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: 28363996 (None)   Terms: , mice
Sent#	Symbols	Sentence	Mnemonics
0		miR-34a and miR-34b/c Suppress Intestinal Tumorigenesis .
1		The p53-inducible miR-34a and miR-34b/c genes are frequently silenced in colorectal cancer .
2		To address the in vivo relevance of miR-34a/b/c function for suppression of intestinal tumor formation , we generated ApcMin/+ mice with deletions of the miR-34a and/or miR-34b/c genes separately or in combination .
3		Combined deletion of miR-34a/b/c increased the number of intestinal stem cells as well as Paneth and Goblet cells , resulting in enlarged intestinal crypts .
4		miR-34a/b/c-deficient ApcMin/+ mice displayed an increased tumor burden and grade and decreased survival .
5		miR-34a/b/c-deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration , which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins .
6		mRNA induction in miR-34a/b/c-deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial-mesenchymal transition , stemness , and Wnt signaling .
7		Accordingly , cells explanted from miR-34a/b/c-deficient adenomas formed tumor organoids at an increased rate .
8		Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases ( INHBB , AXL , FGFR1 , and PDFGRB ) and upregulation of INHBB and AXL in primary colorectal cancer was associated with poor patient survival .
9		In conclusion , our results show that miR-34a/b/c suppress tumor formation caused by loss of Apc and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs .
10		Cancer Res ; 77 ( 10 ) ; 2746-58 .
11		(c) 2017 AACR .

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: 28052020 (Cell)   Terms: in vivo, in vitro, mice
Sent#	Symbols	Sentence	Mnemonics
0		The RNA -binding protein ESRP1 promotes human colorectal cancer progression .
1		Epithelial splicing regulatory protein 1 ( ESRP1 ) is an epithelial cell -specific RNA binding protein that controls several key cellular processes , like alternative splicing and translation .
2		Previous studies have demonstrated a tumor suppressor role for this protein .
3		Recently , however , a pro-metastatic function of ESRP1 has been reported .
4		We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer ( CRC ) by performing loss - and gain-of-function studies , and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches .
5		We found that ESRP1 plays a role in anchorage -independent growth of CRC cells .
6		ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor ( FGFR1/2 ) signalling , Akt activation , and Snail upregulation .
7		Moreover , ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers .
8	✓	High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression .	GE-REG-RO
9		Our findings provide mechanistic insights into a previously unreported , pro-oncogenic role for ESRP1 in CRC , and suggest that fine-tuning the level of this RNA -binding protein could be relevant in modulating tumor growth in a subset of CRC patients .

PMID: 27695973 (Patient)   Terms: prospective, retrospective, prospective studies
Sent#	Symbols	Sentence	Mnemonics
0		Is gastroscopy for fecal immunochemical test positive patients worthwhile ?
1		BACKGROUND :
2		The use of fecal immunochemical test ( FIT ) in the screening for colorectal cancer is long established .
3		However , more than 50 % of patients with positive FITs have a negative colonoscopy .
4		The role of a subsequent oesophago-gastro-duodenoscopy ( OGD ) is debatable .
5		The aim of this study is to evaluate the yield of OGD in patients with positive FITs .
6		METHODOLOGY :
7	Μ	A retrospective review of patients who underwent colonoscopy for a positive FIT between Jan. 2008 and Dec. 2012 was identified from a prospectively collected endoscopy database at the National University Hospital , Singapore .
8		Patients who underwent concurrent or subsequent OGDs for positive FIT formed the study group .
9		We considered any new cancer or significant upper gastrointestinal pathology such as peptic ulcer disease or gastritis requiring treatment as a positive examination .
10		RESULTS :
11		A total of 202 patients underwent both a colonoscopy and an OGD for a positive FIT and formed the study group .
12		One hundred and six ( 525 % ) of them had a positive examination with gastritis and duodenitis representing the most common UGI pathology in 89 ( 441 % ) patients .
13		Twenty-nine ( 144 % ) patients tested positive for helicobacter pylori infection and another 16 ( 79 % ) patients had peptic ulcer disease .
14		There were no UGI cancers detected .
15		One patient had an esophageal leiomyoma that was treated conservatively .
16		CONCLUSION :
17		Routine gastroscopy for FIT positivity has a high diagnostic yield for benign upper gastrointestinal pathology .
18		Well-designed prospective studies to further evaluate the cost-effectiveness of routine gastroscopy in the work up of FIT positivity are warranted to make better clinical practice guidelines .

PMID: 27603340 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The impact of general/visceral obesity on completion of mesorectum and perioperative outcomes of laparoscopic TME for rectal cancer : A STARD-compliant article .
1		To evaluate the impact of visceral obesity on laparoscopic total mesorectal excision ( TME ) and decide the best index to reflect completion of mesorectum and perioperative outcomes .
2		Patients with rectal cancer who underwent laparoscopic TME were enrolled .
3		The data including body mass index ( BMI ) , visceral fat area ( VFA ) , visceral fat area/body surface area ( VFA/BSA ) , mesorectum fat ratio ( MFR ) , pelvic fat area ( PFA ) , pelvic fat ratio ( PFR ) , completion of mesorectum , and other perioperative outcomes were collected .
4		Data were analyzed .
5		A total of 322 patients were enrolled between 2011 and 2014 .
6		There was no significantly difference between the BMI groups on completion of mesorectum and other outcomes ( P >/= 005 ) .
7		However , in VFA groups , completion of mesorectum ( P = 0002 ) , operative time ( P = 002 ) , and incision length ( P = 002 ) were significantly different .
8		In VFA/BSA groups , completion of mesorectum ( P = 0002 ) and incision length ( P = 0009 ) were significantly different .
9		When MFR was equal to 0.48 , completion of mesorectum ( P = 0002 ) , operative time ( P = 0001 ) , incision length ( P = 003 ) , and blood loss ( P = 004 ) were significantly different between the 2 groups .
10		In PFA and PFR groups , there was no significantly difference ( P >/= 005 ) .
11		After the analysis of logistic regression , only VFA was the risk factor of incomplete mesorectum excision .
12		BMI does not reflect the impact of obesity on laparoscopic rectal surgery .
13		VFA is a better index in predicting the influence of visceral obesity on surgical quality and difficulty of laparoscopic rectal surgery than VFA/BSA and MFR .

PMID: 27497687 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		New gold carbene complexes as candidate anticancer agents .
1		Three structurally related gold(I) carbene complexes with bulky hydrophobic ligands i.e. 1-3 were investigated in solution for further consideration as candidate anticancer agents .
2		Cytotoxic assays were subsequently conducted on bone marrow-derived preosteoclast cell line of human origin ( FLG 291 ) and human colon cancer cells (HCT-116) .
3		A far greater cytotoxic activity was measured for compound 1 against HCT-116 cells compared to 2 and 3 ; conversely , all compounds were highly and similarly active against FLG 29.1 cells .
4		Results obtained for the reaction of complexes 1 and 2 with RNase A documented the occurrence of a weak interaction with this model protein and the formation of a tiny amount of the corresponding adduct .
5		Moreover , a certain reactivity of the complex 2 was also detected toward GSH .
6		The general implications of the obtained results are discussed .

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: 27086032 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Cisplatin and its dibromido analogue : a comparison of chemical and biological profiles .
1		The dibromido analogue of cisplatin , cis-PtBr2 ( NH3 ) 2 ( cisPtBr2 hereafter ) , has been prepared and characterised .
2		Its solution behaviour in standard phosphate buffer , at pH 7.4 , was investigated spectrophotometrically and found to reproduce quite closely that of cisplatin ; indeed , progressive sequential release of the two halide ligands typically occurs as in the case of cisplatin , with a roughly similar kinetics .
3		Afterward , patterns of reactivity toward model proteins and standard ctDNA were explored and the nature of the resulting interactions elucidated .
4		The antiproliferative properties were then evaluated in four representative cancer cell lines , namely A549 ( human lung cancer ) , HCT116 ( human colon cancer ) , IGROV-1 ( human ovarian cancer ) and FLG 29.1 ( human acute myeloid leukaemia ) .
5		Cytotoxic properties in line with those of cisplatin were highlighted .
6		From these studies an overall chemical and biological profile emerges for cisPtBr2 closely matching that of cisplatin ; the few slight , but meaningful differences that were underscored might be advantageously exploited for clinical application .

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: 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: 26920229 (Cell)   Terms: in vitro
Sent#	Symbols	Sentence	Mnemonics
0		Water-soluble Ru ( II ) - and Ru ( III )- halide-PTA complexes ( PTA = 1,3,5-triaza-7-phosphaadamantane ) : Chemical and biological properties .
1		Four structurally related Ru ( II )- halide-PTA complexes , of general formula trans - or cis-[Ru ( PTA ) 4X2] ( PTA = 1,3,5-triaza-7-phosphaadamantane , X = Cl ( 1 , 2 ) , Br ( 3 , 4 ) , were prepared and characterized .
2		Whereas compounds 1 and 2 are known , the corresponding bromo derivatives 3 and 4 are new .
3		The Ru ( III ) -PTA compound trans-[RuCl4 ( PTAH ) 2]Cl ( 5 , PTAH = PTA protonated at one N atom ) , structurally similar to the well-known Ru ( III ) anticancer drug candidates ( Na ) trans-[RuCl4 ( ind ) 2] ( NKP-1339 , ind = indazole ) and ( Him ) trans-[RuCl4 ( dmso-S ) ( im )] ( NAMI-A , im = imidazole ) , was also prepared and similarly investigated .
4		Notably , the presence of PTA confers to all complexes an appreciable solubility in aqueous solutions at physiological pH .
5		The chemical behavior of compounds 1-5 in water and in physiological buffer , their interactions with two model proteins - cytochrome c and ribonuclease A - as well as with a single strand oligonucleotide ( 5'-CGCGCG-3' ) , and their in vitro cytotoxicity against a human colon cancer cell line (HCT-116) and a myeloid leukemia ( FLG 291 ) were investigated .
6		Upon dissolution in the buffer , sequential halide replacement by water molecules was observed for complexes 1-4 , with relatively slow kinetics , whereas the Ru ( III ) complex 5 is more inert .
7		All tested compounds manifested moderate antiproliferative properties , the cis compounds 2 and 4 being slightly more active than the trans ones ( 1 and 3 ) .
8		Mass spectrometry experiments evidenced that all complexes exhibit a far higher reactivity towards the reference oligonucleotide than towards model proteins .
9		The chemical and biological profiles of compounds 1-5 are compared to those of established ruthenium drug candidates in clinical development .

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: 26573662 (None)   Terms: , mouse, mice
Sent#	Symbols	Sentence	Mnemonics
0		Avatars Identify Genetic Sources of Drug Response .
1		Using mouse avatars implanted with liver metastases of late-stage colorectal cancers , researchers uncovered mutations in five genes -ERBB2 , EGFR , FGFR1 , PDGFRA , and MAP2K1-that seem to promote cetuximab resistance .
2	Μ	They also found that mutations in IRS2 may boost tumors' vulnerability to anti-EGFR therapy and tested specific therapies in the mice to gauge the drugs' effectiveness .

PMID: 26497743 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Complexity of FGFR signalling in metastatic urothelial cancer .
1		BACKGROUND :
2		Urothelial cancers ( UC ) are the fourth most common tumours worldwide after prostate ( or breast ) , lung and colorectal cancer .
3		Despite recent improvements in their management , UC remain an aggressive disease associated with a poor outcome .
4		Following disease progression on first - line platinum-based chemotherapy , very few effective treatment options are available and none of them have shown significant improvement in overall survival .
5		Alterations of the fibroblast growth factor receptor ( FGFR ) pathway including amplification , mutations and overexpression are common in UC .
6		Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors .
7		MATERIALS AND METHODS :
8		We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547 .
9		RESULTS :
10		To date , the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria .
11		Exploratory biomarker analysis showed FGFR3 , FGFR1 , FGF-ligand and fibroblast growth factor receptor substrate 2 ( FRS2 ) expression in the patient's tumour , together with the presence of a germ - line mutation in the FGFR3 extracellular binding domain .
12		This is not a known hotspot mutation , and the functional significance remains unclear .
13		CONCLUSIONS :
14		The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1 , FGFR3 , FGF-ligand and FRS2 expression .
15		This lends support to the further exploration of FGFR inhibitors in urothelial cancer .
16		Further studies are required to determinate the most effective way to select those patients most likely to respond .

