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| PMID: 27900363 (None) Terms: |
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| 0 | Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification . | ||
| 1 | Identification of the tissue of origin in cancer of unknown primary ( CUP ) poses a diagnostic challenge and is critical for directing site -specific therapy . | ||
| 2 | Currently , clinical decision-making in patients with CUP primarily relies on histopathology and clinical features . | ||
| 3 | Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and , most importantly , guide CUP therapy through identification of actionable lesions . | ||
| 4 | We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft - tissue sarcoma that did not respond to multiagent chemotherapy . | ||
| 5 | Μ | Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous , highly amplified KRAS G12S mutation , compound -heterozygous TP53 mutation/deletion , high mutational load , and focal high-level amplification of Chromosomes 9p ( including PDL1 [CD274] and JAK2 ) and 10p ( including GATA3 ) . | |
| 6 | Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor ( ICI ) therapy with pembrolizumab , which resulted in rapid clinical improvement and a lasting partial remission . | ||
| 7 | Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma . | ||
| 8 | Although neither histopathology nor molecular data were able to pinpoint the tissue of origin , our analyses established several differential diagnoses including triple-negative breast cancer ( TNBC ) . | ||
| 9 | We analyzed 157 TNBC samples from The Cancer Genome Atlas , revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases . | ||
| 10 | |
Collectively , these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype , show the predictive potential of PDL1 amplification for immune checkpoint inhibitors ( ICIs ) , and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers . |
| PMID: 26182302 (Patient) Terms: |
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| 0 | Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site : New Routes to Targeted Therapies . | ||
| 1 | IMPORTANCE : | ||
| 2 | For carcinoma of unknown primary site ( CUP ) , determining the primary tumor site may be uninformative and often does not improve outcome . | ||
| 3 | OBJECTIVE : | ||
| 4 | To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice . | ||
| 5 | DESIGN , SETTING , AND PARTICIPANTS : | ||
| 6 | Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens ( mean , 756x coverage ) using the hybrid-capture-based FoundationOne assay at academic and community oncology clinics . | ||
| 7 | MAIN OUTCOMES AND MEASURES : | ||
| 8 | Presence of targetable genomic alterations ( GAs ) in CUP and responses to targeted therapies . | ||
| 9 | RESULTS : | ||
| 10 | There were 125 adenocarcinomas of unknown primary site ( ACUPs ) and 75 carcinomas of unknown primary site without features of adenocarcinoma ( non-ACUPs ) . | ||
| 11 | At least 1 GA was found in 192 ( 96% ) of CUP specimens , with a mean ( SD ) of 4.2 ( 28 ) GAs per tumor . | ||
| 12 | The most frequent GAs were in TP53 ( 110 [55%] ) , KRAS ( 40 [20%] ) , CDKN2A ( 37 [19%] ) , MYC ( 23 [12%] ) , ARID1A ( 21 [11%] ) , MCL1 ( 19 [10%] ) , PIK3CA ( 17 [9%] ) , ERBB2 ( 16 [8%] ) , PTEN ( 14 [7%] ) , EGFR ( 12 [6%] ) , SMAD4 ( 13 [7%] ) , STK11 ( 13 [7%] ) , SMARCA4 ( 12 [6%] ) , RB1 ( 12 [6%] ) , RICTOR ( 12 [6%] ) , MLL2 ( 12 [6%] ) , BRAF ( 11 [6%] ) , and BRCA2 ( 11 [6%] ) . | ||
| 13 | One or more potentially targetable GAs were identified in 169 of 200 ( 85% ) CUP specimens . | ||
| 14 | Mutations or amplifications of ERBB2 were more frequent in ACUPs ( 13 [10%] ) than in non-ACUPs ( 3 [4%] ) . | ||
| 15 | Alterations of EGFR ( 10 [8%] versus 2 [3%] ) and BRAF ( 8 [6%] versus 3 [4%] ) were more common in ACUPs than in non-ACUPs . | ||
| 16 | Strikingly , clinically relevant alterations in the receptor tyrosine kinase ( RTK ) /Ras signaling pathway including alterations in ALK , ARAF , BRAF , EGFR , FGFR1 , FGFR2 , KIT , KRAS , MAP2K1 , MET , NF1 , NF2 , NRAS , RAF1 , RET , and ROS1 were found in 90 ( 72% ) ACUPs but in only 29 ( 39% ) non-ACUPs ( P <001 ) . | ||
| 17 | CONCLUSIONS AND RELEVANCE : | ||
| 18 | |
Almost all CUP samples harbored atleast 1 clinically relevant GA with potential to influence and personalize therapy . | |
| 19 | The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase ( MAPK ) signaling pathway than the non-ACUP tumors . | ||
| 20 | Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP . |
| PMID: 28455965 (Patient) Terms: |
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| 0 | Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype . | ||
| 1 | Individualizing adjuvant chemotherapy is important in patients with advanced colorectal cancers ( CRCs ) , and the ability to identify molecular subtypes predictive of good prognosis for stage III CRCs after adjuvant chemotherapy could be highly beneficial . | ||
| 2 | We performed microarray-based gene expression analysis on 101 fresh-frozen primary samples from patients with stage III CRCs treated with FOLFOX adjuvant chemotherapy and 35 matched non-neoplastic mucosal tissues . | ||
| 3 | CRC samples were classified into four molecular subtypes using nonnegative matrix factorization , and for comparison , we also grouped CRC samples using the proposed consensus molecular subtypes ( CMSs ) . | ||
| 4 | Of the 101 cases , 80 were classified into a CMS group , which shows a 79% correlation between the CMS classification and our four molecular subtypes . | ||
| 5 | We found that two of our subtypes showed significantly higher disease-free survival and overall survival than the others . | ||
| 6 | Μ | Group 2 , in particular , which showed no disease recurrence or death , was characterized by high microsatellite instability ( MSI-H , 6/21 ) , abundant mucin production ( 12/21 ) , and right-sided location ( 12/21 ) ; this group strongly correlated with CMS1 ( microsatellite instability immune type ) . | |
| 7 | We further identified the molecular characteristics of each group and selected 10 potential biomarker genes from each . | ||
| 8 | When these were compared to the previously reported molecular classifier genes , we found that 31 out of 40 selected genes were matched with those previously reported . | ||
| 9 | |
Our findings indicate that molecular classification can reveal specific molecular subtypes correlating with clinicopathologic features of CRCs and can have predictive value for the prognosis for stage III CRCs with FOLFOX adjuvant chemotherapy . |
| PMID: 28453697 (None) Terms: retrospective, clinical trial, observational studies |
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| 0 | Prediction of overall survival in stage II and III colon cancer beyond TNM system : a retrospective , pooled biomarker study . | ||
| 1 | Background : TNM staging alone does not accurately predict outcome in colon cancer ( CC ) patients who may be eligible for adjuvant chemotherapy . | ||
| 2 | It is unknown to what extent the molecular markers microsatellite instability ( MSI ) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation . | ||
| 3 | Patients and methods : After imputation of missing at random data , a subset of patients accrued in phase 3 trials with adjuvant chemotherapy ( n = 3016 ) -N0147 ( NCT00079274 ) and PETACC3 (NCT00026273) -was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples ( n = 1499 ) , and also externally in different population cohorts of chemotherapy-treated ( n = 949 ) or -untreated ( n = 1080 ) CC patients , and an additional series without treatment annotation ( n = 782 ) . | ||
| 4 | Results : TNM staging , MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies . | ||
| 5 | Concordance indices increased from 0.61-0.68 in the TNM alone model to 0.63-0.71 in models with added molecular markers , 0.65-0.73 with clinicopathological features and 0.66-0.74 with all covariates . | ||
| 6 | In validation cohorts with complete annotation , the integrated time -dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features , with or without molecular markers . | ||
| 7 | |
In patient cohorts that received adjuvant chemotherapy , the relative proportion of variance explained ( R2 ) by TNM , clinicopathological features and molecular markers was on an average 65% , 25% and 10% , respectively . | |
| 8 | |
Conclusions : Incorporation of MSI , BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients , but only modestly increases prediction accuracy in multivariable models that include clinicopathological features , particularly in chemotherapy-treated patients . |
| PMID: 28341242 (None) Terms: |
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| 0 | Adjuvant Chemotherapy for Stage II and III Colon Cancer Following Complete Resection : A Cancer Care Ontario Systematic Review . | ||
| 1 | The objective of this systematic review was to provide current evidence regarding the use of adjuvant systemic chemotherapy for stage II and III colon cancer following curative intent surgery . | ||
| 2 | MEDLINE and EMBASE databases and proceedings of American Society for Clinical Oncology and European Society of Medical Oncology/European Cancer Congress were searched through to August 2015 . | ||
| 3 | Systematic reviews ( with or without meta-analyses ) and randomised controlled trials were included . | ||
