m) resected stage III colon cancer ( CC ) : NCCTG Intergroup Phase III Trial N0147. .
1 Background : FOLFOX is standard adjuvant therapy for resected stage III CC .
2 N0147 assessed the potential benefit of Cmab added to FOLFOX in resected stage III CC .
3 Initially N0147 enrolled pts regardless of KRAS status ; here we report efficacy and toxicity results in mKRAS pts prior to an amendment requiring prospective KRAS testing .
4 Methods : Pts were randomized to 12 biweekly courses of oxaliplatin 85 mg/m2 d1 , with leucovorin 400 mg/m2 , 5FU 400 mg/m2 bolus IV , then 46-hr IV 5FU 2,400 mg/m2 on d1-2 ( mFOLFOX6 ) , without ( arm A ) or with Cmab ( arm D ) 250 mg/m2 d1&8 , with Cmab at 400 mg/m2 , cycle 1 , d1 .
5 Tumors were centrally tested for KRAS .
6 This analysis focuses on pts with mKRAS CC .
7 The primary endpoint was 3-yr disease free survival ( DFS ) .
8 Secondary endpoints included overall survival ( OS ) and toxicity .
9 Results : 658 pts with mKRAS CC were enrolled prior to the prospective collection of KRAS ( Arm A , 340 ; Arm D , 318 ) .
10 Median follow-up is 22.4 months. 3-yr DFS favored FOLFOX alone ( HR 148 , 95% CI 108-203 ; p = 002 ) .
11 No benefit of Cmab was observed in any of the subgroups assessed .
12 OS also favored FOLFOX alone ( HR 167 , CI 100-280 ; p = 007 ) .
13 Increased toxicity and greater differences in outcomes were observed in pts aged 70 ( Table ) .
14 Conclusions : The addition of Cmab to mFOLFOX6 resulted in impaired DFS and a trend toward impaired OS in mKRAS resected stage III CC pts .
15 While some between-arm difference in toxicity and ability to complete the full course of FOLFOX were observed , it is unlikely these factors could account in whole for the poorer outcome with Cmab added to mFOLFOX6 in pts with mKRAS CC .
16 Supported by NIH Grant CA25224 , Bristol-Myers Squibb , ImClone , aanofi-aventis , and Pfizer .
17 OverallAge < 70 ( n = 566 ) Age > = 70 ( n = 92 ) FF+CpFF+CpFF+Cp3-yr DFS70.362.30.0268.063.80.0884.451.50.043-yr OS86.179.10.0785.981.80.2088.065.40.10On-study mortality0.591.90.130.691.820.2202.30.28Any Gr 3 AE52.768.9 < 0.00151.967.60.000257.176.70.05Gr 3 diarrhea7.514.80.0036.713.10.0112.225.60.10Gr 4 neutropenia11.112.90.489.513.10.1820.411.60.26Completed 12 cycles73.768.00.1174.868.50.1066.765.10.88Abbreviations : F , FOLFOX ; F+C = FOLFOX + Cmab ; p , p value .



PMID: AACR_2014-3697
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 SIRT2 is a modulator of response to targeted therapies through regulation of MEK kinase activity .
1 Resistance to targeted therapies is a major problem in cancer treatment .
2 The Epidermal Growth Factor Receptor ( EGFR ) antibody drugs are effective in a subset of colorectal cancers , but the molecular mechanisms of resistance are understood poorly .
3 Genes involved in epigenetic regulation are frequently deregulated in cancer , raising the possibility that such genes also contribute to drug resistance .
4 To address this question , we compiled an shRNA library for chromatin modifying enzymes , chromatin remodelers , and many other factors associated with chromatin regulation .
5 Using this library , we performed a loss of function genetic screen in colon cancer cell lines sensitive to EGFR inhibitors .
6 We identified SIRT2 , a NAD+ dependent deacetylase , as a modulator of the response to EGFR inhibitors in colon and lung cancer .
7 Mechanistically , loss of SIRT2 expression enhanced MEK acetylation , resulting in increased ERK activity .
8 Conversely , overexpression of SIRT2 led to reduced phospho ERK and inhibition of growth .
9 ✓ SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers , respectively .
10 These results warrant a further investigation into a potential role of SIRT2 in resistance to drugs that act in the Receptor Tyrosine Kinase-RAS-RAF-MEK-ERK signaling pathway .



PMID: ASCO_80808-102
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Pilot experience with adjuvant FOLFIRI with or without cetuximab in patients with resected stage III colon cancer : NCCTG Intergroup N0147. .
1 Background : Irinotecan ( CPT-11 ) has antitumor activity against metastatic colorectal cancer alone or with 5-fluorouracil ( 5FU ) /leucovorin ( LV ) .
2 Two arms with CPT-11 , 5FU , and LV (FOLFIRI) +/-cetuximab ( Cmab ) were originally included in N0147 .
3 However , after CALGB 89803 ( J Clin Oncol 25 : 3456 , 2007 ) , PETACC-3 ( J Clin Oncol 27 : 3117 , 2009 ) , and Accord02 ( Ann Oncol 20 : 674 , 2009 ) showed no benefit to a CPT-11 combination in adjuvant therapy , the CPT-11 arms of N0147 were discontinued .
4 We report the outcomes for patients given FOLFIRI and FOLFIRI+Cmab ( F-Cmab ) .
5 Methods : Patients with resected stage III colon cancer were randomized to one of 6 arms including 12 biweekly cycles of FOLFIRI ( CPT-11 180 mg/m2 d1 with LV 400 mg/m2 , 5FU 400 mg/m2 bolus IV , then 46-hr IV 5FU 2,400 mg/m2 on d1,2 ) without or with Cmab 400 mg/m2 d1 cycle 1 , then 250 mg/m2 d1 , 8 .
6 Primary endpoint was 3-year disease-free survival ( DFS ) .
7 Secondary endpoints included overall survival ( OS ) and toxicity .
8 Results : 146 evaluable patients ( Arm B-106 , Arm E-40 ) were enrolled ; median follow-up was 59.6 months ( range 15-72 ) .
9 In pts with wtKRAS ( vs mt ) cancers , trends toward improved DFS ( HR = 0.6 [95% CI 03-11] , p = 0.10 ) and OS ( HR 0.7 [95% CI 03-15] , p = 0.34 ) were observed .
10 The addition of Cmab improved DFS and OS in the overall group and within wtKRAS patients ( Table ) .
11 Grade >= 3 non-hematologic adverse effects were significantly increased in the Cmab arm ( 46% vs. 68% , p = 002 ) .
12 Conclusions : In this small randomized comparison , trends for improved DFS and OS with the addition of Cmab to FOLFIRI were observed in patients with resected stage III colon cancer patients , regardless of KRAS status .
13 Supported by NIH Grant CA25224 , Bristol-Myers Squibb , ImClone , Sanofi-Aventis , and Pfizer .



PMID: ASCO_131065-144
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Prognostic impact of clinicopathologic features in metastatic rectal versus colon cancer. .
1 Background : Variation in outcomes for rectal ( RC ) and colon ( CC ) cancer have been reported , particularly in the advanced disease setting .
2 Established differences in patterns of metastatic spread and recently described molecular analyses suggest differences in clinicopathological features that may impact on prognosis .
3 Here we aim to compare presenting features and outcomes in metastatic RC vs . CC .
4 Methods : Analysis of patients ( pts ) with newly diagnosed metastatic colorectal cancer enrolled onto an Australian prospective multicenter registry .
5 Data collection commenced in July 2009 , with 14 sites now contributing .
6 Disease characteristics , treatment and overall survival ( OS ) were compared for pts with RC vs . CC using the chi square and Cox proportional hazards methods .
7 Results : Of 1,048 pts , 305 ( 29% ) had RC and 730 ( 70% ) CC .
8 Pts with RC were younger ( median age 65 versus 70 years , p < 00001 ) and more likely male ( 64 vs. 55% , p = 001 ) .
9 Significant differences in metastatic spread were observed ; RC pts had more lung ( 40 versus 26% , p < 00001 ) , bone ( 43 vs. 19% , p = 0031 ) and brain ( 16 vs. 01% , p = 0004 ) metastases , whereas pts with CC had more liver ( 67 vs. 58% , p = 0006 ) and peritoneal ( 22 vs. 6% , p < 00001 ) disease .
10 Pts with RC were more likely to have metachronous ( 42 vs. 33% , p = 0005 ) and resectable ( 26 vs. 19% , p = 0015 ) metastatic disease , whereas more pts with CC had palliative primary tumor resections ( 55 vs. 26% , p < 00001 ) .
11 There was no significant difference in chemotherapy use .
12 KRAS mutation status was available for 391 ( 37% ) pts , with a trend towards fewer KRAS mutations in pts with RC ( 34 versus 43% , p = 01328 ) .
13 Adjusted OS was significantly longer for RC pts ( median 30.9 vs. 22.8 months , HR 0.65 ( 052-082 , p = 00002 ) .
14 Conclusions : Significant differences were observed between the presenting features of RC and CC , possibly contributed to by underlying differences in tumor biology .
15 Further exploring these may allow an improved understanding of differences in survival outcome and potentially define differences in the optimal approach to managing metastatic colon versus rectal cancer .
16 Accrual to this patient cohort is continuing , with additional centers being added , and further available molecular data , including MSI and BRAF mutation , is being retrieved .



PMID: AACR_2014-45
(Patient)  
Terms: retrospective study, in vitro
Sent# Symbols Sentence Mnemonics
0 MACC1 expression and KRas13 mutation for improved survival prognosis of colorectal cancer patients .
1 Colorectal cancer ( CRC ) is the third most common cancer worldwide .
2 The metastatic dissemination of the primary tumor is directly linked to patient survival .
3 We previously discovered the gene metastasis-associated in colon cancer 1 ( MACC1 ) .
4 MACC1 has been identified as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and for a variety of solid cancers .
5 MACC1 expression in tumor tissues and patient blood correlates with tumor formation and progression , development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis .
6 Μ Here we aim at the refinement of risk assessment in a retrospective study of 100 CRC patients with tumors staged I , II and III by combinatorial analyses of MACC1 with the KRas and BRaf mutation status .
7 First , we correlated the single parameters , KRas12 , KRas13 , BRaf600 mutation and MACC1 expression with clinical outcome data , such as metastasis-free survival ( MFS ) .
8 Μ We found correlations of high MACC1 expression with shorter MFS ( P < 0001 ) .
9 Likewise , patients with a somatic KRas13 mutation showed decreased MFS ( P = 0003 ) .
10 Interestingly , KRas12 or BRaf600 mutations as well as their wild type counterparts had no impact on survival prognosis .
11 Μ Multivariate analyses combining MACC1 expression level with the single parameters KRas12 , KRas13 and BRaf600 mutation revealed an improved prognosis exclusively for KRas13 mutated tumors vs . MACC1 expression alone .
12 High MACC1 expressers with KRas13 mutation had the poorest median MFS ( 172 months ) compared to MACC1 high/KRas wild type patients ( 372 months ; P = 0039 ) .
13 Further , we addressed the impact of KRas13 on regulation of MACC1 expression in vitro .
14 We used RNAi to analyze the impact of KRas signaling on MACC1 in several CRC cell lines with different KRas mutation status .
15 In addition , we employed HCT116 cells harboring the activating G13D KRAS mutation together with the HCT116-derived sublines Hkh-2 and Hke-3 lacking the mutated KRas13 allele by homologous recombination .
16 Disrupting the constitutive active KRas signaling led to increased MACC1 mRNA and protein expression levels in HCT116 cells , either by knock-down of the endogenous G13D mutated KRas expression by RNAi or through gene targeting .



PMID: ASCO_123215-143
(Patient)  
Terms: phase II trial, phase II study, NCT01308840, Clinical trial
Sent# Symbols Sentence Mnemonics
0 A single-arm phase II trial of gemcitabine , oxaliplatin , and panitumumab in KRAS wild-type advanced biliary tract cancer. .
1 Background : Biliary Tract Cancer ( BTC ) encompasses a group of aggressive , genetically heterogeneous tumors with limited systemic treatment options .
2 Currently platinum and gemcitabine-based therapy is the standard first - line treatment .
3 EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies ; and has shown specific advantages among KRASwild-type genetic subtypes of colon cancer .
4 Methods : Patients with histologically confirmed , previously untreated unresectable or metastatic KRAS wild type biliary tract or gallbladder adenocarcinoma with ECOG performance status ( PS ) 0-2 were eligible .
5 Patients were treated with Panitumumab 6mg/kg , Gemcitabine ( GEM ) 1000 mg/m2 (10 mg/m2/min) , Oxaliplatin ( OX ) 85 mg/m2on days 1 and 15 of each 28 day cycle .
6 The primary objective was to determine the objective response rate ( ORR ) by RECIST criteria v.1.1 .
7 Secondary objectives were to evaluate toxicity , progression free survival ( PFS ) , and overall survival .
8 Results : Of the 38 patients screened , 31 patients were found to have KRAS wild type genotype and enrolled .
9 The median age was 61 years old , 55% males , 100% of patients had an ECOG PS of <1 .
10 Twenty-five patients had intrahepatic cholangiocarcinoma , and 3 each had extrahepatic and gall bladder carcinoma .
11   Twenty-eight patients completed atleast 2 cycles of therapy and were evaluable for response .
12 The ORR was 50% ( 95% CI 238-762 ) .
13 With a median follow-up of 11 months , median PFS was 10.5 months ( 95% CI , 38 - 239 months ) and median OS was 24.8 months ( 95% CI , 90 months-no upper bound ) .
14 The most common grade 3 toxicities were fatigue 23% , anemia 23% , neuropathy 16% , elevated AST/ALT 16% , hyponatremia 13% , nausea 13% , rash 10% , neutropenia 7% , and hypomagnesemia 7% .
15 Grade 4 toxicities included leukopenia 10% , and 1 case ( 3% ) each of gallbladder perforation , hematoma , anemia , hyperkalemia , hyponatremia and hypokalemia .
16 Conclusions : Completed analysis of this phase II study of GEMOX-panitumumab for KRAS wild type advanced BTC reveals encouraging results with promising response rates and PFS .
17 The toxicity profiles were expected and manageable .
18 Further investigation of this regimen and anti-EGFR therapy is warranted .
19 Clinical trial information : NCT01308840 .



PMID: ASCO_187862-199
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Genomic overview of right-sided and left-sided colorectal cancer using comprehensive genomic sequencing. .
1 Background : Although the difference in right vs.left sidedness of colorectal cancer ( CRC ) in response to targeted therapy has been reported , we hypothesized that right-sided colorectal cancer ( RCC ) is more likely to have genetic alterations associated with resistance of anti-EGFR therapy .
2 We tested this hypothesis using comprehensive genomic sequencing ( CGS ) on a set of samples from well-characterized CRC patients .
3 Methods : Two-hundred-one primary colon cancer patients with either RCC or left-sided colorectal cancer ( LCC ) were analyzed .
4 We investigated gene alterations using 415 gene panel , which includes the gene alterations associated with resistance of anti-EGFR therapy : TK receptors ( ERBB2 , MET , EGFR , FGFR1 , and PDGFRA ) , RAS pathway ( KRAS , NRAS , HRAS , BRAF , and MAPK2K1 ) , and PI3K pathway ( PTEN and PIK3CA ) .
5 We defined the patients who had no alterations in any of the genes as all wild-type , who are theoretically considered as responders of anti-EGFR therapy .
6 Other patients with genetic alterations in resistance pathways were defined as mutant -type .
7 Results : Fifty-six patients ( 28% ) and 145 patients ( 72% ) had RCC and LCC , respectively .
8 Mutation of PIK3CA , BRAF , ACVR2A , MSH6 , and CTNNB1 were significantly associated with RCC .
9 Conversely , mutation of APC and TP53 were significantly associated with LCC .
10   Regarding the gene alterations associated with anti-EGFR therapy , only 6 of 56 patients ( 11% ) of RCC were all wild-type ; in contrast to 41 of 145 patients ( 28% ) of LCC that were all wild-type ( P = 0009 ) .
11   In 45 Stage IV patients treated with anti-EGFR therapy , RCC showed significantly worse progression-free survival ( PFS ) than LCC ( P = 0019 ) , and mutant -type RCC showed worse PFS compared to the others ( P = 0018 ) .
12 Conclusions : RCC is more likely to have the genetic alterations associated with resistance of anti-EGFR therapy compared to LCC .
13 Primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes in CRC .



PMID: ASCO_138851-158
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of the CpG island methylator phenotype as a predictive biomarker for adjuvant oxaliplatin-based chemotherapy in colorectal cancer. .
1 Pancreatic ductal adenocarcinoma ( PDAC ) has generally a poor prognosis , but recent data suggest that there are molecular subtypes differing in clinical outcome .
2 This study examines the association between histopathologic heterogeneity , genetic profile , and survival .
3 Tumor histology from 177 resected PDAC patients with follow-up data was subclassified according to predominant growth pattern , and four key genes were analyzed .
4 PDACs were classified as conventional ( 51% ) , combined with a predominant component ( 41% ) , variants and special carcinomas ( 8% ) .
5 Patients with combined PDACs and a dominant cribriform component survived longer than patients with conventional or other combined PDACs .
6 Μ Genetic alterations in atleast two out of four genes were found in 95% of the patients ( KRAS 93% , TP53 79% , CDKN2A/p16 75% , SMAD4 37% ) .
7 Patients with less than four mutations survived significantly longer ( p = 004 ) than those with alterations in all four genes .
8 Patients with either wildtype KRAS or CDKN2A/p16 lived significantly longer than those with alterations in these genes ( p = 0018 and p = 0006 , respectively ) .
9 ✓ Μ Our data suggest that the number of altered genes , the mutational status of KRAS and certain morphological subtypes correlate with the outcome of patients with PDAC . GE-ASS-RO
10 Future pathology reporting of PDAC should therefore include the KRAS status and a detailed morphological description .



PMID: ASCO_71346-103
(Patient)  
Terms: phase III trial
Sent# Symbols Sentence Mnemonics
0 Adjuvant FOLFIRI with or without cetuximab in patients with resected stage III colon cancer : NCCTG Intergroup phase III trial N0147. .
1 Background : Irinotecan ( CPT-11 ) has demonstrated antitumor activity against metastatic colorectal cancer used alone or with 5-fluorouracil ( 5FU ) /leucovorin ( LV ) .
2 Two arms with CPT-11 , 5FU , and LV (FOLFIRI) +/-cetuximab ( Cmab ) were originally included in N0147 .
3 However , after CALGB 89803 ( J Clin Oncol 25 : 3456 , 2007 ) , PETACC-3 ( J Clin Oncol 27 : 3117 , 2009 ) , and Accord02 ( Ann Oncol 20 : 674 , 2009 ) showed no benefit to the three - drug combination in adjuvant therapy , the CPT-11 arms of N0147 were discontinued .
4 We report the outcomes for patients given FOLFIRI +/- Cmab .
5 Methods : Following a signed informed consent patients with resected stage III colon cancer were randomized to one of 6 arms including 12 biweekly cycles of CPT-11 180 mg/m2 d1 with LV 400 mg/m2 , 5FU 400 mg/m2 bolus IV , then 46-hr IV 5FU 2,400 mg/m2 on d1-2 without ( Arm B , FOLFIRI ) or with Cmab ( Arm E ) 400 mg/m2 d1 cycle 1 then Cmab at 250 mg/m2 d1 and 8 .
6 Primary endpoint was 3-year disease-free survival ( DFS ) .
7 Secondary endpoints included overall survival ( OS ) and toxicity .
8 Results : 156 patients ( Arm B-111 , Arm E-45 ) were enrolled ; median follow-up on 81 patients in Arm B was 60.3 months and 58.2 months in Arm E for 41 patients .
9 wtKRAS ( vs mt ) status was associated with improved DFS ( HR = 0.6 [95% CI 04-11] , p = 0.09 ) and OS ( HR 0.7 [95% CI 04-15] , p = 0.38 ) .
10 The addition of Cmab improved DFS and OS in the overall group and within wtKRAS pts .
11 Grade greater than III non-hematologic adverse effects were significantly increased in the Cmab arm ( 46% vs. 64% , p = 005 ) .
12 Conclusions : In this randomized phase III trial adjuvant FOLFIRI resulted in a 3-year DFS lower than that expected for FOLFOX .
13 Trends for improved DFS and OS with the addition of Cmab were observed in patients with resected stage III colon cancer patients , regardless of KRAS status .
14 Supported by NIH Grant CA25224 , Bristol-Myers Squibb , ImClone , Sanofi-Aventis , and Pfizer .
15 Overall ( n = 156 ) wtKRAS ( n = 99 ) BEHR ( 95% CI ; p* ) BEHR ( 95% CI ; p* ) N11145-7227 - 3-yr DFS65%80%0.6 ( 03-11 ; 009 ) 67%88%0.4 ( 01-10 ; 005 ) 3-yr OS83%90%0.4 ( 01-10 ; 004 ) 83%92%0.3 ( 01-13 ; 008 ) * Score test p value .



PMID: ASCO_192404-199
(Patient)  
Terms: in vivo, xenograft, in vitro, Tumor xenograft model
Sent# Symbols Sentence Mnemonics
0 Impact of patient age on molecular alterations in left-sided colorectal tumors. .
1 Background : Src is a nonreceptor tyrosine kinase involved in the crosstalk and mediation of many signaling pathways that promote cell proliferation , invasion and angiogenesis .
2 Elevation of Src activity has been reported in many types of cancers including gastric cancer ( GC ) and biliary tract cancer ( BTC ) .
3 The purpose of this study is to evaluate Src as a therapeutic target and to elaborate the biomarkers of Src inhibitor in GC and BTC .
4 Methods : Ten gastric cancer cell lines ( SNU-1 , 5 , 16 , 216 , 601 , 620 , 638 , 668 , 719 , NCI-N87 ) and 8 biliary tract cancer cell lines ( SNU-245 , 308 , 478 , 869 , 1079 , 1196 , HuCCT1 , TFK1 ) were used .
5 Saracatinib and bosutinib were used as Src inhibitors .
6 MTT assay , colony formation assay and 3D culture were done for determining growth inhibitory effect of Src inhibitors , alone or in combination with chemotherapeutic agents ( 5-FU , gemcitabine , cisplatin ) .
7 Cell cycle analysis was done by FACS Calibur flow cytometer .
8 Matrigel invasion assay and wound healing assay were done .
9 The methods described by Chou and Talalay were used to determine whether a synergistic effect existed between drug combination .
10 Tumor xenograft model was made and used for in vivo test of Src inhibitors .
11 Results : Among 10 GC cells , SNU216 and NCI-N87 were sensitive to Src inhibitor .
12 Μ These sensitive cells showed high levels of pSRC (Y416) and pFAK ( Y861 , Y397 , Y925 ) .
13 These 2 sensitive GC cells are both HER2 amplified cells .
14 However , HER2-positive breast cancer ( BC ) cells ( SKBR3 , BT474 , MDA-MB453 ) were resistant to Src inhibitor .
15 Μ Contrast to these resistant BC cells , SNU216 and N87 showed high expression of integrin V , 4 and 8 .
16 Especially , in case of integrin 8 , the mRNA/protein levels were highest in SNU216 and N87 among all GC cells .
17 Src inhibitor -sensitive GC cells showed the apoptosis by Src inhibitor and synergism with 5-FU in vitro and in vivo .
18 Among 8 BTC cells , 3 cells were sensitive to Src inhibitor ( SNU308 , SNU478 and HuCCT1 ) in terms of growth inhibition and migration/invasion inhibition .
19 Μ Sensitive cells showed high levels of integrin 2 , 3 and 4 .
20 Src inhibitor induced G1 arrest and decreased pSrc , pFAK , and pERK in sensitive cells .
21 Inhibition of pSrc was accompanied with increase of PTEN and decrease of pAKT .
22 Src inhibitor showed the synergistic effects with cytotoxic chemotherapeutic agents ( gemcitabine and cisplatin ) in vitro and in vivo .
23 When the Src was inhibited , pSTAT3 was increased thru increase of IL-6 in some cells .
24 Conclusion : Taken together , Src could be a potential therapeutic target in gastric cancer and biliary tract cancer .
25 The role of integrin as a biomarker for Src inhibitor should be further investigated .