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: 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: 26108735 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Remaining cancer cells within the fibrosis after neo-adjuvant treatment for locally advanced rectal cancer .
1		AIM :
2		To analyse the incidence and distribution of remaining cancer cells within the fibrosis induced by preoperative chemo-radiotherapy ( CRT ) for locally advanced rectal cancer .
3		METHODS :
4		The histopathological specimens from 46 patients operated on with extensive surgery for locally advanced rectal cancer after CRT were examined .
5		The extension of fibrosis in relation to the mesorectal fascia ( MRF ) and the distribution of cancer cells within the fibrosis was examined using routine haematoxylin-eosin staining .
6		In addition , immunohistochemical staining with CK20 was done to examine if cancer cells were missed by routine pathological work up .
7		RESULTS :
8		All specimens showed CRT induced fibrosis .
9		Two specimens showed complete response without viable cancer cells ( ypT0 ) .
10		The fibrosis was limited inside the MRF in three cases , adherent to or involved the MRF in ten cases and in 33 cases the fibrosis was obvious outside as well as inside the fascia .
11		Twenty-one cases showed fibrosis on the surgical resection margin , and in 9 of these cancer cells were found on the surgical margin ( R1 , R2-resection ) .
12		37 patients had R0 resections and among those 24 showed fibrosis beyond the MFR and 13 had scattered cancer cells in the fibrosis along or outside the MRF .
13		CONCLUSIONS :
14		The rate of remaining cancer cells within the fibrosis was high in patients with locally advanced rectal cancer treated with CRT .
15		Frequently cancer cells were detected near the border of the fibrosis .
16		A complete resection of the fibrosis is therefore recommended to achieve an R0 resection after neo-adjuvant treatment .

PMID: 26088290 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Fibroblast Growth Factor Receptor 1 Gene Copy Number and mRNA Expression in Primary Colorectal Cancer and Its Clinicopathologic Correlation .
1		OBJECTIVES :
2		Fibroblast growth factor receptor 1 ( FGFR1 ) has been reported to be overexpressed in colorectal cancer ( CRC ) and suggested to be a therapeutic target .
3		In this study , we investigated FGFR1 expression and amplification in CRC and its correlation with clinicopathologic parameters .
4		METHODS :
5		FGFR1 dual-color fluorescence in situ hybridization and mRNA in situ hybridization were performed on tissue array blocks composed of 291 consecutive primary CRCs .
6		RESULTS :
7	Μ	Of the 291 CRC cases , FGFR1 gene amplification was found in 11 ( 38% ) cases , high FGFR1 polysomy in 4 ( 14% ) cases , and FGFR1 gene copy number ( GCN ) gain ( GCN >2 ) in 77 ( 265% ) cases .
8	✓	FGFR1 GCN gain was significantly associated with left-sided location , lymph node metastasis , distant metastasis , and higher TNM stage ( p <005 ) .	GM-ASS-RO
9	✓	FGFR1 GCN gain also correlated with poor patient survival ( p = 0015 ) .	GM-ASS-RO
10		FGFR1 mRNA overexpression ( score 3-4 ) was present in 11.7% ( 34/291 ) of the patients and was significantly associated with FGFR1 GCN alteration ( Pearson correlation coefficient , r = 0463 ; p <0001 ) .
11		CONCLUSION :
12	✓ Μ	FGFR1 GCN gain was more frequently found ( 265% ) than gene amplification ( 38% ) and correlated with aggressive clinical behavior in consecutive CRC patients .	GM-ASS-DS
13		FGFR1 GCN alteration was associated with a high FGFR1 mRNA level .

PMID: 25934085 (Patient)   Terms: , mouse, mice
Sent#	Symbols	Sentence	Mnemonics
0		Phylogenetic analysis of receptor FgfrL1 shows divergence of the C-terminal end in rodents .
1		FGFRL1 is a member of the fibroblast growth factor receptor ( FGFR ) family .
2		Similar to the classical receptors FGFR1-FGFR4 , it contains three extracellular Ig-like domains and a single transmembrane domain .
3		However , it lacks the intracellular tyrosine kinase domain that would be required for signal transduction , but instead contains a short intracellular tail with a peculiar histidine-rich motif .
4		This motif has been conserved during evolution from mollusks to echinoderms and vertebrates .
5		Only the sequences of FgfrL1 from a few rodents diverge at the C-terminal region from the canonical sequence , as they appear to have suffered a frameshift mutation within the histidine-rich motif .
6	Μ	This mutation is observed in mouse , rat and hamster , but not in the closely related rodents mole rat ( Nannospalax ) and jerboa ( Jaculus ) , suggesting that it has occurred after branching of the Muridae and Cricetidae from the Dipodidae and Spalacidae .
7		The consequence of the frameshift is a deletion of a few histidine residues and an extension of the C - terminus by about 40 unrelated amino acids .
8	Μ	A similar frameshift mutation has also been observed in a human patient with a craniosynostosis syndrome as well as in several patients with colorectal cancer and bladder tumors , suggesting that the histidine-rich motif is prone to mutation .
9		The reason why this motif was conserved during evolution in most species , but not in mice , is not clear .

PMID: 25691251 (Cell)   Terms: in vitro, In vivo, xenograft, mice
Sent#	Symbols	Sentence	Mnemonics
0		AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor ( FGFR ) -expressing colorectal cancer cells .
1		Colorectal cancer ( CRC ) causes significant mortalities worldwide .
2		Fibroblast growth factor ( FGF ) receptor ( FGFR ) signaling is frequently dysregulated and/or constitutively activated in CRCs , contributing to cancer carcinogenesis and progression .
3		Here , we studied the activity of AZD-4547 , a novel and potent FGFR kinase inhibitor , on CRC cells .
4		AZD-4547 inhibited CRC cell growth in vitro , and its activity correlated with the FGFR-1/2 expression level .
5		AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines ( NCI-H716 and HCT-116 ) , but not in FGFR-1/2 null HT-29 cells .
6		Further , AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 ( FRS-2 ) , ERK/mitogen-activated protein kinase ( MAPK ) , and AKT/mammalian target of rapamycin ( AKT/mTOR ) signalings in NCI-H716 and HCT-116 cells .
7		In vivo , AZD-4547 oral administration at effective doses inhibited NCI-H716 ( high FGFR-1/2 expression ) xenograft growth in nude mice .
8		Phosphorylation of FGFR-1 , AKT , and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration .
9		Thus , our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings .

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: 25287912 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Predictive molecular markers in metastases to the central nervous system : recent advances and future avenues .
1		Metastases to the central nervous system ( CNS ) are common in several cancer types .
2		For most primary tumors that commonly metastasize to the CNS , molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies .
3		Therapeutic efficacy of some of these agents has been documented in patients with brain metastases , and molecular testing of CNS metastases should be considered in the clinical setting .
4		Here , we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the European Society of Medical Oncology ( ESMO ) or the National Comprehensive Cancer Network ( NCCN ) for the most relevant primary tumor types : lung cancer ( EGFR mutations , ALK rearrangement , BRAF mutations ) , breast cancer ( HER2 amplification , steroid receptor overexpression ) , melanoma ( BRAF mutations ) , and colorectal cancer ( RAS mutations ) .
5		Furthermore , we discuss emerging therapeutic targets including novel oncogenic alterations ( ROS1 rearrangements , FGFR1 amplifications , CMET amplifications , and others ) and molecular features of the tumor microenvironment ( including immune-checkpoint molecules such as CTLA4 and PD-1/PD-L1 ) .
6		We also discuss the potential role of advanced biomarker tests such as next-generation sequencing and "liquid biopsies" for patients with CNS metastases .

PMID: 25010701 (Patient)   Terms: In vitro, in vitro
Sent#	Symbols	Sentence	Mnemonics
0	✓	SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer .	GE-INV-RO
1		Sporadic colorectal cancer ( CRC ) is a common malignancy and also one of the main causes of cancer deaths worldwide .
2	Μ	Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types , but its role in CRC has not been fully elucidated .
3		Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis .
4		SOX2 was expressed in 11% of the tumors and was significantly associated to BRAFV600E mutation , but not to KRAS mutations ( codon 12 and 13 ) .
5		SOX2 positivity was correlated to poor patient survival , especially in BRAFV600E mutated cases .
6	Μ	In vitro studies showed that cells expressing the constitutively active BRAFV600E had increased SOX2 expression , a finding not found in cells expressing KRASG12V .
7		Furthermore , blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2 .
8	Μ	Since SOX2 overexpression has been correlated to increased migration and invasion , we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases .
9	✓ Μ	Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1 , which has been reported to correlate with liver metastasis in CRC .	GE-ASS-RO
10	✓	Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling , and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis .	GE-REG-RO

PMID: 24628370 (Patient)   Terms: prospective
Sent#	Symbols	Sentence	Mnemonics
0		Filaggrin loss-of-function mutations and incident cancer : a population-based study .
1		BACKGROUND :
2		Loss-of-function mutations in the filaggrin gene ( FLG ) could have opposing effects on cancer risk , as mutations are associated with both 10% higher serum vitamin D levels , which may protect against cancer , and with impaired skin barrier function , which may lead to higher cancer susceptibility .
3		OBJECTIVES :
4		To investigate the association of the FLG genotype and cancer types in four population-based cohorts .
5		METHODS :
6		A total of 13,376 individuals were genotyped for FLG mutations .
7		Information on cancer was obtained from the Danish Cancer Registry .
8		Persons with a history of cancer at baseline were excluded from prospective analyses .
9		RESULTS :
10		There were 1339 incident cancers ( median follow-up 114 years ) .
11		The hazard ratios ( HRs ) and 95% confidence intervals ( CIs ) for FLG mutation carriers vs.wild types were : for any cancer ( HR 095 , 95% CI 078-116 ) , any cancer excluding nonmelanoma skin cancer ( NMSC ) ( HR 105 , 95% CI 084-131 ) , head and neck cancer ( HR 172 , 95% CI 071-415 ) , colorectal cancer ( HR 082 , 95% CI 044-152 ) , bronchus and lung cancer ( HR 134 , 95% CI 077-233 ) , breast cancer ( HR 058 , 95% CI 030-114 ) , uterine cancer ( HR 042 , 95% CI 006-310 ) , prostate cancer ( HR 109 , 95% CI 061-194 ) , urinary cancer ( HR 130 , 95% CI 051-329 ) , malignant melanoma ( HR 103 , 95% CI 041-258 ) and NMSC ( HR 070 , 95% CI 047-105 ) .
12		Among participants aged over 60 years at baseline , we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers .
13		CONCLUSIONS :
14	Μ	The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses .

PMID: 24616020 (Patient)   Terms: in vivo, in vitro, xenograft, mouse model, mouse
Sent#	Symbols	Sentence	Mnemonics
0		Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression .
1		UNLABELLED :
2		The purpose of this study was to identify microRNAs ( miRNAs ) involved in the pathology of colorectal cancer ( CRC ) liver metastasis and investigate their underlying mechanisms .
3		A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays .
4		A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse-transcription polymerase chain reaction ( RT-PCR ) analysis in the 32 patients .
5		In a validated cohort of 99 CRC patients ( 44 with and 55 without liver metastases ) , only miR-214 was validated to be significantly down-regulated in CRC with liver metastases , which was associated with an unfavorable prognosis .
6		Ectopic expression of miR-214 suppressed proliferation , migration , and invasion in vitro , tumor growth and liver metastasis in an in vivo xenograft mouse model , whereas miR-214 knockdown promoted proliferation , migration , and invasion in CRC cell lines .
7		Further studies indicated that fibroblast growth factor receptor 1 ( FGFR1 ) was a potential target of miR-214 .
8		Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 messenger RNA ( mRNA ) and protein levels .
9		FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells , while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells .
10		Moreover , miR-214 expression levels were inversely correlated with FGFR1 in CRC patients .
11		CONCLUSION :
12	✓	Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels , which may contribute to increased CRC liver metastasis .	GE-INV-RO
13		miR-214 may serve as a potential marker to predict survival , and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients .

PMID: 24135816 (Patient)   Terms: In vitro, clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Fibroblast growth factor receptor 1 as a putative therapy target in colorectal cancer .
1		BACKGROUND/AIMS :
2		Resembling a potential therapeutic drug target , fibroblast growth factor receptor 1 ( FGFR1 ) amplification and expression was assessed in 515 human colorectal cancer ( CRC ) tissue samples , lymph node metastases and CRC cell lines .
3		METHODS :
4		FGFR1 amplification status was determined using fluorescence in situ hybridization .
5		Additionally , we assessed protein levels employing Western blots and immunohistochemistry .
6		The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization .
7		Functional studies employed the FGFR inhibitor NVP-BGJ398 .
8		RESULTS :
9		Of 454 primary CRCs , 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor .
10		Of 99 investigated tumors , 18 revealed membranous activated pFGFR1 protein .
11		FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence .
12	Μ	In vitro , a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein .
13		CONCLUSION :
14		FGFR1 is a potential therapeutic target in a subset of CRC .
15		FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors .
16		The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials .

PMID: 24024063 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Iatrogenic sinistral hypertension complicating screening colonoscopy .
1		Colonoscopy is widely accepted as the gold-standard screening technique for detecting malignancies in the distal gastrointestinal tract in patients with symptoms suggestive of colon cancer .
2		However , this procedure is not without risk , including colonic perforation .
3		We report a patient who was managed conservatively after colonoscopy induced perforation .
4		Eighteen months after appearing to make a full recovery , he presented with an upper gastrointestinal bleed .
5		Oesophago-gastro-duodenoscopy ( OGD ) revealed large gastric fundal varices and computed tomography ( CT ) revealed splenic vein thrombosis .
6		The ensuing left-sided ( sinistral ) hypertension explains the development of the fundal varices in the presence of normal liver function .
7		At surgery , a persistent abscess cavity was identified and cultures from this site grew Streptococcus anginosus .
8		Curative splenectomy was performed and the patient made a full recovery .
9		We advocate more prompt operative intervention in selected cases of iatrogenic colonic perforation with primary repair to prevent late complications .

PMID: 23876834 (Patient)   Terms: clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation : subdivision and comparison with ordinary hepatocellular carcinoma .
1		PURPOSE :
2		Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers .
3		This demands a new process of patient selection for clinical trials .
4		PATIENTS AND METHODS :
5		Starting January 1 , 2012 , preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung ( NSCLC ) or colorectal cancer ( CRC ) , who met generic study inclusion criteria .
6		Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing , in situ hybridisation and immunohistochemistry .
7		The clinical course was closely monitored to offer trial participation whenever applicable .
8		RESULTS :
9		Within 12 months , 267 patients ( 188 NSCLC , 79 CRC ) were profiled .
10		Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration .
11	Μ	The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations ( 29% ) , loss of PTEN expression ( 18% ) , EGFR mutations ( 9% ) , HER2 amplification ( 5% ) and BRAF mutations ( 3% ) , while the prevalence of ALK translocations and PIK3CA mutations was extremely low .
12	Μ	In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15% , PTEN expression was lost in 20% and DDR2 was mutated in a single case .
13		KRAS mutations ( 41% ) predominated in CRC , followed by loss of PTEN expression ( 16% ) , PIK3CA ( 5% ) and BRAF ( 5% ) mutations .
14		So far 13 patients ( 5% ) have entered biomarker-stratified clinical trials .
15		Therapeutic decisions for approved drugs were guided in another 45 patients ( 17% ) .
16		CONCLUSION :
17		Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center .
18		Substantial investments in diagnostics and administration are required .

PMID: 23843018 (None)   Terms: xenograft, mouse, mouse xenograft, mouse xenograft model, mice
Sent#	Symbols	Sentence	Mnemonics
0		Distinct K-ras mutation pattern characterizes signet ring cell colorectal carcinoma .
1		Angiogenesis plays an essential role in cancer progression , which therefore has become an attractive target for anticancer treatment .
2		Tumor angiogenesis is tightly regulated by multiple signaling pathways that usually function redundantly ; in addition , crosstalk between these pathways forms a complicated network that is regulated by compensatory mechanisms .
3		Given the complexity of pathogenic mechanisms underlying tumor angiogenesis , most currently used angiogenesis inhibitors that only target single pathways may be insufficient and probably generate drug resistance , thus , increasing the necessity for development of novel anticancer agents .
4		Traditional Chinese medicines ( TCM ) are receiving great interest since they have relatively fewer side-effects and have been used for thousands of years to clinically treat various types of diseases including cancer .
5		Pien Tze Huang ( PZH ) , a well-known traditional Chinese formulation that was first prescribed 450 years ago , has long been used as an alternative remedy for cancers .
6		However , the precise mechanism of PZH's anticancer activity remains to be further elucidated .
7		Using a colorectal cancer mouse xenograft model , in the present study , we evaluated the effect of PZH on tumor angiogenesis and investigated the underlying molecular mechanisms .
8		We found that PZH inhibited tumor growth since PZH treatment resulted in decrease in both tumor volume and tumor weight in CRC mice .
9		In addition , PZH suppressed the activation of several signaling pathways such as STAT3 , Akt and MAPKs .
10		Consequently , the inhibitory effect of PZH on these pathways resulted in the inhibition of tumor angiogenesis as demonstrated by the decrease of microvessel density in tumor tissues .
11		Moreover , PZH treatment reduced the expression of angiogenic factors including iNOS , eNOS , VEGF-A , bFGF as well as their specific receptors VEGFR2 and bFGFR .
12		Altogether , our findings suggest that inhibition of tumor angiogenesis via suppression of multiple signaling pathways might be one of the mechanisms whereby PZH affects cancers .

PMID: 23804704 (None)   Terms: xenograft, phase I study, tumor xenograft models
Sent#	Symbols	Sentence	Mnemonics
0		S49076 is a novel kinase inhibitor of MET , AXL , and FGFR with strong preclinical activity alone and in association with bevacizumab .
1		Aberrant activity of the receptor tyrosine kinases MET , AXL , and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies , notably in instances of primary or acquired resistance to existing or emerging anticancer therapies .
2		This study describes the preclinical characterization of S49076 , a novel , potent inhibitor of MET , AXL/MER , and FGFR1/2/3 .
3		S49076 potently blocked cellular phosphorylation of MET , AXL , and FGFRs and inhibited downstream signaling in vitro and in vivo .
4		In cell models , S49076 inhibited the proliferation of MET - and FGFR2 -dependent gastric cancer cells , blocked MET-driven migration of lung carcinoma cells , and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL .
5		In tumor xenograft models , a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth .
6		MET , AXL , and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab .
7		Accordingly , combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth .
8		Moreover , S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors .
9		On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076 , a phase I study is currently underway in patients with advanced solid tumors .
10		Mol Cancer Ther ; 12(9) ; 1749-62 .
11		(c) 2013 AACR .

PMID: 23700287 (Patient)   Terms: meta-analysis, Phase II/III, clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib : a meta-analysis .
1		BACKGROUND :
2		Regorafenib is a novel receptor tyrosine kinase inhibitor approved for use in metastatic colorectal cancer ( mCRC ) and locally advanced gastrointestinal stromal tumors ( GISTs ) .
3		The drug targets multiple receptors , including VEGF-R1/-R2/-R3 , TIE-2 , FGFR-1 , PDGFR-alpha/beta , KIT , RET , RAF , p38 MAPK .
4		Adverse events include asthenia , hypertension , diarrhea , and hand-foot skin reaction ( HFSR ) , with the latter representing one of the most clinically significant untoward events .
5		The incidence and risk of HFSR with regorafenib have not been systematically investigated .
6		METHODS :
7		We conducted a meta-analysis to ascertain the incidence and risk of developing HFSR in cancer patients treated with regorafenib .
8		Electronic databases ( PubMed , Scopus , Web of Science ) and the ASCO website were searched for publications from January 1998-January 2013 .
9		Eligible studies were limited to Phase II/III clinical trials employing regorafenib ( 160 mg/day ) .
10		The incidence , relative risk ( RR ) , and 95 % CIs were calculated using random - or fixed-effects models based on the heterogeneity of included studies .
11		RESULTS :
12		A total of 1,078 patients treated with regorafenib for mCRC , GIST , renal cell carcinoma ( RCC ) and hepatocellular carcinoma ( HCC ) were included .
13		The overall incidence of all-grade and high-grade HFSR were 60.5 % ( 95 % CI : 48.3-71.6 % ) and 20.4 % ( 95 % CI : 15.4-26.6 % ) , respectively .
14		The RRs of all-grade and high-grade HFSR with regorafenib in comparison to controls were increased for all-grade ( RR = 5.4 , 95 % CI : 3.76-7.76 , p <0.001 ) and high-grade ( RR = 41.99 , 95 % CI : 5.88-299.93 , p <0.001 ) HFSR .
15		The incidence of HFSR varied significantly with tumor type ( p = 0007 ) , and was 71.4 % ( 95 % CI : 57.4-82.3 % ) for RCC , 60.2 % ( 95 % CI : 52.3-67.6 % ) for GIST , 50.0 % ( 95 % CI : 34.2-65.8 % ) for HCC , and 46.6 % ( 95 % CI : 42.3-51.0 % ) for mCRC .
16		CONCLUSION :
17		The incidence and risk of development of HFSR with regorafenib is high , and may vary significantly with tumor type .
18		Knowledge of this is important for patient counseling and clinical trial development , to ensure adherence and maximize clinical outcomes .

PMID: 23610528 (Patient)   Terms: prospective
Sent#	Symbols	Sentence	Mnemonics
0		Integrative genomic analyses on GLI1 : positive regulation of GLI1 by Hedgehog-GLI , TGFbeta-Smads , and RTK-PI3K-AKT signals , and negative regulation of GLI1 by Notch-CSL-HES/HEY , and GPCR-Gs-PKA signals .
1	Μ	Previous studies have revealed that EGFR mutation and/or EML4-ALK gene fusion rate was higher in the non-smoker Asian females with pulmonary adenocarcinoma .
2	Μ	The aim of this study is to determine the distribution of known oncogenic driver mutations in the female non-smoker Asian patients with pulmonary adenocarcinoma. 104 consecutively resected lung adenocarcinomas from 396 non-smoker females ( less than 100 cigarettes in a lifetime ) at a single institution ( Tongji University , Shanghai , China ) were analyzed for mutations in EGFR , EML4-ALK , KRAS , HER2 , BRAF , and PIK3CA. 73 ( 702 % ) tumors harbored EGFR mutations ; among these , 28 were deletions in exon 19 , 44 were L858R missense changes , and eight were T790M mutations. 10 ( 96 % ) harbored EML4-ALK fusions , two harbored KRAS mutations , two harbored BRAF mutations , and two harbored PI3K mutations .
3		A majority of the mutations were mutually exclusive , except two with EGFR mutation and BRAF mutation , one with EML4-ALK fusions and PI3K mutation .
4	Μ	Thus , 82.7 % ( 86 of 104 ; 95 % CI , 754-900 % ) of lung adenocarcinomas from non-smoker females were found to harbor the well-known oncogenic mutations in five genes .
5		Lung cancer in non-smoking Asian females is a distinct entity , with majority of this subgroup being developed by the oncogenic mutations .
6		The prospective mutation examination in this population will be helpful for devising a targeted therapy for a majority of the patients .