| 4 | Patients with completely resected stage III colon cancer have an overall survival benefit from adjuvant chemotherapy . | ||
| 5 | Combination chemotherapy ( 5-fluorouracil/leucovorin/oxaliplatin or capecitabine/oxaliplatin ) provides a larger benefit than monotherapy but with additional toxicity . | ||
| 6 | For stage II colon cancer , a clear overall survival benefit has not been shown . | ||
| 7 | |
However , based on the subgroup analysis available , patients with high-risk stage II disease may benefit from adjuvant chemotherapy . | |
| 8 | |
Patients younger than 70 years of age may derive greater disease-free survival and overall survival benefit from adjuvant chemotherapy ( in combination with oxaliplatin ) compared with those older than 70 years . | |
| 9 | |
Stage II patients with microsatellite instability may have an overall survival detriment if given adjuvant chemotherapy . |
| PMID: 28327908 (Patient) Terms: prospective, Clinical trial, NCT00003835 |
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| 0 | Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 ( Alliance ) . | ||
| 1 | Background : Observational studies suggest that higher levels of 25-hydroxyvitamin D3 ( 25 ( OH ) D ) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients . | ||
| 2 | However , the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown . | ||
| 3 | Patients and methods : We prospectively examined the influence of post-diagnosis predicted plasma 25 ( OH ) D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial ( CALGB 89803 ) . | ||
| 4 | Predicted 25 ( OH ) D scores were computed using validated regression models . | ||
| 5 | We examined the influence of predicted 25 ( OH ) D scores on cancer recurrence and mortality ( disease-free survival ; DFS ) using Cox proportional hazards . | ||
| 6 | Results : Patients in the highest quintile of predicted 25 ( OH ) D score had an adjusted hazard ratio ( HR ) for colon cancer recurrence or mortality ( DFS ) of 0.62 ( 95% confidence interval [CI] , 0.44-0.86 ) , compared with those in the lowest quintile ( Ptrend = 0005 ) . | ||
| 7 | Higher predicted 25 ( OH ) D score was also associated with a significant improvement in recurrence-free survival and overall survival ( Ptrend = 001 and 00004 , respectively ) . | ||
| 8 | The benefit associated with higher predicted 25 ( OH ) D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics , including microsatellite instability and KRAS , BRAF , PIK3CA , and TP53 mutation status . | ||
| 9 | Conclusion : Higher predicted 25 ( OH ) D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival . | ||
| 10 | Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted . | ||
| 11 | ClinicalTrials . | ||
| 12 | gov Identifier : NCT00003835 . |
| PMID: 17372901 (Patient) Terms: In vitro |
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| 0 | L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition . | ||
| 1 | Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas , but their incidence appears to be dependent to ultraviolet light exposure . | ||
| 2 | Thus , BRAF mutations have the highest incidence in non-chronic sun damaged ( CSD ) , and are uncommon in acral , mucosal and CSD melanomas . | ||
| 3 | More recently , activating KIT mutations have been described in rare cases of metastatic melanoma , without further reference to their clinical phenotypes . | ||
| 4 | This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions . | ||
| 5 | In this study , we investigated a group of anal melanomas for the presence of BRAF , NRAS , KIT and PDGFRA mutations . | ||
| 6 | Μ | A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested . | |
| 7 | The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein . | ||
| 8 | Μ | No KIT mutations were identified in tumors with less than 4+ KIT immunostaining . | |
| 9 | Μ | NRAS mutation was identified in one tumor . | |
| 10 | Μ | No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas . | |
| 11 | ✓ | In vitro drug testing of stable transformant Ba/F3 KIT (L576P) mutant cells showed sensitivity for dasatinib ( previously known as BMS-354825 ) , a dual SRC/ABL kinase inhibitor , and imatinib . | GM-ASS-SR |
| 12 | ✓ | However , compared to an imatinib-sensitive KIT mutant , dasatinib was potent at lower doses than imatinib in the KIT (L576P) mutant . | RO-ASS-GM |
| 13 | |
These results suggest that a subset of anal melanomas show activating KIT mutations , which are susceptible for therapy with specific kinase inhibitors . |
| PMID: 26546509 (Patient) Terms: |
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| 0 | A case series of anal melanoma including the results of treatment with imatinib in selected patients . | ||
| 1 | AIM : | ||
| 2 | Anal melanoma is a rare malignancy with a poor prognosis . | ||
| 3 | METHOD : | ||
| 4 | All patients with a diagnosis of anal melanoma treated at a single institution between 2000 and 2012 were identified and their treatment and outcome were evaluated . | ||
| 5 | RESULTS : | ||
| 6 | Sixteen patients had a median survival of 2.9 years . | ||
| 7 | Fourteen had Stage I or II disease with a median survival of 4.0 years and progression-free survival of 1.5 years . | ||
| 8 | When used for disease staging , whole body positron emission tomography/CT identified an additional three sites of metastasis in five patients compared with CT of the chest , abdomen and pelvis . | ||
| 9 | Surgery involved wide local excision or abdominoperineal excision with respective local recurrence rates of 50% and 66% . | ||
| 10 | Eleven patients underwent testing for c-Kit mutations , of whom five were positive . | ||
| 11 | Four of these were treated with the tyrosine kinase inhibitor imatinib , and showed rapid response of metastases outside the central nervous system . | ||
| 12 | CONCLUSION : | ||
| 13 | The outcome of this malignancy remains poor . | ||
| 14 | PET is the modality of choice for disease staging . | ||
| 15 | |
Testing tumours for c-Kit mutations may allow selected patients to participate in trials of tyrosine kinase inhibitors . |
| PMID: 27010960 (Patient) Terms: |
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| 0 | ✓ | KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma . | GM-MRK-DS |
| 1 | OBJECTIVES : | ||
| 2 | There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma . | ||
| 3 | This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer . | ||
| 4 | METHODS : | ||
| 5 | The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material ( primary tumor ; restriction fragment -length polymorphism plus sequencing and TaqMan allelic discrimination ) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma . | ||
| 6 | We used the Kaplan-Meier method , log-rank test , and Cox's model to evaluate the impact of KRAS status on the overall survival ( OS ) , adjusting for age , stage of disease , clinical performance status , CA 19-9 levels , and treatment . | ||
| 7 | RESULTS : | ||
| 8 | Μ | A total of 219 patients ( men : 116 ; mean age : 67+/-9.4 years ) were included : 147 harbored a codon -12 KRAS mutation ( G12D : 73 ; G12V : 53 ; G12R : 21 ) and 72 had a wild-type KRAS . | |
| 9 | ✓ | There was no difference in the OS between patients with a mutant KRAS ( 8 months ; 95% confidence interval ( 95% CI ) : 8.7-12.3 ) and the wild-type ( 9 months ; 95% CI : 8.7-12.8 ; hazard ratio ( HR ) : 1.03 ; P = 0.82 ) . | RO-ASS-GM |
| 10 | ✓ | However , the patients with a G12D mutation had a significantly shorter OS ( 6 months ; 95% CI : 6.4-9.7 ) compared with the other patients ( OS : 9 months ; 95% CI : 10-13 ; HR : 1.47 ; P = 0.003 ; i.e. , wild type : 9 months , G12V : 9 months , G12R : 14 months ) . | GM-ASS-RO, RO-ASS-GM |
| 11 | |
Similar results were observed in the subgroup of 162 patients who received chemotherapy ( HR : 1.66 ; P = 0.0013 ; G12D ( n = 49 ) : 8 months , wild type ( n = 56 ) : 10 months , G12V ( n = 38 ) : 10 months , G12R ( n = 19 ) : 14 months ) . | |
| 12 | ✓ | Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series ( HR : 1.44 ; P = 0.01 ) and in the subgroup of patients that received chemotherapy ( HR : 1.84 ; P = 0.02 ) . | GM-MRK-RO |
| 13 | CONCLUSIONS : | ||
| 14 | ✓ | The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma . | GM-MRK-DS |
| 15 | Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways . |
| PMID: 26156229 (Patient) Terms: |
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| 0 | The combination of intravenous Reolysin and gemcitabine induces reovirus replication and endoplasmic reticular stress in a patient with KRAS -activated pancreatic cancer . | ||
| 1 | BACKGROUND : | ||
| 2 | Activating mutations in RAS are present in the majority of pancreatic cancer cases and represent an ideal therapeutic target . | ||
| 3 | Reolysin is a proprietary formulation of oncolytic reovirus that is currently being evaluated in multiple clinical trials due to its ability to selectively replicate in cells harboring an activated RAS pathway . | ||
| 4 | Here we report for the first time the presence of reovirus replication and induction of endoplasmic reticular ( ER ) stress in a primary tumor specimen collected from a pancreatic cancer patient receiving intravenous Reolysin and gemcitabine . | ||
| 5 | CASE PRESENTATION : | ||