PMID: AACR_2014-4808
(Cell)  
Terms: xenograft, PDX, mouse
Sent# Symbols Sentence Mnemonics
0 Aflibercept is highly active in clinically relevant , patient derived xenografts of colorectal cancer .
1 Aflibercept ( ziv-aflibercept in USA ) , a new fusion protein , targets vascular endothelial growth factor ( VEGF ) -A , VEGF-B , and placental growth factor ( PlGF ) .
2 Aflibercept + FOLFIRI is approved for treating metastatic colorectal cancer ( mCRC ) that is resistant to or has progressed following an oxaliplatin containing regimen .
3 We investigated the pharmacological activity of aflibercept in CRC patient derived xenografts ( PDX ) , most metastases-derived , and characterized PDX molecular and phenotypic properties .
4 In 48 CRC PDX , Whole Exome Sequencing revealed : 85% APC , 79% TP53 , 51% KRAS , 3% NRAS , 25% PIK3CA , 11% PTEN and 8% BRAF mutants .
5 There was no significant association between angiogenic factors , tumor mutation profiles , and response to aflibercept .
6 In tumors , protein levels of human (h) VEGF-A were significantly higher than mouse (m) VEGF-A , hPlGF , and mPlGF ( Chiron et al , ESMO , 2013 ) .
7 Affymetrix probes detected VEGF-A and PIGF but not VEGF-B mRNA in most PDX .
8 There was no significant association between expression of angiogenic factors and response to aflibercept .
9 Histological sections of CRC tumors from PDX , xenografts created from cell lines , and patients tumor specimens indicated that stromal involvement in human tumors was recapitulated in PDX but not in tumors from cell lines .
10 PlGF expression was analyzed by immunohistochemistry on colon cancer tissue arrays .
11 Μ A significant number of colon cancer specimens were positive for PlGF , expressed in tumor cells and stroma .
12 Aflibercept resulted in anti-tumor activity in 47/48 CRC PDX models and complete tumor stasis in 31/48 models .
13 Efficacy data from 5 PDX models responsive to aflibercept and CRC standard of care ( SOC ) drugs , all administered as monotherapies , are below .
14   The robust activity of aflibercept in CRC PDX models that are sensitive to SOC drugs suggest that CRC patients would benefit from aflibercept treatment , independently of mutational status or expression of angiogenic factors .



PMID: AACR_2013-696
(Cell)  
Terms: xenograft, mice, mice bearing human xenograft models, mouse, mouse xenograft, mouse xenograft models
Sent# Symbols Sentence Mnemonics
0 Development of selective CDK8 inhibitors for colorectal cancer and mantle cell lymphoma treatment. .
1 CDK8 is a kinase component of the mediator complex which functions as a bridge between a basal transcriptional machinery and specific transcription factors .
2 Μ CDK8 is amplified and differentially expressed in colorectal cancer and in certain hematological malignancies such as mantle cell lymphomas .
3 Cells that express elevated CDK8 levels are highly dependent on its expression for proliferation .
4 Here we report development of first-in-class selective inhibitors CDK8 .
5 Compounds from the SEL120 series have binding affinities towards CDK8 in the low nM range .
6 Results from the kinome panel indicated that selectivity of SEL120 compounds was comparable with some of the most selective clinical kinase inhibitors .
7 SEL120 compounds reduced viability of mantle cell lymphoma and colorectal cancer cell lines , with particularly good activity in cell lines overexpressing CDK8 and with G13D mutation in KRAS .
8 Μ Slightly lower sensitivity was observed for cells with mutated P53 and other mutations in KRAS/BRAF pathway .
9 In contrast to pan-CDK inhibitors with main target activity on CDK9 , treatment with SEL120 compounds did not repress phosphorylation of PolII and did not cause global transcriptional shutdown .
10 Selective inhibition of CDK8 was sufficient to inhibit both paracrine and autocrine activities of cancer cells and stimulated normal cells .
11 Production of proinflammatory cytokines , such as IL6 was repressed by SEL120 compounds in normal and cancer cells stimulated by sub-optimal doses of chemotherapeutics .
12 SEL120 also reduced both murine and human IL6 in blood of mice bearing human xenograft models .
13 Oral administration of SEL120 revealed favorable pharmacokinetics profile and strong , dose dependent potency in colon cancer mouse xenograft models .
14 Presented data validate inhibition of CDK8 as a promising strategy for anticancer treatment , particularly for CRC and mantle cell lymphomas resistant to current treatments .



PMID: AACR_2016-510
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A novel circulating cell free DNA-based assay in colorectal cancer patients during treatment with systematic chemotherapy .
1 Introduction : Although circulating cell -free DNA ( cfDNA ) in blood plasma is being touted as a frontier noninvasive approaches , its clinical utility still remains questionable .
2 The purpose of this study was to compare the efficacy of cfDNA by comparing blood CEA levels and radiological evaluation in patients with unresectable metastatic colorectal cancer ( mCRC ) who received systemic chemotherapy .
3 Experimental Procedures : In this study , we measured aberrant cancer-specific methylation in cfDNA and the concentration of cfDNA in plasma obtained following each treatment cycle of systemic chemotherapy in three patients with mCRC .
4 To analyze aberrant cancer-specific methylation , we used a modified highly sensitive assay for bisulfite DNA followed by fluorescence-based PCR , as reported previously ( JNCI 2009 ) .
5 This methodology can detect methylation status in eight regions , therefore both recovery score ( RS ) and methylation score ( MS ) , ranged from 0-8 at a given time .
6 We measured RS and MS two-times in each plasma specimen obtained before administration of systemic chemotherapies .
7   Results : In this pilot study , we examined a series of blood plasma obtained from three patients who received oxaliplatin-based chemotherapy together with molecularly-targeted agents .
8 Despite initial tumor shrinkage in the metastases , all patients ultimately developed progressive disease ( PD ) .
9 Patient1 had wild-type KRAS , but had developed a sigmoid colon cancer with synchronous multiple liver and lung metastases .
10 In contrast , Patient2 had mutant KRAS with sigmoid colon cancer and synchronous multiple liver metastasis .
11   Μ Both patients 1 and 2 , demonstrated decreasing levels of CEA after the first - line chemotherapy , along with low methylation scores and concentration of cfDNA .
12 Interestingly , in both patients , MS and concentration level of cfDNA increased prior to radiographic documentation of PD .
13 Μ Patient3 harbored BRAF V600E mutation , and a cancer in the ascending colon with systemic lymph node metastasis .
14 Although , in this case , the tumor development progressed rapidly , similar to patients 1 and 2 , MS and the concentration levels of cfDNA also increased prior to radiographic documentation of rapid PD .
15   Conclusions : Our novel DNA methylation and concentration-based monitoring assay is a novel methodology for capturing DNA methylation in circulating cell -free DNA in plasma , and is useful for the early identification of colorectal cancer patients who are at risk of developing PD prior to radiographic documentation .



PMID: AACR_2014-1473
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Indentification of microRNA signature and deregulation in breast , lung and colon cancer through next generation sequencing and quantitative reverse transcriptase PCR .
1 Global alterations of microRNA expression have been described in a large number of malignancies and microRNA signatures have been used as classifier for diagnosis , prognosis and therapeutic response in cancer .
2 In current study , we compared the global patterns of microRNA expression in breast cancer , lung cancer and colon cancer patients with their normal adjacent tissues through next generation sequencing ( NGS ) .
3 Differentially expressed microRNAs such as let-7 family , miR34 family , miR21 and miR29 family , miR17 , miR92a , miR205 , miR145 as well as other signature microRNAs were further validated through quantitative reverse transcriptase PCR ( qRT-PCR ) .
4 Since microRNAs do not function in isolation , we also compared the expression level of possible targeted mRNAs such as target s for Let-7 family , HMGA2 ( high mobility group AT-hook2 ) , RAS , KRAS ; targets for miR-34 , SNAIL ( zinc finger protein ) , Wnt1 , SIRT1 and CDK6 ; targets for miR-21 , tropomyosin (TPM1) , PDCD4 and PTEN ; targets for MiR29 family , MCL1 , KLF4 through qRT-PCR .
5 Note : This abstract was not presented at the meeting .



PMID: ASCO_183589-199
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Analysis of survival and prognostic factors in metastatic colorectal cancer patients treated with first line bevacizumab. .
1 Background : Colorectal cancer is a major cause of mortality worldwide .
2 Survival has been improved by usage of bevacizumab .
3 Our study aimed to analyze survival and prognostic factors in metastatic colorectal cancer patients treated with first - line bevacizumab .
4 Methods : Files of patients were examined retrospectively and 360 patients treated with first - line bevacizumab were included .
5 Data regarding age , gender , family history , location of the primary , histopathology , KRAS status , surgery and chemotherapy were acquired from the files .
6 Overall response rates ( ORR ) to chemotherapy , progression and exitus dates or dates of last examination were recorded .
7 Median progression-free and overall survival ( PFS and OS ) were calculated .
8 Survival was analyzed with Kaplan-Meier method .
9 Log-rank test and Cox regression model were used for univariate and multivariate analysis , respectively .
10 Results : 201 ( %55,8 ) of the patients were male and 159 ( %44,2 ) were female .
11 Median age at the time of the diagnosis was 59.5. 260 patients ( %72,2 ) had initially stage IV disease .
12 KRAS was mutant in 125 patients ( %34,7 ) .
13 Median PFS was 8.5 months , median OS was 25.3 months and ORR was %51,4 .
14 Median PFS was 8.2 and 9.5 months , median OS was 30.4 and 28.1 months , ORR was %62,6 and %58.4 in KRAS wild type and mutant groups , respectively .
15 In patients with left colon cancer median PFS and OS ( 96 and 271 months ) were superior compared to patients with right colon cancer ( 73 and 194 months ) ( p = 0005 and 0016 , respectively ) .
16 ✓ Location of the primary , histopathologic grade , primary surgery , metastasectomy and KRAS status affected overall survival significantly ( p < 005 ) in univariate analysis . GE-INV-RO
17 In multivariate analysis , histopathologic grade ( p = 0034 ) and metastasectomy ( p = 0001 ) were independent prognostic factors .
18   Conclusions : In our study , response rates and survival of metastatic colorectal cancer patients treated with first - line bevacizumab were similar to previous studies .
19 Left colon cancer patients had superior median PFS and OS compared to right colon cancer patients as shown in recent studies .
20 Histopathologic grade and metastasectomy were independent prognostic factors in correlation with literature .



PMID: AACR_2016-3425
(Patient)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Prediagnostic alcohol consumption and colorectal cancer survival : the Colon Cancer Family Registry .
1 Previous studies have shown an increased risk of colorectal cancer ( CRC ) among moderate to heavy alcohol consumers relative to non-drinkers ; however , the relationship between alcohol and CRC survival remains unclear .
2 Using data from the international Colon Cancer Family Registry ( CCFR ) , we assessed the association between pre-diagnostic alcohol intake and survival outcomes after CRC diagnosis , overall and stratified by patient and tumor attributes .
3 CRC cases were identified via population-based cancer registries at four CCFR study sites , with diagnoses of incident , invasive CRC from 1997 to 2006 .
4 Study participants completed a risk factor questionnaire at enrollment which included information on several pre-diagnostic behaviors , including consumption of wine , beer , and liquor .
5 Prospective follow-up for survival outcomes was conducted for 4858 CRC cases with complete data on alcohol consumption .
6 Using Cox proportional hazards regression models with delayed entry to account for the time between diagnosis and study enrollment , we compared non-drinkers ( i.e. , alcohol intake <1 drink per week ) to individuals who consumed , on average , <1 serving of alcohol per day ( but 1 per week ) , and those who consumed 1 serving per day in the years preceding

CRC diagnosis .

7 Separate analyses were carried out for overall and disease-specific survival .
8 All models were adjusted for age at diagnosis , sex , study site , year of diagnosis , smoking history , CRC screening history , and body mass index .
9 Over a mean follow-up of 7.5 years , 1872 ( 39% ) study participants died , 1110 ( 59% ) of whom died from CRC .
10 Pre-diagnostic beer and liquor consumption were not associated with CRC survival ; however , consumption of 1 serving of wine per day was modestly associated with more favorable overall [hazard ratio ( HR ) = 0.80 , 95% confidence interval ( CI ) : 0.63-1.00] and disease-specific survival ( HR = 0.83 , 95% CI : 0.62-1.12 ) .
11 In stratified analyses , having consumed 1 serving of wine per day was slightly , but not statistically significantly , more strongly associated with overall survival among men than among women ( HR = 071 vs. 091 , respectively , p-heterogeneity = 012 ) and among those aged 50 than those aged >50 years ( HR = 066 vs. 084 , p-heterogeneity = 035 ) .
12 Similar patterns were noted with respect to disease-specific survival .
13 There were no differences in the relationships between wine consumption and survival outcomes stratified by tumor site , microsatellite instability , BRAF-mutation , or CpG island methylator phenotype status .
14 These results suggest that wine consumption prior to CRC diagnosis is modestly associated with more favorable survival after CRC diagnosis .
15 This modest inverse association does not appear to be limited to specific colorectal tumor subtypes and extends beyond overall survival to disease-specific outcomes .



PMID: ASCO_151339-156
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Molecular profile of synchronous metastatic colon cancer and anaplastic thyroid cancer in a patient with Lynch Syndrome. .
1 Background : Lynch Syndrome is an autosomal dominant disorder caused by either germline mutation in a DNA mismatch repair gene : MLH1 , MSH2 , MSH6 , or PMS2 , or epigenetic silencing of MSH2 .
2 The syndrome consists of early onset malignancies and multiplicity of cancers .
3 Colonic malignancies predominate with the frequency and distribution of extracolonic cancers dictated by the mutated gene .
4 Μ Methods : A 54 year old man with a family history of Lynch Syndrome and a MSH6 mutation was found to have synchronous colonic adenocarcinomas on screening colonoscopy .
5 Within weeks he presented with a rapidly enlarging anaplastic thyroid cancer ( ATC ) .
6 On PET/CT he was found to have liver metastases ( biopsy confirmed as colonic ) and pulmonary metastases ( biopsy confirmed as ATC ) .
7 Tumor tissue from his colon and thyroid was sent for FoundationOne analysis of 343 genes .
8 Cell free circulating tumor DNA ( CtDNA ) was sequenced for 54 genes using Guardant360 technology with blood taken post-thyroidectomy .
9 Results : FoundationOne sequencing is shown below .
10 The only shared mutation was the germline MSH6 .
11 Of the 16 mutated genes , 4 were included in the Guardant360 panel .
12 Μ The APC and KRAS mutations were detected in the CtDNA , as was a separate FBXW7 mutation and EGFR and ERBB2 mutations not seen in the Foundation One data .
13 Conclusions : This patient is 1 of 3 cases of ATC in Lynch Syndrome , and the first associated with MSH6 and synchronous colon cancer .
14 Molecular profiling shows a hypermutated phenotype , consistent with a loss of mismatch repair .
15 The unique signatures in the anaplastic and colonic primaries are more likely indicative of tissue -specificity while the discordance with CtDNA may represent tumor heterogeneity , evolution of the tumor during chemotherapy , or the limits of our current technology .



PMID: ASCO_174949-195
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Oncopre : A new chemotherapy benefit prediction algorithm to assist treatment decision making. .
1 Background : Clinical decision support tools ( CDSTs ) can help physicians make complex treatment decisions and inform care .
2 For colon cancer , CDSTs such as Adjuvant! Online and Numeracy were widely used to estimate the effects of adjuvant treatment and guide conversations with patients .
3 Existing CDSTs , however , do not consider more contemporary predictive and prognostic factors , such as microsatellite instability ( MSI ) , BRAF mutational status , or the presence of additional high risk clinical or pathological features ( HRFs ) , in their assessment of outcomes .
4 Current CDSTs are also not optimized for handheld devices .
5 Methods : We developed ONCOPRE , which is an adjuvant chemotherapy benefit calculator for colon cancer that addresses the limitations of current CDSTs .
6 Based on a comprehensive review of epidemiological data and results of landmark trials , ONCOPRE was devised to predict 5-year colon cancer recurrence and death .
7 To validate ONCOPRE , we compared its predictions with those generated by existing CDSTs as well as real-world data from 7 tertiary cancer centers across Canada .
8 Results : ONCOPRE is able to predict 5-year DFS and OS of patients with colon cancer based on age , sex , TNM status , and contemporary risk factors such as MSI status , BRAF mutations , and other HRFs .
9 ONCOPREs predictions compare favorably with real-world data and predictions from other CDSTs .
10   ONCOPREs predictions are typically more optimistic than historical outcomes , and this likely reflects the fact that current day colon cancer patients experience better prognosis with the use of modern therapy and improved supportive care .
11 These attributes make ONCOPRE a potentially new benchmark among CDSTs that can reliably predict colon cancer outcomes .
12   Conclusions : ONCOPRE ( http : //wwwoncoprecom/beta/ ) represents a new CDST that can assist in adjuvant treatment decision-making and patient counseling .
13 We make the case that the next generation of CDSTs in oncology must take into account more contemporary clinical , biochemical , and genetic risk factors since these elements significantly affect outcomes .
14 The ONCOPRE platform serves as a potential model on which to develop prediction tools for other forms of cancers .



PMID: ASCO_176030-198
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Novel , simplex and multiplex assays for BRAF mutation detection. .
1 Background : Clinical decision support tools ( CDSTs ) can help physicians make complex treatment decisions and inform care .
2 For colon cancer , CDSTs such as Adjuvant! Online and Numeracy were widely used to estimate the effects of adjuvant treatment and guide conversations with patients .
3 Existing CDSTs , however , do not consider more contemporary predictive and prognostic factors , such as microsatellite instability ( MSI ) , BRAF mutational status , or the presence of additional high risk clinical or pathological features ( HRFs ) , in their assessment of outcomes .
4 Current CDSTs are also not optimized for handheld devices .
5 Methods : We developed ONCOPRE , which is an adjuvant chemotherapy benefit calculator for colon cancer that addresses the limitations of current CDSTs .
6 Based on a comprehensive review of epidemiological data and results of landmark trials , ONCOPRE was devised to predict 5 year colon cancer recurrence and death .
7 To validate ONCOPRE , we compared its predictions with those generated by existing CDSTs as well as real-world data from 7 tertiary cancer centers across Canada .
8 Results : ONCOPRE is able to predict 5-year DFS and OS of patients with colon cancer based on age , sex , TNM status , and contemporary risk factors such as MSI status , BRAF mutations , and other HRFs .
9 ONCOPREs predictions compare favorably with real-world data and predictions from other CDSTs .
10   ONCOPREs predictions are typically more optimistic than historical outcomes , and this likely reflects the fact that current day colon cancer patients experience better prognosis with the use of modern therapy and improved supportive care .
11 These attributes make ONCOPRE a potentially new benchmark among CDSTs that can reliably predict colon cancer outcomes .
12   Conclusions : ONCOPRE ( http : //wwwoncoprecom/ ) represents a new CDST that can assist in adjuvant treatment decision-making and patient counseling .
13 We make the case that the next generation of CDSTs in oncology must take into account more contemporary clinical , biochemical , and genetic risk factors since these elements significantly affect outcomes .
14 The ONCOPRE platform serves as a potential model on which to develop prediction tools for other forms of cancers .



PMID: AACR_2012-4420
(Cell)  
Terms: Clinical trial, rat
Sent# Symbols Sentence Mnemonics
0 Serum regulates reovirus-mediated cytopathy in K-Ras activated colorectal cancer and intestinal epithelial cell lines .
1 Background : The oncolytic potency of replication competent REOvirus has been demonstrated in various cancers .
2 The activity is most pronounced in Kras mutant cancer cells , which account for 30-40 % of all cancers .
3 Herein we simultaneously utilized isogenic human derived colorectal cancer cell lines that differ only by the presence of mutant Kras and normal rat intestinal epithelial cells with inducible Kras to evaluate whether the presence of oncogenic Kras alters the sensitivity of colon cancer cells to reovirus .
4 Methods : Reovirus was obtained from Oncolytics Biotech Inc .
5 Rat IEC's harboring IPTG inducible mutant Ras oncogene ( IEC-iKras ) were treated with reovirus IPTG .
6 The infectivity was maintained at a multiplicity of infection ( MOI ) of 2 .
7 MTT assay was performed at 72 hours to determine cell vability ( CV ) .
8 Similar experiments were also performed with HCT116 ( Kras mut ) and its isogenic derivative Hke3 [ ( Kras wild type ( WT ) ] .
9 Cells were cultured and treated in both serum rich ( SR ) and serum free ( SF ) media to determine the effect of growth factors on sensitivity to reovirus .
10 Alterations in gene expression were determined by real time PCR and protein expression by western blot .
11 Results : The activity of reovirus was observed in all cell lines studied .
12 Reduction in CV was greater in Kras mutant HCT116 compared to WT Hke3 cells .
13 Consistently , induction of Kras in IEC cells increased the potency of reovirus .
14 ✓ Furthermore , this effect was more prominent in cells cultured in SF suggesting that growth factors in the serum may attenuate the effect of mutant Kras on reovirus sensitivity .
15 Expression of the cell cycle regulator , p21 was preferentially increased upon reovirus infection in Kras mutant compared to WT cells , and in cells cultured in SF compared to SR conditions .
16 ✓ Conclusion : Oncogenic Kras mutations increase the sensitivity of colon cancer cells to Reovirus .
17 Clinical trials are underway testing reovirus in patients with Kras mutant metastatic colorectal cancer .



PMID: ASCO_126850-144
(Patient)  
Terms: prospective study
Sent# Symbols Sentence Mnemonics
0 Circulating tumor DNA ( ctDNA ) as a marker of recurrence risk in stage II colon cancer ( CC ) . .
1 Background : Markers that better define recurrence risk for patients ( pts ) with stage II CC are urgently required , potentially defining a subset that would most benefit from adjuvant chemotherapy ( CTX ) and intensive surveillance .
2 An alternative strategy to standard analyses of the resected surgical specimen is to directly examine plasma for evidence of residual disease .
3 Recently , ctDNA has shown promise as a blood biomarker in advanced colorectal cancer ; here we explore the potential of this marker in stage II CC .
4 Methods : In this prospective study , plasma samples are being collected at 4-10 weeks post-op in 250 stage II CC pts , with serial 3 monthly samples on a subset of 175 pts .
5 Adjuvant CTX is at clinician discretion , blinded to ctDNA analysis .
6 Surveillance includes 3 monthly CEA and 6 monthly CT imaging for 2 years .
7 Μ All samples were sent to Johns Hopkins Kimmel Cancer Center , where tumor tissue was analyzed for hotspot mutations in TP53 , APC , KRAS , NRAS , BRAF , PIK3CA , CTNNB1 , SMAD4 , and FBXW7 using a massively parallel sequencing platform ( Safe-SeqS ) .
8 Μ The identified mutation was queried and quantified in plasma using the same platform , blinded to clinical data .
9 Results : Preliminary data is available on 78 of the 190 pts enrolled to date .
10 Median age is 66 years , 25/78 ( 32% ) received adjuvant CTX .
11 Μ At least 1 mutation was found in all tumors , with matching ctDNA detectable in 6/78 ( 77% ) plasma samples. 10 ( 128% ) recurrences have occurred at a median follow-up of 507 days , including 5 of 6 pts with detectable ctDNA and 5 of 72 with no detectable ctDNA ( Table ) .
12 Pts with detectable ctDNA had a shorter recurrence-free survival ( median 234 days versus undefined , HR 2309 , log-rank p < 00001 ) .
13 In an exploratory analysis of the correlation between ctDNA and clinicopathologic features , detectable ctDNA maintained prognostic significance , including for T3 tumors ( HR for time to recurrence 8055 , log-rank p < 00001 ) .
14 Conclusions : Early data suggests ctDNA is a promising marker of recurrence risk in stage II CC .
15 Preliminary analyses suggests this may be independent of clinicopathologic features .



PMID: ASCO_177006-195
(Cell)  
Terms: xenograft, in vitro, mice
Sent# Symbols Sentence Mnemonics
0 ✓ Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer. .
1 Background : Oncogenic BRAFV600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer ( CRC ) .
2 In BRAFV600E mutant CRCs , treatment failure may be related to BRAFV600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism .
3 Methods : BRAF isogenic RKO CRC cells and RKO , HT29 , WiDr cell lines were treated with cobimetinib the small molecule MCL-1 inhibitor , A-1210477 .
4 Apoptosis was measured by Annexin V staining and caspase cleavage .
5 Gene knockdown or overexpression was achieved by lentivirus ; ERK siRNA was utilized .
6 Competitive RT-PCR was performed for MCL-1 mRNA expression .
7 HT-29 cells with control or MCL-1 shRNA were xenografted into SCID mice , treated with cobimetinib or vehicle , and tumor volume was measured .
8 Results : We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose -dependent manner using CRC cell lines isogenic for BRAF .
9 BRAFV600E -induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate ( MCL-1Thr163 ) and stabilize MCL-1 .
10 Upregulation of MCL-1 was mediated by MEK/ERK shown by ERK siRNA that suppressed MCL-1 .
11 Stabilization of MCL-1 by phosphorylation was shown by a phosphorylation-mimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover , respectively .
12 MEK /ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced pro-apoptotic BIM to a greater extent than did vemurafenib in BRAFV600E cell lines .
13 MCL-1 knockdown versus control shRNA significantly enhanced cobimetinib-induced apoptosis in vitro and in HT29 colon cancer xenografts .
14 A-1210477 also enhanced cobimetinib-induced apoptosis in vitrothat was due to disruption of the interaction of MCL-1 with pro-apoptotic BAK and BIM .
15 Knockdown of BIM attenuated BAX , but not BAK , activation by cobimetinib plus A-1210477 .
16 Conclusions : BRAFV600E -mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism .



PMID: ASCO_194901-199
(Patient)  
Terms:
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0 RAS mutation testing and cetuximab use for colorectal cancer at VA Hospitals. .
1 Background : Extended RAS testing in colorectal cancer predicts response to therapy with EGFR -directed therapies cetuximab and panitumumab .
2 In 2010 VA policy recommended testing of all potentially treatable metastatic colon cancer patients for KRAS mutations .
3 We explored the uptake of RAS testing within the VA system and characterized mutation frequency and cetuximab use .
4 Methods : We extracted records of VA patients with first primary colorectal cancers diagnosed between 2011 and 2015 from the VA Central Cancer Registry ( VACCR ) .
5 We included patients who had RAS testing from 4 commercial laboratories contracted with the VA .
6 We gathered genomic testing results from the commercial vendors .
7 We calculated descriptive statistics of mutation sites and used multivariable logistic regression to evaluate predictors of mutations and cetuximab use .
8 Results : Colon cancer diagnoses decreased in the VA from 4285 cases in 2011 to 3275 cases in 2015 and we observed a concurrent increase in KRAS testing from 4.7% in 2011 ( 202 cases ) to 10.3% in 2015 ( 336 cases ) ( p < 0001 ) .
9 KRAS tested patients were 65.7% white , 26.1% black , 3.1% Hispanic , and 2.8% female .
10 Among 1717 patients tested , 588 had mutations ( 342% ) , with 441 ( 75% ) in codon 2 , 117 ( 199% ) in codon 13 , 23 ( 39% ) in codon 61 .
11 There were no differences in mutation rates by age , race , ethnicity , or gender categories .
12 A total of 189 patients received cetuximab ; 11 of 558 ( 19% ) KRAS mutants and 178 of 1095 ( 162% ) KRAS wildtype received cetuximab .
13 Across all patients , increasing age in years predicts for cetuximab non-use ( OR 0983 , 95% CI 097-099 ) ; gender , race , and ethnicity did not .
14 Μ Conclusions : We found a significant increase in KRAS testing between 2011 and 2015 , with mutation patterns reflective of the US population .
15 Μ We found a low rate of inappropriate cetuximab use among patients with KRAS mutations , as well as an also low rate of cetuximab use among KRAS wild type patients among which it may be indicated .
16 Further study is warranted to understand patterns of appropriate and inappropriate use of targeted agents .



PMID: ASCO_144132-156
(Patient)  
Terms:
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0 Relationship between metformin use and recurrence and survival in patients ( pts ) with resected stage III colon cancer ( CC ) receiving adjuvant chemotherapy : Results from NCCTG N0147 ( Alliance ) . .
1 Background : Although preclinical and epidemiological data suggest that metformin may have antineoplastic properties in CC , the impact of metformin use on pt survival in stage III CC undergoing curative resection is unknown .
2 Methods : Before randomization to FOLFOX +/- cetuximab , 1958 stage III CC pts enrolled on N0147 study completed a questionnaire that included information on diabetes mellitus ( DM ) and metformin use .
3 Cox models assessed the association between metformin use and outcomes of disease free survival ( DFS ) , overall survival ( OS ) and time to recurrence ( TTR ) , adjusting for clinical/pathological factors .
4 Results : 1691 ( 86% ) , 115 ( 6% ) and 152 ( 8% ) of 1958 pts reported no history of DM , DM with metformin use , or DM with no metformin use , respectively .
5 The two treatment arms were pooled since metformin use showed homogeneous effects on outcomes across arms .
6 There was no difference in DFS , OS and TTR irrespective of metformin use when DM pts were compared to non-DM pts , after adjusting for tumor/pt factors ( Table ) .
7 Within the cohort of DM pts ( n = 267 ) , DFS ( HR = 0.90 ; 95% CI : 0.59-1.35 ; p = 0.595 ) , OS ( HR = 0.99 ; 95% CI : 0.65-1.49 ; p = 0.948 ) and TTR ( HR = 0.87 ; 95% CI : 0.56-1.35 ; p = 0.534 ) were similar in metformin users compared to non-users .
8 Survival outcomes were comparable regardless of duration of metformin use ( < 1 , 1-5 , 6-10 , 11+ years ) before randomization ( p = 0361 for DFS ; p = 0068 for OS ) .
9 Μ There were no interaction effects observed between metformin use and clinical/pathological factors ( KRAS , BRAF mutation status , tumor site , T/N stage , gender , and age ) .
10   Conclusions : Stage III CC patients treated with adjuvant chemotherapy who used metformin experienced similar DFS , OS , or TTR compared to non-DM pts or DM pts without metformin use .



PMID: AACR_2015-4902
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Detecting low abundant mutations in circulating cell free DNA and FFPE samples .
1 Detection of low abundant alterations in oncogenes from circulating cell free DNA ( cfDNA ) samples or formaldehyde fixed-paraffin embedded samples ( FFPE ) has been a challenge for the community .
2 Additionally , cfDNA and FFPE samples are typically limited in the amount of material that can be obtained , and often the FFPE samples are highly degraded , compounding the ability to sequence them and to perform accurate variant calling .
3 To overcome these challenges , we have developed a single tube , multiplexed amplicon sequencing technology that employ hundreds of primer pairs for amplification of targeted loci , producing ready-to-run libraries for Illumina sequencing platforms .
4 The resulting amplicons are less than 150 bp in length , enabling amplification and sensitive detection of mutations from cfDNA-sized DNA fragments or highly damaged DNA .
5 A 200+ amplicon panel across 55 genes was developed to target known clinically relevant oncological mutations .
6 The panel design encompasses single exons ( e.g . BRAF ) as well as comprehensive exon coverage of entire genes ( e.g . TP53 ) .
7 DNA was extracted from FFPE , and cfDNA was extracted from fresh plasma .
8 DNA was quantified by qPCR using 2 primer pairs targeting ALU repeat regions. 10ng of DNA input was used to perform the multiplexed PCR .
9 Libraries were quantified by qPCR and sequenced with MiSEQ V2 reagents , paired end reads .
10 Alignment was performed using Burrows-wheeler Aligner ( BWA ) and variant calling was performed with atleast two validated publicly available tools and confirmed manually by IGV .
11 A variety of tools were used to validate allele technology was used to validate the sequencing data .
12 We interrogated 80 FFPE samples using our amplicon technology .
13 The percent of on-target bases was over 95% and the coverage uniformity was over 98% , where uniformity is the percent based covered over 20% of the mean coverage .
14 Μ Out of the 40 colorectal cancer samples tested , 17 showed mutations in KRAS .
15 Out of the 20 melanoma samples ( Cure line ) also analyzed , 9 were positive for BRAF V600E .
16 The presence of those mutations was confirmed using myTprimerTM KRAS and BRAF qPCR assay .
17 The limit of detection of the assay was set at 3% due to the inherent noise caused by the damage from the FFPE samples .
18 For cell lines with known mutations , the sensitivity was 0.5% .
19 No false positive or false negative were reported. 20 FFPE samples from different cancer types were also assessed .
20 Μ Mutations were identified in ERBB2 ( cervical cancer ) , ALK ( lung cancer ) and TP53 ( colon cancer ) genes , as well as MET amplification ( lung cancer ) .
21 Cell free DNA provides a non-invasive tool to monitor cancer progression and treatment efficacy .
22 Tumor DNA , matching blood DNA and cfDNA from 10 cancer patients will be subjected to our multiplex PCR oncology panel .
23 Data of this study will be presented .
24 Our results show that this unique multiplex PCR panel is an excellent tool to assess multiple oncogenes in limiting clinical samples , enabling high throughput , cost effective NGS analysis .



PMID: ASCO_191215-199
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Quantitative MR imaging biomarkers of tumor heterogeneity predict prognosis in metastatic colorectal lesions. .
1 Background : Intra-tumor heterogeneity is an independent determinant of patient survival outcomes in several tumor subtypes .
2 Spatial variations in tumor enhancement on MRI is a macroscopic imaging marker of tumor heterogeneity .
3 The goal of this study is to evaluate the potential role of MRI-based enhancement heterogeneity measures as predictors of survival in patients with metastatic colorectal cancer .
4 Methods : We retrospectively analyzed T1-weighted contrast-enhanced MRI images of metastatic hepatic lesions in 41 patients ( mean age 572 142 years ) who were diagnosed with stage IV colorectal cancer between 2007 and 2013 .
5 Tumor Kras mutation status and patient survival data for up to 95 months was available for all patients .
6 The largest metastatic hepatic lesion was identified by a radiologist and manually segmented. 14 Haralick texture features were extracted from each lesion .
7 Cox proportional hazards regression analysis was used to assess the association between the enhancement heterogeneity measures and patient survival , with adjustment for Kras mutation status as a potential confounder .
8 Backward stepwise feature selection was performed using p > 0.1 ( Wald test ) to select for statistically significant features .
9 Results : Mean survival time was 393.9 months for the study population ( 5141 months for Kras-wildtype and 3751 for Kras-mutants ) .
10   68% of the patients had left-sided colon cancer ; 21% had concurrent pulmonary metastases and 0.5% had concurrent brain metastasis. 61% , 27% and 12% of patients were on Flofox , Folfiri or other chemotherapeutic regimen , respectively .
11 Texture matrix homogeneity ( HR > 10 ; p = 0016 ) , inverse difference moment ( HR < 01 ; p = 0020 ) , entropy ( HR < 01 ; p = 0033 ) and standard deviation ( HR > 10 ; p = 0006 ) exhibited significant independent association with patient survival .
12 With the exception of entropy , these features maintained significant contribution to survival prediction independent of Kras mutation status .
13 Conclusions : MRI-based quantitativeintra-metastasis heterogeneity measures are associated with patient survival and may add information beyond genetic mutation status to optimize prognosis prediction in metastatic colon cancer .



PMID: AACR_2015-2981
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 The epithelial to mesenchymal transition ( EMT ) produces colorectal cancer subpopulations with strikingly different mutation profiles .
1 The epithelial-mesenchymal transition ( EMT ) has been well-recognized as an important mechanism promoting cancer cell invasion and stemness , metastasis and therapeutic resistance .
2 While the EMT-related differential gene expression has been extensively elucidated , genetic understanding of this process in cancer is largely lacking .
3 Μ Using unsupervised analysis , we previously identified an intrinsic differential gene expression signature in colorectal cancer ( CRC ) that was prognostic and highly correlated ( p = 10134 ) to EMT .
4 Μ Thus , we hypothesized that whole exome sequencing ( WES ) , guided by gene expression phenotype , might identify mutations underpinning the EMT program .
5 We first sorted 2144 CRC tumors based on their assigned degree ( scores ) of EMT .
6 Ten tumors from the bottom 15% of tumors and nine tumors from the top 15% of tumors were selected , with paired normal control tissues .
7 The WES data were then processed to identify non-synonymous SNVs , indels and LOH .
8 Μ We observed a striking difference in the mean number of variation per tumor ( p < 104 ) for those with low ( epithelial-like ) vs.high ( mesenchymal-like ) EMT scores ( low = 282 vs. high = 3 ) .
9 Μ Further analysis suggests that there may be two subpopulations in the low EMT tumors those with >400 mutations ( 4/10 , avg 608 ) that were subsequently confirmed for microsatellite instability ( MSI ) status through BAT testing where indels in TGFBR2 were seen often with BRAF mutations ( 3/4 ) ; those with 12-144 mutations ( 6/10 , avg 65 ) , which still demonstrated significant increases in mutation accounts compared to the high EMT tumors ( 0-5 mutations , avg 28 ) .
10 Μ Surprisingly , unlike their low EMT counterparts , the high EMT tumors displayed almost no known driver gene mutations ( except a TP53 mutation observed in one high EMT sample with p < 001 ) .
11 This potentially important finding was confirmed by analysis of another 468 CRC tumors that underwent targeted exome sequencing of 1321 cancer-related genes ; that is , tumors in the subgroup lacking mutations of common driver genes such as APC ( truncated mutations ) , KRAS , TP53 and BRAF (V600E) had significantly higher EMT scores compared to other subgroups .
12 Μ Moreover , WES identified a limited number of mutated genes in high EMT tumors , among which FAM186A was the most frequently mutated gene with p < 104 .
13 Μ Alternately , RNAseq was also performed on five high and three low EMT samples for whole transcriptome analysis , which identified a list of the most deregulated genes , isoforms and coding sequences ( e.g . SPP1 , THBS2 , THBS4 and SNAIL1 upregulated in high EMT tumors ) as well as novel mutations ( e.g . CDCP1 that was reported as a cell surface marker of migrating colon cancer stem cells ) .
14 Therefore , our next-generation sequencing analysis has discovered the most mesenchymal-like CRCs as a novel , genetically distinct subpopulation lacking common driver mutations .



PMID: ASCO_176773-195
(Patient)  
Terms:
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0 Left versus right sided colorectal cancer : Teasing out drivers of disparity in outcomes in metastatic disease. .
1 Background : Patients ( pts ) with metastatic colorectal cancer ( mCRC ) arising from a right sided colon cancer ( RCC ) have an inferior survival versus pts with a left sided primary ( LCC ) .
2 Previous analyses have suggested that multiple factors contribute .
3 Methods : The Treatment of Recurrent and Advanced Colorectal Cancer ( TRACC ) Registry has prospectively collected data on consecutive mCRC pts at 32 sites ( Australia and Hong Kong ) from July 2009 .
4 LLC were defined as those distal to the splenic flexure .
5 We analysed patient , tumour , treatment and outcome data .
6 Results : Of 1763 patients , median age 67 years ( range 18 100 ) , 1201 patients ( 681% ) had a LCC .
7 RCC were more common in pts 70 years old ( 539% versus 385% , p < 001 ) and females ( 507% , p < 001 ) .
8 Where tested , KRAS ( 509% versus 415% , p < 001 ) and BRAF ( 191% versus 64% , p < 001 ) mutations were more common in RCC .
9 Where tested , dMMR was more common in RCC ( 110% versus 32% , p < 001 ) .
10 Pts with a RCC more often had peritoneal metastases ( 259% versus 125%% , p < 001 ) and were less likely to have liver metastases ( 698% versus 779% , p < 001 ) or resection of metachronous metastases ( 318% versus 436% , p < 001 ) .
11 LCC more commonly received chemotherapy in the 1st ( 861% versus 803% , p = 002 ) and 2nd ( 497% versus 430% , p = 004 ) line setting .
12 There was no difference in ECOG performance status or co-morbidity for LCC versus RCC .
13 Overall survival for pts with a RCC was 20.6 months versus 27.9 months for LCC L-sided tumours ( HR 1395 , p < 0 0001 ) .
14 Conclusions : Our data confirms that pts with mCRC arising from a RCC have an inferior survival .
15 This appears multifactorial due to associations with adverse clinical and molecular features , metastatic pattern , and less therapy , some of which are related .
16 A multivariate analysis is being performed .



PMID: ASCO_82277-102
(None)  
Terms: prospective, retrospective, clinical trial
Sent# Symbols Sentence Mnemonics
0 My Cancer Genome : Web-based clinical decision support for genome -directed lung cancer treatment. .
1 Background : Lung cancer has traditionally been treated according to histologic subtype with a plateau in the efficacy of combination chemotherapy .
2 Μ Recent advances have identified oncogenic driver mutations in lung cancer that predict response to targeted therapies .
3 However , knowledge resources are limited regarding the clinical relevance of such mutations .
4 Μ Methods : We performed a literature review regarding the prevalence and clinical significance of various treatments for ~40 mutations in 10 genes ( EGFR , KRAS , BRAF , NRAS , PIK3CA , MEK1 , AKT1 , HER2 , PTEN , and ALK ) for non-small cell lung cancer ( NSCLC ) .
5 Data from prospective and retrospective trials as well as preclinical studies was collected .
6 Results : ~100 articles/abstracts were synthesized into the publicly available My Cancer Genome website ( mycancergenomeorg ) which launched in Jan 2011 .
7 Content includes information about the oncogene pathway ( e.g . What is EGFR - ) , the clinical significance of the gene for a specific type of cancer ( e.g . EGFR in NSCLC ) , and a summary of clinically relevant data related to a particular gene mutation ( e.g . EGFR Exon 19 deletion in NSCLC ) .
8 Information regarding mutation directed clinical trials open for accrual both at Vanderbilt Ingram Cancer Center and worldwide is provided using a direct query of clinicaltrials .
9 gov .
10 This decision support tool is integrated into Vanderbilts electronic medical record to provide actionable decision support for mutation directed treatment prioritization and clinical trial availability .
11 Clinicians , patients , and researchers with access to the internet can also access the website freely and directly .
12 Conclusions : My Cancer Genome is an international resource to assist clinicians in prioritizing genome directed cancer therapies .
13 The first implementation includes content for NSCLC .
14 We are now expanding the content to include melanoma , breast cancer , colon cancer and other malignancies .
15 New data will be incorporated on an ongoing basis .
16 We welcome public/private partnerships to expand content and make this a truly global resource .



PMID: AACR_2015-3930
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Targeted cancer gene sequencing identifies potential causative novel candidate mutations among Caucasian colon carcinogenesis .
1 Much of the sporadic colorectal cancer's ( CRC ) underlying genetic cancer driver mutations are unknown in patients from specific ethnic groups .
2 Here , we report the identification of distinct novel variants from adenoma and CRC patients in mismatch repair ( MMR ) genes MHS3 and MSH6 , and in PIK3CA and APC .
3 Μ We developed a panel of 20 frequently altered colon cancer genes comprised of ACVR2A , APC , ARID1A , BRAF , FAM123B , FBXW7 , KRAS , MSH2 , MSH3 , MSH6 , NRAS , PIK3CA , POLE , PTEN , SMAD2 , SMAD4 , SOX9 , TCF7L2 , TGFBR2 , and TP53 for targeted sequencing in 65 colon tissues , comprised of 1 normal tissue sample , 2 adenomas , and 63 tumors .
4 Multiplex PCR and Ion Torrent sequencing was used to examine 98.8% of the targeted exons and splice junctions at a depth of sequencing that allowed for high confidence variant calling ( most bases were covered by 500 reads ) .
5 After alignment and variant calling , we annotated the variants with information from the 1000 Genomes Project , COSMIC , Polyphen2 , and PFAM domain and transcription factor motifs .
6 Μ Excluding synonymous SNVs , 3 variants in adenoma , and 692 variants in tumors were detected .
7 Two were known pathogenic variants ( MSH6 pR965H and APC pR1432X ) .
8 Μ Novel variants ( 286 , 244 , and 115 ) were found in MMR genes ( MSH6 and MSH3 ) , APC , and PIK3CA , respectively .
9 Most of the MMR ( n = 98 ) , APC ( n = 128 ) , and PIK3CA ( n = 43 ) variants are deleterious .
10 Notably , among the 63 CRC cases , [ ( 29/61 = 46% ) 46% ) for MSH3 , MSH6] [ ( 19/63 = 30% ) ( 30% ) for PIK3CA] [31/63 = 49% ) ( 49% ) for APC ) ] carried likely deleterious MMR , PIK3CA and APC mutations , respectively , suggesting the value of a broad cancer gene panel .
11 Μ These finding further highlight the relevance of APC , PIK3CA genes in CRC onset but also the potential underestimation of the MSI-H in sporadic CRC as many of the novel mutations in MMR gens detected here were of a deleterious nature .



PMID: AACR_2017-5495
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 GANT61 -induced cell death involves inhibition of transcription and DNA licensing at GLI sites in the promoters of GLI -dependent target genes in human colon carcinoma cells. .
1 The GLI genes , GLI1 and GLI2 , are transcriptional regulators of the Hedgehog signaling response , binding at promoters to GACCACCCA-like consensus sequences .
2 From genetic and biochemical studies , GLI2 is the primary mediator of HH signaling , which activates GLI1 to transcriptionally regulate target genes .
3 In cancers both GLI1 and GLI2 are oncogenes , aberrantly and constitutively activated by oncogene -driven signaling pathways , in particular KRAS/BRAF in colon cancer .
4 GANT61 , a specific GLI inhibitor , induced extensive cytotoxicity in human models of colon cancer , indicating GLI to be a critical target in cancer cell survival .
5 We have determined FOXM1 to be a transcriptional target of GLI1 at a GCCCACCCA consensus sequence .
6 In HT29 cells , inhibition of GLI binding to the FOXM1 promoter by GANT61 led to inhibition of binding of the pause-release factors DSIF , NELF , and p-TEFb in the region of the TSS , with inhibition of binding of Pol II at both GLI and TSS sites .
7 In R-loop regions , RNA : DNA hybrid formation was reduced at both the GLI and TSS sites in the FOXM1 promoter by GANT61 , sensitive to RNaseH .
8 Bisulfite conversion/PCR also determined >50% reduction in ssDNA ( C- > T conversions ) in the GLI binding region in GANT61-treated cells .
9 Data support GANT61 -induced inhibition of GLI -dependent transcription at the PIC before R-loops are formed .
10 Pretreatment of HT29 cells with α-amanitin ( Pol II inhibitor ) reduced GANT61 -induced γH2AX foci , indicating the importance of transcription in GANT61 -induced DNA damage .
11 Co-localization of GLI1 and BrdU foci , inhibited by GANT61 , indicated GLI1 and DNA replication were linked .
12 By co-immunoprecipitation , GLI1 bound the DNA replication licensing factors ORC4 , CDT1 , and MCM2 , decreased in the presence of GANT61 .
13 By confocal microscopy , significant co-localization of GLI1 and ORC4 foci was inhibited by GANT61 , and enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter .
14 In addition to non-transcriptional mechanisms of interaction between GLI1 and DNA licensing factors , CDT1 was found to be a transcription target of GLI1 at a putative GACCACCCG consensus sequence in the promoter .
15 ChIP analysis determined significant enrichment of ÎłH2AX at this site in GANT61-treated HT29 cells .
16 Overexpression of CDT1 in HT29 cells reduced GANT61 -induced cell death and cleavage of caspase-3 , indicating a significant role of DNA replication licensing in the mechanism of induction of GANT61 -induced cell death .
17 In summary , we have demonstrated inhibition of GLI -dependent transcription by GANT61 at the PIC during the initiation of RNA synthesis , and the importance of inhibiting DNA replication licensing at sites in promoter regions that bind the transcription factor GLI1 by both non-transcriptional and transcriptional mechanisms .



PMID: AACR_2017-728
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Development and validation of ColoScape™ - a new colorectal cancer mutation detection assay. .
1 Introduction : Colorectal cancer is a highly preventable disease as early detection increases rates of patient survival to near 100% .
2 Herein we report the development and validation of a novel multigene mutation biomarker real-time PCR based assay for qualitative detection of colorectal cancer associated biomarkers that comprise tumor specific mutations in the following genes : APC ( Exon 15 ) , KRAS ( Exon 2 ) , BRAF ( Exon 15 ) and CTNNB1 ( Exon 3 ) called ColoScapeTM .
3 The assay allows the sensitive detection of the presence or absence of mutations in the targeted regions of the genes interrogated .