PMID: 23462625 (None)   Terms: Phase I trial, Phase II, Phase III, This review, phase I
Sent#	Symbols	Sentence	Mnemonics
0		Frequent occurrence of low grade cases among metastatic gastrointestinal stromal tumours .
1		Regorafenib is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types , in preclinical and clinical studies .
2		Preclinical data show inhibitory activity of angiogenic , stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1 , 2 and 3 , tyrosine - protein kinase receptor TIE-2 , platelet-derived growth factor receptor beta , fibroblast growth factor receptor 1 , proto - oncogene tyrosine-protein kinase receptor Ret , mast/stem cell growth factor receptor Kit , RAF proto - oncogene serine/threonine-protein kinase and wild-type and V600E mutant serine/threonine - protein kinase B-raf .
3		Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3-weeks-on/1-week-off schedule , or 100 mg daily on a continuous schedule , with adverse effects typical of other multikinase inhibitors .
4		Phase II studies demonstrated clinical benefit in a variety of tumor types , mostly associated with prolonged stable disease .
5		Phase III studies include the CORRECT trial , which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies .
6		There is still much work to be done to determine the role of regorafenib in the future of cancer therapy .
7		This review will focus on the development of regorafenib , from early preclinical work through phase I , II and III trials , as well as highlighting the current role and potential future directions of this novel agent .

PMID: 23435872 (None)   Terms: this review, clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Regorafenib for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi-target inhibitor .
1		Intracellular signals for cancer cell growth , proliferation , migration , and survival are frequently triggered by protein tyrosine kinases ( TKs ) .
2		The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes .
3		However , intrinsic resistance may limit the benefit of these drugs , and multiple escape routes compensate for the inhibited signaling .
4		The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents .
5		In this scenario , regorafenib has emerged as a novel , orally active , multitarget compound with potent activity against a number of angiogenic and stromal TKs , including vascular endothelial growth factor receptor 2 ( VEGFR-2 ) , tyrosine kinase with immunoglobulin-like and EGF-like domains 2 ( TIE-2 ) , fibroblast growth factor receptor 1 ( FGFR-1 ) , and platelet-derived growth factor receptor ( PDGFR ) .
6		Moreover , the drug has the capability of blocking KIT , RET and V600 mutant BRAF .
7		Starting from interesting preclinical results , this review describes the clinical development of regorafenib in gastrointestinal malignancies , focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors .

PMID: 22751462 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Gastrointestinal adenocarcinomas of the esophagus , stomach , and colon exhibit distinct patterns of genome instability and oncogenesis .
1		A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy .
2		Using data from high-density genomic profiling arrays , we conducted an analysis of somatic copy-number aberrations in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers .
3		Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors .
4	Μ	We identified 64 regions of significant recurrent amplification and deletion , some shared and others unique to the adenocarcinoma types examined .
5		Amplified genes were noted in 37% of gastric/esophageal tumors , including in therapeutically targetable kinases such as ERBB2 , FGFR1 , FGFR2 , EGFR , and MET , suggesting the potential use of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared with colorectal cancers .
6		Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes , including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated , including by functional experiments in tissue culture .
7		Together , our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas , potentially informing novel opportunities for targeted therapeutic interventions .

PMID: 22701813 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Fibroblast growth factor receptor 2 : expression , roles , and potential as a novel molecular target for colorectal cancer .
1		The fibroblast growth factor receptor ( FGFR ) family consists of four members , named FGFR1 , 2 , 3 , and 4 .
2		All 4 FGFRs and their ligands , fibroblast growth factors ( FGFs ) , are expressed in colorectal cancer ( CRC ) .
3		Recent studies have shown that FGFR2 plays important roles in cancer progression ; therefore , it is of great interest as a novel target for cancers .
4		Expression of FGFR2 regulates migration , invasion , and growth in CRC .
5		Expression of the FGFR2 isoform FGFR2 IIIb was associated with well-differentiated histological types , and its specific ligand , FGF7 , enhanced angiogenesis and adhesion to type-IV collagen via FGFR2 IIIb in CRC .
6		FGFR2 IIIc is detected in CRC , but its roles have not been well elucidated .
7		Interactions between FGFR2 IIIb and IIIc and FGFs may play important roles in CRC via autocrine and/or paracrine signaling .
8		Several kinds of molecular-targeting agents against FGFR2 have been developed ; however , it is not clear how a cancer treatment can most effectively inhibit FGFR2 IIIb or FGFR2 IIIc , or both isoforms .
9		The aim of this paper is to summarize the roles of FGFR2 and its isoforms in CRC and clarify whether they are potent therapeutic targets for CRC .

PMID: 22577890 (None)   Terms: This review, Phase I, Phase III, mouse models, mouse
Sent#	Symbols	Sentence	Mnemonics
0		Regorafenib for cancer .
1		INTRODUCTION :
2		Regorafenib ( BAY 73-4506 ) is a novel , orally active , diphenylurea multikinase inhibitor of VEGFR1-3 , c-KIT , TIE-2 , PDGFR-beta , FGFR-1 , RET , RAF-1 , BRAF and p38 MAP kinase .
3		AREAS COVERED :
4		This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies .
5		The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile .
6		Current clinical developments , especially in colorectal cancer ( CRC ) and gastrointestinal stromal tumor ( GIST ) , are addressed .
7		Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed .
8		EXPERT OPINION :
9		Regorafenib ( BAY 73-4506 ) is a novel , orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed .
10		The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets .
11		Regorafenib has promising antineoplastic activity in various tumor types .
12		Two large , randomized Phase III pivotal registration studies in patients with GIST and CRC , respectively , already completed enrolment , with final results being awaited .
13		Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing .
14		Moreover , regorafenib has recently been granted Orphan Drug Status for GIST tumors and 'fast track' status for both GIST and CRC by the FDA .

PMID: 21561874 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Guidelines for the management of iron deficiency anaemia .
1		BACKGROUND :
2		Iron deficiency anaemia ( IDA ) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists .
3		Gastrointestinal ( GI ) blood loss from colonic cancer or gastric cancer , and malabsorption in coeliac disease are the most important causes that need to be sought .
4		DEFINING IRON DEFICIENCY ANAEMIA :
5		The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B) .
6		Any level of anaemia should be investigated in the presence of iron deficiency (B) .
7		The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B) .
8		Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A) .
9		Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C) .
10		Serum ferritin is the most powerful test for iron deficiency (A) .
11		INVESTIGATIONS :
12		Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A) .
13		All patients should be screened for coeliac disease (B) .
14		If oesophagogastroduodenoscopy ( OGD ) is performed as the initial GI investigation , only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B) .
15		In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma , lower GI investigation should still be considered even if coeliac disease is found (B) .
16		Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA , but either is acceptable (B) .
17		Either is preferable to barium enema , which is useful if they are not available .
18		Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease , or if the haemoglobin cannot be restored or maintained with iron therapy (B) .
19		In patients with recurrent IDA and normal OGD and colonoscopy results , Helicobacter pylori should be eradicated if present .
20		(C) .
21		Faecal occult blood testing is of no benefit in the investigation of IDA (B) .
22		All premenopausal women with IDA should be screened for coeliac disease , but other upper and lower GI investigation should be reserved for those aged 50 years or older , those with symptoms suggesting gastrointestinal disease , and those with a strong family history of colorectal cancer (B) .
23		Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B) .
24		In patients with iron deficiency without anaemia , endoscopic investigation rarely detects malignancy .
25		Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C) .
26		Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C) .
27		Rectal examination is seldom contributory , and , in the absence of symptoms such as rectal bleeding and tenesmus , may be postponed until colonoscopy .
28		Urine testing for blood is important in the examination of patients with IDA (B) .
29		MANAGEMENT :
30		All patients should have iron supplementation both to correct anaemia and replenish body stores (B) .
31		Parenteral iron can be used when oral preparations are not tolerated (C) .
32		Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C) .

PMID: 20811704 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer .
1	Μ	A series of 88 conventional follicular and Hurthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry .
2	Μ	A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS , K-RAS , and N-RAS genes .
3		Forty-nine percent of conventional follicular carcinomas had RAS mutations , 36% had PAX8-PPAR gamma rearrangement , and only one ( 3% ) had both .
4		In follicular adenomas , 48% had RAS mutations , 4% had PAX8-PPAR gamma rearrangement , and 48% had neither .
5		Follicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1 , tended to present at a younger patient age and be smaller size , and were almost always overtly invasive .
6		In contrast , follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive .
7		Hurthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations .
8		These results suggest that conventional follicular thyroid carcinomas develop through atleast two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement .

PMID: 20406842 (Cell)   Terms: in vivo, xenograft
Sent#	Symbols	Sentence	Mnemonics
0		Assessment of the in vivo antitumor effects of ENMD-2076 , a novel multitargeted kinase inhibitor , against primary and cell line -derived human colorectal cancer xenograft models .
1		PURPOSE :
2		This in vivo study was designed to investigate the efficacy of ENMD-2076 , a small-molecule kinase inhibitor with activity against the Aurora kinases A and B , and several other tyrosine kinases linked to cancer , including vascular endothelial growth factor receptor 2 , cKit , and fibroblast growth factor receptor 1 , against murine xenograft models of human colorectal cancer ( CRC ) .
3		EXPERIMENTAL DESIGN :
4		HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 ( 100 or 200 mg/kg ) orally daily for 28 days .
5		Tumor growth inhibition , dynamic contrast-enhanced magnetic resonance imaging , and ( 18 ) FDG-positron emission tomography were conducted to assess the antiproliferative , antiangiogenic , and antimetabolic responses , respectively .
6		Effects on proliferation were also analyzed by immunohistochemical methods .
7		Additionally , three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 ( 100 mg/kg ) and assessed for tumor growth inhibition .
8		RESULTS :
9		In the HT-29 xenograft model , ENMD-2076 induced initial tumor growth inhibition followed by regression .
10		Treatment was associated with significant tumor blanching , indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging .
11		Positron emission tomography scanning showed significant decreases in ( 18 ) FDG uptake at days 3 and 21 of treatment , which was associated with a marked reduction in proliferation as assessed by Ki-67 .
12		All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition .
13		CONCLUSIONS :
14		ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging , supporting clinical investigation of this agent in CRC .

PMID: 19082464 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0	✓	Overexpression of the fibroblast growth factor receptor -1 gene correlates with liver metastasis in colorectal cancer .	GE-ASS-RO
1		Expression of the fibroblast growth factor ( FGF ) -1 , FGF-2 , fibroblast growth factor receptor ( FGFR ) -1 , and FGFR-2 genes has been reported in various cancers and is associated with poor outcomes in patients with solid tumors .
2		This study examined the relations between the relative expression of the FGF genes and clinicopathological factors , especially invasion and metastasis , in patients with colorectal cancer .
3		We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal carcinoma .
4		The relative expression levels of FGF-1 , FGF-2 , FGFR-1 , and FGFR-2 mRNA in cancer and in normal adjacent mucosa were measured by quantitative real-time , reverse-transcription polymerase chain reaction .
5		The relative expression level of the FGFR-2 gene was higher in normal adjacent mucosa than in cancer , whereas the relative expression levels of the FGF-1 , FGF-2 , and FGFR-1 genes were similar .
6		FGFR-1 gene expression levels were higher in the presence than in the absence of liver metastasis .
7	✓	An analysis of the relation between clinicopathological features and gene expression showed that overexpression of FGFR-1 correlated with liver metastasis .	GE-ASS-RO
8	✓	Our results suggested that overexpression of the FGFR-1 gene might lead to liver metastasis in colorectal cancer .	GE-REG-RO
9		Overexpression of the FGFR-1 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer .

PMID: 19047154 (Cell)   Terms: xenograft, mice, orthotopic tumors
Sent#	Symbols	Sentence	Mnemonics
0		TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche .
1		The aim of this study was to investigate the inhibitory effect of TSU68 [(Z) -5-[ ( 1,2-dihydro-2-oxo-3H-indol-3-ylidene ) methyl]-2,4-dimethyl-1H-pyrrole-3-p ropanoic acid ; SU6668] , an inhibitor of vascular endothelial growth factor receptor 2 , platelet-derived growth factor receptor beta , and fibroblast growth factor receptor 1 ( FGFR1 ) , on colon cancer liver metastasis , and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis .
2		First , we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice , followed by twice-daily administration of TSU68 ( 400 mg/kg/d ) or vehicle .
3		Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group ( P<0001 ) .
4		Next , we analyzed the gene expression profile in premetastatic liver using microarrays .
5		Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumor-bearing mice compared with non-tumor-bearing mice .
6		Moreover , CXCL1 expression was significantly decreased by TSU68 treatment .
7	Μ	CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors .
8		The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group ( P<0001 ) .
9		The amount of interleukin-12 ( IL-12 ) p40 in the portal vein was significantly decreased by TSU68 ( P = 002 ) .
10		Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis .
11		These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response , which might be an alternative mechanism used by antiangiogenic agents .

PMID: 18790474 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Axis inhibition protein 2 ( AXIN2 ) polymorphisms and tooth agenesis .
1		[ The diagnostic and predictive role of kit ( CD117 ) ] .

PMID: 17016444 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Absence of tyrosine kinase mutations in Japanese colorectal cancer patients .
1		Tyrosine kinases , which are important regulators of intracellular signal-transduction pathways , have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention .
2	Μ	Recently , systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain atleast one mutation in the tyrosine kinases .
3		To further explore these mutations , we examined all reported mutations of NTRK3 , FES , KDR , EPHA3 , NTRK2 , JAK1 , PDGFRA , EPHA7 , EPHA8 , ERBB4 , FGFR1 , MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines .
4	Μ	Unexpectedly , among 24 colorectal cancer cell lines , only two cell lines ( LoVo and CaR1 ) harbored mutation C1408T (R470C) in MLK4 gene .
5		The mutation rate was extremely low compared to that previously reported .
6	Μ	Therefore , we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients .
7		Surprisingly , none of the 46 samples contained any of the mutations reported .
8		Based on our study , we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future .

PMID: 16636668 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		High-resolution analysis of chromosome rearrangements on 8p in breast , colon and pancreatic cancer reveals a complex pattern of loss , gain and translocation .
1		The short arm of chromosome 8 , 8p , is often rearranged in carcinomas , typically showing distal loss by unbalanced translocation .
2		We analysed 8p rearrangements in 48 breast , pancreatic and colon cancer cell lines by fluorescence in situ hybridization ( FISH ) and array comparative genomic hybridization , with a tiling path of 0.2 Mb resolution over 8p12 and 1 Mb resolution over chromosome 8 .
3		Selected breast lines ( MDA-MB-134 , MDA-MB-175 , MDA-MB-361 , T-47D and ZR-75-1 ) were analysed further .
4		Most cell lines showed loss of 8p distal to a break that was between 31 Mb ( 5' to NRG1 ) and the centromere , but the translocations were accompanied by variable amplifications , deletions and inversions proximal to this break .
5		The 8p12 translocation in T-47D was flanked by an inversion of 4 Mb , with a 100 kb deletion at the proximal end .
6		The dicentric t ( 8 ; 11 ) in ZR-75-1 carries multiple rearrangements including interstitial deletions , a triplicated translocation junction between NRG1 and a fragment of 11q ( unconnected to CCND1 ) , and two separate amplifications , of FGFR1 and CCND1 .
7		We conclude that if there is a tumour suppressor gene on 8p it may be near 31 Mb , for example WRN ; but the complexity of 8p rearrangements suggests that they target various genes proximal to 31 Mb including NRG1 and the amplicon centred around ZNF703/FLJ14299 .

PMID: 15897558 (Cell)   Terms: In vivo, xenograft, in vivo
Sent#	Symbols	Sentence	Mnemonics
0		In vivo target modulation and biological activity of CHIR-258 , a multitargeted growth factor receptor kinase inhibitor , in colon cancer models .
1		PURPOSE :
2		To evaluate the therapeutic and biological effects of CHIR-258 , an orally bioavailable , potent inhibitor of class III-V receptor tyrosine kinases , in colon cancer models .
3		EXPERIMENTAL DESIGN :
4		The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models .
5		RESULTS :
6		CHIR-258 inhibits vascular endothelial growth factor receptor 1/2 , fibroblast growth factor receptor 1/3 , and platelet-derived growth factor receptor beta ( PDGFRbeta ) and shows both antitumor and antiangiogenic activities in vivo .
7		Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose -dependent inhibition of vascular endothelial growth factor receptor 1 and PDGFRbeta phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase ( ERK ) levels , indicating modulation of target receptors and downstream signaling .
8		In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions , including large , established tumors ( 500-1,000 mm(3) ) .
9		Immunohistochemical analysis showed a reduction of phosphorylated PDGFRbeta and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors .
10		These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density .
11		CHIR-258 inhibited the phosphorylation of PDGFRbeta and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours .
12		Significant antitumor activity was observed with intermittent dosing schedules , indicating a sustained biological activity .
13		CONCLUSION :
14		These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor .
15		CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies .

PMID: 15558020 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Reciprocal relationship in gene expression between FGFR1 and FGFR3 : implication for tumorigenesis .
1		Immunohistopathological and molecular genetic features of a case in which gastrointestinal stromal tumor recurred five times .

PMID: 14760097 (None)   Terms: In vivo, in vivo, mice, tumor model
Sent#	Symbols	Sentence	Mnemonics
0		In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model .
1		PURPOSE :
2		The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging ( DCE-MRI ) the antiangiogenic effect of SU6668 , an oral , small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 ( Flk-1/KDR ) , platelet-derived growth factor receptor , and fibroblast growth factor receptor 1 .
3		EXPERIMENTAL DESIGN :
4		A s .
5		c .
6		tumor model of HT29 human colon carcinoma in athymic mice was used .
7		DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume , accepted surrogate markers of tumor angiogenesis .
8		CD31 immunohistochemical staining was used for assessing microvessels density and vessels area .
9		Experiments were performed after 24 h , and 3 , 7 , and 14 days of treatment .
10		RESULTS :
11		DCE-MRI clearly detected the early effect ( after 24 h of treatment ) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core ( respectively ) .
12		A substantial decrease was also observed in average fractional plasma volume in the rim ( 59% ) and core ( 35% ) of the tumor .
13		Histological results confirmed magnetic resonance imaging findings .
14		After 3 , 7 , and 14 days of treatment , postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery ; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor .
15		Histology also revealed a strong decrease in the thickness of peripheral viable tissue , with a greatly reduced vessel count .
16		SU6668 greatly inhibited tumor growth , with 60% inhibition at 14 days of treatment .
17		CONCLUSIONS :
18		DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668 .

PMID: 11562278 (Cell)   Terms: clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Cell cycle regulation in the G1 phase : a promising target for the development of new chemotherapeutic anticancer agents .
1		As a result of substantial advances in recent cancer biology , cell cycle regulation in the G1 phase has attracted a great deal of attention as a promising target for the research and treatment of cancer .
2		Many of the important genes associated with G1 regulation have been shown to play a key role in proliferation , differentiation and oncogenic transformation and programmed cell death ( apoptosis ) .
3		Currently , a variety of "cytostatic" agents that affects G1 progression and/or G1/S transition are being evaluated in clinical trials .
4		Flavopiridol is a potent inhibitor of cyclin-dependent kinases ( CDKs ) .
5		UCN-01 was originally found to be a PKC-selective protein kinase antagonist .
6		More recent studies have revealed that this agent can also inhibit several CDKs and the checkpoint kinase CHK1 .
7		FR901228 , MS-27-275 and SAHA are histone deacetylase inhibitors that induce changes in the transcription of specific genes via the hyperacetylation of histones .
8		The proteasome inhibitor PS-341 disrupts the degradation process of intracellular proteins , including cell cycle regulatory proteins such as cyclins .
9		R115777 , SCH66336 and BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent p21 ras oncogene activation .
10		Rapamycin derivative CCI-779 downregulates signals through S6 kinase and FRAP ( FKBP-rapamycin associating protein ) , affecting the expression levels of mRNAs important for progression from G1 to S phase. 17-Allylaminogeldanamycin targets the Hsp-90 ( heat shock protein-90 ) family of cellular chaperones regulating the function of signaling proteins .
11		TNP-470 (AGM-1470) , a fumagillin derivative shows antiangiogenic action through binding to MetAP-2 ( methionine aminopeptidase-2 ) .
12		The antitumor sulfonamide E7070 , causing a cellular accumulation in the G1 phase , has been shown to suppress the activation of CDK2 and cyclin E expression in HCT116 colorectal cancer cell line highly sensitive to the drug .
13		With respect to several growth factor receptors such as EGFR , PDGFR , bFGFR and VEGFR , potent and specific inhibitors of receptor tyrosine kinases have been also examined as hopeful drug candidates .
14		In this report , we review the current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase , with particular focus on the compounds undergoing clinical investigations .

PMID: 7664263 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Expression of vascular endothelial growth factor and its receptor , KDR , correlates with vascularity , metastasis , and proliferation of human colon cancer .
1		We studied the correlation between expression of vascular endothelial growth factor ( VEGF ) , basic fibroblast growth factor ( bFGF ) , and their receptors with vascularity , metastasis , and proliferative index of human colon cancers .
2		Immunohistochemical analyses using antibodies against VEGF , bFGF , their receptors ( KDR , flt-1 , bek , and flg ) , factor VIII , and proliferating cell nuclear antigen were carried out on archival specimens of 52 human colon carcinomas and 10 adenomas .
3		Vessels were quantitated by light microscopy ( x200 ) , and the intensity of staining for VEGF and bFGF was assessed on a scale of 0-3+ .
4		The presence or absence of immunostaining for KDR , flt-1 , bek , and flg was evaluated in endothelial cells , and proliferation was determined by counting the number of proliferating cell nuclear antigen-positive cells per 500 tumor cells .
5		Expression of VEGF and KDR was higher in metastatic than in nonmetastatic neoplasms and directly correlated with the extent of neovascularization and the degree of proliferation , whereas expression of bFGF , flt-1 , bek , and flg did not differ among tumor types .
6		Vessel counts were greater in metastatic tumors than in nonmetastatic tumors .
7		These findings support the hypothesis that VEGF is an important angiogenic factor in primary and metastatic human colon cancer .
8		VEGF expression and vessel counts may aid in predicting patients at risk for metastasis from colon cancer .

PMID: 7923141 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Identification of a novel variant form of fibroblast growth factor receptor 3 ( FGFR3 IIIb ) in human colonic epithelium .
1		Although several tyrosine kinase -type growth factor receptors have been demonstrated in human colonic epithelial cells , the full spectrum of growth factor receptors has not been identified .
2		Low stringency screening of a complementary DNA library prepared from the human colon cancer-derived cell line HT-29 with a probe containing the tyrosine kinase domain of human c-src kinase led to the identification and isolation of a clone containing a receptor class tyrosine kinase .
3		This putative receptor was found to be identical to the human fibroblast growth factor receptor 3 ( FGFR3 ) except for a region of 150 nucleotides ( 50 amino acids ) encoding the presumptive ligand -binding domain , where it exhibited only 32% homology with the previously described FGFR3 .
4		The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain , suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2 .
5		By prior convention , the previously reported from of FGFR3 was designated IIIc due to its high degree of homology with the IIIc domain of FGFR1 ( 83% homology ) and the IIIc domain of FGFR2 ( 81% homology ) .
6		However , the ligand -binding domain of FGFR3 found in the HT-29 cell line was more highly divergent from all previously reported FGFR immunoglobulin-like domain IIIs than any other two members of this receptor family .
7		Therefore , we propose to designate the newly reported form as the FGFR3 IIIb variant .
8		Genomic polymerase chain reaction confirmed that the IIIb-containing exon occupies a position 5' relative to the IIIc-containing exon within the FGFR3 gene .
9		Northern blot analysis using a probe encompassing sequences unique to the FGFR3 IIIb mRNA confirmed the expression of a 4.4-kilobase transcript in two colon cancer-derived cell lines as well as normal human colonic mucosa .
10		Using a technique combining reverse transcriptase polymerase chain reaction with restriction endonuclease digestion , cell lines , primary cells , and tissues were assessed for IIIb and IIIc transcripts ; expression of the IIIb variant was associated with an epithelial lineage , while the IIIc variant was expressed predominantly in nonepithelial cells and tissues .