| 6 | We describe the case of a 54-year old patient diagnosed with pancreatic adenocarcinoma in February 2012 . | ||
| 7 | Μ |
Analysis of a tumor biopsy revealed an activating KRAS mutation (G12D) and the patient was started on first - line treatment with Reolysin in combination with gemcitabine in March 2012 . | |
| 8 | Stable disease was achieved with significant improvement in cancer-related pain . | ||
| 9 | Following 25 cycles of treatment over 23 months , a second biopsy was collected and immunohistochemical analyses revealed the presence of reovirus replication and induction of the ER stress-related gene GRP78/BIP and the pro-apoptotic protein NOXA . | ||
| 10 | Importantly , co-localization of reoviral protein and active caspase-3 was also observed in the biopsy specimen . | ||
| 11 | CONCLUSION : | ||
| 12 | |
This is the first report of reoviral protein detection in primary tumor biopsies taken from a pancreatic cancer patient receiving intravenous Reolysin therapy . | |
| 13 | The accumulation of reoviral protein was associated with ER stress induction and caspase-3 processing suggesting that Reolysin and gemcitabine treatment exhibited direct pro-apoptotic activity against the tumor . |
| PMID: 25748236 (None) Terms: in vivo, Pdx, mice |
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| 0 | ✓ | Constitutively active Akt1 cooperates with KRas (G12D) to accelerate in vivo pancreatic tumor onset and progression . | GM-REG-RO |
| 1 | BACKGROUND AND AIMS : | ||
| 2 | Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics . | ||
| 3 | Mutation of KRAS is the most frequent early event in pancreatic tumor progression . | ||
| 4 | AKT isoforms are frequently activated in pancreatic cancer , and reports have implicated hyperactivation of AKT1 , as well as AKT2 , in pancreatic tumor formation . | ||
| 5 | The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer . | ||
| 6 | METHODS : | ||
| 7 | Μ | Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly in human pancreatic ductal adenocarcinoma . | |
| 8 | RESULTS : | ||
| 9 | ✓ | Active Akt1 ( Akt1 ( Myr ) , containing a myristoylation sequence ) cooperated with active mutant KRas (G12D) to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway . | GM-REG-RO |
| 10 | Μ | Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms ( PanINs ) , and accelerated time to metastasis was found in Akt1 ( Myr )/KRas (G12D) mice . | |
| 11 | CONCLUSIONS : | ||
| 12 | In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes , which resulted in aggressive disease within a few months of age , Akt1 ( Myr )/KRas (G12D) mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals . | ||
| 13 | The Akt1 ( Myr )/KRas (G12D) model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies . |
| PMID: 27308320 (None) Terms: |
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| 0 | Pancreatitis promotes oncogenic Kras ( G12D )- induced pancreatic transformation through activation of Nupr1 . | ||
| 1 | During the initiation stage of pancreatic adenocarcinoma induced by oncogenic Kras , pancreatic cells are exposed to both a protumoral effect and an opposing tumor suppressive process known as oncogene -induced senescence . | ||
| 2 | Pancreatitis disrupts this balance in favor of the transforming effect of oncogenes by lowering the tumor suppressive threshold of oncogene -induced senescence through expression of the stress protein Nupr1 . |
| PMID: 27305732 (Patient) Terms: |
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| 0 | A Comparison of Clinical Outcomes Between HPV Positive and HPV Negative Squamous Cell Carcinomas of the Oropharynx . | ||
| 1 | Human papilloma virus ( HPV ) infection is now recognized as a major risk factor for the development of oropharyngeal head and neck cancers , specifically HPV type 16 . | ||
| 2 | HPV-16 positive oropharyngeal cancer may in fact represent a distinct disease entity which is associated with improved prognosis and survival ( National Cancer Institute , 2016 ) . | ||
| 3 | In this study , we examined the characteristics of patients with early stage HPV-16 positive oropharyngeal squamous cell carcinoma and their post-operative course contrasting the findings to patients with HPV-16 negative tumors . | ||
| 4 | Overall , it was noted that 30-day readmissions and surgical site infections are not affected by the HPV status of the tumor . | ||
| 5 | Μ | Robotic surgery is used more frequently with patients who were positive for the HPV infection , and the data suggest that there is a trend toward shorter length of hospital stays as well as a difference in postoperative complications . |
| PMID: 27061545 (Patient) Terms: retrospective |
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| 0 | Human papilloma virus status evaluation and survival description in selected oropharyngeal and laryngeal squamous cell carcinoma patients from Hungary . | ||
| 1 | PURPOSE : | ||
| 2 | Many patients with oropharyngeal squamous cell carcinomas do not have any of the traditional risk factors associated with head and neck squamous cell cancers ( HNSCC ) . | ||
| 3 | Epidemiologic and molecular studies have identified human papillomavirus ( HPV ) as a causative agent , viral tumors presenting a better survival and being important risk factors together with the long established ones , tobacco and alcohol consumption , in head and neck cancers . | ||
| 4 | The purpose of this study was to establish the incidence of HPV-associated HNSCCs , to identify the most frequent HPV type and to evaluate the overall survival and recurrence rates of HPV-positive cases in comparison with HPV-negative HNSCCs . | ||
| 5 | METHODS : | ||
| 6 | A retrospective analysis from the database of the National Institute of Oncology from Budapest was performed and the following parameters were analyzed : age , age at diagnosis , gender , primary tumor location , tumor histopathology , TNM stage , HPV status , date of recurrence , last visit and date of death . | ||
| 7 | RESULTS : | ||
| 8 | Out of 81 patients with HNSCCs 55 ( 679% ) were male and 26 ( 321% ) female . | ||
| 9 | HNSCCs were more frequent in men ( 211 : 1 ) and the majority of the patients ( 817% ) were diagnosed in advanced stages ( TNM III and IV ) . | ||
| 10 | HPV status was evaluated in nearly half ( 4814% ) of the patients and HNSCCs were positive for HPV in 43.6% of the cases . | ||
| 11 | These were more frequent in patients over 50 years ( 7666% ) , in men ( 7647% ) and in oropharyngeal location ( 941% ) . | ||
| 12 | HPV-16 type was associated with malignancy in 82.35% of the cases . | ||
| 13 | Disease recurrence was more frequent in HPV-negative ( 3181% ) versus HPV-positive cases ( 2941% ) and mortality rate was inferior in HPV-positive 33.33% versus negative ( 3809% ) tumors ( p = 052 ) . | ||
| 14 | CONCLUSIONS : | ||
| 15 | In Hungary HNSCCs are more frequent in men than in women . | ||
| 16 | HPV positivity is higher in men versus women and in oropharyngeal versus laryngeal location . | ||
| 17 | Overall survival rate was superior in HPV-positive versus HPV-negative cases . | ||
| 18 | Disease recurrence was more frequent in HPV-negative versus HPV-positive cases . |
| PMID: 25803099 (None) Terms: |
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| 0 | Human papillomavirus and tonsillar and base of tongue cancer . | ||
| 1 | In 2007 , human papillomavirus ( HPV ) type 16 was recognized as a risk factor by the International Agency for Research on Cancer , for oropharyngeal squamous cell carcinoma ( OSCC ) , where tonsillar and base of tongue cancer ( TSCC and BOTSCC ) dominate . | ||
| 2 | Furthermore , patients with HPV-positive TSCC and BOTSCC , had a much better clinical outcome than those with corresponding HPV-negative cancer and other head and neck cancer . | ||
| 3 | Μ | More specifically , survival was around 80% for HPV-positive TSCC and BOTSCC vs. 40% five-year disease free survival , for the corresponding HPV-negative tumors with conventional radiotherapy and surgery , while this could not be observed for HPV-positive OSCC at other sites . | |
| 4 | In addition , the past 20-40 years in many Western Countries , the incidence of HPV-positive TSCC and BOTSCC has risen , and >70% are men . | ||
| 5 | |
This has resulted in a relative increase of patients with HPV-positive TSCC and BOTSCC that may not need the intensified chemo-radiotherapy ( with many more severe debilitating side effects ) often given today to patients with head and neck cancer . | |
| 6 | ✓ | However , before tapering therapy , one needs to enable selection of patients for such treatment , by identifying clinical and molecular markers that together with HPV-positive status will better predict patient prognosis and response to therapy . | GE-REG-RO |
| 7 | |
To conclude , there is a new increasing group of patients with HPV-positive TSCC and BOTSCC with good clinical outcome , where options for better-tailored therapy are needed . | |
| 8 | For prevention , it would be of benefit to vaccinate both girls and boys against HPV16 infection . | ||
| 9 | For potential future screening the ways to do so need optimizing . |
| PMID: 27658789 (None) Terms: clinical trial, prospective |
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| 0 | Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice . | ||
| 1 | OPINION STATEMENT : Biliary tract cancers are relatively uncommon , have an aggressive disease course and a dismal clinical outcome . | ||