PMID: AACR_2015-3826
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 A reversible DNA methylation signature precedes sporadic mutations in the colorectal adenoma-dysplasia-cancer development .
1 Background and aims : New generation sequencing and array technologies now allow the systematic investigation and comparison of genetic or epigenetic alterations in AD-CRC .
2 The colorectal adenoma-dysplasia-cancer ( AD-CRC ) development is characterised by sporadic ( <45% frequency ) mutations in a limited number of genes .
3 Μ Recent epigenetic investigations showed that methylation of selected genes occurs in high frequency ( >95% ) in early stages of cancers already .
4 Aims : Evaluation of the role of epigenetic and genetic alterations in the AD-CRC development using new generation sequencing and DNA methylation arrays .
5 Materials and methods : DNA was isolated from fresh frozen biopsy specimens ( 20 normal ; 33 adenomas ; 17 CRCs ) .
6 First , a multiplex PCR panel was designed to amplify mutation hot spots of 12 selected genes ( APC , BRAF , CTNNB1 , EGFR , FBXW7 , KRAS , MSH6 , NRAS , PIK3CA , SMAD2 , SMAD4 , TP53 ) .
7 Further DNA methylation analysis of 94 genes was performed on Human Colon Cancer EpiTect Methyl II Signature PCR Array ( Qiagen ) from the same DNA specimen .
8 After RNA isolation whole genome expression analysis was performed with HGU133plus2 microarrays ( Affymetrix ) from 49 normal , 49 adenoma and 49 CRC specimens and on HT-29 cells with and without 5-aza-deoxycytidin treatment .
9 Immunohistochemistry confirmation of expression changes on protein level was performed using tissue microarrays .
10 Μ Results : Mutations were found in 76% of adenomas and 78% of the cancer cases .
11 Μ The average number of mutations found in mutated samples was 1 ; 1,8 ; 1,9 and 2,3 in low grade adenomas , high grade adenomas , carcinomas and serrated adenomas , respectively .
12 Μ The APC suppressor gene was mutated in adenomas more frequently than in carcinomas ( 36% vs. 24% ) .
13 Μ The most frequently mutated genes were APC , TP53 and KRAS with 36% , 18% and 26% frequencies in adenomas and 24% , 47% and 45% frequencies in carcinomas .
14 DNA methylation was found in 100% of the investigated colorectal adenoma and cancer specimens .
15 Eight genes were found to be methylated in all of the cases .
16 This gen set included SFRP1 , MAL , SLIT2 , SST , VIM ; another set of genes ( DKK1 , SLI3 , TMEFF2 ) was found to be hypermethylated in adenomas and cancers in >75% of the cases .
17 In adenomas 56 genes , in dysplasias 40 in cancer 37 genes were methylated ( >50% of the cases ) .
18 The effect of methylation could be confirmed by decreased mRNA and protein expression .
19 Demethylation treatment successfully restored the expression profile of the top methylated genes .
20 Conclusion : Methylation of gene sets occurred in early premalignant stages followed by somatic mutations in increasing number through the AD-CRC development .
21 Demethylation treatment could reverse the systematic , robust methylation alterations .
22 Epigenetic alterations precede the somatic mutations of the AD-CRC and show higher significance in CRC development than genetic .



PMID: AACR_2015-4910
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Sensitive , specific and highly multiplexed mutation detection for cancer management .
1 Mutations in RAS , RAF , EGFR and PIK3CA genes are present in a number of cancers including colon , lung and breast cancers .
2 Importantly , many of these mutations are predictive biomarkers of clinical outcomes for targeted therapies .
3 This has led to a growing demand for detection of multiple mutations simultaneously .
4 Multiplex formats allow a greater amount of information to be obtained from each sample .
5 Μ PASS primer technology can sensitively and specifically identify the presence of SNPs and somatic DNA changes ( point mutations , deletions and insertions ) with sensitivity up to 1 in 1,000 ( 01% ) .
6 PASS primers selectively amplify nucleic acid variants and create amplicons that are markedly different from the parent sequence .
7 The method is superior to ARMS PCR for multiplexing , particularly when mutations are present at the same , adjacent or nearby loci .
8 PASS primers consist of two target specific regions separated by an insert sequence ( IS ) which is not complementary to the target .
9 A long 5 target-specific region anchors the primer and a short 3 region targets the variant base/s thus directing highly specific binding and extension .
10 During amplification , the IS sequences are incorporated into amplicons , introducing 10 base difference between the starting single base variant and the resulting amplicon .
11 This reduces competition between primers during amplification and facilitates robust discrimination between amplicons during detection .
12 MNAzyme qPCR is a robust alternative to other probe based real-time qPCR protocols such as TaqMan and Beacons .
13 MNAzymes are bi-specific , catalytic oligonucleotide complexes which form in the present of target and cleave universal reporter probes .
14 The bi-specificity , and the use of well-characterised universal probes sets ( suitable for use with any group of targets ) , makes MNAzyme qPCR more amenable to multiplexing .
15 Μ When combined with PASS , MNAzyme qPCR easily discriminates between amplicons since MNAzymes are tailored to specifically detect both the distinct IS and the original mutation .
16 PASS MNAzyme qPCR has been used to facilitate multiplex detection of RAS , RAF , EGFR and PIK3CA mutations .
17 As many as eight mutations located at codons 12 and 13 of RAS have been successfully detected in a single well using three channels on a standard PCR machine .
18 The technology is even more powerful when combined with newer instruments with higher multiplex capabilities such as Biocartis Idylla automated platform .
19 Μ A multiplexed KRAS/BRAF assay , which detects 18 mutations , was evaluated using colon cancer and melanoma FFPE samples .
20 The results showed >96% concordance with sequencing and significantly specificity compared to the singleplex Therascreen KRAS test .
21 Since PASS MNAzyme qPCR affords greater multiplex capacity , along with high specificity and sensitivity , it provides a superior tool for ascertaining mutations from tumour tissues and is particularly well suited for use with liquid biopsies .
22 Note : This abstract was not presented at the meeting .



PMID: ASCO_41265-74
(None)  
Terms: Phase III Trial, phase III trial
Sent# Symbols Sentence Mnemonics
0 Adjuvant mFOLFOX6 with or without cetuxiumab ( Cmab ) in KRAS wild-type ( WT ) patients ( pts ) with resected stage III colon cancer ( CC ) : Results from NCCTG Intergroup Phase III Trial N0147. .
1 Background : FOLFOX is standard adjuvant therapy for stage III CC .
2 Adding Cmab to FOLFOX benefits pts with metastatic CC WT KRAS tumors .
3 N0147 assessed the potential benefit of Cmab added to FOLFOX .
4 Methods : 21-56 days following resection and informed consent , KRAS status was centrally determined .
5 Pts with wtKRAS CC were randomized to 12 biweekly cycles of oxaliplatin 85 mg/m2 d1 , with leucovorin 400 mg/m2 , 5FU 400 mg/m2 bolus IV , then 46-hr IV 5FU 2,400 mg/m2 on d1-2 ( mFOLFOX6 ) , without ( arm A ) or with Cmab ( arm D ) 250 mg/m2 d1&8 , with Cmab at 400 mg/m2 , cycle 1 , d1 .
6 Primary endpoint was 3-yr disease free survival ( DFS ) .
7 Secondary endpoints included overall survival ( OS ) and toxicity .
8 Planned accrual of 2,070 wtKRAS pts provided 90% power to detect hazard ratio ( HR ) of 1.33 with 2-sided =0.05 ; with interim analyses after 25% , 50% , and 75% of planned events .
9 Results : 1,760 wtKRAS pts ( Arm A-858 , Arm D-902 ) were enrolled at the time of closure ; median follow-up on 1,624 pts is 15.9 months .
10 Trial closed to accrual when preplanned interim analysis after 50% of planned events demonstrated no benefit to addition of Cmab. 3-yr DFS favored FOLFOX alone ( HR 118 , 95% CI 092-152 ; p = 033 ) .
11 No benefit of Cmab was observed in any subgroups assessed .
12 Any grade 3 AE , diarrhea , and failure to complete 12 cycles was significantly increased in arm D .
13 Increased toxicity and greater differences in all outcomes were observed in pts aged 70 ( Table ) .
14 Conclusions : In this randomized phase III trial the addition of Cmab to mFOLFOX6 was of no benefit for pts with resected stage III wtKRAS CC .
15 Supported by NIH Grant CA25224 , Bristol-Myers Squibb , ImClone , Sanofi-Aventis , and Pfizer .
16 OverallAge < 70 ( n = 1,397 ) Age > = 70 ( n = 227 ) FF+CpFF+CpFF+Cp3-yr DFS74.173.30.3373.375.20.8778.064.80.053-yr OS87.382.10.0687.883.40.1983.975.40.17On-study mortality0.581.440.070.400.650.501.875.840.12Any Gr 3 AE45.065.4 < 0.00143.862.8 < 0.00153.580.3 < 0.001Gr 3 diarrhea8.014.5 < 0.0016.712.00.00116.828.70.04Gr 4 neutropenia9.09.70.628.08.30.8615.818.00.67Completed 12 cycles77.365.6 < 0.00177.368.60.00177.649.6 < 0.001Abbreviations : F , FOLFOX ; F+C , FOLFOX + Cmab ; p , p value .



PMID: AACR_2014-467
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 New molecular model identifying the critical role of the GLI2 oncogene in human colonic epithelial cell ( HCEC ) transformation .
1 Colorectal cancer , comprising 85% sporadic non-hereditary tumors , is the third in cancer incidence and the second leading cause of cancer mortality in the United States .
2 Initiating mutations in key genes , APC , KRAS and p53 , determine transformation and early oncogenesis in the colon .
3 The initiating mutation in the APC tumor suppressor gene activates Wnt signaling .
4 Progression mostly requires mutation in the KRAS oncogene , facilitating cytoplasmic- > nuclear translocation of -catenin .
5 Mutation in p53 coincides with the transition from adenoma - > carcinoma .
6 While the specific genetic mutations that determine oncogenesis in colon cancer are well documented , the fundamental biologic mechanisms that determine synergism in effecting transformation remain poorly understood .
7 The GLI genes are transcription factors that regulate Hedgehog signaling , which is activated in colon cancer .
8 GLI1 and GLI2 are oncogenes , induce transformation , and determine oncogenesis in glioma , medulloblastoma ( GLI1 ) , and basal cell carcinoma ( GLI2 ) .
9 We have demonstrated in colon carcinoma cells that GLI2 is activated by oncogenic KRAS , activates GLI1 , and determines cell survival .
10 In immortalized HCEC cells with defined genetic mutations , we discovered that GLI2 is activated during transformation , dependent on synergistic interactions between mAPC and KRAS[G12V] pathways in the presence of inactive p53 .
11 This renders cells dependent on GLI for survival .
12 In isogenic HCEC models , KRAS[G12V] determines -catenin subcellular trafficking between membrane adherens junctions ( AJ ) , cytoplasm and nucleus .
13 This is apparent following inhibition of ERK ( AJ - > cytoplasm ) and/or GSK3 ( AJ - > nucleus ) that determine -catenin subcellular localization .
14 Further , we have identified GLI2 as a new Wnt target gene , transcriptionally regulated by Wnt -dependent TCF4 , which binds to consensus sequences in the GLI2 promoter .
15 Oncogenic KRAS signaling channels through and converges on GLI2 to drive GLI2 to a higher activating state .
16 GLI2 is transcriptionally regulated by an ERK -dependent mechanism that requires the GLI cofactor , ZIC2 .
17 Thus , GLI2 is activated by both Wnt and oncogenic KRAS signaling pathways .
18 In summary , we present a new molecular model that identifies the GLI2 oncogene as a critical determinant of human colonic epithelial cell transformation .
19 These studies will : 1 ) define the key mutational events and biologic mechanisms that functionally activate the oncogene GLI2 during colonic epithelial cell transformation ; 2 ) define the role of GLI2 in early oncogenesis ; 3 ) identify key molecules and potential new targets that determine transformation ; 4 ) lead to improved therapeutic strategies specific to colorectal cancer .



PMID: ASCO_184450-199
(Patient)  
Terms: phase III trial
Sent# Symbols Sentence Mnemonics
0 Clinical utility of colon cancer molecular subtypes : Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort. .
1 Background : The molecular subtyping of colon cancers ( CC ) has been the subject of several recent publications , leading to an international consensus .
2 The clinical relevance of these molecular classifications remains to be evaluated on large prospective patient cohorts using a tool that can be widely used on formalin-fixed paraffin-embedded ( FFPE ) samples .
3 Methods : We aimed to evaluate the clinical relevance of two molecular subtyping systems , CMS ( Guinney et al 2015 ) and CCMST ( Marisa et al 2013 ) , on the PETACC-8 cohort , a randomized phase III trial comparing adjuvant FOLFOX with or without cetuximab in patients with stage III CC .
4 For each of these two classification systems , a predictor tool was developed and adapted to FFPE samples .
5 The NanoString nCounter platform was used to screen 196 genes .
6 Predictors were built from 249 frozen tumor samples previously used to build our classification system and 61 new paired FFPE/frozen samples .
7 Both predictors were then applied to 1781 PETACC-8 FFPE samples .
8 Subtypes associations to clinical and molecular features were analyzed .
9 Results : The CMS predictor assigned 297 samples to CMS1 ( 17% ) , 585 to CMS2 ( 34% ) , 68 to CMS3 ( 4% ) and 770 to CMS4 ( 45% ) .
10 CMS were significantly associated with several molecular and clinical features , including MSI status ( 49% in CMS1 , p < 0001 ) , CIMP status ( 47% in CMS1 , p < 0001 ) , KRAS mutation ( 75% in CMS3 , p < 0001 ) , BRAF mutation ( 34% in CMS1 , p < 0001 ) , tumor location ( less proximal tumors in CMS2 , p < 0001 ) , validating the predictor tool developed .
11 The classification was significantly associated to prognosis in multivariate analysis , CMS4 subtype having a shorter overall survival ( hazard ratio = 17 , p= 0021 ) .
12 A deleterious effect of cetuximab was observed in CMS1 ( p < 005 ) .
13 Similar results were obtained with the CCMST classification .
14 Conclusions : We validated molecular CC subtyping predictors for both CMS and CCMST classifications on PETACC-8 FFPE samples .
15 The prognostic value of CMS and CCMST classifications was confirmed , stem-like tumors being associated with a poor prognosis .
16 These results pave the avenue for widely use of the CC molecular classification in clinical routine .



PMID: AACR_2013-3998
(Cell)  
Terms:
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0 The IGF1 receptor/insulin receptor dual kinase inhibitor BMS-754807 targets the cancer stem cell population in addition to its synergism with Lapatinib in colorectal cancer. .
1 Colon cancer is the second leading cause of cancer mortalities each year .
2 Current treatment options include drugs that target the epidermal growth factor ( EGF ) pathway .
3 However , the use of these drugs is limited to individuals that are wild type for KRAS .
4 New therapies are needed for patients who develop resistance to EGF-based therapies , as well as for the 40% of patients whose tumors have mutated KRAS .
5 Our approach has been to target pathways that regulate cancer cell metabolism .
6 The insulin and insulin-like growth factor -1 ( IGF1 ) pathways regulate glucose metabolism , cell growth , cell motility and anti-apoptotic pathways .
7 In colon cancer , IGF1 and insulin enhance tumor growth , promote metastasis and increase the cancer stem cell ( CSC ) population .
8 In order to target the insulin and IGF-1 pathways simultaneously , we utilized the small molecule , dual kinase inhibitor BMS-754807 which inhibits the Insulin receptor ( IR ) and IGF1 receptor ( IGF1R ) with equal potency .
9 We previously reported that the drug effectively reduced cell viability in a panel of eight colon cancer cell lines .
10 In combination when combined with Lapatinib , an EGFR/HER2 small molecule dual kinase inhibitor , the drug showed synergistic effects on viability in a subset of cell lines .
11 In order to determine the mechanism of the observed synergy , we examined whether EGFR and IGF1R were interacting directly as has been observed in breast cancer .
12 Co-immunoprecipitation experiments in colorectal cancer cells , did not demonstrate an interaction between the EGFR and IGF1R .
13 Examination of the signaling pathways in our panel of cell lines has determined that the regulation of ERK appears to be a critical determinant in sensitivity to the combination therapy .
14 In both of the sensitive lines , AKT was strongly activated by IGF1 , while ERK was strongly activated by EGF , but less substantially by IGF1 .
15 However in the cell lines that were insensitive to the BMS-754807/Lapatinib combination , substantial activation of ERK was observed in the absence of either EGF or IGF1 .
16 Therefore constitutive ERK activation in the absence of EGF signaling may be the determinant for sensitivity to the combined therapy .
17 Finally , we examined the efficacy of BMS-754807 in the targeting colon cancer stem cells .
18 In our panel of eight cell lines , BMS-754807 strongly inhibited colonsphere formation from the CSC population in three cell lines , and showed moderate inhibition in four of the five remaining lines .
19 Of interest is the fact that the cells that were most sensitive to BMS-754807 in sphere formation were the most resistant in viability assays , and did not synergize with Lapatinib .
20 These results are encouraging as we continue to develop strategies that specifically target the cancer stem cell , and indicate that BMS-754807 has multiple potential mechanisms of action in colon cancer .



PMID: AACR_2013-165
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Predicting risk of colorectal cancer depending on tumor pathology features for first-degree relatives of persons with colorectal cancer. .
1 Background : We hypothesised that colorectal cancer ( CRC ) risk for relatives of persons diagnosed with CRC could be predicted by tumor molecular pathology features .
2 Methods : We studied a cohort of 5200 first-degree relatives ( 2550 women ) of 792 probands with an incident invasive CRC who were recruited to the Australasian Colorectal Cancer Family Registry via population cancer registries .
3 We excluded 32 families that were known to be Lynch syndrome .
4 For the probands , a standardised tumor morphology review had been conducted ; BRAF V600E mutation testing had been performed ; and the DNA mismatch repair ( MMR ) status was determined by microsatellite instability and/or immunohistochemistry for MMR proteins .
5 We calculated standardized incidence ratios ( SIR ) by comparing the number of CRCs observed in relatives with the number expected based on Australian incidence rates specific for age and sex .
6 We also compared CRC risks for relatives of probands depending on the presence or absence of specific tumor pathology features .
7 Results : We observed 191 CRCs in relatives at mean age at diagnosis of 62.7 ( SD 143 ) years and SIR was 2.14 ( 95% confidence interval , CI 185-248 ) .
8 Compared with the general population , an increased risk of CRC was observed for relatives of probands with MMR-proficient CRC ( SIR 198 , 95% CI 171-232 ) , MMR-deficient CRC ( SIR 360 , 95% CI 220-623 ) , rectal cancer ( SIR 171 , 95% CI 136-218 ) , distal colon cancer ( SIR 212 , 95% CI 163-282 ) and proximal colon cancer ( SIR 290 , 95%CI 227-375 ) .
9 An increased risk of CRC was observed for relatives of probands with proximal colon cancer compared with rectal cancer ( hazard ratio , HR 170 , 95% CI 121-239 , p = 0002 ) and for relatives of probands with MMR-deficient CRC compared with MMR-proficient CRC ( HR 184 , 95% CI 109-312 , p = 002 ) .
10 There was no evidence of increased risk of CRC for relatives of probands with other pathology features of CRC ( tumor grade , margin , peritumoral lymphocytes , tumor infiltrating lymphocytes , Crohn-like reactions , venous invasion , BRAF mutation and contiguous adenoma ) compared with those without these features .
11 Conclusions : First-degree relatives of persons with MMR-deficient CRC ( not caused by Lynch syndrome ) have a higher risk of CRC compared with first-degree relatives of persons with MMR-proficient CRC .



PMID: AACR_2012-1078
(Cell)  
Terms:
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0 ErbB/Pi3K signaling contributes to EGFR ligand expression in colorectal cancer cells .
1 Background : Cellular expression of EGFR ligands is tightly regulated and is thought to be maintained by an autocrine signaling component in colorectal cancer cells .
2 More importantly , the expression levels of individual ligands have gained recent interest since their expression of their mRNA was found to be linked to anti-EGFR therapy response .
3 Since the expression of these ligands can be regulated by EGFR signaling elicited by EGF , we decided to investigate the contribution of MAPK as well as the PI3K axis , to EREG expression , in K-Ras wild-type colon cancer cells .
4 Methods Colon cancer cells were used to interrogate EGFR downstream signaling .
5 Several inhibitors targeting the ErbBs and the MAPK and PI3K/Akt pathways were used to dissect the pathways downstream of EGFR maintaining ligand mRNA levels in the lim1215 colon cancer cell line .
6 Additionally , we used ER and AR reporter assays to selectively evaluate involvement of the EGFR pathway in transcriptional regulation of the pathway .
7 Consequently , blockade and activation of EGFR pathway members was assessed by Western Blot .
8 Results We show that Ereg and Areg mRNA levels are specifically maintained by erbb1 signaling .
9 Treatment of lim1215 cells with inhibitors blocking Erbb1 ( cetuximab ) or ErbB1/Erbb2 ( lapatinib ) did results in near complete inhibition of Ereg and Areg expression in Kras/pi3K wild-type cells , while blockade of ErbB2 alone ( which is activated in these cells ) with Trastuzumab did not decrease Ereg nor Areg mRNA levels .
10 Downstream of EGFR , we show that MEK signaling is not required for maintenance of EREG and AREG levels in lim1215 cells .
11 Conversely , blockade of PI3K signaling by Akt inhibitors or PI3K inhibitors abolished EREG mRNA levels in these cells .
12 This was reflected by the ability of overexpressed Akt to induce EREG and AREG reporter activity in 293T cells .
13 In contrast , this activation could be rescued by the addition of Akt and PI3K inhibitors , but not MEK inhibitors in cellular media .
14 Conclusions In this work we show that PI3K signaling is required for the transcription of EGFR ligands in colon cancer cells .
15 In this regard , this provides additional insights to the recent findings that link PI3K/Akt signaling to Receptor Tyrosine Kinase expression and activation in cancer cells .
16   Therefore , a global understanding of the signaling networks that control ligand availability and receptor abundance will be crucial in combining ErbB pathway inhibitors in the treatment of kras wild-type colon cancers .



PMID: ASCO_42556-74
(None)  
Terms:
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0 Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer ( CC ) : Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. .
1 Background : We presented the prognostic ( prog ) impact of molecular markers ( MM ) on relapse free survival ( RFS ) of stage II-III CC ( ASCO proc 2009 , 27 , abstr 4002 ) .
2 We analyze now the impact of the 8 same MM on the overall survival ( OS ) after relapse of stage II-III CC in PETACC 3 , an adjuvant trial with 3278 patients ( pts ) .
3 Methods : 1,564 blocks were prospectively collected , tumor ( Tu ) DNA extracted and 8 MM assessed as described previously .
4 Markers prog value was analysed by Cox regression for OS , multivariate analysis ( MA ) and Kaplan-Meier estimates of median survival ( MS ) .
5 Time to recurrence ( TTR ) of 18m defined early relapse ( ER ) , >18m late relapse ( LR ) .
6 Results : 392 out 990 relapsing pts were assayed for the 8 MM , 221 ER , 171 LR .
7 The MA investigating prog factors impacting on OS after relapse is presented in the Table .
8 ✓ BRAF , Tu site , and TTR were found to be major predictors of OS after relapse . GN-MRK-RO
9 MS ( 95%CI ) according to BRAF was 7.5 m ( 48-112 ) vs. 25.2m ( 211-295 ) p = 1.9e-11 , according to Tu site 16.1 m ( 126-190 ) vs. 27.6 m ( 229-336 ) p = 2.71e-06 , according to TTR 17.9m ( 155-203 ) vs. 30.0 m ( 247-384 ) p = 0.00032 .
10 Similar MS according to Tu site ( 162 m vs. 286 m , p = 452e-14 ) and TTR ( 184 m vs. 305 m , p = 218e-08 ) were observed in the full relapsing pts set ( n = 990 ) .
11 Conclusions : Whereas BRAF and Tu site had no prog value on RFS of stage II-III CC ( Roth AD , doi : 10.1200/JCO.2009.23.3452 ) , BRAF , Tu site , and TTR are strong determinants of CC OS after relapse and should imperatively be used to stratify studies in metastatic CC .
12 The independent effects of Tu site and TTR might be indicative of additional non-yet-identified MM .
13 HR ( 95% CI ) P value TTR (ER/LR) 1.60 ( 123-209 ) 0.0005 Age1.00 ( 099-101 ) 0.98 Sex1.24 ( 095-162 ) 0.11 Tu grade1.52 ( 102-225 ) 0.04 Stage1.53 ( 100-236 ) 0.051 Tu site ( right/left ) 1.69 ( 129-221 ) 0.0002 Treatment group1.09 ( 084-139 ) 0.52 Microsat .