PMID: AACR_2012-2426 (Cell)   Terms: in vivo, mice
Sent#	Symbols	Sentence	Mnemonics
0	✓	Role of fibroblast growth factor receptor 1 ( FGFR1 ) in liver metastasis of colorectal cancer .	GE-INV-RO
1		Liver metastasis is one of the main cause of death among patients with colorectal cancer ( CRC ) .
2		However , accurate prediction of liver metastasis of CRC is difficult at the inception of diagnosis .
3		Activated receptor tyrosine kinases ( RTKs ) are the main mediators of the signaling pathway related to cell survival , proliferation , differentiation or apoptosis .
4		To determine if any of these RTKs are involved in liver metastasis from CRC , we performed phospho-receptor tyrosine kinase array with matched 20 colon normal mucosa , primary tumor , metastatic liver tumor , and liver normal tissue proteins using Human Phospho-RTK Array ( 2009 AACR , #4951 ) .
5		In RTK activation profiling , FGFR1 activation was increased in a high proportion of metastatic liver tumor ( p < 005 ) .
6		To evaluate the functional roles of FGFR1 , DLD-1 and LoVo colon cancer cells were treated with FGFR1 specific siRNA or RTK inhibitor .
7		Inhibition of FGFR1 inhibited phosphorylation of PI3K/AKT and ERK , a downstream cellular signaling molecule of FGFR ; whereas , mTOR , p70S6K , JNK and Src activities were not affected .
8		Also , we compared the cell migration and invasion ability by wound healing assay and invasion assay .
9		The invasion capacity and wound closing were significantly delayed by FGFR1 inhibition ( p <005 ) .
10		To evaluate in vivo anti-metastatic effect of FGFR1 , we used an orthotropic liver metastasis model , generated by injecting LoVo colon cancer cells into spleen of BALB/c nu/nu mice .
11		In control group , multiple large metastatic foci were evident , whereas the extent of liver metastasis was dramatically reduced in TKI-258 ( 50mg/kg/d ) treated group ( 489% , p < 005 ) .
12		Immunoexpression of the p-FGFR1 was much more intense in control than TKI-258 treated tumor tissues .
13		Biological effects were also confirmed that FGFR1 inhibition resulted in a significant reduction of ERK activation and Ki-67 positive cells in tumor tissues .
14		In conclusion , FGFR1 might be a good target for liver metastasis of CRC .

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_140519-158 (Patient)   Terms: retrospective, prospective, Clinical trial
Sent#	Symbols	Sentence	Mnemonics
0	✓	Genomic alterations to predict response to irinotecan-based chemotherapy in metastatic colorectal cancer. .	GM-REG-RO
1		Background : No evidence exists concerning the superiority of oxaliplatin versus irinotecan-based chemotherapy for metastatic colorectal cancer .
2		The choice is currently made by the clinicians according to awaited toxicity and association with targeted therapy .
3		The correlation between response to chemotherapy ( oxaliplatin and irinotecan containing regimens ) and genomic alterations was investigated in metastatic colorectal cancer patients included in the ProfiLER protocol ( NCT 02029001 ) .
4		Methods : From 03/2013 to 03/2014 , 62 patients with metastatic colorectal cancer were included in the ProfiLER trial .
5	Μ	Tumor samples were analyzed for mutations/insertions/deletions and copy number variations using target high-throughput sequencing ( NGS ) and comparative genomic hybridization array ( CGH ) .
6		Clinical data were collected retrospectively .
7		We defined irinotecan and/or oxaliplatin responders as patients having CR , PR , SD as best response and non-responders as those having PD as best response .
8		Results : 50/62 tumor samples fulfilled DNA quality requirements .
9		CGH was feasible in 40 patients ( 645% ) .
10		Among these 40 patients , 36 received oxaliplatin and irinotecan .
11	✓	None of the genomic alterations correlated to response to oxaliplatin .	GM-ASS-RO
12	Μ	Conversely , analysis of the CGH and NGS data revealed different genomic alterations of tumors in patients receiving Irinotecan , allowing the separation between Irinotecan responders ( IriR , n = 27 ) and non-responders ( IriNR , n = 9 ) ( Table ) .
13		Conclusions : Specific genomic alterations of CRC cells seem to be associated with responses to systemic combination Irinotecan based-chemotherapy , including high GI , specific chromosomal gains , and tyrosine kinases mutations .
14		A prospective validation of the CGH profile is planned and definitive results will be presented at the meeting .
15		Clinical trial information : NCT 02029001 .

PMID: ASCO_166917-176 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		PD-L1 expression correlation with TP53 gene mutation status in lung cancer but not in colorectal cancer. .
1		Background : Expression of PD-L1 is , in general , associated with response to immunotherapy .
2		However , it is believed that additional intrinsic factors play a role in determining the potential of response to immunotherapy .
3		Toward this goal we investigated the relationship between mutation profile and PD-L1 expression in lung and colorectal cancers .
4		Methods : Molecular profiling using a panel of gene 24 genes was performed by next generation sequencing ( NGS ) on 158 non-small cell lung cancer ( NSCLC ) and 42 colorectal cancers .
5		The genes studied included ERBB2 , FGFR1 , FGFR2 , FGFR3 , SRC , JAK3 , ERBB4 , ERBB2 , and SMAD4 .
6		In addition , these tumors were studied for the expression of PD-L1 using immunohistochemistry ( IHC ) .
7		PD-L1 expression was performed using standard IHC approach using SP142 clone ( Spring Biosciences ) .
8		Results : The level of PD-L1 expression was significantly ( P = 00005 ) lower in colorectal cancer as compared with NSCLC .
9		The NSCLC cohort had significantly ( P = < 00001 ) more cases with 3 or more genes mutated as compared with colorectal cancer .
10		However , there was no significant difference in TP53 mutation frequency between the two tumor types .
11		There was no correlation between PD-L1 expression and the presence or absence of 3 or more gene mutations in either NSCLC or colorectal cancer .
12		However , PD-L1 expression was significantly ( P = 001 ) higher in tumors with TP53 mutation in the NSCLC cohort , but not in the colorectal carcinoma cohort ( P = 05 ) .
13		This was true whether PD-L1 level was used as a continuous variable or if it was dichotomized at 20% ( P = 002 ) or 40% ( P = 003 ) cutoffs .
14		Conclusions : There is significant difference between NSCLC and colorectal cancers in PD-L1 expression levels .
15		More importantly , TP53 mutation in NSCLC correlates with the expression of PD-L1 protein , but not in colorectal cancer despite similar rate of mutation of the TP53 between the two tumor types .
16		This suggests a possible difference in the mechanism of regulating PD-L1 expression between the two tumor types .

PMID: ASCO_166568-176 (Patient)   Terms: clinical trial, Clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		The Nationwide Cancer Genome Screening Project in Japan , SCRUM-Japan GI-SCREEN : Efficient identification of cancer genome alterations in advanced colorectal cancer. .
1		Background : We conduct the nationwide cancer genome screening project in Japan from February 2014 .
2	Μ	Since February 2015 , we introduced Next Generation Sequencing method to detect cancer genome alterations in advanced colorectal cancer ( aCRC ) , called as SCRUM-Japan GI-SCREEN 2013-01-CRC .
3		The objective is to evaluate the frequency of cancer genome alterations in aCRC and to identify patients who are candidate for clinical trial for corresponding targeting agents .
4		Methods : This study is ongoing with the participation of 20 major cancer centers .
5		Patients with aCRC who plan to or receive systemic chemotherapy were eligible .
6	Μ	Twenty ng of DNA and 10 ng of RNA were extracted from formalin-fixed paraffin embedded ( FFPE ) tumor samples and were analyzed by the Oncomine Cancer Research Panel ( OCP ) which allows to detect gene mutation , copy number variant ( CNV ) and fusions across 143 genes in a CLIA certified CAP accredited laboratory .
7	Μ	The detected genomic variant data were classified according to whether genetic driver of cancer , including gain - and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase .
8		Results : As of October 31st in 2015 , a total of 393 aCRC patients were enrolled and 360 samples were available .
9		Out of 360 samples , 345 samples were analyzed and 15 samples are currently under analysis .
10		The sequence with the OCP was successfully performed in 257 tumors ( 745% ) .
11	Μ	The most frequently detected mutations were TP53 ( 669% ) , APC ( 564% ) , KRAS ( 389% ) , PIK3CA ( 121% ) , and BRAF ( 109% ) , and CNVs were ERBB2 ( 35% ) , FLT3 ( 23% ) , MYC ( 19% ) , and FGFR1 ( 16% ) .
12	Μ	No gene fusion was detected so far .
13		Patients with BRAF , PIK3CA or FGFR1 mutation were enrolled in early clinical trials .
14		We plan to conduct the investigator initiated studies targeting aCRC patients with ERBB2 amplification and those with BRAF non-V600E mutations .
15	Μ	Conclusions : This nationwide screening system is efficient to detect rare mutations in aCRC .
16		This novel knowledge provides an intriguing background to investigate new target approaches in these patients and represents a progress toward more precision medicine .
17		Clinical trial information : UMIN000016343 .

PMID: AACR_2013-3488 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Surveying colorectal cancer genome for clinically actionable genomic amplifications with droplet digital PCR. .
1		New cancer therapies are increasingly geared towards exploiting critical genetic and genomic features specific to the tumor .
2		These mutations and genomic aberrations are the basis for precision cancer medicine .
3		Thus , rapid molecular characterization of clinical cancer samples has become increasingly important for cancer targeted therapy development .
4		Our study addresses this need by identifying druggable gene amplifications in colorectal cancer ( CRC ) .
5		Along these lines , we developed an accurate and rapid droplet-digital PCR ( ddPCR ) assay to analyze cancer-specific copy number variations ( CNV ) in 13 genes with oncogenic function that are the targets of specific cancer therapies .
6		These genes were selected based on the availability of approved and early-phase targeted therapeutics that inhibit their oncogenic function .
7		Using TCGA data , we vetted our targets by identifying frequent CRC amplifications and a correlation with gene expression .
8		The ddPCR method involves emulsifying matched-normal cancer sample DNA that provides specific advantages for highly sensitive and specific detection of cancer CNVs .
9		Post-amplification , emulsion droplets are streamed single-file into a capillary that leads past a two-color detector , where the positive droplets for the target and reference genes are counted for quantitation .
10		This technology requires nanogram amounts of genomic DNA , thus facilitating the study of clinical cancer samples from small biopsies .
11		It works well with genomic DNA extracted from formalin fixed paraffin embedded tumor samples .
12	Μ	Furthermore , we demonstrated high sensitivity for detecting copy number amplifications even in samples containing a prominent fraction of normal tissue .
13		We are extending our analysis to the full 13 druggable gene targets and evaluating patterns of mutual exclusivity and co-occurrence among a cohort of over 200 CRC tumors with information on clinical outcome .
14	Μ	For example , we have demonstrated FGFR1 amplifications in 5.2% of our CRC tumor population .
15	Μ	For ERBB2 variations in the same cohort , we detected amplifications in 3.6% of our population .
16		ERBB2 and FGFR1 amplification events displayed a mutually exclusive pattern of segregation ( p value <00001 per Chi-squared test with Yates correction ) .
17		This efficient and inexpensive assay offers a significant potential to extend personalized therapeutic options available to CRC patients .