| 2 | Until recently , there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy . | ||
| 3 | The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease . | ||
| 4 | Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice . | ||
| 5 | Mutation profiling has highlighted the genomic differences between the intra , extrahepatic cholangiocarcinoma , and gallbladder cancer . | ||
| 6 | The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity . | ||
| 7 | There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma . | ||
| 8 | KRAS and p53 mutations are associated with an aggressive disease prognosis while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma . | ||
| 9 | FGFR and IDH mutations have promising agents in clinical trials at this time . | ||
| 10 | An estimated 15 % of gallbladder cancers have Her2/neu amplification and can be targeted by trastuzumab . | ||
| 11 | On the other hand , an estimated 10-15 % of cholangiocarcinomas have DNA repair mutations and may be candidates for immune therapies with checkpoint inhibitors . | ||
| 12 | |
The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed , prospective , and multi-center clinical trials . |
| PMID: 26022204 (Patient) Terms: retrospective |
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| 0 | HER2/neu -directed therapy for biliary tract cancer . | ||
| 1 | BACKGROUND : | ||
| 2 | Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy . | ||
| 3 | Μ | Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation . | |
| 4 | HER2/neu amplification is associated with response to HER2/neu -directed therapy in breast and gastric cancers . | ||
| 5 | However , the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown . | ||
| 6 | PATIENTS AND METHODS : | ||
| 7 | We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu -directed therapy between 2007 and 2014 . | ||
| 8 | Clinical data were retrieved from medical records , and imaging studies were independently reviewed . | ||
| 9 | RESULTS : | ||
| 10 | |
Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu -directed therapy ( trastuzumab , lapatinib , or pertuzumab ) during the study period . | |
| 11 | Μ | In the gallbladder cancer group , HER2/neu gene amplification or overexpression was detected in eight cases . | |
| 12 | |
These patients experienced disease stability ( n = 3 ) , partial response ( n = 4 ) , or complete response ( n = 1 ) with HER2/neu -directed therapy . | |
| 13 | ✓ | One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy . | GM-ASS-RO |
| 14 | |
The duration of response varied from 8+ to 168 weeks ( median 40 weeks ) , and three patients are still on therapy . | |
| 15 | |
One patient developed HER2/neu amplification as a secondary event after FGFR -directed therapy for FGF3-TACC3 gene fusion . | |
| 16 | |
The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations , and no radiological responses were seen in these patients despite HER2/neu -directed therapy . | |
| 17 | CONCLUSIONS : | ||
| 18 | HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study . |
| PMID: 22433475 (Patient) Terms: phase II study, phase II |
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| 0 | HER2/neu may not be an interesting target in biliary cancers : results of an early phase II study with lapatinib . | ||
| 1 | PURPOSE : | ||
| 2 | Biliary cancers ( BCs ) respond poorly to chemotherapy . | ||
| 3 | Lapatinib is a dual inhibitor of epidermal growth factor receptor ( EGFR ) and HER2/neu , both implicated in cholangiocarcinogenesis . | ||
| 4 | This trial was designed to determine the safety and efficacy of lapatinib in BC . | ||
| 5 | METHODS : | ||
| 6 | A Fleming phase II design with a single stage of 25 patients was used . | ||
| 7 | The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles . | ||
| 8 | Tumor and blood specimens were analyzed for expression of HER2/neu and EGFR . | ||
| 9 | RESULTS : | ||
| 10 | Nine patients with BC enrolled in this study . | ||
| 11 | The study was terminated early because of futility . | ||
| 12 | The most common toxicities were nausea and fatigue ( 78% ) and diarrhea ( 67% ) . | ||
| 13 | No responses were observed . | ||
| 14 | Of 8 evaluable patients , 4 ( 50% ) had stable disease . | ||
| 15 | Median progression-free survival was 2.6 months ( 95% CI 16-44 ) and median overall survival was 5.1 months ( 95% CI 20-165 ) . | ||
| 16 | Μ | No somatic mutations in EGFR ( exons 18-21 ) or HER2/neu were found . | |
| 17 | We did not find evidence of HER2 overexpression . | ||
| 18 | CONCLUSIONS : | ||
| 19 | Lapatinib is well tolerated but failed to show activity as a single agent in treating patients with BC . | ||
| 20 | |
Despite the small patient population , our study is consistent with previous findings , suggesting that targeting HER2/neu does not appear to be an effective therapy for BC . |
| PMID: 28280620 (Patient) Terms: Clinical trial |
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| 0 | Potential actionable targets in appendiceal cancer detected by immunohistochemistry , fluorescent in situ hybridization , and mutational analysis . | ||
| 1 | BACKGROUND : | ||
| 2 | Appendiceal cancers are rare and consist of carcinoid , mucocele , pseudomyxoma peritonei ( PMP ) , goblet cell carcinoma , lymphoma , and adenocarcinoma histologies . | ||
| 3 | Current treatment involves surgical resection or debulking , but no standard exists for adjuvant chemotherapy or treatment for metastatic disease . | ||
| 4 | METHODS : | ||
| 5 | Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory . | ||
| 6 | A total of 588 samples with appendix primary tumor sites were identified ( male/female ratio of 2 : 3 ; mean age =55 ) . | ||
| 7 | Sixty-two percent of samples were adenocarcinomas ( used for analysis ) ; the rest consisted of 9% goblet cell , 15% mucinous ; 6% pseudomyxoma , and less than 5% carcinoids and 2% neuroendocrine . | ||
| 8 | Tests included sequencing [Sanger , next generation sequencing ( NGS ) ] , protein expression/immunohistochemistry ( IHC ) , and gene amplification [fluorescent in situ hybridization ( FISH ) or CISH] . | ||
| 9 | RESULTS : | ||
| 10 | Profiling across all appendiceal cancer histological subtypes for IHC revealed : 97% BRCP , 81% MRP1 , 81% COX-2 , 71% MGMT , 56% TOPO1 , 5% PTEN , 52% EGFR , 40% ERCC1 , 38% SPARC , 35% PDGFR , 35% TOPO2A , 25% RRM1 , 21% TS , 16% cKIT , and 12% for TLE3 . | ||
| 11 | Μ | NGS revealed mutations in the following genes : 50.4% KRAS , 21.9% P53 , 17.6% GNAS , 16.5% SMAD4 , 10% APC , 7.5% ATM , 5.5% PIK3CA , 5.0% FBXW7 , and 1.8% BRAF . | |
| 12 | CONCLUSIONS : | ||
| 13 | Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins ( BCRP and MRP1 ) , which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment . | ||
| 14 | The incidence of low TS ( 79% ) could be used as a backbone of therapy ( using inhibitors such as 5FU/capecitabine or newer agents ) . | ||
| 15 | Therapeutic options includeTOPO1 inhibitors ( irinotecan/topotecan ) , EGFR inhibitors ( erlotinib , cetuximab ) , PDGFR antagonists ( regorafenib , axitinib ) , MGMT ( temozolomide ) . | ||
| 16 | Clinical trials targeting pathways involving KRAS , p53 , GNAS , SMAD4 , APC , ATM , PIK3CA , FBXW7 , and BRAF may be also considered . | ||
| 17 | Overall , appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers ( can we say this , any statistical analysis done? ) and have differential expression from colorectal cancers . | ||
| 18 | |
These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration , in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers ( supported by a grant from Caris Life Sciences ) . |
| PMID: 26160192 (None) Terms: |
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| 0 | A mutation spectrum that includes GNAS , KRAS and TP53 may be shared by mucinous neoplasms of the appendix . | ||
| 1 | Appendiceal mucinous tumors ( AMTs ) are classified as low-grade appendiceal mucinous neoplasms ( LAMNs ) or mucinous adenocarcinomas ( MACs ) , although their carcinogenesis is not well understood . | ||
| 2 | As somatic activating mutations of GNAS are considered to be characteristic of LAMNs while TP53 mutations have been shown to be specific to MACs , MACs are unlikely to result from transformation of LAMNs . | ||
| 3 | However , emerging evidence also shows the presence of GNAS mutations in MACs . | ||
| 4 | We examined 16 AMTs ( 11 LAMNs and 5 MACs ) for genetic alterations of GNAS , KRAS , BRAF , TP53 , CTNNB1 , and TERT promoter in order to elucidate the possibility of a shared genetic background in the two tumor types . | ||
| 5 | Μ | Extensive histological examination revealed the presence of a low-grade component in all cases of MAC . | |
| 6 | Μ | GNAS mutations were detected in two LAMNs and in one MAC , although the GNAS mutation in this MAC was a nonsense mutation ( Q227X ) expected not to be activating mutation . | |
| 7 | Μ | TP53 mutations were detected in three LAMNs ; they were frequently detected in MACs . | |
| 8 | Μ | KRAS mutations were detected in three LAMNs and three MACs , and CTNNB1 mutations were detected in two LAMNs . | |
| 9 | Μ | KRAS mutation and activating mutation of GNAS occurred exclusively in AMTs . | |
| 10 | Μ | BRAF and TERT mutations were not detected . | |