PMID: AACR_2014-5316
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Quantitative cancer analysis using digital PCR : Absolute counting of DNA ( solid tumors and liquid biopsies in glioma , breast , and colon cancer ) and RNA ( mRNA and miRNA using One-Step RT-dPCR ) .
1 Background : There is a need for more accurate and sensitive methods to quantify nucleic acids present in precious samples and non-invasively collected liquid biopsy material .
2 Digital PCR ( dPCR ) is one technology with recent advances in automation , enabling researchers to sensitively quantify a sample's nucleic acids by adding up digital fluorescent counts of single target molecules .
3 Particularly exciting are the emerging uses of cell -free nucleic acids found in peripheral body fluids for dynamic measurements of total body mutational burden of heterogeneous cancers , potentially reducing the need for multiple invasive tumor biopsies .
4 In addition , combined measurement of mRNA and miRNA RNA biomarkers from a single sample , for example from cell -free exosomes , is of clinical interest .
5 Here we present results from several studies using dPCR for DNA and cDNA molecule counting with various cancers , as well as in a first time demonstration quantifying RNA directly with multiple miRNA species , and mRNA together with miRNA .
6 Method & Results : Picoliter droplet digital PCR was used to perform single molecule counting .
7 Standard qPCR assay reagents for each target were combined in duplex or multiplex formats together with samples , and partitioned into millions of 5 picoliter-sized droplets on a RainDance RainDropTM dPCR system .
8 Each sample was then thermal cycled prior to digital fluorescent quantification .
9 In separate studies we show quantification of mutant IDH1 mRNA ( cDNA converted ) in glioma patient cerebrospinal fluid extracellular vesicles , PIK3CA mutations and methylation of CyclinB2 and Retinoic Acid Receptor promoters in breast tumor DNA , KRAS and BRAF mutations in colorectal cancer plasma cell -free DNA , and multiplexed miRNA biomarkers from plasma ( cDNA converted ) .
10 In addition , we show direct quantification of mRNA molecules in highly precise multiplex One-Step RT-dPCR measurements across a wide dynamic range .
11 Finally , we show simultaneous One-Step RT dPCR direct digital counting of miRNA and mRNA molecules .
12 Conclusion : Droplet digital PCR is a highly sensitive and precise approach to quantify nucleic acids without the need for standard curves .
13 With the RainDance RainDrop dPCR platform there are sufficient partitions and compatibility with various robust chemistries to apply dPCR to DNA and RNA analyses from a variety of biofluids and neoplasms , enabling accurate absolute counting of multiple target molecules across a wide dynamic range .



PMID: ASCO_123407-143
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Measurement of circulating tumor DNA as a cancer biomarker in gastrointestinal malignancies using a novel next-generation sequencing method. .
1 Background : Circulating tumor DNA ( ctDNA ) holds promise as a highly specific cancer biomarker .
2 The presence of mutant tumor-derived DNA fragments in the blood provides an opportunity to non-invasively assess tumor mutation profiles and to quantify changes in tumor DNA levels over time .
3 Methods : After obtaining informed consent , plasma samples were collected prospectively at multiple time points in a cohort of patients ( pts ) with various gastrointestinal ( GI ) malignancies in the locally advanced , metastatic and adjuvant settings .
4 Hotspot regions of genes known to be commonly mutated in GI tumors were amplified by multiplexed PCR , and the resultant amplicons were subjected to next-generation ultra-deep sequencing .
5 Μ Suppression of sequencer and PCR errors allowed mutations to be identified and quantified with a sensitivity of approximately 1 variant in 5,000 molecules .
6 Sample-specific barcoding allowed simultaneous analysis of up to 96 samples .
7 Μ Results : 29 out of 74 available samples from 17 pts were analyzed for the presence of ctDNA. 3 pts had KRAS mutations exclusively. 2 pts had mutations in two of the evaluated genes : KRAS plus PIK3CA and KRAS plus TP53. 2 pts with measurable mutant ctDNA had samples analyzed at multiple time points .
8   One of these patients with locally advanced pancreatic cancer initially had a KRAS G12D mutation which disappeared after treatment with chemo-radiation therapy , but then he developed significantly rising levels of a different KRAS G12L mutation just preceding the diagnosis of liver metastases by imaging .
9   A second pt with metastatic colon cancer had high levels of ctDNA prior to treatment that decreased dramatically after initiation of mFOLFOX and bevacizumab therapy .
10 Conclusions : Our initial analysis indicates that our technique is able to quantify multiple mutations at very low copy numbers accurately in this cohort of pts with GI cancers .
11 Moreover , we were able to monitor changes in mutation type and quantity using this non-invasive liquid biopsy approach .
12 Analysis of remaining samples is ongoing , and additional longitudinal data will be presented .



PMID: AACR_2017-5167
(Cell)  
Terms: in-vitro
Sent# Symbols Sentence Mnemonics
0 Stem-like colorectal cancer cell lines show response to the ERK1/2 inhibitor , SCH772984 , alone and in combination with neratinib. .
1 Background : We have recently shown an association of colorectal tumor subtypes with differential response to chemotherapy in patients ( pts ) , and to targeted therapy in cell lines .
2 Pts enrolled in NSABP/NRG C-07 with stem-like tumors had a poor prognosis regardless of stage or treatment , highlighting the importance of finding new treatments for stem-like tumors .
3 Our in-vitro data showed that KRAS mutant ( mt ) cell lines of the intrinsic inflammatory subtype were sensitive to the combination of MEK-162 and neratinib , but stem-like subtype cell lines were resistant regardless of KRAS mt status .
4 The purpose of this study was to extend our observations to xenograft models and to identify new agents that target the stem-like subtype .



PMID: AACR_2012-4833
(Patient)  
Terms: in vivo, in vitro
Sent# Symbols Sentence Mnemonics
0 Activation of ERBB2 signaling causes resistance to the EGFR -directed therapeutics antibody cetuximab .
1 The epidermal growth factor receptor directed antibody , cetuximab ( Cmab ) , is an effective therapy for patients ( pts ) with colorectal cancer ( CRC ) particularly with KRAS and BRAF wild type .
2 Treatment in all pts is limited eventually by the development of acquired resistance but little is known about the underlying mechanism . We established 3 Cmab resistant cell lines HCC827CR , GEOCR and A431CR through the exposure to increasing concentration of Cmab .
3 In order to determine why these cell lines were resistant to Cmab we performed genome wide copy number analyses and analysis of ERBB family ligands .
4 We analyzed the growth of Cmab sensitive and resistant cells in vitro and in vivo .
5 Furthermore , we obtained clinical specimens from colon cancer pts treated with Cmab based therapy .
6 Μ Specimens obtained prior to therapy and at the time of Cmab resistance were evaluated . Genome -wide copy number analysis detected the localized genomic amplification in HCC 827CR , which was identified as ERBB2 and confirmed using FISH .
7 Μ Amplification of ERBB2 was also detected in the GEO CR cells .
8 ERBB2 inhibition , with either trastuzumab or lapatinib , restored the Cmab sensitivity in those cell lines .
9 In drug sensitive cell lines , Cmab effectively inhibited growth and ERK1/2 signaling both of which were inhibited in presence of ERBB2 amplification .
10 Μ In contrast , despite detecting ERBB2 activation in the A431 CR cells we did not identify ERBB2 amplification .
11 Instead we detected increased levels of the ERBB3 ligand heregulin .
12 The disruption of ERBB2/ERBB3 herterodimerization using pertuzumab restored Cmab sensitivity in A431CR in vitro and in vivo .
13   CRC patients with ERBB2 amplification ( n = 13 ) treated with Cmab based therapy survived significantly shorter than pts without ERBB2 amplification ( n = 220 ) ( The median OS 89 versus 149 days , p = 00013 ; log-rank test ) .
14 Μ We also identified evidence of ERBB2 amplification at the time of acquired drug resistance using either tumor biopsies or by analyzing serum HER2 extracellular domain ( ECD ) .
15 We further analyzed plasma heregulin from CRC patients and the concentrations ranged widely ( Median , 1622 pg/ml ; range 0-18,045 pg/ml ) .
16 Pts who achieved response to Cmab therapy ( n = 16 ) had significantly lower heregulin concentration than pts without response ( n = 49 ) ( Mean , 1,050 versus 3,601 pg/ml , p < 0001 ; unpaired t test ) .
17 In addition we identified a significant increase in plasma heregulin levels obtained at the time of clinic cetuximab resistance compared to pre-treatment specimens ( p = 00313 ) .
18 Μ We identify activation of ERBB2 signaling , either through ERBB2 amplification or through heregulin upregulation , as a mechanism of both de novo and acquired cetuximab resistance .
19 These results suggest that ERBB2 inhibitors , in combination with Cmab , may represent a rational therapeutic strategy in Cmab-resistant cancers .



PMID: ASCO_158705-173
(None)  
Terms: prospective, phase III study, NCT02364024, Clinical trial
Sent# Symbols Sentence Mnemonics
0 Validation of the prognostic impact of lymphocyte infiltration ( LI ) in patients ( pts ) with stage III colon cancer ( CC ) treated with adjuvant FOLFOX+/- cetuximab : A PETACC8 translational study. .
1 Background : The prognostic value of LI of CC has been demonstrated by several groups .
2 However no validated test is available for clinical practice .
3 We previously described an automated and reproducible method for testing LI ( Allard MA et al2012 ) and aimed to validate it for clinical use .
4 Methods : According to NIH criteria , we designed a prospective analysis of this biomarker in pts included in the PETACC8 phase III study .
5 Primary objective was to compare % of pts without recurrence at 2 years in pts with high versus low LI ( #NCT02364024 ) .
6 Secondary objectives were comparison of disease free ( DFS ) and overall ( OS ) survivals , and prognostic value of LI on these endpoints .
7 Automated testing of LI was performed on virtual slides without access to clinical data .
8 Results : Among the 1,220 CC pts enrolled , LI was high , low and not evaluable in 241 ( 20% ) , 790 ( 65% ) and 189 ( 15% ) , respectively .
9 High and low LI groups did not differ except for treatment arm ( p = 004 ) and microsatellite status ( MSI/MSS ) status ( p = 004 ) .
10 Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in pts with high and low LI respectively ( p = 002 ) .
11 Pts with high LI also had better DFS and OS ( table ) .
12 Stage , grade , KRAS status and LI were the only prognostic markers in multivariate analysis .
13 Μ Sub - group analyses revealed that high LI had better DFS and OS in MSS pts , and in pts without KRAS codon 12-13 mutation , but not in MSI neither in KRAS mutated pts .
14 Conclusions : This is the first prospective validation of a LI testing in pts with stage III CC treated with FOLFOX adjuvant .
15 Automated testing of LI also had a prognostic value for DFS and OS .
16 Funding : Merck-Serono , Sanofi , Rgion Ile de France .
17 Clinical trial information : NCT02364024 DFS LI*3 yrs rate ( % ) HR [95% CI] POverall72 versus 811.4 [11-19] 0.01KRAS wt pts77 versus 831.5 [10-22] 0.03pMMR pts72 versus 801.4 [11-19] 0.02 OS LI*5 yrs rate ( % ) Overall80 versus 891.7 [12 - 25] 0.005KRAS wt82 versus 901.7 [10 - 28] 0.03pMMR79 versus 891.7 [12 - 26] 0.008 Multivariate analysis ( OS ) pN status : 2 versus 12.4 [17-34] <0.001pT status : [4-3] versus [2-1] 4.3 [14 - 135] 0.01Histological grade : high versus low1.6 [11-23] 0.02KRAS : M versus WT1.5 [11-22] 0.02LI*1.7 [11-27] 0.02*Low versus High .



PMID: AACR_2013-2737
(Patient)  
Terms: in vivo, mouse model, mouse
Sent# Symbols Sentence Mnemonics
0 Spontaneous genomic alterations identified in a chimeric model of colorectal cancer guide effective combinatorial therapy. .
1 Colon cancer is the second most common cause of cancer mortality in the western world .
2 We generated a mouse model of colon cancer in which a conditional mutation of p53 is combined with inducible delta131-beta-Catenin over-expression in the intestinal epithelium .
3 After 4-12 months of beta-Catenin induction , small adenomas and large solitary nodules of invasive adenocarcinomas developed in either the upper or lower intestinal tract , while the remainder of the intestine appeared normal .
4 Molecular analysis revealed that EGFR and MET were expressed in advanced adenocarcinomas but not early stage adenomas .
5 Although propagating mouse colon tumors has been very challenging , we nevertheless successfully established one tumor line through direct in vivo propagation in the kidney capsule .
6 This tumor line , CB42 , grew aggressively and metastasized to ancillary lymph nodes as well as the lung in a subcutaneous metastasis assay and grew in the liver when seeded there by intra splenic injection .
7 Treatment with a MET inhibitor Crizotinib , had no effect on either primary tumor growth , or metastasis .
8 By comparing the genome of CB42 with other colon tumors that did not propagate , we discovered an amplicon on chromosome five containing genes that correlated with propagation and metastasis .
9 Μ In addition , whole genome sequencing revealed that CB42 harbored a mutation in KRAS .
10 Results from combination therapies against key genetic alterations will be presented .



PMID: AACR_2015-2661
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Bilateral blockade of MEK - and PI3K-driven pathways is effective in the treatment of KAS mutant mucinous colorectal cancer cells .
1 Purpose .
2 A significant proportion of sporadic colorectal cancers ( CRCs ) ( 10-15% ) are of the mucinous subtype ( >50% of the tumor ) .
3 Mucinous colorectal adenocarcinomas ( MCAs ) are clinically , morphologically and molecularly distinct from nonmucinous CRCs as they show a different spectrum of genetic alterations ( higher KRAS mutations , MSI-H , lower p53 , high MUC2 ) and exhibit more aggressive behavior ( more prone to peritoneal dissemination and lymph node involvement ) .
4 MCAs are associated with poorer response to chemotherapy and have limited treatment options .
5 The purpose of this study was to test the effectiveness of combinatorial targeting of two KRAS-associated parallel pathways in an attempt to counter adaptive resistance associated with single pathway inhibition .
6 Methods .
7 Two KRAS mutant MCA cell lines LS174T and RW7213 were treated with two small molecule inhibitors , GDC0973 and GDC0941 , to block mitogen -activated extracellular regulated kinase kinase ( MEK ) and phosphoinositide 3-kinase ( PI3K ) respectively .
8 Adaptive resistance of these two cell lines to the PI3K inhibitor ( PI3Ki ) was examined by protein phospho-receptor tyrosine kinase ( RTK ) arrays , western blots and immunocytochemistry .
9 Results .
10 Μ Bioinformatic analysis of the colon cancer datasets in the cancer genome atlas ( TCGA ) showed increased mutation rates in mucinous over nonmucinous CRCs for effectors of RAS-RAF-MEK-ERK ( 80% versus 419% ) and PI3K-AKT-mTOR ( 60% versus 218% ) pathways .
11 Both MCA cell lines were sensitive to MEK inhibitor ( MEKi ) treatment .
12 In contrast , these cell lines , though initially sensitive to PI3Ki , later became resistant .
13 Concomitant with the development of resistance were a ) increase in phosphorylated RTKs including IR , IGF-1R , EGFR , ErbB2 b ) increase in phosphorylated ERK and AKT , c ) nuclear translocation of the transcription factor FOXO3A and d ) a decrease in proapoptotic protein BIM .
14 Combinatorial treatment of PI3Ki and MEKi synergistically reduced viability of MCA tumor cells with attendant decrease in phosphorylated ERK and AKT and increase in BIM .
15 Conclusions .
16 Our data suggest cellular dependence ( addiction ) of KRAS-mutant mucinous CRC cells on hyperactivation of MEK and PI3K pathways .
17 Interestingly , PI3K single agent inhibition initially triggers pathway downregulation and reduced tumor cell viability but later leads to development of adaptive resistance .
18 Our studies suggest this resistance involves dynamic rewiring of signaling circuits mediated through FOXO3A nuclear localization , relief of RTK inhibition , MEK-ERK activation and BIM reduction .
19 Adaptive resistance however , can be overcome by co-targeting of PI3K and MEK .
20   Our studies thus provide a rational basis for MEKi and PI3Ki combination therapy for KRAS mutant CRCs .



PMID: AACR_2013-2147
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Generation of primary cell lines from advanced colon cancer : a tool for screening novel anticancer molecules. .
1 For diversely heterogeneous diseases like cancer , a major challenge in the development of new drugs is using appropriate in vitro testing platform .
2 Although high throughput screening of new compounds requires a large panel of genetically well characterized cell lines , their numbers are far less than requirement of biophrama .
3 On top of this the translational potential of cell line panel is limited because most of the commercially available cell lines have been generated from metastatic site and highly transformed , therefore do not represent the true state of the disease .
4 In this context , we have developed two early passage patient derived primary colorectal cancer ( CRC ) cell lines .
5 Using this improved in vitro testing system we tested the efficacy of a number of anticancer agents against CRC .
6 Cell lines were generated by enzymatic disaggregation method .
7 The tissues were obtained after informed consent from patient .
8 The tumor tissues were sectioned into to small pieces ( 1mm ) and were digested using 0.5% Collagenase for 2-4 hrs at 37C .
9 The single cell suspensions were cultured in DMEM supplemented with 10% fetal bovine serum .
10 The epithelial cells were propagated up to passage 2 and were cryopreserved for further applications .
11 Mutational ( K-RAS , BRAF , PIK3CA , PTEN ) and standard CRC specific marker ( such as mucin ) analyses were done in order to confirm the authenticity of these lines .
12 The cell viability was evaluated using MTT assay following treatment with Standard of Care ( SOC ) agents ( both single and combinations ) .
13 Additionally for screening of selected FDA approved NSAIDs like Aspirin , Etoricoxib , Ibuprofen , Indomethacin , Mefenamic acid , Methotrexate and Nimesulide ( repurposing ) were performed at their respective CMAX concentrations after 48 hrs of treatment .
14 Our results showed that , the SOCs when tested as single agents did not show any significant cell death .
15 However , when treated in combination with Irinotecan , Fluorouracil and Leucovorin in the presence and absence of Avastin a significant augmentation of cell death was observed in both the cell lines .
16 Further , Mefenamic acid , Methotrexate , Ibuprofen and Aspirin exhibited a significant cytotoxic effect in both cell lines after 48 hrs of treatment .
17   Together , these results demonstrate that COX-2 inhibitors could be developed as a as an effective anticancer therapeutics for colorectal cancer treatment and primary cell line model provides a rapid and more reliable screening platform .



PMID: ASCO_148030-156
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Extended follow-up results of a phase 1B study (BRIM7) of cobimetinib (C) and vemurafenib (V) in BRAF-mutant melanoma. .
1 Background : NCCN guidelines recommend screening all CRC patients diagnosed at age 70 years and those > 70 who meet Bethesda Criteria with either immunohistochemistry ( IHC ) for MMR protein expression or PCR for microsatellite instability ( MSI ) , and also recommend tumor sequencing for RAS/BRAF mutations in all CRC patients with metastatic disease .
2 MMR status is also needed for management of all stage II colon cancer patients , and BRAF mutational status is useful in work up of MMR-deficient ( dMMR ) tumors .
3 Μ We hypothesized that the higher mutational burden of dMMR tumors would permit their identification on the basis of the mutation count in an NGS panel , thus allowing a single multi - gene NGS assay to reliably detect not only RAS/RAF mutations but also MMR deficiency .
4 Methods : Under an IRB waiver , an institutional electronic database was queried to identify all CRC analyzed with MSK-IMPACT , our custom 341 - gene NGS assay .
5 Μ Tumor mutational load , defined as the raw number of somatic mutations identified , was determined for each case and compared between MMR-proficient and MMR-deficient cases .
6 Results : We identified 149 unique CRC patients tested with MSK-IMPACT .
7 Μ Of these , 93 had MMR status available , including 8 dMMR cases. 83 of 85 ( 98% ) of MMR-proficient cases had 16 or fewer mutations , while two outliers with 158 and 250 mutations each were found to be POLE-mutant .
8 ✓ MMR-deficient tumors had a higher mutational load with a significantly higher median number of somatic mutations ( 49 , range 23-67 ) than MMR-proficient tumors ( 6 , range 0-16 ) , p = 0.0024 . RO-ASS-GM
9 Conclusions : This preliminary analysis suggests that using a cut-off for mutational load , such as 20 mutations for MSK-IMPACT , may provide a highly sensitive and specific means of screening for MMR deficiency with the same assay used for tumor genotyping .
10 Μ If validated , the use of a single multi - gene sequencing assay to screen for both dMMR and RAS/BRAF mutations could be cost effective , particularly in metastatic CRC , but also in early stage disease , while providing additional genetic information that may be useful for research purposes .
11 Larger numbers of known dMMR tumors are currently being analyzed with MSK-IMPACT to validate this hypothesis .



PMID: ASCO_152036-156
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Selective sensitization of Ras-mutant ( Ras-m ) cancer cells to DNA-damaging chemotherapy by Wee1 inhibition with AZD1775. .
1 Background : Human cancers harboring Ras-mutated (m) oncogenes are resistant to current EGFR-targeted therapies .
2 Given the many patients with Ras-m cancers , limited treatment options available , and their poor outcomes , there is a great need to develop treatment modalities that effectively target these tumor types .
3 We previously reported that Ras-m tumors activate the ATR/Chk1 DNA damage checkpoint through signaling from wild-type ( wt ) Ras proteins , thus conferring resistance to DNA damaging chemotherapeutic agents in vitro and in vivo.1 Consequently , we hypothesized that abrogating the ATR/Chk1 DNA damage checkpoint by downstream Wee1 kinase inhibition would selectively sensitize Ras-m and BRaf-m tumors to DNA damaging chemotherapy .
4 Methods : Toassess whether a Wee1 kinase inhibitor ( KI ) enhanced the cytotoxicity of DNA damaging agents in Ras-m and Raf-m cells , we utilized a selected panel of colon cancer cell lines with the following mutational backgrounds ( 2-3 cell lines/group ) : 1 ) Ras-m/p53-m ; 2 ) Ras wt/p53-m ; 3 ) Ras-m/p53 wt and 4 ) BRaf-m/p53-m. 4 log dose response cell viability assays were used to determine the single agent IC50 for the topoisomerase 1 inhibitor , SN38 , and the Wee 1 KI AZD1775 .
5 Cells were then treated with the two agents at doses ranging in a 5-fold difference below each individual IC50 ( 004X , 02X ) .
6 For all viability assays , cells were plated in 96-well plates in triplicate ; viability was determined by MTT assay .
7 Results : AZD1775 treated Ras-m/p53-m cells were ~10-100 fold more sensitive to SN38 .
8 Notably , Wee1 inhibition did not sensitize Ras wt/p53-m or Ras-m/p53 wt cells to SN38 .
9 Wee1 inhibition in BRaf-m/p53-m cells led to a modest ~3-5 fold sensitization to SN38 , with the exception of one cell line which showed ~ 270 fold sensitization .
10 Conclusions : The Wee1 KI AZD1775 strongly enhances the antitumor effect of SN38 in this panel of Ras-m/p53-m cancer cells but not in cancer cells where either p53 alone or Ras alone were mutated .
11 Although this is a limited panel of cell lines , our findings support further testing of this combination in human tumors harboring concomitant Ras and p53 mutations .
12 Supported by NYU GI Cancer Fund. 1 .



PMID: ASCO_33458-65
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Genetic and proteomic features associated with survival after treatment with erlotinib in first - line therapy of non-small cell lung cancer. .
1 Background . : The efficacy of programmed death-1 ( PD-1 ) blockade in epidermal growth factor receptor gene ( EGFR ) mutation-positive non-small cell lung cancer ( NSCLC ) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors ( TKIs ) is unknown .
2 We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR .
3 Μ Patients and Methods . : We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment ( cohort A ) .
4 Programmed death-ligand 1 ( PD-L1 ) expression and tumor-infiltrating lymphocyte ( TIL ) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry .
5 Μ Whole-exome sequencing of tumor DNA was performed to identify gene alterations .
6 The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients ( cohort B ) .
7 ✓ Results . : In cohort A , median progression-free survival ( PFS ) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients , respectively ( P = 0.099 ; hazard ratio [HR] of 0.48 with a 95% confidence interval [CI] of 0.20-1.24 ) . GM-ASS-RO
8 Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of >/= 1% or <1% , respectively ( P = 0084 ; HR of 037 , 95% CI of 010-121 ) .
9 PFS tended to increase as the PD-L1 expression level increased with cutoff values of >/= 10% and >/ = 50% .
10 The proportion of tumors with a PD-L1 level of >/= 10% or >/= 50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B .
11 Nivolumab responders had a significantly higher CD8 + TIL density and nonsynonymous mutation burden .
12   Conclusion . : T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment , possibly as a result of a higher PD-L1 expression level , than are T790M-positive patients .