PMID: AACR_2016-647 (Patient)   Terms: xenograft, PDX, mouse models, mouse
Sent#	Symbols	Sentence	Mnemonics
0		In situ detection of human and mouse species-specific molecules in patient derived xenograft mouse models .
1		Patient derived xenograft ( PDX ) mouse models are widely used in targeted cancer therapy study and cancer drug development .
2		With human cancer tissues embedded into mouse microenvironment , both human and mouse derived molecules contribute to the proliferation and invasion of the implanted tumor cells .
3		In order to explore the working mechanisms of targeted therapy and evaluate its anti-cancer effects , it is important to uncover the expression and spatial relation of targeted molecules in situ .
4		Although profiling methods such as microarray and RNAseq can address the origin of relevant gene transcripts , they lose tissue spatial and cell morphology information by using tissue lysates .
5		Immunohistochemistry ( IHC ) can preserve tissue and cell morphology information , however good antibodies are not readily available for every target molecule .
6	Μ	In addition , IHC cannot detect long non-coding RNA targets .
7		It is therefore crucial to find a broadly applicable method to separately detect human and mouse derived genes in PDX tissue samples .
8		Species-specific probes targeting on seven cancer related genes , EGFR , ERBB2 , FGFR1 , FGFR2 , FGFR4 , PECAM1 and TGFB1 , were designed for RNAscope in situ hybridization assays .
9		The assays were performed in colorectal cancer ( CRC ) PDX sections and liver cancer PDX TMAs .
10		The RNA expression results were categorized into 5 grades according to manufacturer's scoring guidelines .
11		Probe species-specificity of human probes and mouse probes was tested in human colon cancers and mouse colons .
12		Both tissues passed quality control by hybridizions with probe-Hs-PPIB/probe-Mm-Ppib and probe-dapB .
13		All human species-specific probes produced negative results in mouse colons , whereas mouse species-specific probes generated signals for Egfr , Erbb2 , Fgfr2 , Pecam1 and Tgfb1 ( score 2 or more than 2 ) in mouse colons .
14		No mouse species-specific probe signals were observed in human colon cancers .
15		In CRC PDX sections , human species-specific probes detected signals of ERBB2 and FGFR4 ( score 3 ) in colorectal tumor cells whereas mouse species-specific probes detected signals for Fgfr1 , Pecam1 and Tgfb1 ( score 2 or more than 2 ) in stroma areas .
16		In liver cancer PDX TMAs , human EGFR , ERBB2 , FGFR1 , FGFR2 , FGFR4 and TGFB1 ( score 2 or more than 2 ) were identified by species-specific probes in liver cancer cells ; mouse Egfr , Fgfr1 , Pecam1 and Tgfb1 signals ( score 2 or more than 2 ) were observed in the stroma regions .
17		RNAscope duplex assays identified both human FGFR1 and mouse Fgfr1 probe signals in the same sections with different colors .
18		RNAscope technology using species-specific probes can detect in situ human and mouse genes , respectively , which provides a powerful method to uncover the location of targeted cancer therapy related genes , their expression levels and the spatial correlation of positive cells with surrounding cells .
19		This method will facilitate targeted therapy studies and cancer drug development in PDX mouse models .

PMID: ASCO_190873-199 (None)   Terms: retrospective
Sent#	Symbols	Sentence	Mnemonics
0		Genomic profiling of young adults with colorectal cancer : A single-institution experience. .
1		Background : 2-8% of all colorectal cancer ( CRC ) cases are in younger adults ( YAs ) , patients ( pts ) less than age 50 .
2		However , current understanding of CRC in YAs is inadequate , especially that of sporadic onset .
3		We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice .
4		Methods : Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing ( NGS ) through a customized 22 - gene Ion AmpliSeq Mutation Panel as part of clinical care .
5		Commonly mutated areas of select genes ( including AKT1 , ALK , BRAF , EGFR , ERBB2/4 , FBXW7 , FGFR1/2/3 , KRAS/NRAS , MET , NOTCH1 , PIK3CA , PTEN , TP53 ) were sequenced from tumor sections .
6		Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016 .
7		Results : 258 CRC pts underwent genomic profiling. 57 pts ( 221% ) were YAs at diagnosis ( range 22-49 years ) ; 20 pts ( 78% ) were 40 years old or younger. 31 YA pts ( 544% ) had metastatic disease .
8	Μ	Of the YAs with CRC , 18 pts ( 316% ) were diagnosed with R-sided colon , 16 pts ( 281% ) with L-sided colon , and 22 pts ( 386% ) with rectal cancer. 110 genomic alterations were found in YA pts , with a mean of 1.9 mutations per tumor ( range 0-6 ) ; 35 ( 318% ) of these in 32 ( 561% ) YA pts were actionable .
9		Of these 110 alterations , 41.8% were in TP53 , 28.2% in KRAS/NRAS , 10.0% in PIK3CA , 3.6% in BRAF , 3.6% in FBXW7 , and 2.73% in PTEN. 6 YA pts ( 105% ) had microsatellite instability ( MSI-H ) .
10		Only 1 pt had concomitant MSI-H and a BRAF mutation ; 4 pts with BRAF mutations were microsatellite stable .
11		Comparing our YA pts to a separate cohort of pts age > 50 who had testing done , no significant difference was seen in mutation incidence in KRAS/NRAS ( p = 10 ) , TP53 ( p = 03 ) , PIK3CA ( p = 0128 ) , or BRAF ( p = 10 ) .
12		Conclusions : Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice .
13		There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts .
14		Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts , and could impact future care of this cohort .

PMID: AACR_2016-880 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Mapping the metastatic colorectal cancer phospho-proteome for predicting response to cetuximab .
1		Metastatic malignant melanoma or stage IV melanoma is the most deadly skin cancer , claiming an estimated 10,000 deaths every year .
2		The occurrence of metastatic malignant melanoma to the breast and ovary is uncommon , and can represent a challenge for the diagnosis and clinical management .
3		We investigated and correlated the morphologic , immunohistochemical and molecular aspects of these tumors .

PMID: AACR_2014-5267 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Pro-inflammatory CXCL8 signaling potentiates survival of K-Ras mutant colorectal cancer cells .
1		Background : Pro-inflammatory signaling within the tumor microenvironment is proposed to aid tumor progression and metastasis in a number of cancer types , including colorectal cancer ( CRC ) .
2		The pro-inflammatory chemokine , CXCL8 (interleukin-8) has been associated with tumor size , Dukes stage , liver metastasis and overall survival in CRC .
3		This chemokine is expressed by multiple cell types within the tumor microenvironment including tumor cells , innate immune , and vascular endothelial cells .
4		Additionally , the elevated expression of both CXCL8 receptors , CXCR1 and CXCR2 , in CRC tumor epithelium relative to normal adjacent tissue indicates that CRC is receptive to both an autocrine tumor-derived stimulus and a paracrine stromal-derived stimulus .
5		Objectives : Our first objective was to characterise how mutation of the oncogene K-Ras may regulate CXCL8 expression and signaling in CRC cells in vitro .
6		Secondly , we sought to characterise the importance of CXCL8 in modulating survival of K-Ras mutant CRC cells .
7		Results : Mutation of K-Ras or the catalytic subunit of phosphatidyl-inositol-3 kinase ( PI3KCA ) is indicated in 35-40% and 15-18% of colorectal adenocarcinomas , respectively .
8		The HCT-116 cell line harbours mutations in both K-Ras and PI3KCA .
9		Basal CXCL8 , CXCL1 and CXCR1/2 levels were significantly elevated in K-Ras mutant HCT-116 cells relative to isogenic HKH-2 K-Ras wild-type cells .
10		Treatment with inhibitors of AKT and/or MEK attenuated CXCL8 transcript levels and secretion in K-Ras mutant cells , but conversely increased CXCR1/2 gene expression .
11	Μ	Attenuation of CXCL8 gene expression using siRNA demonstrated a concurrent loss of cell viability in CRC cells ; this effect was significantly marked in K-Ras mutant HCT-116 cells , consistent with increased dependence of these cells on elevated CXCL8 signaling .
12		Moreover , attenuation of CXCR2 signaling potentiated the sensitivity of K-Ras mutant HCT-116 cells to oxaliplatin and 5-FU .
13		In addressing mechanisms underpinning CXCL8-promoted resistance , treatment with recombinant human CXCL8 was shown to increase expression of anti-apoptotic proteins Bcl-XL and Bcl-2 and furthermore , induce phosphorylation of multiple tyrosine kinases (RTKs) including EGFR , c-MET and FGFR1 .
14		Furthermore , blockade of CXCR2 signaling attenuated oxaliplatin-induced increases in anti-apoptotic protein expression in HCT-116 cells .
15		Conclusions : CXCL8 signaling is elevated in K-Ras and PI3KCA mutant cancers .
16		The up-regulation of autocrine CXCL8 signaling is linked to the promotion of cell survival , principally mediated through the inhibition of apoptosis and promotion of RTK signaling .
17		The clinical relevance of CXCL8 signaling in modulating outcome of K-Ras mutant CRC to current treatments remains to be determined .
18		However , CXCL8 -directed therapies may be relevant as chemo-sensitizing agents in K-Ras and/or PIK3CA mutant tumors .

PMID: ASCO_35000-65 (None)   Terms: phase I study
Sent#	Symbols	Sentence	Mnemonics
0		A phase I study of XL228 , a potent IGF1R/AURORA/SRC inhibitor , in patients with solid tumors or hematologic malignancies. .
1		Background : XL228 is a protein kinase inhibitor targeting IGF1R , the AURORA kinases , FGFR1-3 , ABL and SRC family kinases .
2		It is being evaluated in a phase 1 trial in patients ( pts ) with advanced malignancies .
3		Methods : XL228 is administered as weekly 1-hour IV infusions .
4		Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose , pharmacokinetics , and pharmacodynamic effects using FDG-PET , signal pathway analysis in tumor and normal tissue biopsies , and plasma marker analysis .
5		MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer .
6		Results : Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg .
7		The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade ( Gr ) 4 neutropenia , and Gr 3 neutropenia requiring dose skipping .
8		XL228 is generally well tolerated ; one serious adverse event of drug -related Gr 3 vomiting has been observed .
9		Common drug -related adverse events include Gr 1 nausea , fatigue , decreased appetite , and flushing , and Grade 1-2 hyperglycemia ( fasting ) lasting up to 4 hours post - infusion .
10		XL228 exposure was approximately dose-proportional ; the mean terminal half-life ( t1/2 , z ) ranged from 27 to 54 hours .
11	Μ	Low accumulation was observed after weekly administration .
12		Protein phosphorylation measurements in skin , hair , and blood samples demonstrate inhibition of IGF1R , SRC and FGFR1 signaling by XL228 , including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42% , respectively , in a pt dosed at 5.4mg/kg .
13		Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response ( confirmation pending ) and 9 additional pts ( of 30 evaluable ) with stable disease ( SD ) lasting >3 months , including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide .
14		For pts with SD , the median time on study is currently 5.9 months ( range 33+ to 133+ ) .
15		Conclusions : XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity .

PMID: AACR_2013-905 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Design and synthesis of regorafenib analogues against signal transducers and activators of transcription 3 in hepatocellular carcinoma cells. .
1		Background : Regorafenib has been approved for the treatment of metastatic colorectal cancer ( m-RCC ) by FDA .
2		The major targets of regorafenib are membrane-bound and intracellular kinases including RET , VEGFR1 , VEGFR2 , VEGFR3 , KIT , PDGFR-alpha , PDGFR-beta , FGFR1 , FGFR2 , TIE2 , DDR2 , Trk2A , Eph2A , RAF-1 , BRAF , BRAFV600E , SAPK2 , PTK5 , and Abl pathways .
3		In HCC , signal transducers and activators of transcription 3 ( STAT3 ) is a key transcription factor involving in cell proliferation and survival in hepatocellular carcinoma cells , Targeting STAT3 by small molecule is a promising strategy in HCC therapy .
4		Methods : We have designed and synthesized a series of regorafenib analogues without kinase inhibitory activity .
5		These compounds are treated with and analyzed in terms of STAT3 activity in HCC cell lines .
6		Also , Effects of regorafenib analogues induced cell death are evaluated .
7		Results : We demonstrate that regorafenib and its analogues repress STAT3 phosphorylation , subsequently abrogate STAT3 -regulated protein , Mcl-1 and cyclin D1 and further induce apoptosis in HCC cells .
8		Overexpression of STAT3 in PLC-5 cells attenuates apoptotic effect with regorafenib and its analogues treatment , suggesting STAT3 , atleast , is a major target .
9		Interestingly , the new analugues of regorafenib are devoid of kinase inhibitory activity which implies the involvement of other regulation factors .
10		The activity of negative regulator of STAT3 , such as protein tyrosine phosphatases , is under investigation .
11		In summary , the new analogues provide a lead for the design of a new class of agents that inhibit STAT3 along and synergize with clinical drugs in HCC .

PMID: ASCO_133879-144 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Molecular evaluation of primary tumor ( PT ) and synchronous liver metastasis in colorectal cancer ( srLmCRC ) patients after cetuximab-based chemotherapy. .
1		Background : Molecular heterogeneity among PT and LmCRC is not yet defined .
2		Next Generation Sequencing ( NGS ) in clinical practice could increase the change of identifying multiple molecular driver alterations calling for therapy .
3		This study evaluates mutations in PT and sLmCRC exon2 KRAS wt patients who underwent chemotherapy ( CT ) containing cetuximab .
4		Methods : Genomic analysis was conducted in 7 sLmCRC pts : before CT on a PT biopsy , after CT on a PT surgical specimen and all srLmCRC .
5		A total of 54 lesions were examined .
6		DNA libraries were generated using the Ion AmpliSeq Colon and Lung Cancer Panel including 22 mutated genes ( KRAS , EGFR , BRAF , PIK3CA , AKT1 , ERBB2 , PTEN , NRAS , STK11 , MAP2K1 , ALK , DDR2 , CTNNB1 , MET , TP53 , SMAD4 , FBXW7 , FGFR3 , NOTCH1 , ERBB4 , FGFR1 , FGFR2 ) and sequenced on a Ion PGM system Results : A partial response was achieved in all pts , with a median PFS of 11 months ( 4-15 ) .
7		Molecular analysis of genes correlated with target therapy is shown in the following table ( K = KRAS ; N = NRAS ; P = PIK3AC ; M = MET ; m= - ; wt= + ) .
8		Pt 1 showed heterogeneity in PT before and after CT with KRASm clonal selection and related expression of the mucinous pattern ; in srLmCRC : 5/9 KRASm exon2 , 1/9 PIK3CAm exon20 , 2/9 KRASm exon2 and PIK3CA exon20 .
9		In pt 7 NRASm exon2 was identified in PT before and after CT ; differences in srLmCRC : 3/5 no mutation , 1/5 NRASm exon2 , 1/5 PIK3CAm exon20 .
10	Μ	The other cases showed rare mutations : SMAD4 ( pt 2 ) , TP53 ( pts 2,5,6,7 ) , FBXW7 ( pt1 ) .

PMID: AACR_2017-4380 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Integrative genomics analysis of metastatic colorectal cancer. .
1		We performed an integrated clinical and bioinformatic analysis of colorectal cancers ( CRCs ) genotyped at our institution from 4/2014-7/2016 to comprehensively characterize genomic alterations in metastatic CRC ( mCRC ) .
2		We analyzed 1008 samples ( 474 primaries , 534 metastases ) from 985 mCRC patients and 128 early stage CRCs sequenced with MSK-IMPACT , a hybridization capture next generation sequencing assay .
3		Metastatic CRCs were divided into 3 groups by mutation burden and MSIsensor algorithm score : microsatellite stable ( MSS ) ( n = 939 ; 95% ) , microsatellite-high ( MSI-H ) ( n = 41 ; 4% ) , and ultra-mutated ( n = 5 ; 1% ) .
4		Early stage CRC were enriched for MSI-H due to clinical selection and were 53% MSS , 44% MSI-H , and 4% ultra-mutated .
5	Μ	Ultra-mutated tumors exhibited >100 mutations and harbored hotspot mutations in POLE in 8 cases and a potential novel POLE alteration in 1 case .

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_158961-173 (Patient)   Terms: Phase II study
Sent#	Symbols	Sentence	Mnemonics
0		Phase II study of dovitinib in patients ( Pts ) progressing on anti-vascular endothelial growth factor ( VEGF ) therapy. .
1		Background : Prior work identified the fibroblast growth factor ( FGF ) pathway as a mediator of resistance to anti-VEGF therapy .
2		We tested dovitinib , an oral inhibitor of both FGFRs and VEGFRs in pts progressing on anti-VEGF treatment .
3		Methods : Pts with measurable advanced colorectal cancer ( CRC ) or non-small cell lung cancer ( NSCLC ) with progression despite treatment with an anti-VEGF agent within 56 days , good performance status ( PS ) and adequate organ function were eligible .
4		A pre-treatment tumor biopsy was followed by treatment with dovitinib 500 mg on a 5 day on / 2 day off schedule for 28-day cycles .
5		The primary endpoint of response ( RECIST 11 ) was evaluated every 2 cycles .
6		Secondary endpoints included toxicity and the disease control rate at 8 weeks .
7		Intratumor mRNA expression was analyzed using a Next Generation Sequencing based expression array and circulating angiogenic factors analyzed by a multiplex bead-based assays and ELISAs .
8		Results : Ten pts ( 9 CRC , 1 NSCLC ) treated previously with bevacizumab (8) or ziv-aflibercept (2) enrolled .
9		The study closed with termination of dovitinib development .
10		No responses were observed in 7 evaluable pts ; 3 withdrew consent during cycle 1 .
11		The best response was stable disease in 1 patient .
12		Common toxicities included gastrointestinal , metabolic , and biochemical derangements .
13		All pts experienced atleast 1 grade 3 or higher treatment-related adverse event , most commonly fatigue , elevated GGT , and lymphopenia .
14		Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA .
15		Dovitinib modulated circulating VEGF pathway components ; however , no hyperphosphatemia was observed and plasma FGF2 increased continuously .
16		Conclusions : We found no evidence for the activity of dovitinib in pts with CRC progressing on anti-VEGF therapy and could not confirm potent FGFR inhibition .
17		Toxicities were significant .
18		In tumors progressing despite anti-VEGF therapy , a multitude of pro-angiogenic mediators are expressed , including members of the FGF pathway .

PMID: ASCO_151523-156 (None)   Terms: clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Measuring the impact of Next Generation Sequencing ( NGS ) technique implementation in metastatic colorectal cancer ( mCRC ) drug development program. .
1		Background : Molecular screening and biomarker enrichment strategies in mCRC trials may impact patient ( pt ) s outcome .
2		The introduction of NGS technologies in clinical investigation may enhance pt inclusion through the discovery of a wider set of mutations ( mt ) in oncogenes and tumor suppressor genes .
3		Methods : From March/2012 to December/2014 411 pts with chemorefractory mCRC underwent genetic tumor profiling as part of the molecular enhancement strategy in our early drug development program .
4		Base extension chemistry followed by mass detection ( MassARRAY , Sequenom ) ( SQ ) was used including 268 frequent hotspots in 25 oncogenes with a sensitivity of 10% of mutant alleles .
5		Since June/2014 , Amplicon sequencing ( NGS ) was implemented assessing mt in 59 oncogenes and tumor suppressors with a sensitivity of 3% mutant alleles .
6		Results : From March/2012 to Jun/2014 324 pts were screened using SQ , 261 mt were detected : 0.80 mt per patient .
7		A total of 117 pts ( 36% ) resulted wild-type ( wt ) after the test .
8		Frequency of mt were : 48.77% KRAS , 16.67% PI3KCA , 7.41% NRAS , 7.41% BRAF , along with minor events : 2 mt in AKT1 and 1 mt in PDGFRA , GNAS and ERBB2 allowing a total of 89 inclusions on matched targeted therapies ( 2747% inclusion rate per total samples ) .
9		From Jun/2014 to Dec/2014 78 pts were screened with NGS , 5 pts ( 6% ) were wt .
10		A total of 160 mt were detected ( 183 mt per patient ) : 44.83% KRAS , 4.6% NRAS , 51.72% TP53 , 43.68% APC , 5.75% BRAF , 5% PI3KCA , 4.6% SMAD4 , 3.45% PTEN and 1mt in GNAS , AKT2 , MET , STK11 , FBXW7 , JAK3 , FGFR1 , NOTCH1 , MSH6 , RNF43 , RET and NF2 providing 21 inclusions to treatment with targeted therapy ( 264% inclusions per total samples ) .
11		Conclusions : Our results show that NGS techniques allow the identification of a wider spectrum of mts per patient compared to prior generation genomic tests , although this has failed to be translated yet into higher inclusion rates in clinical trials with targeted agents .
12		An enhanced discovery of mutations in tumor suppressor genes , thus far out of therapeutic reach and other factors like recent implementation of NGS and the increasing search for more specific molecular populations can contribute to this fact .

PMID: ASCO_183877-199 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Clinical and genomic alterations features of patients with advanced colitis associated cancers ( CAC ) . .
1		Background : CAC are a catastrophic complication of inflammatory bowel disease .
2		The spectrum of genomic alterations ( GA ) in CAC is different than that of sporadic colorectal cancer ( CRC ) ( Yaeger et al . PMID 27063727 ) .
3		While the prognosis for CAC patients ( pts ) may be worse than that of sporadic CRC pts , there is little data regarding outcome for metastatic CAC pts treated with standard chemotherapy regimens .
4		We reviewed demographic features and clinical outcome for pts with metastatic CAC in the context of somatic tumor GA .
5		Methods : We identified small and large bowel CAC cases seen at Memorial Sloan Kettering between 2003 and 2015 with tissue available for study .
6		Hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes was used to comprehensively characterize GA .
7		The electronic medical record of each patient was reviewed .
8		Demographic and clinical data was extracted and outcome reviewed in the context of somatic tumor GA .
9		Results : Clinical features for 17 pts with metastatic CAC are shown below .
10		All pts with initial stage III CAC received FOLFOX adjuvant therapy .
11		First - line treatment for metastatic disease included FOLFOX/FOLFIRINOX/FU-LV in 10 previously untreated pts and FOLFIRI after adjuvant therapy .
12		Median duration of survival from time of metastatic disease was 14.8 months , ( 95% CI 57-243 ; range 2-68+ months ) , substantially less than that expected for pts with Stage IV CRC .
13		Only 4 patients survived for > 24 months .
14	Μ	GA were identified in TP53 ( 87% ) and KRAS ( 33% ) ; potentially targetable alterations were found in 8 pts ( IDH1 (1) , EML4-ALK(1) , ERBB2 (1) ; FGFR1/2 (3) ; BRAF (1) ; PIK3CA(1) .
15		2 pts received a targeted agent based on GA ; 1 partial response to a FGFR inhibitor is ongoing .
16		No patient had a hyper-mutated tumor .
17		Conclusions : Metastatic CAC pts have an exceedingly poor prognosis , with survival well below that expected for sporadic CRC .
18	✓	BRAF mutations associated with poor outcome in sporadic CRC are rare in CAC. 47% of CAC pts had potentially targetable GA .	GM-ASS-RO