| 11 | Μ | Overexpression of p53 was observed in only two MACs , and p53 immunostaining clearly discriminated the high-grade lesion from a low-grade component in one . | |
| 12 | These findings suggest that p53 overexpression plays an important role in the carcinogenesis of AMTs and that , in addition to mutations of GNAS , KRAS and TP53 alterations might be shared by AMTs , thus providing evidence for the possible progression of LAMNs to MAC . |
| PMID: 27959342 (None) Terms: , orthotopic animal tumours |
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| 0 | Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer . | ||
| 1 | Μ | Androgen receptor ( AR ) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer ( CRPC ) , but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation . | |
| 2 | Here we identify the small molecule Ailanthone ( AIL ) as a potent inhibitor of both full-length AR ( AR-FL ) and constitutively active truncated AR splice variants ( AR-Vs ) . | ||
| 3 | AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90 , thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4 , and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours . | ||
| 4 | In addition , AIL blocks tumour growth and metastasis of CRPC . | ||
| 5 | Finally , AIL possesses favourable drug -like properties such as good bioavailability , high solubility , lack of CYP inhibition and low hepatotoxicity . | ||
| 6 | |
In general , AIL is a potential candidate for the treatment of CRPC . |
| PMID: 28144969 (Cell) Terms: in vitro |
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| 0 | High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases . | ||
| 1 | BACKGROUND : | ||
| 2 | The relation between androgen receptor ( AR ) gene amplification and other mechanisms behind castration-resistant prostate cancer ( CRPC ) , such as expression of constitutively active AR variants and steroid -converting enzymes has been poorly examined . | ||
| 3 | Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this , with the long-term goal of identifying novel molecular targets for treatment . | ||
| 4 | METHODS : | ||
| 5 | Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases ( n = 40 ) and by PCR-based copy number variation analysis . | ||
| 6 | Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR . | ||
| 7 | Protein localization was analyzed using immunohistochemistry and confocal microscopy . | ||
| 8 | The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC , and effects on cell proliferation , colony formation , migration , and invasion were determined in vitro . | ||
| 9 | Extracellular vesicles ( EVs ) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis . | ||
| 10 | Protein content was identified by LC-MS/MS analysis . | ||
| 11 | Blood coagulation was measured as activated partial thromboplastin time ( APTT ) . | ||
| 12 | Functional enrichment analysis was performed using the MetaCore software . | ||
| 13 | RESULTS : | ||
| 14 | Μ | AR amplification was detected in 16 ( 53% ) of the bone metastases examined from CRPC patients ( n = 30 ) , and in none from the untreated patients ( n = 10 ) . | |
| 15 | Μ | Metastases with AR amplification showed high AR and AR-V7 mRNA levels , increased nuclear AR immunostaining , and co-amplification of genes such as YIPF6 in the AR proximity at Xq12 . | |
| 16 | The YIPF6 protein was localized to the Golgi apparatus . | ||
| 17 | YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation , and in enhanced EV secretion . | ||
| 18 | EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and , accordingly , decreased the APTT in a dose -dependent fashion . | ||
| 19 | CONCLUSIONS : | ||
| 20 | ✓ | AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs . | |
| 21 | Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients . | ||
| 22 | Prostate 77 : 625-638 , 2017 . | ||
| 23 | (c) 2017 Wiley Periodicals , Inc . |
| PMID: 28089830 (Cell) Terms: in vivo |
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| 0 | Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells . | ||
| 1 | EglN prolyl hydroxylases , a family of oxygen-sensing enzymes , hydroxylate distinct proteins to modulate diverse physiopathological signals . | ||
| 2 | Aberrant regulations of EglNs result in multiple human diseases , including cancer . | ||
| 3 | Different from EglN1 which function largely depends on the role of hypoxia-induce factor alpha ( HIFalpha ) in tumors , the functional significance and the upstream regulatory mechanisms of EglN2 , especially in prostate cancer setting , remain largely unclear . | ||
| 4 | Here , we demonstrated that dysregulation of EglN2 facilitated prostate cancer growth both in cells and in vivo . | ||
| 5 | Notably , EglN2 was identified highly expressed in human prostate cancer tissues . | ||
| 6 | Mechanically , Cullin 3-based E3 ubiquitin ligase SPOP , a well-characterized tumor suppressor in prostate cancer , could recognize and destruct EglN2 . | ||
| 7 | Meanwhile , androgen receptor ( AR ) , playing a pivotal role in progression and development of prostate cancer , could transcriptionally up-regulate EglN2 . | ||
| 8 | Μ | Pathologically , SPOP loss-of-function mutations or AR amplification , frequently occurring in prostate cancers , could significantly accumulate EglN2 abundance . | |
| 9 | Therefore , our study not only underlines an oncogenic role of EglN2 in prostate cancer , but also highlights SPOP as a tumor suppressor to down-regulate EglN2 in prostate cancer . |
| PMID: 26154128 (Patient) Terms: |
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| 0 | Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients . | ||
| 1 | Pancreatic adenocarcinoma has the worst mortality of any solid cancer . | ||
| 2 | Μ | In this study , to evaluate the clinical implications of genomic alterations in this tumour type , we perform whole-exome analyses of 24 tumours , targeted genomic analyses of 77 tumours , and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients . | |
| 3 | Μ | These analyses reveal somatic mutations in chromatin-regulating genes MLL , MLL2 , MLL3 and ARID1A in 20% of patients that are associated with improved survival . | |
| 4 | We observe alterations in genes with potential therapeutic utility in over a third of cases . | ||
| 5 | Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA ( ctDNA ) at diagnosis . | ||
| 6 | Detection of ctDNA after resection predicts clinical relapse and poor outcome , with recurrence by ctDNA detected 6.5 months earlier than with CT imaging . | ||
| 7 | These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention . |
| PMID: 25719666 (None) Terms: |
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| 0 | Whole genomes redefine the mutational landscape of pancreatic cancer . | ||
| 1 | Pancreatic cancer remains one of the most lethal of malignancies and a major health burden . | ||
| 2 | We performed whole - genome sequencing and copy number variation ( CNV ) analysis of 100 pancreatic ductal adenocarcinomas ( PDACs ) . | ||
| 3 | Chromosomal rearrangements leading to gene disruption were prevalent , affecting genes known to be important in pancreatic cancer ( TP53 , SMAD4 , CDKN2A , ARID1A and ROBO2 ) and new candidate drivers of pancreatic carcinogenesis ( KDM6A and PREX2 ) . | ||
| 4 | Patterns of structural variation ( variation in chromosomal structure ) classified PDACs into 4 subtypes with potential clinical utility : the subtypes were termed stable , locally rearranged , scattered and unstable . | ||
| 5 | Μ | A significant proportion harboured focal amplifications , many of which contained druggable oncogenes ( ERBB2 , MET , FGFR1 , CDK6 , PIK3R3 and PIK3CA ) , but at low individual patient prevalence . | |
| 6 | Genomic instability co-segregated with inactivation of DNA maintenance genes ( BRCA1 , BRCA2 or PALB2 ) and a mutational signature of DNA damage repair deficiency . | ||
| 7 | |
Of 8 patients who received platinum therapy , 4 of 5 individuals with these measures of defective DNA maintenance responded . |
| PMID: 25714017 (None) Terms: clinical trial |
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| 0 | Molecular landscape of pancreatic cancer : implications for current clinical trials . | ||
| 1 | Despite recent improvements , overall survival for advanced adenocarcinoma of the pancreas continues to be poor . | ||
| 2 | In comparison to other tumor types that have enjoyed marked survival benefit by targeting aberrant cell signaling pathways , standard of care treatment for pancreatic cancer is limited to conventional cytotoxic chemotherapy . | ||
| 3 | Multiple pathway aberrations have been documented in pancreatic cancer . | ||
| 4 | Μ | A review of the COSMIC database reveals that most pancreatic cancers contain somatic mutations , with the five most frequent being KRAS , TP53 , CDKN2A , SMAD4 , and ARID1A , and multiple other abnormalities seen including , but not limited to , mutations in STK11/LKB1 , FBXW7 , PIK3CA , and BRAF . | |
| 5 | In the era of tumor profiling , these aberrations may provide an opportunity for new therapeutic approaches . | ||
| 6 | Yet , searching clinicaltrials . | ||
| 7 | gov for recent drug intervention trials for pancreatic adenocarcinoma , remarkably few ( 10 of 116 ( 86% ) ) new study protocols registered in the last three years included a molecular/biomarker stratification strategy . | ||