PMID: ASCO_162961-176
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 DNA repair defect and RAS mutation in Schistosoma mansoni-associated colorectal cancer patients : Carcinogenesis steps or mere coincidence? .
1 Background : Data on Schistosoma mansoni-associated colon cancer is scarce .
2 Infestion induces inflammation which may trigger genetic mutations .
3 We report two pts and potentially implicated carcinogenesis .
4 Methods : KRAS/NRAS exons 2 , 3 and 4 were amplified by PCR and second-generation sequencing by Illumina MiSeq .
5 Pts were tested for MSI using immunohistochemistry antibodies MLH1 , MSH2 , MSH6 , and PMS2 .
6 Results : 1 ) 45 year-old female , abdominal pain , weight loss and diarrhea .
7 Colonoscopy Oct 2014 , 3 cm tumor in cecum .
8 Right colectomy in Jan 2015 .
9 Well differentiated mucinous adenocarcinoma. 2.5 x 1.5 x 1.5 cm invasion into muscularis propria .
10 No perineural or lymphovascular invasion .
11 Mild tumor inflammatory infiltrate .
12 Free margins , metastasis to 1 of 24 lymph nodes .
13 Ileal schistosomiasis found .
14 MSI confirmed ( loss of MLH1 and PMS2 ) .
15 All-RAS mutation negative .
16 Six-month adj CAPOX .
17 Last visit Dec 2015. 2 ) 47 year-old male , hepatosplenic form .
18 Right hemicolectomy in 2012 due to complications of appendicitis .
19 Mar 2014 , splenectomy and esophageal varices clamp due to GI hemorrhage .
20 He presented diarrhea and in Nov 2014 , colonoscopy showed 2 cm tumor next to ileum-transverse colon anastomosis .
21 Mar 2015 , segmental colectomy .
22 Ileum : granulomatous reaction in response to Schistosoma eggs ; Merkel diverticula ; 3.5 x 1.8 cm mucinous moderately differentiated adenocarcinoma infiltrating subserosa , free margins , lymphovascular invasion present , perineural infiltration absent .
23 Mild tumor lymphocytic infiltrate .
24 No lymph nodes were identified in the specimen .
25 Other findings : diffuse granulomatous reaction in response to Schistosoma eggs in ileum and colonic mucosa .
26 MSI negative .
27 Μ Exon 2 KRAS mutation ( c38G > A : pG13D ) was identified .
28 No adj chemo .
29 Last visit Dec 2015 .
30 Conclusions : age of patients and mucinous subtype were in accordance with literature .
31 RAS mutation , along with the presence of MSI , may be implicated in the carcinogenesis of Schistosoma mansoni-associated colorectal cancer or represent coincidental events .
32   If the first is right , it would determine screeeing , treatment and prognosis implications among Schistosoma mansoni infested patients .



PMID: AACR_2017-179
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Plasma membrane lipid therapy : disruption of oncogenic Ras spatiotemporal organization by membrane-targeted dietary bioactives ( MTDB ) . .
1 Programmed cell death receptor ligand 1 ( PD-L1 ) expression : Epidermal growth factor receptor ( EGFR ) and Kirsten RAS ( KRAS ) mutations in second - line therapy ( 2L ) non-small cell lung cancer ( NSCLC ) patientsA Danish cohort study. .



PMID: AACR_2013-2782
(Cell)  
Terms: in vivo, in vitro, tumor models, mice
Sent# Symbols Sentence Mnemonics
0 Utilization of in vivo human isogenic cancer models in the new era of targeted therapies. .
1 The explosion of knowledge regarding the genetic underpinnings of human cancer heralds a new era of targeted therapy .
2 To date , in vivo cell based screening has proven a useful tool in almost all drug development programs .
3 Cells used in such screens are usually harvested from cancer patients that harbor the specific mutation of interest , but these cells almost invariably contain many other additional mutations making it difficult to ascertain the specific functions of molecules being screened .
4 Thus the lack of true control cells hampers the development of new cancer therapeutics .
5 Μ Using cell lines generated with Horizon Discovery's proprietary rAAV-based GENESIS gene editing platform , we have established a comprehensive range of isogenic cancer models for our in vivo compound screening program to service our clients in academia and industry , with mutations in a wide variety of genes including KRAS , PIK3CA , PTEN , IDH1 and p53 .
6 These isogenic tumor models comprise pairs of cell lines which share the same genetic background , differing only by the mutation of interest and therefore allowing definitive studies of specific genetic variances to be performed .
7 The same isogenic pairs of lines can be used for in vitro and in vivo experiments to ensure continuity and relevance of results .
8 We have carried out intensive validation of these models in vivo to ensure the lines generate robust tumor growth in mice and the matched tumors differ only in the genetic composition of target gene .
9   Μ In a POC study , colon cancer cell lines with the KRAS G13D mutation have been demonstrated to respond to Cetuximab treatment , consistent with recent findings in the clinic .
10   These results challenge the current clinical practice of only using Cetuximab as a therapeutic for KRAS wild type patients , and provide the basis for expanding the usage of the drug to benefit more patients .
11 In summary , we have established a series of reliable in vivo isogenic models with precise and highly specific genetic modifications as predictors of clinical effect .
12   They will provide a valuable tool in the drug discovery and development arena to drive forward personalized medicine by enabling novel target validation , expansion of the target population for existing therapeutics , and definition of patient responsive genotypes .



PMID: ASCO_146447-156
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Evaluation of clinical and histological criteria and outcome in management of hereditary non-polyposis colorectal carcinoma ( HNPCC ) . .
1 Background : Lynch syndrome , or HNPCC , is the most common inherited colorectal carcinoma ( CRC ) syndrome accounting for 2-5% of all cases .
2 Pathologists initiate IHC testing based on patient age and defined histological criteria .
3 This study aimed to evaluate the efficiency of these criteria and their clinical outcome .
4 Methods : All CRC cases diagnosed at The Ottawa Hospital ( TOH ) from January 2012-July 2013 reviewed .
5 Cases with MMR deficiency were reviewed for Genetics referral rates , treatment , and outcomes .
6 Results : Of 480 cases of CRC , 90 ( 19% ) cases had IHC performed for MMR status with 45 ( 9% ) cases having intact MMR gene expression (MSS) and 45 ( 9% ) deficient ( 39 MLH1 , 4 MSH2 , 1 MSH6 and 1 PMS2 ) ( MSI ) .
7 Μ MLH1 deficient tumors analyzed for BRAF mutation ; 9/39 ( 23% ) were negative. 16/90 ( 18% ) patients had strong family history of HNPCC-associated malignancies ( 8 MSS , 8 MSI ) ; 15 ( 17% ) had personal history of multiple HNPCC-associated cancers ( 5 MSS , 10 MSI ) .
8   Μ 31 patients treated with adjuvant chemotherapy ( 20 MSS , 11 MSI ) ; 15 patients referred for genetic counseling. 3 germline pathogenic mutations identified ( 1 each in MLH1 , MSH2 and PMS2 ) with 4 cases pending and 2 inconclusive .
9 Histological criteria that were informative are : right colon cancer ( 82% versus 44% , p = 00004 ) , intraepithelial lymphocytes ( IEL ) ( 67% versus 31% , p = 0007 ) , high histologic grade ( 60% versus 22% , p = 00003 ) and any amount of mucinous differentiation ( 60% versus 27% , ( p = 00014 ) .
10 Criteria without statistical significance were mucinous carcinoma ( > 70% ) , Crohns-like lymphoid aggregate ( CLLA ) , stage and tumor size .
11 Conclusions : MSI-H colon cancers are biologically distinctive in their behaviour and outcome .
12 Testing for MSI-H and BRAF-methylation by IHC shows correlation with genetic testing .
13 At TOH incidence of MSI-H with current detection is 0.6% of total CRC cases .
14 Standardization of histological criteria will increase detection rate .
15 We recommend testing on any CRC that fulfils any of the following criterions : age < 70 years , right colon , IEL , high grade or mucinous differentiation .
16 Using this strategy , 62% of total CRC cases need to be tested with a positive predictive value of 57% and negative predictive value of 92% .



PMID: ASCO_34724-65
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 AVASTERB OUEST : A prospective cohort study of unresectable metastatic colon cancer treated successively by FOLFIRI bevacizumab and cetuximab irinotecan. .
1 Background : Bevacizumab and cetuximab regimen are approuved since 2005 in Europe for Metastatic Colorectal Cancer Patients ( MCCP ) .
2 Very few studies have reported data concerning the sequence ( FOLFIRI BEVA and after failure CETUXIMAB - CAMPTO ) in MCCP from the real world .
3 Methods : Since 2003 , in west of France , ( Bretagne-Pays de Loire ) , a network called OMIT ( Observatoire des Mdicaments et Innovations Thrapeutiques ) directed by Regional Health Agencies has been created .
4 This structure gathered prospectively data from MCCP treated with targeted therapies .
5 Since 2006 , a cohort of MCCP treated successively by FOLFIRI BEVACIZUMAB ( same protocol : same dose ) as first line to progression or unacceptable toxicity and CETUXIMAB - CAMPTO after the first line failure was constitued ( AVASTERB cohort ) .
6 Criteria for initial unresectability of metastic lesions was based on investigator's evaluations during local comitee ( surgeons and oncologists ) .
7 In order to have a large follow up , the 35 first patients of the cohort were studied in this abstract .
8 Age , sex , response rate to the different regimens , secondary metastatic lesion resection , time to progression to the different regimens , follow up and overall survival are the criterias studied .
9 Results : Median age 60 years ( 49-83 ) , Males : 60% , colon 71% , rectum : 17% , colorectal jonction : 12% .
10 Response rate ( OR+SD ) with Folfiri Bevacizumab : 45.7%. 17% of the patients underwent hepatic surgery with curative intent ( all during Folfiri bevacizumab ) Time to progression with Bevacizumab : 6 months .
11 Fifty eight percent of the patients are still alive with a median follow up of 25 months ( 11-29 ) Median overall survival was not reached .
12 The 12 months and 24 months overall survival rates are respectively 71.4% and 45.7% ( date of point : 01/01/2009 ) .
13 Actualisation of the data will be provided during the meeting Conclusions : The results from this prospective unselected cohort of MCCP treated with the sequence FOLFIRI BEVA and after failure CETUX-CAMPTO from the real world show promising TTP , and overall survival .
14   The study of the Kras mutation and others biomarkers could improve these results by personalization of the treatment .
15 This part of our study is actually ongoing .



PMID: ASCO_184471-199
(Patient)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 Association of high microsatellite instability ( MSI-H ) with a high immunoscore ( IS ) compared to PD-L1 expression and increased survival in patients ( pts ) with metastatic colorectal cancer ( mCRC ) treated with oxaliplatin ( Ox ) and fluoropyrimidine ( FP ) : A pooled analysis of the AIO KRK 0207 and RO91 trials. .
1 Background : MSI-H is an established prognostic marker in early colon cancer .
2 Moreover , MSI-H , tumor immune cell infiltration and PD-L1 expression are also discussed as potential predictive biomarkers for immunotherapy .
3 However , little is known about the prognostic value of these biomarkers and their association among each other in mCRC .
4 Methods : We analyzed samples from pts .
5 with mCRC uniformly treated with a FP and Ox within two randomized AIO trials ( KRK 0207 and RO91 ) .
6 MS status was assessed by immunohistochemistry ( IHC ) of mismatch repair proteins and subsequent fragment length analysis in case of protein loss or incoherent results .
7 PD-L1 expression was determined by IHC ( 1% expression threshold ) .
8 Tumor lymphocytic infiltration ( CD8 and CD45RO ) was scored according to the immunoscore ( IS ) concept by Galon et al ( J Transl Med 2016 ) .
9 Results : 41/550 cases ( 75% ) displayed MSI-H .
10 The mean IS of the total population was 0.57 ( SD 097 ) , the IS of MSI-H pts .
11 was significantly higher ( mean of 24 ; SD 14 ; p00001 ) .
12 17 cases were PD-L1 positive ( pos ) ( 3 % ) , only four of these were MSI-H .
13 MSI-H status was significantly correlated with a higher IS , but not with PD-L1 expression ( table 1 ) .
14 There was no difference in median overall survival ( mOS ) between MSI-H and MS stable ( MSS ) pts. ( mOS MSI-H/MSS : 17.6/22.5 months ( mos ) , log rank : p = 0.85 ) , PD-L1 negative ( neg ) and pos .
15 pts. ( mOS PD-L1 neg./pos. : 22.1/28.9 mos. , log rank : p = 0.49 ) and IS high or low pts. ( mOS IS high/low : 21.1/22.1mo. , log rank : p = 0.25 ) .
16 Conclusions : In contrast to early stage colon cancer , none of these parameters was prognostic in mCRC patients .
17 Panel-sequencing with a total of 35 genes including RAS , BRAF and POL-E on cases with PD-L1 expression , high IS or MSI-H status to further characterize these cases will be reported .
18 Clinical trial information : AIO-R091 , AIO-KRK-0207 : EudraCT-Nr : 2008-007974-39 .
19 Correlation of PD-L1 expression , immunoscore ( IS ) and MS status .



PMID: AACR_2017-5766
(Patient)  
Terms: prospective, mice
Sent# Symbols Sentence Mnemonics
0 High-content microscopy-based screening of colorectal organoids. .
1 High-content screening of cells has become a widespread approach for cellular assays due to its capacity to capture complex biological processes .
2 However , conventional cell culture is limited with respect to cell and tissue architecture .
3 Organoids are a unique model system for the intact and diseased intestinal epithelium .
4 The 3D model can be used for the functional study of cancer development and , potentially , prospective therapeutic testing of drugs in patient derived tumor organoids .
5 Here , we present a high-content microscopy based screening workflow to study organoid self-organization and growth with up to single cell resolution .
6 After seeding of organoid fragments in a basal membrane extract , screening plates are incubated to allow for organoid formation .
7 Subsequent treatment and incubation is followed by staining and imaging on a high-throughput microscopy platform followed by automated image analysis using open-source software .
8 Profiling of both complete organoids and their individual architecture enables the quantitative description of population and tissue heterogeneity in the context of various perturbations .
9 Μ We generated four distinct colon organoid lines from mice carrying mutations of APC and KRAS in different combinations .
10 These are profiled for differential phenotypic responses to a library of >1000 drug -like compounds .
11 Also , this methodology is used to screen for clinically relevant differential treatment responses in patient derived tumor and normal colon organoids .
12 Hence , based on this work we are able to analyze gene - drug interactions in early colon cancer development and drug response of patient derived colorectal cancer organoids .



PMID: AACR_2016-3967
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Amplicon-based NGS detects targeted variants in paired tissue and ctDNA samples .
1 Circulating tumor DNA ( ctDNA ) in blood stream has been recognized as an essential sample source for non-invasive biopsy of cancer patients .
2 Μ With next generation sequencing ( NGS ) technology it is possible to detect multiple cancer relevant mutation spots simultaneously .
3 Μ In order to understand the correlation of mutation spectrum between DNA from original solid tumor and DNA from plasma , we analyzed paired DNA samples with amplicon-based NGS .
4 Paired frozen tissue and plasma samples were collected from 17 colon cancer patients under the IRB protocol .
5 Tissue DNA was extracted with NucleoSpin Tissue kit of Clontech .
6 The ctDNA was extracted from 0.5ml of plasma with Quick-cfDNA Serum & Plasma Kit from Zymo Research .
7 The library was prepared with Accel-Amplicon 56G Oncology Panel of Swift Biosciences , Inc .
8 This panel generates 263 amplicons covering 56 clinically relevant oncology-related genes .
9 Input ctDNA from plasma was 0.5 to 10 ng depending on the sample yield .
10 The sequencing was conducted on Illumina's Miseq with MiSeq Reagent Kits v2 ( 300cycles ) .
11 FastQ files were generated by Miseq Reporter .
12 Non-synonymous variant calls by the tissue DNA sequencing were defined by coverage depth ( 30 ) , frequency ( >5% ) , and forward/reverse balance (0) .
13 The defined non-synonymous variant calls were searched from variant calls by the paired ctDNA sequencing with the cutoff frequency at 0.1% .
14 Μ In 17 paired colon cancer samples , 86 non-synonymous variant calls were identified by tissue DNA sequencing .
15 Μ The variant calls of tissue DNA samples showed 56 of 86 variants matched variant calls in the paired ctDNA samples .
16 Among 56 variant calls in ctDNA , 44 variant calls were assumed as germline variants according to the 1000 genome reference and similar frequency of the variant call between paired tissue DNA and ctDNA .
17 There were 12 variant calls deemed somatic variant calls by the literature references and the differential frequency of the variant call between paired tissue DNA and ctDNA .
18 Μ The 12 detected somatic variant calls were clustered in seven cases .
19 Twelve somatic variant calls with frequency ( % ) in tissue and plasma DNA samples are shown as APC S1456 frame shift ( 418 versus 617 ) , KRAS G12D ( 37.0 versus 5.0 ) , TP53 G105R ( 56.0 versus 11.3 ) , HNF1A P291 frame shift ( 36.8 versus 2.41 ) , HNF1A P291 frame shift ( 27.1 versus 1.2 ) KRAS G12D ( 23.1 versus 0.3 ) , ERBB4 I377T ( 8.3 versus 0.5 ) , PTEN L267 frame shift ( 124 versus 04 ) , MAKP2K1 L57N ( 23.9 versus 0.7 ) , TP53 R273C ( 25.8 versus 0.3 ) , TP53 H178D ( 12.1 versus 1.1 ) , TP53 T377 frame shift ( 11.2 versus 0.1 ) .
20 Μ Remaining 30 somatic variant calls were detected only in tissue DNA samples .
21 Our results indicated that the simultaneous detection of somatic variants of multiple genes in ctDNA samples with the amplicon-based DNA sequencing is applicable with variant frequency over 0.1% .
22 The NGS analysis of paired tissue DNA and ctDNA is a reliable evaluation for cancer related mutations in ctDNA .



PMID: ASCO_166885-176
(Patient)  
Terms: phase II trial, clinical trial
Sent# Symbols Sentence Mnemonics
0 Association of gene signature to identify molecular subtypes with clinical outcomes of 1st - line cetuximab ( cet ) treatment for metastatic colorectal cancer ( mCRC ) . .
1 Background : Recently , several groups have reported on classifications of CRC using gene expression data to identify distinct subtypes ( Guinney J , et al Nat med 2015 ) .
2 Some studies found one subtype which has poor prognosis and does not respond to cet ( Sadanandam A , et al Nat Med 2013 ; De Sousa E Melo F , et al Nat Med 2013 ) .
3 However , few subtyping studies focused on efficacy of cet as an initial therapy for mCRC .
4 We therefore investigated whether the gene signature will predict outcomes in mCRC patients ( pts ) received 1st - line cet treatment .
5 Methods : We analyzed total RNA isolated from tissue samples of 77 KRAS wild-type pts enrolled in 2 phase II trials ( JACCRO CC-05 : UMIN000004197 or CC-06 : UMIN000007022 ) evaluating cet plus oxaliplatin-based chemotherapy as 1st - line treatment .
6 Gene expression levels were measured by HTG EdgeSeq Oncology Biomarker Panel , which is comprised of probes targeting 2560 genes implicated in numbers of pathways , using next generation sequencing for quantitative analysis of targeted RNAs .
7 Univariate Cox regression analysis was conducted for all genes that passed QC filtering .
8 Hierarchical clustering was performed using genes under 0.005 of the Cox p-value .
9 Results : The patient cohort comprised 57% males , median age of 63 years , 90% of performance status 0 and 15% of right colon cancer .
10 The Cox regression analysis identified 24 genes to be with less than 0.005 of p-value for overall survival ( OS ) .
11 Μ CDX2 , which recently identified to be a novel prognostic marker in colon cancer ( N Engl J Med 2016 ) , ranked as first gene associated with OS as well as progression-free survival ( PFS ) ( p= 55610-5 , FDRp= 0058 and p= 50910-5 , FDRp= 0053 , respectively ) .
12 The hierarchical clustering using the 24 genes could classify all participants into 3 groups and the Kaplan-Meier curve of the groups had a significant difference in OS ( mean 136 vs. 198 vs. 281 months , p= 284e-06 ) but not in PFS .
13 Conclusions : Multigene -expression signature may predict outcomes of 1st - line cet treatment in mCRC pts .
14 These preliminary data warrants further confirmation clinical trials : validation of our findings in FIRE3 trial is ongoing .



PMID: AACR_2015-322
(Patient)  
Terms: xenograft, mouse, mouse xenograft
Sent# Symbols Sentence Mnemonics
0 Establishment and genomic characterization of enteroid cultures from human colonic adenomas and adenocarcinomas .
1 Introduction Characterized enteroid cultures of human colon cancer can more precisely model the diversity of colonic neoplasia for the study of cancer initiation , progression and potentially prevention .
2 Using tissue from colon resections and endoscopic biopsies , we have successfully isolated and cultured 14 colorectal adenomas and 2 adenocarcinomas to date .
3 We have maintained these enteroid cultures for up to 2 years and established a working cryorepository .
4 Μ Specific epithelial cell lineage markers and the stem cell marker Lgr5 can be detected throughout the culture period .
5 Methods Enteroid cultures have been initiated and maintained in a serum-free medium containing EGF and pituitary extract .
6 However , approximately half of all neoplasms do not establish in this reduced medium .
7 In contrast , most neoplasms develop and expand in an enriched culture medium containing serum , Wnt , R-spondin , Noggin , and EGF .
8 We have also created a mouse xenograft from an adenoma expanded in the reduced media ; this graft was then successfully reintroduced into culture .
9 Using whole exome sequencing , we are investigating how the genetic background of individual patients contributes to 1 ) variability in the establishment and expansion of enteroid cultures 2 ) tumor heterogeneity in neoplasms and xenografts , and 3 ) the stability of genomic signatures in enteroids over time in culture .
10 Μ Results Twenty-two damaging somatic variants identified in a single colon tumor were preserved in enteroid culture after 2 months in reduced medium .
11 Μ Variants included a frameshift mutation in APC and missense mutations in KRAS and TP53 .
12 Μ The allele frequency of most variants increased in enteroid culture , suggesting that cells lacking these mutations failed to propagate ( including stromal/immune cells ) , or cells carrying these mutations expanded at a faster rate .
13 Ten mutations not present in the original tumor were acquired over time in enteroid culture .
14 Μ These mutations included a missense variant of TRPS1 , a putative prognosticator of colon cancer .
15 The mutations acquired in enteroid culture may reflect genetic instability in the source neoplastic tissue , or the emergence of subpopulations that were below level of detection in the source tissue .
16 Three mutations were present in the tumor and lost in enteroid culture ; this presumably reflects the loss of a subset of cells expressing these variants .
17 Conclusion Changes in allele frequencies suggest that neoplasms are heterogeneous , with shifting cell populations that are differentially affected by culture conditions .
18 This heterogeneity can be further interrogated by comparing allele frequencies in the original tumor with those in enteroids established in reduced or enriched media .
19 This platform can provide further understanding of genetic determinants that underlie the risk for colorectal cancer , as well as strategic insights into the enteroid model as a sophisticated system for the study of tumor biology .



PMID: ASCO_175307-195
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Is the primary tumor location ( PTL ) associated with differential gene expression profiles in patients with metastatic colorectal cancer ( mCRC ) ? Analysis of the FIRE1-trial. .
1 Background : Site -differential molecular characteristics of PTL as well as its influence on overall survival have been reported .
2 In our study , we investigated the association of PTL with gene - and pathway-wise RNA expression as well as its representation in RAS mutational status subgroups .
3 Methods : The phase-III-trial FIRE-1 compared the efficacy of FuFIRI and mIROX in patients with mCRC .
4 Formalin-fixed , paraffin-embedded pretreatment samples from 166 FIRE-I patients were collected .
5 The splenic flexure was used for differentiation between left colon cancer ( LC ) and right colon cancer ( RC ) .
6 RAS mutated PTs ( RASmut ) had PCR confirmed mutations in KRAS gene ( Exon 2 , 3 , or 4 ) or in NRAS gene ( Exon 2 , 3 , or 4 ) .
7 RNA expression profiling used the nCounter(R) PanCancer Pathways Panel including DNA damage control and TGF - .
8 We also studied a set of selected genes ( Aprataxin , AREG , CD3EAP , CES1 , CES2 , CMPK1 , DPD , DUT , ERCC1 , ERCC5 , EREG , FGF2 , GSTP1 , KLC3 , MTHFR , PPP1R13L , RCC1 , TOPO1 , TP , TS , and UGT1A1 ) .
9 The gene -wise analyses used Limma and the permutated t-test with appropriate multiple testing adjustment .
10 Holistic pathway investigation used GlobalAncova and the global tests .
11 RAS mutation status and its correlation with tumor side were included as factors in both analyses .
12 Additionally , gene - and pathway-wise analyses were performed in RASmut and RASWTsubgroups .
13 Results : A total of 83 ( 50% ) of 166 patients had any RAS mutation .
14 A total of 28 ( 17% ) patients had PTs on the right side and 13 of those ( 46% ) were RASmut .
15 The top ten differentially expressed genes between LC and RC are MMP9 , ERCC3 , MAP3K1 , RRAS2 , SOCS3 , RB1 , TGF1 , LEFTY1 , NKD1 , and CDC25B ( unadjusted p-values < 0005 ) .
16 Potential enrichment in the DNA damage control pathway was found ( p = 0008 ) .
17 The RAS subgroup analyses showed a non-overlapping top ten list .
18 Side specific effects may exist for the TGF - pathway and the selected gene set in RASWTpatients .
19 Conclusions : No strong association between PTL and gene expression showed up in mCRC tumors nor RAS subgroups .
20 Potentially differential gene expression may exist for specific genes , two pathways and our selected gene set .



PMID: AACR_2013-494
(Cell)  
Terms: ex vivo, in vitro, In vitro, in vivo, clinical trial, mice, tumor xenografts, mouse
Sent# Symbols Sentence Mnemonics
0 Immunomodulatory effects of a small molecule dipeptidyl peptidase inhibitor , Ari-4175 , are mediated through NK cell activation in a colorectal cancer model. .
1 Introduction : A possible mechanism of the antitumor effect of many therapeutic monoclonal antibodies is antibody -dependent cellular cytotoxicity ( ADCC ) mediated by NK cells .
2 We recently observed that an inhibitor of dipeptidyl peptidase ( DPP ) 4-like serine proteases , Ari-4175 , significantly slowed the growth of K-RAS mutated HCT-116 tumor xenografts in nude mice , either as a single agent or in combination with cetuximab .
3 Ari-4175 is not directly cytotoxic in vitro , and since it was able to overcome , in vivo , the resistance to blockade of the epidermal growth factor receptor engendered by the KRAS mutation in the HCT-116 colorectal cancer ( CRC ) cell line , we tested the hypothesis that the mechanism of the antitumor activity involves the activation of NK cells , resulting in the enhancement of ADCC .
4 Methods : Ari-4175 was administered orally to C57Bl/6 mice at 200 g q .
5 d .
6 x5 days/week .
7 Peripheral blood or spleens were assayed for immune parameters , ex vivo , at various time points .
8 Expression of surface markers on myeloid and NK cells were monitored by flow cytometry .
9 Natural cytotoxicity and ADCC were assayed using HCT116 cells and cetuximab using a flow cytometry-based assay .
10 Cytokines were measured in mouse serum using Luminex assays .
11 Results : Treatment of mice with Ari-4175 induced up-regulation of the activation marker CD69 on NK cells on day 2 , followed by up-regulated expression of FcRIIIA ( CD16 , which mediates ADCC ) on day 7 .
12 Coordinate with these changes in surface markers detected in peripheral blood samples , splenocytes from Ari-4175-treated mice exhibited significantly increased in vitro natural cytotoxicity responses toward the HCT116 colon cancer cell line .
13 The treated mice exhibited increased serum levels of inflammatory cytokines , including IL-1 , IL-6 , MCP-1 , GCSF , and IL-2 .
14 In addition to the impacts on NK cells , we also observed a significant expansion of a distinct CD45+CD14+Gr-1+MHC-IICDllb+CD11cvariable myeloid cell population in both peripheral blood and spleens of mice after one week of treatment with Ari-4175 .
15 Conclusion : The prolyl peptidase inhibitor , Ari-4175 , showed dramatic anti-tumor effect in KRAS mutant colorectal cancer xengrafts when given alone or in combination with cetuximab .
16 In vitro data suggest that the therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevating expression of CD16 on NK cells .
17 In addition , Ari-4175 appears , in vivo , to expand a unique myeloid cell population , which may be responsible for an inflammatory cytokine response and subsequent activation of NK cells .
18 Our study provides a mechanistic rationale for testing Ari-4175 in a clinical trial and possible biomarker endpoints for evaluation in peripheral blood samples .



PMID: AACR_2013-1198
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Presence of non-canonical tumorigenesis pathways in early-onset sporadic rectal cancer. .
1 Chromosomal instability ( CIN ) caused by -Catenin dependent aberrant activation of canonical Wnt signaling or Microsatellite instability ( MSI ) triggered by inactivation of mismatch repair ( MMR ) pathway , are the two major genetic instability pathways that drive classical age-related sporadic colorectal cancer ( CRC ) .
2 Activation of canonical Wnt signaling and MSI are primary tumor initiating events in about 80% and 15% of late-onset CRC cases , respectively .
3 Canonical Wnt signaling is also reported as a secondary event in tumors primarily driven by MSI .
4 These inferences are based on seminal studies that included a disproportionately greater number of colon tumors ( as compared to rectal tumors ) .
5 Recent genome -wide studies have suggested colon and rectal cancer to be a single entity , though several other studies appear to indicate otherwise .
6 Exclusive studies on rectal cancer ( RC ) , especially the early-onset sporadic subtype , have been fewer .
7 Despite a recent trend of increased worldwide incidence , early-onset sporadic rectal cancer ( EOSRC ) is not well understood .
8 Μ We profiled canonical Wnt , KRAS and p53 ( components of the classical colorectal carcinoma progression model ) and MSI status in a panel of 298 colorectal cancer samples. 41% of EOSRC samples did not harbor Wnt or MSI pathways ; the high proportion of a double negative entity was neither identified in late-onset RC samples nor in colon cancer samples .
9 KRAS mutation frequency was also significantly lower in EOSRC ( 24% ) .
10 Μ Since CIN is a hallmark of canonical Wnt activation driven CRC , we profiled genome -wide DNA copy number alterations ( CNAs ) in microsatellite stable EOSRC samples and surprisingly identified extensive chromosomal aberrations in both Wnt active and Wnt inactive subtypes suggesting the interesting possibility of presence of CIN in the absence of canonical Wnt activation .
11 Several CNAs were detected exclusively in Wnt inactive samples ( being absent in Wnt active samples ) and were validated by quantitative PCR .
12 Μ As expected , a few CNAs , such as an amplification detected at 17q12 ( ERBB2/GRB7 ) , were present in both subtypes .
13 Μ Genome -wide transcript profiling performed in parallel revealed the elevated expression of genes located within the amplifications , validated by quantitative reverse transcription PCR ( Q-RT-PCR ) .
14 Μ More importantly , aberrant activation of non-canonical signaling pathways was identified in a subset of the double negative EOSRC samples , based on unsupervised ( hierarchical clustering ) and supervised ( significance analysis of microarrays and gene set enrichment analysis ) analyses of the transcriptome data .
15 Elevation of non-canonical pathway gene transcripts was confirmed by Q-RT-PCR .
16 Our study has therefore revealed presence of unique tumorigenesis pathways in EOSRC samples distinct from canonical pathways that drive late-onset CRC .



PMID: ASCO_176506-195
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Clinical efficacy and safety of regorafenib ( REG ) in the treatment of metastatic colorectal cancer ( mCRC ) in daily practice in Germany : Interim results of the prospective multicentre noninterventional RECORA study. .
1 Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors .



PMID: AACR_2017-5662
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 MEK inhibitors potentiate tumor immune surveillance by enhancing cancer cell response of IFNÎł. .
1 FDA approved mitogen -activated protein kinase ( MAPK ) kinase ( MEK ) targeting inhibitors such as trametinib have recently been reported to enhance anti-tumor immunity in multiple preclinical models .
2 It is hypothesized that the combination of such MEK inhibitors with immune checkpoint blockade will have synergistic effects and cause further tumor regression .
3 Immune checkpoint inhibitors such as anti-PD-1 overcome immunosuppressive signaling in the activated T cells , yielding higher levels of Interferon -gamma ( IFNÎł ) release .
4 IFNÎł plays a key role in a wide range of immune responses by direct activation of JAK-STAT1 pathway through the binding of IFNÎł receptor .
5 JAK-STAT1 regulates transcription of downstream effector genes that are involved in tumor immune surveillance .
6 Many studies have shown that in cancer cells , transcription of T cell chemokines CXCL9,10,11 , as well as PD-L1 and MHC-I are induced upon stimulation with IFNÎł .
7 While there are some recent studies indicating MEK inhibitors enhance T cell activity and function , here we report for the first time that targeted inhibition of MEK increases tumor cells response to IFNÎł and results in significant upregulation of target genes including T cell chemokines , MHC-I , as well as PD-L1 .



PMID: ASCO_176761-195
(None)  
Terms: Retrospective, retrospective
Sent# Symbols Sentence Mnemonics
0 Retrospective review of outcomes in patients ( pts ) with synchronous metastatic rectal cancer ( mRC ) receiving initial non-surgical management. .
1 Background : Management of mRC trends toward initial non-surgical management of the primary tumor based on studies demonstrating low complications rates from un-resected primary colonic tumors .
2 The fixed location of the rectum may increase local complications .
3 This study characterizes complications of pts with synchronous mRC with an intact primary tumor .
4 Methods : A retrospective review of records from 2001 to 2013 identified pts with mRC by ICD-9/10 codes .
5 Pts with treatment-nave mRC without significant local symptomatology were evaluated .
6 Time to complications and death were calculated .
7 Pathology , stage , baseline CEA , RAS , BRAF and initial treatment were evaluated for prognostic significance .
8 Results : Forty-four pts were identified with mRC ; eight were excluded for initial resection for a symptomatic primary .
9 Among the 36 evaluable pts treated with initial chemotherapy , 14 ( 39% ) developed complications related to the primary tumor , of whom 5 ( 14% ) developed two or more complications .
10 Six ( 17% ) required operative intervention due to primary tumor complications ( two died prior to planned procedure ) .
11 Complications were : perforations/abscesses/fistulae (6) , bowel obstruction (5) , severe bleeding (5) , urinary obstruction/infection (3) and , pain requiring palliative treatment (1) .
12 Interventions included blood transfusions (5) , stents (3) , radiotherapy (3) , I&D/drains (3) and , nephrostomy (2) .
13 Of 22 pts who did not develop any complications , 15 underwent curative resection of all sites of disease .
14 Six remain disease free and nine relapsed , all distantly .
15 None of the 14 who developed complications underwent curative operation .
16 The median time to complication was 2.5 months .
17 Median overall survival was 37 and 52 months for those with and without complications , respectively .
18 Median time from complication to death was 21 months .
19 Pts aged > 50 versus < 50 were more likely to have complications of the primary tumor ( 57% versus 21% ) .
20 Conclusions : mRC pts with intact primary tumors may develop complications at a higher rate ( 39% ) than those with colon cancer ( 11% ) .
21 These findings will need to be confirmed with larger datasets and examine for specific treatment effects .



PMID: ASCO_189051-199
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Colorectal cancer sidedeness and its association with survival and tumor biology in operable patients. .
1 Background : Recent data from patients with metastatic disease enrolled on trials of systemic chemotherapy have suggested that the sidedness of colorectal cancer ( CRC ) is associated with survival differences with better response seen with right sided tumours .
2 The biological explanation for these differences has not been confirmed and there have been concerns that the differences relate predominantly to patient selection in clinical trial design .
3 This study examines survival differences by side in sequential patients with newly diagnosed , operable CRC .
4 Methods : Data for 3281 consecutive patients from the Northern Sydney Local Health District from 1998 to 2012 who underwent surgical resection of their CRC were retrospectively collected .
5 Survival was assessed by log-rank test , association between sidedness and tumor biology by chi squared analysis and multivariate analysis by Cox regression .
6 Results : Overall , there was a survival difference between left and right sided colon cancer and rectal cancer ( p < 0022 ) .
7 However , stage for stage , only stage 3 patients demonstrated a survival difference with right sided colon cancers ( median OS 671 months , p = 0009 ) but not left sided colon cancers ( 704 months p = 0132 ) having inferior survival compared to rectal cancers ( 832 months ) .
8 In terms of biological associations , right sided tumors were more associated with advanced age ( p < 0001 ) , female gender ( p < 0001 ) , more advanced T and m stage ( p < 0001 ) , high grade ( p < 0001 ) , thin walled vessel invasion ( p < 0001 ) , discontinuous extratumoral nodules ( DETN ) ( p < 0001 ) , peritumoral lymphocytic response ( p = 0002 ) , BRAFV600E mutation ( p < 0001 ) , mismatch repair deficiency ( p < 0001 ) , low lymphocyte-to-monocyte ratio ( LMR ) ( p < 0001 ) and high neutrophil-to-lymphocyte ratio ( p < 0001 ) .
9 In multivariate analysis , age ( p < 0001 ) , T stage and m stage ( p = 0001 ) , grade ( p = 0002 ) , extra venous permeation ( p = 0.034 ) , DETN ( p = 009 ) , MMR-BRAF combined status ( p = 0001 ) and LMR ( p < 0001 ) remained independently significant .
10 Conclusions : There appears to be a difference in survival related to tumor site only in stage 3 CRC .
11 Differences in tumor biology could account for these findings .



PMID: ASCO_188433-199
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Activation of intracellular signaling pathways as a new type of biomarkers for selection of target anticancer drugs. .
1 Background : Anticancer target drugs ( ATDs ) specifically bind and inhibit molecular targets that play important roles in tumorigenesis .
2 More than 150 different ATDs have been approved for clinical use worldwide , and the clinicians are faced with the problem of choosing the best therapeutic solution for each patient .
3 The problem of efficient ATD selection remains largely unsolved and personalized approaches are needed to select the best ATD candidates for individual patients .
4 Methods : We propose a new approach termed OncoFinder .
5 It is based on digesting gene expression profiles for the analysis of activation of intracellular signalling pathways as a marker for the selection of target therapies .
6 The original bioinformatic algorithms were integrated with the databases featuring molecular drug targets , compositions of signalling pathways , including the functional role of each gene product , for more than 1700 pathways ( Buzdin , FrontGenet 2014 ; Ozerov , Nature Communications 2016 ) .
7 Results : We showed that pathway activation strengths are more stable and reliable biomarkers of cancer than the expressions of individual genes .
8 OncoFinder allows to detect changes at the level of pathway activation and to predict the effectiveness of drugs based on the knowledge of their molecular targets .
9   We applied it to find new biomarkers of clinical response to the ATD cetuximab ; for modelling the combined chemotherapy of acute myeloid leukemia and combined anti-VEGF/BRAF therapy of melanoma .
10   For two unrelated datasets obtained for colon cancer patients before treatment with the ATD bevacizumab , we were able to distinguish between those who responded to treatment and not ( p < 001 ) .
11 We next assayed biopsies for kidney cancer patients with known responses to the ATD sorafenib .
12 The responders and non-responders showed a significant difference ( p = 002 ) .
13 Finally , the OncoFinder platform was prospectively used for decision making support to patients with advanced metastatic solid tumors ( n = 23 ) .
14 The efficiency of the ATD treatment was 61% ( complete + partial response , RECIST ) .
15 Conclusions : OncoFinder method may be effective for predicting response to ATD based on high throughput gene expression profiles .



PMID: AACR_2015-706
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Inflammatory and stem-like colorectal cell lines show differential response to MEK-162 and neratinib in combination .
1 Background : Improvement of colorectal cancer ( CRC ) treatment depends on finding new effective agents and associated biomarkers that can predict patient response to drugs .
2 Recent cell culture experiments show that a combination of MEK and pan ERBB inhibitors may be efficacious in treating CRC ( Sun et al 2014 ) .
3 The purpose of this study was to determine whether a cell line's response to targeted agents would correlate with its mutation profile and/or gene expression subtype .
4 Μ Methods : K-RAS mutation status of 7 cell lines were identified and classified into stem-like or inflammatory subtypes using gene expression data from the cancer cell line encyclopedia and an algorithm described by Sadanandam et al .
5 We tested 5 stem-like cell lines ( SW480 , SW620 , HCT116 , C2BBE1 , HS675T ) and 2 inflammatory cell lines ( NCI-H747 , SW837 ) for response to inhibitors of the RAS/RAF and PI3K pathways .
6 MEK-162 and neratinib were tested as single agents and in combination , using cell viability and clonogenic assays .
7 Results : Cell lines varied in response to the drugs when used as single agents .
8 All cell lines were resistant to the EGFR inhibitor ( Gefitinib ) at concentrations 5 M .
9 Two pan ERBB inhibitors ( neratinib and afatinib ) showed IC50 values at or >4 M and 2 MEK inhibitors ( Selumetinib and MEK162 ) had IC50 values at or >1M .
10 The inflammatory cell lines , SW837 and NCI-H747 , had greater sensitivity to the MEK inhibitors (IC50 value 1M) while the KRAS mutant stem-like cell lines were relatively more resistant ( SW480 , SW620 ) with IC50 values 4-5 M .
11 Stem-like cell lines with WT-KRAS ( C2BBE1 , HS675T ) were even more resistant ; IC50s were not achieved at concentrations of 5 M .
12 Similar results were obtained in clonogenic growth assay .
13 The MEK and pan ERBB inhibitor combinations were more effective at decreasing cell viability and inducing apoptosis in inflammatory cell lines than in stem-like cell lines .
14 This combination effectively inhibited 60-70% of cell viability in inflammatory cell lines at a dose of 0.5 M and 0.062 M for neratinib and MEK-162 respectively .
15 The lethality of this combination was the same even if the doses were reversed ( 05 M MEK-162 and 0062 M neratinib ) .
16 In contrast , we observed that this combination was not nearly as effective against stem-like cell lines irrespective of KRAS mutation status .
17 Profiling of the phosphorylation status of proteins in the RAF-MEK-ERK signaling pathway after exposure to the MEK-162 plus neratinib combination showed a substantial inhibition of ERK phosphorylation in inflammatory cell lines but not in 4 of the 5 stem-like cell lines .
18 Conclusion : This study demonstrates that colon cancer cell lines classified as the inflammatory subtype are sensitive to the combination of MEK-162 plus neratinib at concentrations at which cell lines of the stem-like subtype are resistant .
19 The PA DOH disclaims responsibility for analysis , interpretations , or conclusions .



PMID: AACR_2016-2783
(Cell)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Integrated genomics and epigenomics analysis reveals genome -wide effect of the DNA methyltransferase inhibitor 5-azacitidine ( Aza ) on regulation of transcription .
1 DNA methyltransferase inhibitors ( DNMTi ) such as 5-azacytidine ( Aza ) are clinically used in treating hematologic malignancies .
2 Promising effects were also observed in solid tumors , although the exact mechanism underlining the efficacy was unclear .
3 There has been accumulating evidence suggesting an enhanced immune response to the tumor cells following such epigenetic therapies .
4 Cancer immunotherapies targeting checkpoint inhibition in combination with epigenetic agents such as a DNMTi could hold promise for those patients that do not respond to immunotherapies alone .
5 Aza was also found to stimulate an interferon response in tumor cells via inducing expression of endogenous retroviruses .
6 In this study , we were interested to further explore the mechanisms of AZA on transcription regulation across the whole regulome .
7 HCT-116 is a colon cancer cell line genetically defined by microsatellite instability ( MSI ) and mutations in KRAS (G13D) and PIK3CA (H1047R) .
8 In this study , HCT-116 cells were treated with DMSO ( control ) or 1M Aza for 42 and 96 hours .
9 RNA-seq , Mass spectrometry proteomics , RRBS , Chip-Seq , ATAC-Seq and Hi-C data was collected .
10 Data was analyzed by integrative computational methods .
11 Treatment with Aza resulted in global demethylation at CpG islands ( CGI ) , which was moderately correlated with increased expression of the corresponding genes .
12 Μ DNA methylation , DNA accessibility , H3K4me3 ( active promoter histone mark ) , H3K27me3 ( repressive histone mark ) and RNA expression revealed and cross-verified different states of genomic regions .
13 Μ Pathway and gene set enrichment analysis found activation of anti-viral defense and interferon pathways , as well as increased expression of cancer-testis antigens .
14 IRF7 expression was increased by Aza , and IRF binding motifs were the most enriched TF motifs at the immediate promoter regions of the up-regulated genes .
15 The data also suggested that Aza may remove gene repression by disrupting the scaffolding function of DNMTs .
16 The effects of Aza on promoter -enhancer interactions were also examined by Hi-C .
17 In conclusion , we found that DNMTi such as Aza regulates gene transcription through multiple modes of actions .



PMID: ASCO_48441-74
(Patient)  
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Sent# Symbols Sentence Mnemonics
0 ✓ Use of EGF a+61G and TS-5'UTR 2R/3R polymorphisms to predict complete pathologic response in locally advanced rectal cancer patients undergoing preoperative cetuximab-based chemoradiation followed by surgery. . GM-REG-RO
1 Background : Cetuximab has demonstrated significant clinical activity in metastatic colon cancer , however , cetuximab-containing neoajuvant chemoradiation has not been shown to improve local control or survival in locally advanced rectal cancer patients based upon recent phase II trials .
2 THIS LINE WITH 600 OR MORE CHARS HAS BEEN REMOVED.
3 Methods : 130 patients ( 74 men and 56 women ) with locally advanced rectal cancer ( 4 with stage II , 109 with stage III and 15 with stage IV , 2 unknown ) who were enrolled in phase II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included .
4 Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was performed using PCR-RFLP assays .
5 ✓ Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response ( pCR ) that was determined by a modified Dworak classification system ( grade 0-III versus grade IV : complete response ) . GM-ASS-RO
6 Results : Germline polymorphisms of EGF and TS were predictive for histopathologic response : 63 patients with EGF +61 G allele ( AG + GG ) had a 25% rate of pCR whereas the 50 patients with AA genotype had only a 2% rate of pCR ( p < 0001 ) .
7 In addition , the pCR rate of 69 patients with any 2R repeats in the TS 5'UTR ( 2R/2R + 2R/3R ) was 20% while it was 0% in the 23 patients with the 3R/3R genotype ( p = 0006 ) .
8 Conclusions : This study suggests EGF A+61G and TS 5'UTR 2R/3R polymorphisms to be predictive markers for complete pathologic response to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer .



PMID: ASCO_171336-176
(Patient)  
Terms: retrospective
Sent# Symbols Sentence Mnemonics
0 Genomic aberrations in advanced solid malignancies using next generation sequencing : A single institution experience. .
1 Background : The paradigm in the treatment of cancer is changing such that , treatment based on molecular targets and associated pathways is at the forefront rather than chemotherapy .
2 The identification of different molecular drivers utilizing NGS technology has led to better understanding of advanced malignancies .
3 Μ Recently , the prevalence of potentially targetable genomic abnormalities in primary and metastatic breast cancer utilizing NGS method found that 84% of the evaluated cancers harbored atleast one genomic alteration linked to potential treatment options .
4 Validation of this NGS testing in 2,221 clinical cases revealed clinically actionable targets in 76% of tumors , corresponding to three times the number of actionable targets detected by other current diagnostic tests .
5 It is for these reasons that the genomic landscape needs to be better characterized Methods : Medical records of all patients referred to the phase 1 clinic at our institution who had NGS performed were reviewed retrospectively from January 2014 to December 2015 .
6 Results : 159 cases were identified ; 65 males and 94 were females .
7 Mean age was 54.51 Years ( Range 25-83 years ) .
8 Gastrointestinal cancers accounted for 47.2% cases while gynecological , lung and breast cancer accounted for 11% , 10% and 9% respectively .
9 There was an average of 15.31 aberrations per cancer ( range : 4 - 66 ) .
10 An average of 4.73 aberrations per cancers were found to be clinically relevant , while the rest were variance of unknown significance .
11 FGF , CDK , KRAS , PI3K and FGFR were the most common clinically relevant aberrations and they accounted for 6% , 5.2% , 4.9% , 3.9% and 1.5% of the clinically relevant aberrations respectively .
12 Breast cancer and Colon cancer accounted for 31% and 21% of the PIK3 aberrations .
13 Cholangiocarcinoma , breast cancer accounted for 90% ( 45% each ) of FGFR aberrations .
14   Conclusions : In this single institution study for phase 1 trials , we found a small but significant number of patients amenable to targeted therapy .



PMID: ASCO_54621-74
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Mutation-based detection of molecular tumor margins in colorectal liver metastasis. .
1 Background : Defining adequate resection margins of liver metastasis especially after preoperative chemotherapy is based on empirically determined recommendations and random screening of macroscopic and microscopic tissue sections surrounding the liver metastasis .
2 Mutations are highly specific for tumors and therefore can be used as a marker to accurately determine molecular tumor margins .
3 Methods : In our study we evaluated 12 patients with metastatic colon cancer who underwent partial hepatectomy of 1-6 liver metastasis .
4 Samples were obtained by 2-4 punch biopsies in different directions of surrounding liver tissue at 4 , 8 , 12 and 16 mm distance to the macroscopic tumor border .
5 A total of 88 samples were analyzed .
6 Tumor specific mutations including KRAS , PIK3CA , APC and TP53 were determined by sequencing tumor tissue .
7 Μ DNA was isolated from biopsies of surrounding liver tissue and analyzed by BEAMing , a highly sensitive PCR based method of mutation detection .
8 Molecular results were correlated with microscopic tissue analysis and clinical data .
9 Results : We were able to detect tumor DNA in surrounding liver tissue in 3 out of 12 patients with 4 samples positive at 4 mm and all samples negative at 8 , 12 and 16 mm distance to the macroscopic tumor border with negative control samples .
10   Μ In average 1,047 mutant single stranded DNA fragments were found in 150,000 analyzed DNA fragments. 3 out of 10 patients with previous chemotherapy had positive molecular margins , whereas the 2 patients with naive liver tissue were tested negative for tumor DNA in their marginal zones .
11 Conclusions : The measurement of tumor DNA in tissue is a highly sensitive molecular marker of tumor margins identifying consistently negative margins at > 0.4 cm distance to the macroscopic tumor border in all samples .
12   Tumor DNA as a marker of molecular tumor margins could be helpful in determining accurate biological resection guidelines of liver metastasis and can help to understand the process of tumor reduction after preoperative chemotherapy .