| 8 | Enhanced efforts to target subsets of patients with pancreatic cancer in order to optimize therapy benefit are warranted . |
| PMID: 21531001 (Patient) Terms: |
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| 0 | PIK3CA mutations and amplification in endometrioid endometrial carcinomas : relation to other genetic defects and clinicopathologic status of the tumors . | ||
| 1 | Alterations of the PIK3CA gene occur in endometrial carcinomas , but their role in the carcinogenesis of those malignancies is still poorly understood . | ||
| 2 | In this study , PIK3CA mutations and amplification in 196 endometrioid endometrial carcinomas and 20 endometrial hyperplasias were assessed by single-strand conformation polymorphism ( PCR-SSCP ) , sequencing , and quantitative polymerase chain reaction . | ||
| 3 | Results were correlated with mutations in the PTEN , KRAS , and CTNNB1 genes and with the clinicopathologic parameters of the tumors . | ||
| 4 | Μ | PIK3CA mutations were found in 39 ( 20% ) carcinomas . | |
| 5 | Μ | Six new mutations were identified . | |
| 6 | Μ | No PIK3CA mutations were found in endometrial hyperplasias . | |
| 7 | Μ | PIK3CA amplification was observed in 24 ( 122% ) carcinomas and in 2 ( 10% ) hyperplasias . | |
| 8 | Μ | The PIK3CA mutations and amplifications ( with the exception of 6 cases ) occurred independently . | |
| 9 | PIK3CA mutations were significantly associated with PTEN mutations ( P = 0414 ) and tended to be associated with CTNNB1 ( P = 0833 ) , but not with KRAS mutations . | ||
| 10 | Conversely , the PIK3CA amplifications significantly negatively correlated with PTEN mutations ( P = 0038 ) and did not coexist with CTNNB1 and KRAS mutations . | ||
| 11 | The PIK3CA mutations were significantly associated with poorly differentiated tumors ( P = 0423 ) . | ||
| 12 | Interestingly , PIK3CA amplifications , but not mutations , were strongly associated with older age ( >/ = 63 years , P = 0018 ) . | ||
| 13 | Our data show that mutations and amplification of PIK3CA are significant genetic alterations in endometrioid endometrial carcinomas associated with adverse clinicopathologic parameters ( grade and stage ) . | ||
| 14 | These data also demonstrate that PIK3CA mutations cooperate with PTEN mutations , suggesting an additive effect to PTEN , whereas PIK3CA amplification can , as an isolated event , enable the development of those tumors . | ||
| 15 | ✓ | Moreover , for the first time , a possible role of PIK3CA amplification in initiation and progression of endometrial carcinomas in older women is suggested , but this preliminary suggestion requires further research . | GM-INV-RO |
| PMID: 19261849 (None) Terms: in vitro |
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| 0 | Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation . | ||
| 1 | Although 75% of endometrial cancers are treated at an early stage , 15% to 20% of these recur . | ||
| 2 | We performed an integrated analysis of genome -wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease . | ||
| 3 | Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes , including significant differences in disease-free survival . | ||
| 4 | Μ | To identify possible mechanisms for these differences , we performed a global genomic survey of amplifications , deletions , and loss of heterozygosity , which identified 11 significantly amplified and 13 significantly deleted regions . | |
| 5 | ✓ | Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster . | GE-ASS-RO |
| 6 | Moreover , samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase ( PI3K ) , a signature that was shared by aggressive tumors without PIK3CA amplification . | ||
| 7 | Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature , high protein expression of the PI3K pathway member STMN1 , and an aggressive phenotype in test and validation datasets . | ||
| 8 | However , mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype . | ||
| 9 | ✓ | STMN1 expression had independent prognostic value . | GE-ASS-RO |
| 10 | The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer . |
| PMID: 17258789 (Patient) Terms: |
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| 0 | Alternate molecular genetic pathways in ovarian carcinomas of common histological types . | ||
| 1 | We evaluated alterations in p53 , PIK3CA , PTEN , CTNNB1 ( beta-catenin ) , MLH1 , and BRAF among common histological subsets of epithelial ovarian tumors to characterize patterns of alterations of different molecular pathways . | ||
| 2 | There were 12 clear cell , 26 endometrioid , and 51 serous carcinomas evaluated by direct DNA sequencing for mutations in p53 , PIK3CA , PTEN , BRAF , and CTNNB1 . | ||
| 3 | Methylation-specific polymerase chain reaction ( PCR ) assessed MLH1 promoter methylation status . | ||
| 4 | Μ | Quantitative PCR identified PIK3CA amplification in 22 EC and 94 SC . | |
| 5 | Μ | p53 mutations were identified in 25 ( 49% ) of 51 SC , 11 ( 42% ) of 26 EC , and 1 ( 83% ) of 12 CC neoplasms and were more common in grade 3 EC ( P = 045 ) and advanced-stage EC ( P = 007 ) . | |
| 6 | Μ | PIK3CA mutations were identified in 3 ( 25% ) of 12 CC , 3 ( 12% ) of 26 EC , and 0 of 51 SC . | |
| 7 | PTEN mutations were significantly more common in EC ( 8/26 , 31% ) compared with CC ( 0/12 ; P = 04 ) and SC ( 2/51 , 4% ; P = 002 ) . | ||
| 8 | Μ | CTNNB1 mutations were identified , 6 ( 23% ) EC and no CC or SC ( P = 008 ) . | |
| 9 | Μ | Both PTEN and CTNNB1 mutations were more common in low-grade EC , whereas PIK3CA mutations occurred only in grade 3 cancers . | |
| 10 | PTEN and PIK3CA mutations were more common in p53 wild-type tumors ( P = 003 ) . | ||
| 11 | Μ | PIK3CA amplification occurred in fewer EC ( 0/22 ) versus SC ( 19/94 , 20% ; P = 002 ) and were slightly more common in p53 wild-type compared with p53 mutant SC ( P = 08 ) . | |
| 12 | Of 26 EC , 22 ( 85% ) had a mutation in one of the genes studied compared with 4 33% of 12 CC ( P = 003 ) . | ||
| 13 | Women with EC had significantly better overall survival ( P = 0008 ) , and this remained significant after accounting for stage ( P = 04 ) . | ||
| 14 | Mutations in p53 or in PTEN/PIK3CA are alternative pathways in ovarian carcinogenesis . | ||
| 15 | Activation of PIK3CA occurs by gene amplification in SC but via somatic mutation of PIK3CA or PTEN in EC and CC . | ||
| 16 | PIK3CA mutations are associated with high-grade tumors , whereas PTEN and CTNNB1 mutations are associated with low-grade tumors . | ||
| 17 | Mutations in p53 , PIK3CA , PTEN , and CTNNB1 account for most EC tumors ; most CC remain unexplained . | ||
| 18 | EC histology is a favorable prognostic factor . |
| PMID: 14677066 (Cell) Terms: xenograft, in vitro, mice |
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| 0 | A novel cell line and xenograft model of ampulla of Vater adenocarcinoma . | ||
| 1 | Ampulla of Vater cancers ( AVC ) are of clinical relevance , as they represent more than one-third of patients undergoing surgery for pancreaticoduodenal malignancies and have a better prognosis than periampullary cancers of pancreaticobiliary origin . | ||
| 2 | The availability of cellular models is crucial to perform cell biology and pharmacological studies and clarify the relationship between AVC and pancreatic and biliary cancers . | ||
| 3 | Numerous cell lines are available for pancreatic and biliary adenocarcinomas , while only two have been reported recently for AVC . | ||
| 4 | These were derived from a poor and a well-differentiated AVC , and both had wild-type K - ras and mutated p53 . | ||
| 5 | We report the establishment of a novel AVC cell line ( AVC1 ) derived from a moderately differentiated cancer , having a mutated K - ras , wild-type p53 , and methylated p16 . | ||
| 6 | Thus , our cell line adds to the spectrum of available in vitro models representative of the different morphological and molecular presentations of primary AVC . | ||
| 7 | We further characterized AVC1 for the expression of relevant cell surface molecules and sensitivity to chemotherapeutic agents of common clinical use . | ||
| 8 | It expresses MHC-I and CD95/Fas , while HLA-DR , CD40 , CD80 , CD86 , MUC-1 , MUC-2 , and ICAM-1/CD54 are absent . | ||
| 9 | It has a low to moderate sensitivity to both 5-FU and gemcitabine , at variance with much higher sensitivity displayed by two pancreatic ductal carcinoma cell lines . | ||
| 10 | Lastly , AVC1 can be readily xenografted in immunodeficient mice , making it a suitable model for pre-clinical studies . |
| PMID: 23303473 (Patient) Terms: |
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| 0 | Molecular characteristics of a pancreatic adenocarcinoma associated with Shwachman-Diamond syndrome . | ||
| 1 | BACKGROUND : | ||
| 2 | Shwachman-Diamond syndrome ( SDS ) is characterized by hypoplasia of the bone marrow and exocrine pancreas and a high risk of leukemia . | ||
| 3 | It is unknown whether solid tumors are part of the disease phenotype . | ||
| 4 | PROCEDURE : | ||
| 5 | We performed copy number alterations using Affymetrix human SNP 6.0 array . | ||
| 6 | Furthermore , we did direct sequencing of pancreatic cancer-related genes and immunohistochemical expression of selective proteins . | ||
| 7 | RESULTS : | ||
| 8 | Among 41 patients with SDS who enrolled on the registry , we identified one male patient with a solid tumor : moderately differentiated pancreatic ductal adenocarcinoma . | ||
| 9 | Μ | The tumor harbored 41 copy number alterations ( CNAs ) and had no regions of loss of heterozygosity ( LOH ) . | |
| 10 | None of these CNAs were exclusive to the tumor . | ||
| 11 | One copy of the tumor suppressor genes CTNNA3 and LGALS9C was lost in both the peripheral blood and tumor . | ||
| 12 | Μ | Direct sequencing of TP53 , KRAS , and NRAS revealed no mutations . | |
| 13 | Immunohistochemical staining for cyclin D1 , E-cadherin , p53 MLH1 and MSH2 and beta-catenin , was similar to that seen in non-hereditary pancreatic cancer . | ||
| 14 | CONCLUSIONS : | ||
| 15 | Our case raises the possibility that solid tumors are associated with SDS , thereby broadening the clinical phenotype of the disease . | ||
| 16 | The relatively young age at cancer diagnosis and the specific involvement of the pancreas make the possibility of an association with SDS likely . | ||
| 17 | Similar to leukemia in SDS , the pancreatic cancer developed in hypoplastic tissues . | ||
| 18 | This observation and the relative genomic stability of the tumor strengthen the hypothesis of improved adaptation of malignant clones among a population of disadvantaged cells as a mechanism for tumor expansion in SDS . |
| PMID: 14677066 (Cell) Terms: xenograft, in vitro, mice |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | A novel cell line and xenograft model of ampulla of Vater adenocarcinoma . | ||
| 1 | Ampulla of Vater cancers ( AVC ) are of clinical relevance , as they represent more than one-third of patients undergoing surgery for pancreaticoduodenal malignancies and have a better prognosis than periampullary cancers of pancreaticobiliary origin . | ||
| 2 | The availability of cellular models is crucial to perform cell biology and pharmacological studies and clarify the relationship between AVC and pancreatic and biliary cancers . | ||
| 3 | Numerous cell lines are available for pancreatic and biliary adenocarcinomas , while only two have been reported recently for AVC . | ||
| 4 | These were derived from a poor and a well-differentiated AVC , and both had wild-type K - ras and mutated p53 . | ||
| 5 | We report the establishment of a novel AVC cell line ( AVC1 ) derived from a moderately differentiated cancer , having a mutated K - ras , wild-type p53 , and methylated p16 . | ||
| 6 | Thus , our cell line adds to the spectrum of available in vitro models representative of the different morphological and molecular presentations of primary AVC . | ||
| 7 | We further characterized AVC1 for the expression of relevant cell surface molecules and sensitivity to chemotherapeutic agents of common clinical use . | ||
| 8 | It expresses MHC-I and CD95/Fas , while HLA-DR , CD40 , CD80 , CD86 , MUC-1 , MUC-2 , and ICAM-1/CD54 are absent . | ||
| 9 | It has a low to moderate sensitivity to both 5-FU and gemcitabine , at variance with much higher sensitivity displayed by two pancreatic ductal carcinoma cell lines . | ||
| 10 | Lastly , AVC1 can be readily xenografted in immunodeficient mice , making it a suitable model for pre-clinical studies . |
| PMID: 23303473 (Patient) Terms: |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Molecular characteristics of a pancreatic adenocarcinoma associated with Shwachman-Diamond syndrome . | ||
| 1 | BACKGROUND : | ||
| 2 | Shwachman-Diamond syndrome ( SDS ) is characterized by hypoplasia of the bone marrow and exocrine pancreas and a high risk of leukemia . | ||
| 3 | It is unknown whether solid tumors are part of the disease phenotype . | ||
| 4 | PROCEDURE : | ||
| 5 | We performed copy number alterations using Affymetrix human SNP 6.0 array . | ||
| 6 | Furthermore , we did direct sequencing of pancreatic cancer-related genes and immunohistochemical expression of selective proteins . | ||
| 7 | RESULTS : | ||
| 8 | Among 41 patients with SDS who enrolled on the registry , we identified one male patient with a solid tumor : moderately differentiated pancreatic ductal adenocarcinoma . | ||
| 9 | Μ | The tumor harbored 41 copy number alterations ( CNAs ) and had no regions of loss of heterozygosity ( LOH ) . | |
| 10 | None of these CNAs were exclusive to the tumor . | ||
| 11 | One copy of the tumor suppressor genes CTNNA3 and LGALS9C was lost in both the peripheral blood and tumor . | ||
| 12 | Μ | Direct sequencing of TP53 , KRAS , and NRAS revealed no mutations . | |
| 13 | Immunohistochemical staining for cyclin D1 , E-cadherin , p53 MLH1 and MSH2 and beta-catenin , was similar to that seen in non-hereditary pancreatic cancer . | ||
| 14 | CONCLUSIONS : | ||
| 15 | Our case raises the possibility that solid tumors are associated with SDS , thereby broadening the clinical phenotype of the disease . | ||
| 16 | The relatively young age at cancer diagnosis and the specific involvement of the pancreas make the possibility of an association with SDS likely . | ||
| 17 | Similar to leukemia in SDS , the pancreatic cancer developed in hypoplastic tissues . | ||
| 18 | This observation and the relative genomic stability of the tumor strengthen the hypothesis of improved adaptation of malignant clones among a population of disadvantaged cells as a mechanism for tumor expansion in SDS . |
| PMID: 17230526 (Patient) Terms: |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | ✓ | Effects of base excision repair gene polymorphisms on pancreatic cancer survival . | GM-INV-RO |
| 1 | To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer , we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M . | ||
| 2 | D . | ||
| 3 | Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006 . | ||
| 4 | Genotypes were determined using genomic DNA and the MassCode method . | ||
| 5 | Overall survival was analyzed using the Kaplan-Meier plot , log-rank test and Cox regression . | ||
| 6 | We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival . | ||
| 7 | ✓ Μ | The median survival time ( MST ) was 35.7 months for patients carrying atleast 1 of the 2 homozygous variant POLB GG or CC genotypes , compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes ( p = 002 , log rank test ) . | GM-ASS-RO |
| 8 | ✓ | The homozygous variants of hOGG1 G2657A , APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders . | GM-ASS-RO |
| 9 | ✓ Μ | In combined genotype analysis , a predominant effect of the POLB homozygous variants on survival was observed . | GM-INV-RO |
| 10 | When POLB was not included in the model , a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying atleast one of the adverse genotypes . | ||
| 11 | These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer . | ||
| 12 | These observations need to be confirmed in a larger study of homogenous patient population . |
| PMID: 16844323 (Patient) Terms: case, control |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Selected polymorphisms of DNA repair genes and risk of pancreatic cancer . | ||
| 1 | BACKGROUND : | ||
| 2 | Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis . | ||
| 3 | O(6)- methylguanine-DNA methyltransferase ( MGMT ) is the major protein that removes alkylating DNA adducts , and apurinic/apyrimidinic endonuclease 1 ( APE1 ) and X-ray repair cross-complementing group 1 ( XRCC1 ) play important roles in the base excision repair pathway . | ||
| 4 | METHODS : | ||
| 5 | We investigated the association between polymorphisms of MGMT ( Leu(84) Phe and Ile(143) Val ) , APE1 (Asp(148) Glu) , and XRCC1 ( Arg(194) Trp and Arg(399) Gln ) and risk of pancreatic cancer in a case-control study . | ||
| 6 | Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers . | ||
| 7 | Controls were frequency matched to patients by age at enrollment ( +/-5 years ) , gender , and race . | ||
| 8 | We estimated odds ratios ( ORs ) and 95% confidence intervals ( CIs ) by using unconditional logistic regression models . | ||
| 9 | RESULTS : | ||
| 10 | There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer . | ||
| 11 | However , the XRCC1 ( 194 ) polymorphism had a significant interaction with the APE1 ( 148 ) ( p = 0005 ) or MGMT ( 84 ) polymorphism ( p = 002 ) in modifying the risk of pancreatic cancer . | ||
| 12 | CONCLUSIONS : | ||
| 13 | This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer . | ||
| 14 | Larger studies are required to validate these preliminary findings . | ||
| 15 | The mechanism of the combined genotype effects remains to be elucidated . |
| PMID: 16520463 (Patient) Terms: |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Single nucleotide polymorphisms of RecQ1 , RAD54L , and ATM genes are associated with reduced survival of pancreatic cancer . | ||
| 1 | PURPOSE : | ||
| 2 | Our goal was to determine whether single nucleotide polymorphisms ( SNPs ) in DNA repair genes influence the clinical outcome of pancreatic cancer . | ||
| 3 | PATIENTS AND METHODS : | ||
| 4 | We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma . | ||
| 5 | All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M . | ||
| 6 | D . | ||
| 7 | Anderson Cancer Center ( Houston , TX ) from February 1999 to August 2004 and observed through August 2005 . | ||
| 8 | Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival . | ||
| 9 | Kaplan-Meier plot , log-rank test , and Cox regression were used to compare survival of patients according to genotype . | ||
| 10 | RESULTS : | ||