PMID: ASCO_98611-114
(Patient)  
Terms: xenograft, in vivo, PDX, mice
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0 Integrated next-generation sequencing and patient-derived xenografts to personalized cancer treatment. .
1 Background : The knowledge of actionable somatic genomic alterations present in each tumor is making possible the era of personalized cancer treatment .
2 Μ Methods : Using massively parallel sequencing we performed whole exome sequencing analysis of tumor and matched normal blood samples of 8 patients ( 2 pancreatic adenocarcinoma , 1 neuroendocrine tumor , 1 glioblastoma , 1 uveal melanoma , 1 colon cancer ) to identify putatively actionable tumor specific genomic alterations .
3 We used 2 in silico methods ( Polyphen and SIFT ) to estimate the functional significance of a given confirmed mutation .
4 Primary xenografts ( PDX ) , generated by direct engraftment of tumor samples from the patients into immunocompromised mice , were used as an in vivo platform that provided the opportunity to test proposed personalized medicine strategies .
5 Results : At this time exome sequencing analyses have been performed for 5 patients ( 1 patient died prematurely , 1 tumor sample was insufficient , 1 result is pending ) .
6 More than 30 million bases of target DNA were analyzed in the tumor and normal samples in every case , with atleast 70 distinct reads at each base .
7 Μ Tumor specific mutations ( Muts ) and copy number variations ( CNVs ) were identified : 5 Muts in the neuroendocrine tumor ; 62Muts/6CNVs and 38Muts/10CNVs in the pancreatic tumors ; 63Muts/23CNVs in the glioblastoma ; 5 Muts in the melanoma .
8 All samples profiled contained actionable alterations with the most relevant mutations affecting NF1 , PTPN11 , EPHA3 , CDKN2A , FAS ( glioblastoma ) ; PI3KCA , ARID1A , ARID1B , DDR2 , SMAD4 , TP53 , KRAS , PTCHD3 ( pancreatic ) ; CREB3L3 , ITPR2 ( neuroendocrine ) ; GNA11 , TAOK3 ( melanoma ) .
9 PDX from the pancreatic cancer patient was treated with a PI3K inhibitor and dasatinib , reported to be effective in discodin domain receptor 2 ( DDR2 ) mutant cancer with no effect .
10   Μ Accordingly treatment of that patient with dasatinib was not effective and the level of this mutation in the tumor was observed to be low .
11 Conclusions : Detection of actionable tumor-specific genomic alterations in the clinical setting is feasible .
12 In silico methods and primary xenografts can help in the challenge of linking confirmed mutations to protein function and ultimately to clinical utility .



PMID: ASCO_188908-199
(None)  
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0 Evaluation of the quality of cancer treatment in a population of patients ( pts ) with metastatic colorectal cancer ( mCRC ) in routine clinical practice in different regions of Russia. .
1 Background : In Russia , there are no federal screening programs for detecting early stage of colon cancer ; therefore we can assess the impact of various factors that could potentially affect the mortality of pts with mCRC Methods : We conducted a survey with 13 question according treatment of pts with CRC in 17 regional comprehensive cancer centers in 14 regions of Russia , with a total population of 26.347 billion .
2 Results of the survey were conducted by methods of descriptive statistics .
3 Effects of factors on mortality rate in regions were analyzed by a regression model Results : Only 34% pts with stage II-III received adjuvant chemotherapy .
4 Mutation status of KRAS gene has been evaluated only in 33% pts with mCRC .
5 In 2013 , metastasectomy was performed only 13% of pts .
6   Only 80% of pts who needed systemic treatment received chemotherapy ( CT ) : doublets of CT ( XELOX/FOLFOX/FLOX or FOLFIRI/XELIRI/IFL ) - 49% , monotherapy of fluoropyrimidines - 39% of pts , bevacizumab in 14% and anti-EGFR antibodies - 5% pts .
7 Only 14% of pts with mCRC was placed central vein devices .
8 Second line CT was performed in 47% pts : doublets in 54% , monotherapy of fluoropyrimidines - in 24% pts , bevacizumab - 13% and anti-EGFR antibody - 8% .
9   Third - line treatment was performed in 25% of pts : anti-EGFR antibodies - in 7.5% .
10 According to regression analysis adjuvant chemotherapy ( = 001 ) , bevacizumab only in the 1st line ( = 001 ) , and installation of central venous devises ( = 007 ) and anti-EGFR antibody in the 1st line ( = 01 ) in wtKRAS pts had independent positive effect on the mortality rate in regions .
11   Μ We revealed a significant reverse connection between a high mortality rate in the region and administration of fluoropyrimidine monotherapy as 1st line treatment of metastatic disease ( p = 001 ) Conclusions : The mortality with colorectal cancer is depended of complex factors that reflect the health care organization in the region , both at the stage of treatment of pts with early-stage and metastatic disease .
12 We revealed that targeted agents are the most effective only in the 1st line settings .



PMID: ASCO_183783-199
(Cell)  
Terms: in vitro
Sent# Symbols Sentence Mnemonics
0 Enhancing targeted therapy of tumors with activating FGFR alterations. .
1 Background : Emerging evidence points to the Fibroblast Growth Factor Receptor ( FGFR ) kinase family as a promising target in multiple cancer types including lung squamous cell carcinoma , cholangiocarcinoma , gastric , bladder and breast cancer .
2 Although several FGFR kinase inhibitors have entered clinical trials , single agent clinical efficacy has been modest and resistance invariably occurs .
3 A comprehensive understanding of the molecular basis of resistance to FGFR inhibitors is urgently needed to enable the successful application of anti-FGFR therapy in the clinic .
4 Methods : We utilized a systematic genome -wide open reading frame ( ORF ) screen to identify genes whose upregulation confers resistance to the FGFR inhibitors BGJ398 and FIIN-3 in FGFR1-amplified H2077 lung cancer cells .
5 In an orthogonal approach , we established resistant clones of FGFR1-amplified and FGFR3-translocated cell lines by chronic exposure to BGJ398 , and characterized these by high-throughput gene expression analysis .
6 Μ Results : We identified 34 candidate genes , including expected findings such as a mutant KRAS allele and MET overexpression .
7 Intriguingly , we also identified novel candidate resistance mechanisms involving the genes of the TAM family , which encode the transmembrane receptors Tyro3 , Axl and Mertk .
8 These tyrosine kinases may serve as a secondary target to augment FGFR therapy .
9 We validated that the TAM family confers resistance to FGFR inhibitors in different FGFR dependencies including FGFR1-amplified lung cancer , FGFR2-amplified gastric and colon cancer and FGFR3-translocated bladder cancer , with AXL having the greatest rescue .
10 Notably , gene profiling of resistant clones also implicates the TAM family , with both receptors and their ligands upregulated in the majority cases .
11 Moreover , concurrent TAM blockade augments the response to FGFR inhibition in vitro and provides a promising therapeutic strategy to overcome resistance .
12 Conclusions : TAM kinases are important mediators of resistance to FGFR inhibitors and the dual blockade of FGFR and TAM provides a novel approach to enhance the efficacy of anti-FGFR therapy .



PMID: ASCO_132007-144
(Patient)  
Terms: Clinical trial
Sent# Symbols Sentence Mnemonics
0 A phase 1 mechanism of action study of intratumoral or intravenous administration of enadenotucirev , an oncolytic Ad11/Ad3 chimeric group B adenovirus in colon cancer patients undergoing resection of primary tumor. .
1 Background : To date convincing clinical success with oncolytic viruses tends to be associated with intra-tumoral ( IT ) administration and evidence for successful systemic delivery of viruses to tumor cells by intravenous ( IV ) infusion remains sparse .
2 Enadenotucirev ( E or ColoAd1 ) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated preclinical activity in a metastatic model of colorectal cancer ( CRC ) and in human tumor biopsies ex-vivo [Kuhn et al , PLoS ONE 2008 ; 3 (6) : e2409] .
3 Μ Serological studies suggest that the prevalence of neutralising antibodies against group B adenoviruses is low , which may permit systemic delivery [Holterman et al , J Virol 2004 Dec ; 78 ( 23 ) : 13207-15] .
4 CRC patients ( Pts ) scheduled for resection of primary tumor present a pre-surgical window of opportunity to evaluate IV and IT delivery to tumor , lymph nodes and normal margins in resected tissues .
5 Methods : Pts with histologically confirmed CRC scheduled for surgical removal of primary tumor receive E delivered either IV on day (D) 1 , 3 and 5 at a dose of 1e12 viral particles ( vp ) over 5 min ( 5 pts ) ; or IT at a dose of 1e11 vp/mL with a variable volume injected based on the tumor surface area ( 5 pts ) .
6 Surgery is performed 7 15 days post first dose of E .
7 The primary objective is to assess the pattern and extent of E spread in the tumor , normal tissue and draining lymph nodes as visualised by IHC staining of E hexon protein .
8 Evidence of immune modulation associated with virus activity is assessed by co-staining for markers including CD8 , CD11b , CD57 and CD25 .
9 Additional staining includes the primary uptake receptors of E ( CD46 , DSG-2 ) and markers of endothelial cells (CD31) and myofibroablasts (SMA) that may influence viral delivery or spread .
10 Additional analyses include electron microscopy and qPCR .
11 Other objectives are assessment of safety , viral kinetics and immune response following IV and IT administration .
12 Correlation with routine tumor biomarkers e.g . K-ras , BRAF , PI3K , PTEN , SPARC will also be evaluated .
13 To date 3 pts have been treated , 1 IT and 2 IV , and 3 pts are scheduled for treatment .
14 Clinical trial information : EUDRACT 2013-000562-11 .



PMID: AACR_2013-2205
(Patient)  
Terms: xenograft, in vivo, tumor graft models, mice
Sent# Symbols Sentence Mnemonics
0 Integrated next generation sequencing and patient-derived xenografts to personalized cancer treatment. .
1 Background : The knowledge of actionable somatic genomic alterations present in human tumors is enabling the new era of personalized cancer treatment .
2 The great intellectual challenge lies in linking confirmed mutations to protein function .
3 Personalized tumor graft models ( Avatars ) can aid in the process of genomic analyses interpretation to ultimately move from molecular profile to medication .
4 Μ Methods : Using massive parallel sequencing we performed whole exome sequencing analysis of tumor and matched normal blood samples of 23 patients ( pts ) with advanced solid tumors ( 7 lung cancer , 7 pancreatic cancer , 1 neuroendocrine tumor , 2 glioblastoma , 1 uveal melanoma , 2 melanomas and 3 colon cancer ) to identify putatively actionable tumor-specific genomic alterations .
5 Avatar models generated by direct engraftment of tumor samples from the pts into immunocompromised mice were used as an in vivo platform to test proposed treatment strategies .
6 Results : Successful exome sequencing analyses has been obtained for 21 pts ( 1 patient died prematurely , 1 sample was insufficient ) .
7 Μ Tumor specific mutations ( Muts ) and copy number variations were identified ranging from 5 to 952 and 0 to 36 respectively .
8 All samples profiled contained clinically meaningful genomic alterations .
9 A successful Avatar model was generated for 10 out of 17 pts .
10 Two engraftment failures corresponded to EGFR mutant lung tumors resected while pts were receiving erlotinib , which initially grew but then regressed .
11 Some of the most relevant drugabble alterations were : KRAS , CHEK1 , FGFR2 , IGF1R , MET , BRCA1 , XPC , NOTCH , CREB3LB , GNA11 , SMAD4 and EGFR .
12 In occasions druggable alterations such as muts in NF1 , PTPRC , PI3KA and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and accordingly treatment of the pts with these drugs was not effective .
13 In one case , loss of STK11 lead to testing of mTOR and SRC inhibitors resulting in tumor regression both in the Avatar and in the clinic .
14 At present time 10 pts have received a personalized treatment : 2 pts , as expected based on the Avatar model , did not response ; 4 pts resulted in durable partial remissions and 4 pts are currently on treatment with disease stabilization .
15 Μ In one of the EGFR mutant lung pts the genomic analysis revealed traces of an acquired mutation and allowed decision making at an earlier time point , prior to relapse .
16 Overall , there was a remarkable correlation between drug activity in the Avatar and clinical outcome in the pts , in terms of drug resistance and sensitivity .
17 Conclusion : The detection of actionable tumor-specific genomic alterations in the clinical setting is feasible .
18 However predicting treatment response to known oncogenes is complex and requires detailed information of how different genetic backgrounds function .
19   Avatar models are a powerful investigational platform for therapeutic decision making and help to guide cancer treatment in the clinic .



PMID: AACR_2014-4283
(Patient)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Whole genome sequencing is superior to cancer panels to aid in decision-making in patients with advanced malignancies .
1 Background : It is increasingly common to use targeted cancer panels to assess for informative or actionable targets to guide cancer treatment .
2 We compared the utility of information obtained from such a panel compared to whole genome and transcriptome sequencing .
3 Methods : Eligible subjects with incurable cancers for whom there were limited or no standard chemotherapy options , have several samples analyzed : a fresh tumour biopsy ; a blood sample for normal comparison ; and archival tumours when available .
4 Μ Samples underwent both the Ion Torrent AmpliSeq cancer panel analysis and comprehensive DNA (80X) and RNA sequencing followed by in-depth bioinformatic analysis to identify somatic mutations , copy number alterations , structural rearrangements , and corresponding gene expression changes that may be cancer drivers or provide informative ( diagnostic ) or actionable/druggable targets .
5 Aberrant pathways were matched to drug databases and manual literature reviews undertaken to identify drugs that may be useful or potentially contraindicated ; a report is generated and discussed in a multidisciplinary team .
6 Results : Between July 2012 - November 2013 , 51 subjects have consented and 45 have been sequenced : 12 breast , 7 lung ; 4 colorectal , 3 squamous , 3 adrenal ; 2 pancreas ; 2 sarcomas , and 1 of each of nasopharynx , primary unknown , CLL-peripheral mantle cell , parotid , anal , appendix , peripheral T - cell , prostate , ovary , endometrial , glioma , and mesothelioma .
7 The median number of lines of chemo prior to sequencing was 3 .
8 Μ Of the first 40 cases , the panel did not yield informative or actionable results in 60% of cases : 36% of the cases the panel did not detect any somatic variants and in a further 24% TP53 mutations were the only variants identified .
9 In the other 40% of cases , the panel might have identified an informative abnormality but when put into context of the pathways that can be drawn with the whole genome and transcriptome data the detected panel abnormalities were not comprehensive enough to guide treatment decisions .
10 Μ Examples include : in two colon cancer patients the panel detected a KRAS mutation in one and a RET mutation in the other , however both were actually inactivating mutations and therefore unlikely to be good targets .
11 In contrast , the full genomic data was informative in 70% of cases and treatments were delivered based on the results in 60% , in this heavily pretreated population .
12 Conclusions : The future of cancer medicine lies in genomic profiling to assist therapeutic decision-making .
13 The cancer panel has advantages in terms of speed and cost ; however it has not been as informative for identifying candidate druggable driver events and it has missed critical genomic abnormalities that have changed diagnoses .
14 Given the complexity of the cancer genome it is our observation that the panels do not provide the depth and context required to make treatment decisions for the majority of patients with cancer .



PMID: AACR_2012-3084
(Cell)  
Terms: , mouse, mice
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0 Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription by suppressing vitamin D receptor gene expression in mouse colon epithelial cells .
1 The active metabolite of vitamin D , 1,25 dihydroxyvitamin D ( 1,25 ( OH ) 2D ) , binds to the vitamin D receptor ( VDR ) and stimulates anti-cancer transcriptional events in many cell lines including colon cancer cells .
2 However , we found that tumors which form in the distal colon of mice with an APC allele deletion had significantly lower VDR mRNA levels compared to RNA isolated from the distal colon of wild-type mice ( -92% , p005 ) .
3 These data suggest that colon carcinogenesis may impair 1,25 ( OH ) 2D -regulated chemoprevention in colon epithelial cells .
4 APC inactivation and KRAS activation are early events in the development of distal colon that may suppress VDR gene expression .
5 Compared to immortalized colonic epithelial cells derived from the Immorto mouse ( YAMC ) , cells from a cross between APCmin and Immorto mice ( IMCE ) , and YAMC cells overexpressing the v-Ha-RAS gene ( YAMC-RAS ) have significantly lower VDR mRNA ( -80% ; p005 ) expression .
6 Previous research shows that constitutively active ( ca ) RAS signaling suppresses 1,25 ( OH ) 2D action in many cell lines so we conducted additional studies on the impact of this mutation .
7 YAMC-RAS cells had a significant reduction in 1,25 ( OH ) 2D -induced CYP24 mRNA expression ( -40% ; p005 ) .
8 Consistent with lower VDR mRNA levels , YAMC-RAS cells also had lower VDR protein levels than YAMC cells and the suppression of 1,25 ( OH ) 2D -induced CYP24 expression in YAMC-RAS was overcome with VDR over-expression .
9 The mechanism for RAS -mediated suppression of VDR mRNA levels was further explored .
10 First we hypothesized that caRAS signaling expression reduced VDR mRNA stability , however , YAMC and YAMC-RAS cells treated with 4 g/ml of the transcription inhibitor actinomycin D for up to 12 h had no significant difference in the VDR mRNA half-life ( about 8 h ) .
11 Μ Next we examined whether caRAS signaling reduced accessibility within chromosomal regions in the VDR gene previously identified as necessary for VDR gene expression .
12 Using a DNAse I hypersensitivity assay we found that in YAMC-RAS cells there was a significant reduction ( p005 ) in chromosome accessibility on the proximal promoter ( -23% , 300 bp upstream of exon 1 ) , an enhancer region located 6 kb upstream of the transcriptional start site ( -56% ) , and an enhancer region located in exon 2 ( -100% ) compared to the YAMC cells .
13 These data show that caRAS signaling suppresses 1,25 ( OH ) 2D -mediated gene transcription in colon epithelial cells by reducing VDR gene transcription .



PMID: AACR_2014-4261
(None)  
Terms: Prospective
Sent# Symbols Sentence Mnemonics
0 Prospective next generation sequencing ( NGS ) of rare or poor prognosis cancers .
1 2-Oxo-3 , 4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor ( FGFR ) inhibitors .



PMID: ASCO_185771-199
(None)  
Terms:
Sent# Symbols Sentence Mnemonics
0 Association of immune-related genes to neutrophil-lymphocyte ratio ( NLR ) with survival of cetuximab treatment for metastatic colorectal cancer ( mCRC ) : JACCRO CC-05/06AR. .
1   Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab .



PMID: ASCO_105514-133
(None)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Characteristics of colorectal cancer in patients younger than 40 years compared to older patients. .
1 Background : The incidence of colorectal cancer ( CRC ) in younger patients ( pts ) is increasing .
2 There is limited data on tumor characteristics and treatment outcome in this population .
3 Methods : Patients with CRC treated at the Karmanos Cancer Center from 2005 to 2011 were studied .
4 Younger ( 40 years ) and older ( >40 years ) groups from a predominantly inner city population were compared for patient and tumor characteristics , treatment patterns , and survivals .
5 T-tests and Fishers exact tests were used to determine statistical differences between age groups while the Kaplan-Meier method was used to estimate survival .
6 Results : 42 pts were 40 ( range , 17-40 years ) and 96 pts were > 40 ( range , 42-88 years ) .
7 Mean ages for the groups were 33 and 60 years , respectively .
8 There was no statistically significant difference in the distribution of race , gender , stage or KRAS mutation status between the two groups ; however , older pts had a higher mean body mass index compared to younger pts ( 28 versus 23 , p < 0001 ) .
9 Older pts were more likely to have a right colon primary ( OR = 75 , p = 004 ) , while younger pts had higher likelihood of having sigmoid primary ( OR = 34 , p = 0002 ) and worse grade ( poorly differentiated ) tumors ( OR = 83 , p <0001 ) .
10 There were no significant differences between metastatic status or sites of metastases between the two groups .
11 Significantly more young pts underwent surgery than older pts ( 92% versus 62% , p = 0005 ) .
12   FOLFOX plus bevacizumab was the most commonly used first line treatment for both groups .
13 The median survival estimates were 16.9 ( 81-239 ) and 17.1 months ( 133-310 ) for the younger and older pts , respectively .
14 Importantly , the one-year survival rates were similar for both groups : 41% for both ( p = 1 ) .
15 On the multivariate analysis , whether pts had a primary in the right or sigmoid colon was the only independent predictor of survival .
16 Conclusions : Younger pts with colon cancer were diagnosed at a similar stage of the disease as older pts , but more likely to have poorly differentiated tumors .
17 Younger pts were more likely to receive surgical interventions ; however , both groups had equivalent one-year survivals .
18 These results support the need for further prospective investigation in a larger population .



PMID: ASCO_165924-176
(Patient)  
Terms: phase II trial
Sent# Symbols Sentence Mnemonics
0 Immune-related genes to predict clinical outcome of cetuximab ( cet ) treatment for metastatic colorectal cancer ( mCRC ) : Immuno-Oncology assay research. .
1 Μ Background : CRC Subtyping Consortium identified 4 molecular subtypes , one of which was classified by factors including activation or expression of immune-related pathways ( Guinney J , et al Nat med 2015 ) .
2 The antitumor activity of cet requires antibody-dependent cell -mediated cytotoxicity ( ADCC ) driven by natural killer ( NK ) cells .
3 Strategies to amplify the NK cell activation may improve the efficacy of cet ( Kohrt HE , et al J Clin Invest 2014 ) , suggesting the ADCC activity may be affected by extracellular immune mechanisms .
4 We therefore investigated whether immune-related genes will predict outcome in mCRC patients ( pts ) treated with cet .
5 Methods : We measured expression levels of 354 immune-related genes implicated in the host immune response to tumors by HTG EdgeSeq Oncology Biomarker Panel , which comprises 2560 gene probes , using next generation sequencing for quantitative analysis of targeted RNAs .
6 Total RNA isolated from tissues of 77 KRAS wild-type pts ( 57% males , median age of 63 years , 90% of performance status 0 , and 15% right-colon cancer ) enrolled in 2 phase II trials ( JACCRO CC-05 : UMIN000004197 or CC-06 : UMIN000007022 ) of 1st - line therapy with FOLFOX or SOX plus cet was analyzed .
7 Univariate Cox regression analysis was performed for all genes that passed QC filtering .
8 Hierarchical clustering was performed using genes under 0.01 of the Cox p-value .
9 Results : In progression-free survival , the clustering using 2 significant genes , RIPK1 and CEACAM5 , could divide all participants into 2 groups and the Kaplan-Meier ( KM ) curve had a significant difference ( mean 32 vs. 117 months , p= 761e-08 ) .
10 In overall survival ( OS ) , 2 groups were classified based on the clustering using 7 genes and the KM curves were significantly different ( mean 108 vs. 260 months , p= 579e-06 ) .
11 The Cox regression analysis revealed that IRF3 and BMP4 had strong associations with OS ( p= 60210-4 , adjusted FDRp= 0043 and p= 86910-4 , FDRp= 0043 , respectively ) .
12 Conclusions : Our study demonstrates that immune-related genes may identify subtypes associated with clinical outcome of 1st - line cet treatment for mCRC .
13 Further studies to validate the findings are warranted .



PMID: AACR_2017-2247
(Patient)  
Terms: prospective
Sent# Symbols Sentence Mnemonics
0 Associations between total T-lymphocytes and colorectal cancer survival in a prospective cohort study of older women. .
1 Background : The increased number of T-lymphocytes residing in the tumors of colorectal cancer ( CRC ) patients is consistently shown to predict better survival of CRC patients independent of stage .
2 In addition to tumor itself , T-lymphocytes also infiltrate normal tissues adjacent to tumors ; however , little is known about how the inter-individual T - cell variability in tumor-adjacent tissues affects CRC prognosis .
3 Our goal was to characterize total T - cells in colorectal tumor and tumor-adjacent tissues and study their associations with all-cause and CRC-specific survival in the Iowa Women’s Health Study .