| 11 | ✓ | The RecQ1 A159C , RAD54L C157T , XRCC1 R194W , and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001 , .004 , .001 , and .02 , respectively . | GM-ASS-RO |
| 12 | A strong combined effect of the four genotypes was observed . | ||
| 13 | ✓ | Patients with none of the adverse genotypes had a mean survival time of 62.1 months , and those with one , two , or three or more at-risk alleles had median survival times of 27.5 , 14.4 , and 9.9 months , respectively ( log-rank P <001 ) . | GM-ASS-RO |
| 14 | There is a significant interaction between the RecQ1 gene and other genotypes . | ||
| 15 | ✓ | All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors . | GN-MRK-RO |
| 16 | CONCLUSION : | ||
| 17 | These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer . |
| PMID: 12183419 (Patient) Terms: case, control |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | A population-based study of the Arg399Gln polymorphism in X-ray repair cross - complementing group 1 ( XRCC1 ) and risk of pancreatic adenocarcinoma . | ||
| 1 | XRCC1 ( X-ray repair cross-complementing group 1 ) is a base excision repair protein that plays a central role in the repair of DNA strand breaks and base damage from a variety of endogenous and exogenous oxidants including tobacco smoke . | ||
| 2 | One genetic polymorphism ( G-->A , Arg-->Gln at codon 399 ) occurs within a poly ( ADP-ribose ) polymerase binding region and within the central breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1 . | ||
| 3 | The variant 399Gln allele of XRCC1 has been associated with elevated biomarkers of DNA damage in human cells . | ||
| 4 | We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic DNA , and questionnaire information from 309 cases of pancreatic adenocarcinoma and 964 controls that were part of a population-based , case-control study conducted in the San Francisco Bay Area between 1994 and 2001 . | ||
| 5 | We genotyped individuals using a mass spectrometry-based method . | ||
| 6 | Because smoking and obesity are known and suspected pancreas cancer risk factors , and have been associated with DNA damage and oxidative stress in target tissues , we estimated odds ratios ( ORs ) , interaction contrast ratios ( ICRs ) , and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index ( in kg/m(2) ) . | ||
| 7 | We also assessed potential gene - gene interactions between polymorphisms in XRCC1 and CYP1A1 , GSTT1 , and GSTM1 . | ||
| 8 | We found little or no evidence for an association between XRCC1 genotype and pancreatic cancer among Caucasians , African-Americans , or Asians . | ||
| 9 | There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men . | ||
| 10 | Relative to never active or passive smokers with the Arg/Arg genotype , the age - and race-adjusted ORs and ICRs ( 95% confidence limits ) for heavy smoking ( >or = 41 pack-years ) were : for Gln/Gln or Arg/Gln genotypes [women OR = 7.0 ( 24 , 21 ) , ICR = 3.1 ( 003 , 62 ) ; men OR = 2.4 ( 11 , 50 ) , ICR = 1.3 ( -020 , 28 ) ] ; and for the Arg/Arg genotype [women OR = 2.2 ( 073 , 64 ) ; men OR = 1.5 ( 068 , 32 ) ] . | ||
| 11 | Analyses of combined genotypes suggested an interaction between XRCC1 ( Gln/Gln or Arg/Gln ) and GSTT1/GSTM1-null/null among women but not among men . | ||
| 12 | There was no evidence of interaction between XRCC1 genotype and body mass index . | ||
| 13 | Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced pancreatic cancer . | ||
| 14 | Our findings , including stronger associations and interactions among women , require replication in additional study populations . |
| PMID: 18544627 (Patient) Terms: case, control |
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| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Polymorphisms in DNA repair genes , smoking , and pancreatic adenocarcinoma risk . | ||
| 1 | Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage , including damage from tobacco exposure . | ||
| 2 | Single-nucleotide polymorphisms ( SNP ) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development . | ||
| 3 | We performed a clinic-based , case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls . | ||
| 4 | Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1 , XPD/ERCC2 , XPC , XPF/ERCC4 , OGG1 , and XRCC1 were compared after adjusting for age , sex , and smoking history . | ||
| 5 | Subgroup analysis by sex and smoking history was performed . | ||
| 6 | Μ | Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio ( OR ) , 0.59 ; 95% confidence interval ( 95% CI ) , 0.40-0.85] . | |
| 7 | Heavy smokers ( >40 pack-years ) had increased risk for cancer if they were carriers of atleast one minor allele for XPD/ERCC2 at D312N ( OR , 278 ; 95% CI , 128-604 ) or D711D ( OR , 219 ; 95% CI , 101-473 ) . | ||
| 8 | No other significant differences in risk were identified . | ||
| 9 | Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer . |
| PMID: 16520463 (Patient) Terms: |
|||
| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Single nucleotide polymorphisms of RecQ1 , RAD54L , and ATM genes are associated with reduced survival of pancreatic cancer . | ||
| 1 | PURPOSE : | ||
| 2 | Our goal was to determine whether single nucleotide polymorphisms ( SNPs ) in DNA repair genes influence the clinical outcome of pancreatic cancer . | ||
| 3 | PATIENTS AND METHODS : | ||
| 4 | We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma . | ||
| 5 | All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M . | ||
| 6 | D . | ||
| 7 | Anderson Cancer Center ( Houston , TX ) from February 1999 to August 2004 and observed through August 2005 . | ||
| 8 | Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival . | ||
| 9 | Kaplan-Meier plot , log-rank test , and Cox regression were used to compare survival of patients according to genotype . | ||
| 10 | RESULTS : | ||
| 11 | ✓ | The RecQ1 A159C , RAD54L C157T , XRCC1 R194W , and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001 , .004 , .001 , and .02 , respectively . | GM-ASS-RO |
| 12 | A strong combined effect of the four genotypes was observed . | ||
| 13 | ✓ | Patients with none of the adverse genotypes had a mean survival time of 62.1 months , and those with one , two , or three or more at-risk alleles had median survival times of 27.5 , 14.4 , and 9.9 months , respectively ( log-rank P <001 ) . | GM-ASS-RO |
| 14 | There is a significant interaction between the RecQ1 gene and other genotypes . | ||
| 15 | ✓ | All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors . | GN-MRK-RO |
| 16 | CONCLUSION : | ||
| 17 | These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer . |
| PMID: 17230526 (Patient) Terms: |
|||
| Sent# | Symbols | Sentence | Mnemonics |
| 0 | ✓ | Effects of base excision repair gene polymorphisms on pancreatic cancer survival . | GM-INV-RO |
| 1 | To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer , we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M . | ||
| 2 | D . | ||
| 3 | Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006 . | ||
| 4 | Genotypes were determined using genomic DNA and the MassCode method . | ||
| 5 | Overall survival was analyzed using the Kaplan-Meier plot , log-rank test and Cox regression . | ||
| 6 | We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival . | ||
| 7 | ✓ Μ | The median survival time ( MST ) was 35.7 months for patients carrying atleast 1 of the 2 homozygous variant POLB GG or CC genotypes , compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes ( p = 002 , log rank test ) . | GM-ASS-RO |
| 8 | ✓ | The homozygous variants of hOGG1 G2657A , APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders . | GM-ASS-RO |
| 9 | ✓ Μ | In combined genotype analysis , a predominant effect of the POLB homozygous variants on survival was observed . | GM-INV-RO |
| 10 | When POLB was not included in the model , a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying atleast one of the adverse genotypes . | ||
| 11 | These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer . | ||
| 12 | These observations need to be confirmed in a larger study of homogenous patient population . |
| PMID: 18544627 (Patient) Terms: case, control |
|||
| Sent# | Symbols | Sentence | Mnemonics |
| 0 | Polymorphisms in DNA repair genes , smoking , and pancreatic adenocarcinoma risk . | ||
| 1 | Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage , including damage from tobacco exposure . | ||
| 2 | Single-nucleotide polymorphisms ( SNP ) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development . | ||
| 3 | We performed a clinic-based , case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls . | ||
| 4 | Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1 , XPD/ERCC2 , XPC , XPF/ERCC4 , OGG1 , and XRCC1 were compared after adjusting for age , sex , and smoking history . | ||
| 5 | Subgroup analysis by sex and smoking history was performed . | ||
| 6 | Μ | Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio ( OR ) , 0.59 ; 95% confidence interval ( 95% CI ) , 0.40-0.85] . | |
| 7 | Heavy smokers ( >40 pack-years ) had increased risk for cancer if they were carriers of atleast one minor allele for XPD/ERCC2 at D312N ( OR , 278 ; 95% CI , 128-604 ) or D711D ( OR , 219 ; 95% CI , 101-473 ) . | ||
| 8 | No other significant differences in risk were identified . | ||
| 9 | Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer . |