bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel RAS internal tandem duplication involving the switch II domain disrupts GAP-binding and activates oncogenic signaling.
Authors: Lou Emil , Turbyville Thomas , Simanshu Dhirendra , Yang Rendong , Columbus John , Stephens Bob , Sciacca Drew , Sarver Anne , Subramanian Subbaya , Nissley Dwight , Nelson Andrew 
Published: May 2019

e15069 Background: Recent clinical guidelines for expansion of molecular testing of oncogenic RAS mutations in colorectal carcinoma have led to increased identification of mutations in this patient population. The clinical characteristics of NRAS-mutated colorectal carcinoma have not been well established because of the lower prevalence of these mutations (< 6%) as compared to oncogenic KRAS mutations. Here, we report the discovery of a novel internal tandem duplication (ITD) mutation of NRAS, which disrupts the Switch II domain in an index case of a patient with widely disseminated colorectal cancer. Methods: Hotspot next generation sequencing of a brain metastasis using a clinical solid tumor panel identified this novel NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) was performed to identify other genetic factors potentially driving the disease. Results: The above approach confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). No other clearly pathogenic driver mutations were identified. Structural biology and biochemical analyses demonstrated that the inserted 15 amino acids prevented binding to GAP protein, leading to sustained RAS activation and increased interaction with RAF to stimulate downstream MAPK activation. Conclusions: These genomic and biochemical studies indicate that a novel NRAS ITD was the primary driver mutation of this aggressive colorectal carcinoma. Identical or similar ITDs in NRAS and KRAS may also drive other forms of colorectal cancer and other aggressive malignancies and represent a new subset of RAS-driven drug-resistant cancers.
Structured literature review (SLR) and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in gastric, colorectal, and esophageal cancers.
Authors: Amonkar Mayur , Lorenzi Maria , Zhang Jacky , Mehta Shivani , Liaw Kai-Li 
Published: May 2019

e15074 Background: Pembrolizumab is approved in the US for treatment of unresectable/metastatic MSI-H/dMMR solid tumors progressing after standard prior treatment. While some data exist on MSI-H/dMMR prevalence in colorectal cancer (CRC), data on other gastrointestinal (GI) cancers is sparse. Methods: An SLR covering solid tumor types identified English language publications using immunohistochemistry (IHC) for all 4 MMR proteins or polymerase chain reaction (PCR) techniques using specified NCI or Promega marker panels. A targeted review was conducted for CRC due to larger volume of publications in this tumor type. MEDLINE, EMBASE, Cochrane databases and key cancer congresses were searched for relevant articles. Among eligible studies, meta-analyses were performed (random effects model) on the prevalence of MSI-H and dMMR among gastric, colorectal and esophageal cancers. If possible, prevalence estimates were also obtained by geography, disease stage, and histology. Results: Of 1,176 citations retrieved in the full review, 35, 17 and 6 studies reported prevalence of MSI-H and/or dMMR in gastric, CRC, and esophageal cancers, respectively. Among gastric cancers, MSI-H pooled prevalence (with 95% CI) from 32 studies (16,308 patients) was estimated at 11% (9-12%) and dMMR pooled prevalence from 4 studies (854 patients) was estimated at 8% (2-17%); in stage 4 cancers, the prevalence was 7% (4-9%; 10 studies; 383 patients). In CRC, MSI-H pooled prevalence from 14 studies (8,156 patients) was estimated at 13% (10-16%) and dMMR pooled prevalence from 4 studies (11,434 patients) was estimated at 10% (5-15%). For stage 4 CRC, the prevalence was 5% (1-10%; 4 studies; 252 patients). Among esophageal cancers, MSI-H pooled prevalence from 6 studies (731 patients) was estimated at 4% (0-11%). Conclusions: This comprehensive SLR provides prevalence estimates of MSI-H and dMMR across 3 key GI tumors based on published data. The prevalence estimates of MSI-H among gastric cancer and CRC were similar to their corresponding dMMR prevalence estimates. MSI-H prevalence appeared to be lower for advanced stage gastric cancer and CRC.
Tumor stroma percentage (TSP) and intrinsic subtypes in stage II/III colon cancer: NRG Oncology/NSABP C-07 trial.
Authors: Kim Rim S , Gavin Patrick G , Paik Soonmyung , Allegra Carmen Joseph , Jacobs Samuel A. , Pogue-Geile Katherine L. , Lucas Peter C. 
Published: May 2019

e15075 Background: Recent molecular subtype studies of colorectal cancer (CRC) have identified various genomic signatures. Regardless of the variety of studies, poor prognosis is associated with stem-like or mesenchymal subtypes, which are largely contributed by stromal cells or cancer-associated fibroblasts (CAF) and are driven by transforming growth factor-beta (TGF-ß) signaling. Tumor stroma percentage (TSP) in CRC morphologically evaluated on H&E slides has been reported as an independent prognostic parameter in stage II/III colon cancer patients (pts). We tested the association of TSP with molecular subtypes in NRG Oncology/NSABP C-07, in which pts with a stem-like or mesenchymal subtype had a poor prognosis regardless of chemotherapy regimen. Methods: Ninety seven pts with available archived whole-section H&E images from C-07 were reviewed for TSP for the stromal proportion in the most invasive part of the primary tumor as stroma-high (>50%) or stroma-low (≤50%) as described in other studies. The population was selected to be enriched with stem-like subtype. Subtypes were determined by modified centroids based on Assigner (CRCA) classifier using archived nCounter data, described previously. Results: Of 23 pts, 22 (95.7%) with stroma-high tumor (TSP >50%) were classified with the stem-like subtype. One stroma-high pt had a tumor with a non-stem-like subtype. Of 56 pts with stem-like subtype tumors, 22 were classified as stroma-high, whereas 1/41 with non-stem-like tumors was classified as stroma-high (P=0.00007). Conclusions: TSP is strongly associated with stem-like subtype of poor prognosis in stage II/III CRC and identifies a subset of stem-like subtype. Further study may reveal TSP as a simple biomarker for treatment resistance and potential therapies targeting stromal cells or CAF driven by TGF-ß signaling. SUPPORT: sanofi; U10CA180868, -180822, U24CA196067, PA DoH; NSABP. No. of samples with TSP >50 according to CRCA subtypes. Clinical trial information: NCT00004931. [Table: see text]
DNA methylation profiling from circulating tumor DNA for early-detection of colorectal cancer.
Authors: Zhang Wei , Sui Jinke , Wu Xianrui , Cao Fuao , Yu Guanyu , Wang Chenyang , Zhang Zhihong , Li Bingsi , Fang Shuai , Han-Zhang Han , Lou Zheng , Gong Haifeng , Liu Lianjie , Zheng Nanxin , Hao Liqiang , Lan Ping 
Published: May 2019

e15076 Background: Colorectal cancer (CRC) develops as a result of neoplastic progression, which often takes decades, providing a window for early detection. Unfortunately, there has been little success in developing blood-based screening method due to the low amount of ctDNA present in the circulation, especially in patients with early stage disease. The role of aberrant DNA methylation, occurring very early in tumorigenesis, has been well elucidated. In this prospective study, we evaluated the potentiality of DNA methylation status obtained from ctDNA as an early detection method. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were extracted using modified wald-test with an adjusted p-value < 0.05 and fold-change > 2. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. We performed targeted bisulfite sequencing on plasma samples of 67 (stage I: 13, II:29, III: 23, IV: 2) Chinese CRC patients and 144 healthy individuals to construct a model for deriving markers that are differentially methylated and their associated weight. The model was validated in 2 independent cohorts. Results: We constructed a model using a support vector machine (SVM)-based machine learning classifier based on top 4,000 differentially methylated regions (DMRs) selected by random forest between tumor and normal plasma samples. Subsequently, 5-fold cross-validation with 100-time repeats were performed to gain a robust estimation of model performance, achieving a sensitivity of 91%, specificity of 98% and area under curve (AUC) of 98.6%. The model was subsequently validated in 2 independent cohorts: one consisted of 57 stage I-III CRC patients and 74 healthy individuals and another one with 47 stage IV patients and the same 74 healthy individuals. The model yielded a sensitivity of 83% and 95% for the early and late stage cohorts, respectively. A specificity of 95% was obtained for both cohorts. Conclusions: Our findings demonstrated the potential of profiling DNA methylation, which can effectively distinguish cancerous from healthy, for the purpose of screening. This method has potential to serve as a supplementary or alternative approach in early detection.
KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.
Authors: Yang Liu , Jiang Jiahong , Chang Lianpeng , Xu Yaping , Ni Chao , Huang Dongsheng 
Published: May 2019

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.
Evaluating cancer outcomes of outpatient colonoscopies in elderly patients older than 85 years of age.
Authors: Lee Joy A , Bi Xia , Huang Connie Y , Coyle Walter 
Published: May 2019

e15079 Background: With increasing life expectancy, the incidence of colorectal cancer increases. Currently, there are few studies on cancer outcomes of outpatient colonoscopy in patients older than 85 years of age. Methods: The database at Scripps was queried for all outpatient colonoscopies performed under moderate sedation between April 1, 2012 to March 31, 2017 on patients aged 85 years and older. Patient demographics, indication for procedure, and endoscopic findings were obtained. Variables including location and stage of tumor, subsequent treatments, and overall mortality were analyzed. Results: 322 outpatient colonoscopies were reviewed. Median age was 86 years. 53% were females. Screening colonoscopies accounted for 2.1% of procedures. 40 (12.4%) colon cancers were detected. 38 (95%) were adenocarcinomas and 2 (5%) were neuroendocrine tumors. 26 (65%) were right sided colon cancers. Among those diagnosed with cancer, anemia was the most common indication followed by positive fecal occult blood test (FOBT). 20 (50%) of these patients had a FOBT within the past year. Of those FOBTs, 18 (90%) were positive. Median age of patients with colon cancer was 88 years. 70% were females. 12 (30%) patients had never had a colonoscopy. 19 (47.5%) were diagnosed at an advanced stage (stage III or IV). 32 (80%) pursued surgery, 10 (25%) received chemotherapy, and 5 (12.5%) received radiation. 3 (7.5%) patients received supportive care only. 1-year mortality was 22.5% and 3-year mortality was 40% from the time of diagnosis. Conclusions: To date, this is the first study in the United States that examines cancer outcomes in an elderly population undergoing an outpatient colonoscopy. Overall, patients over the age of 85 with colorectal cancer have good outcomes that are comparable to that of the general population and colonoscopies should be considered for appropriate candidates.
The prognostic value of KRAS mutation in locally advanced rectal cancer.
Authors: Bakalov Veli , Hasan Shaakir , Abel Stephen , Babar Laila , Shaikh Hira , Raj Moses S. , Finley Gene Grant , Monga Dulabh K. , Kirichenko Alexander V. , Wegner Rodney E 
Published: May 2019

e15090 Background: The prognostic value and prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). Methods: We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status.Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. Results: Of the 784 eligible patients, 506 and 278 were KRAS negative (KRAS-) and KRAS positive (KRAS+). Median survival was 63.6 months and 76.3 months for KRAS+ and KRAS-patients, with propensity adjusted 3 and 5-year survival of (79.9% vs. 83.6%) and (56.7% vs 61.9%) respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS+ disease was associated with poorer survival on unadjusted and propensity adjusted multivariable analyses (Table). Conclusions: Our analysis of KRAS+ LARC suggest that KRAS+ disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted. [Table: see text]
Effect of PTPRB on metastasis of colorectal carcinoma and induction of epithelial-mesenchymal transition.
Authors: Weng Xingyue , Zheng Shu 
Published: May 2019

e15099 Background: Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Metastasis and recurrence are believed to be responsible for limiting long-term survival of patients with CRC. Protein tyrosine phosphatase, receptor type B ( PTPRB) belongs to the protein tyrosine phosphatase family. Multiple studies have previously demonstrated that dysregulation of PTPRB function and expression has been shown to correlate with carcinogenesis and tumor progression in multiple cancer types. Methods: In this study, we used CRC cell lines to explore the expression of PTPRB and to analyze the biological function of PTPRB protein. Surgical tumor specimens were collected for immunohistochemical staining to evaluate PTPRB expression.Real-time polymerase chain reaction (PCR) and western blot analysis were used to confirm genes and proteins of interest, respectively. Results: PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent non-tumor tissues and in CRC cell lines with high metastasis potential. PTPRB knockdown decreased the number of invasive CRC cells in a vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression decreased E-cadherin expression and promoted vimentin expression, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted metastasis in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Conclusions: PTPRB is upregulated in CRC and overexpression of PTPRB promotes the metastasis of CRC. Moreover, our study revealed the effect of PTPRB on promoting EMT, as reflected in increased vimentin and decreased E-cadherin expression. PTPRB is a novel therapeutic target for the treatment of CRC.
Prediction of trifluridine/tipiracil (TAS-102) effectiveness in patients with refractory metastatic colorectal cancer (mCRC): Real-life data from the Czech Republic.
Authors: Grell Peter , Dvorak Josef , Vocka Michal , John Stanislav , Tuskova Helena , Buchler Tomas , Borilova Simona , Selingerova Iveta , Vyzula Rostislav , Petruzelka Lubos B. , Kiss Igor , Obermannova Radka 
Published: May 2019

e15102 Background: TAS-102 is effective in refractory mCRC and significantly improved survival versus placebo. Currently no predictive biomarkers are established and used in clinical practice. Methods: We analyzed data of 160 patients treated with TAS-102 in real clinical practice in Czech Republic. Different factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated. Results: Baseline patients’ characteristics: median age 66 years (range 28-83), 106 patients were male (66.3 %), ECOG PS 0 had 38.1 %, RAS wt 45 %. Anti-VEGF treatment had 83.1 %, anti-EGFR 43.8 %. Median number of TAS-102 treatment line was 3 (range, 2 – 8), median TAS-102 cycles 3 (range 1 – 27). At the time of analysis 15 % continued in treatment, 73.7 % discontinued due to progression, 6.9 % due to toxicity, 3.8 % decided to discontinue in treatment. Median PFS was 3.3 months (95% CI, 3.0 – 3.5), and median OS 10.2 months (95% CI, 8.9 – 11.8). Factors significantly associated with PFS and/or OS were: PS, time from diagnosis of mCRC, initiation of TAS-102 treatment > 3 months from last fluoropyrimidine, baseline CRP, WBC, neutrophils count, monocytes count, NLR, neutropenia ≥ G2, diarrhea ≥ G1, thrombocytopenia ≥ G2, required TAS-102 dose reduction and cycle delay. We developed a scoring system TAScore from factors at the beginning of treatment (PS 0, initiation of TAS-102 > 3 months from fluoropyrimidine, time from diagnosis of mCRC, baseline CRP, WBC, monocytes count < 0.5 × 109/L). For each factor patient received 1 point, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS according to risk group was: 5.7 months for high risk (11 patients), 8.7 for intermediate (63), 12.8 for favorable (59) (P < 0.0001). TAScore was also associated with PFS: 2.4 months for high risk, 2.9 intermediate and 3.9 for favorable risk group (P < 0.0001). Conclusions: TAS-102 is effective in patients with refractory mCRC. We propose simple scoring system TAScore to help with precise patient selection at the beginning of TAS-102 treatment.
Optimizing cut-offs for high neutrophil-to-lymphocyte ratio as poor survival prognostic factor in colorectal cancer.
Authors: Namuche Fernando , Leon Jorge , Montenegro Paola Catherine , Flores Claudio J. 
Published: May 2019

e15111 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Needing to use all the possible tools for an accurate diagnosis and early treatment. Neutrophil-to-lymphocyte ratio (NLR) has been associated as poor prognostic factor in OS and PFS in CRC. There is no data that support this statement in Latin America. It is of a special utility in our country the detection of a simple and reproducible prognostic biomarker that guides the use of more advanced tests. Our objective was to explore the factors associated with OS in the local-locally advanced and metastatic settings. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We divided our population into two groups: Local-locally advanced (L-LA) (516 pts) and debut metastatic- recurrence (M-R) (108 pts). We performed a ROC curve analysis to determine an appropriate cut-off value for NLR in both groups (L-LA:NLR ≥3, M-R:NLR ≥5). A univariate survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: Pts with high NLR had significantly shorter OS in L-LA [HR, 12.1; 95% CI,5.019-29.211; p < 0.001] M-R [HR, 5.382; 95% CI,2.835-10.217; p < 0.001] than pts with low NLR. In the multivariate model, NLR retained a significant association with OS in both groups. Cox regression demonstrated that in L-LA setting sex, histologic grade and lymph node involvement; and in M-R setting sidedness, histologic grade, LVI and metastasectomy performed were independently risk factors for a shorter OS. Conclusions: High NLR is associated with poor prognosis (with our cut-offs L-LA:NLR ≥3, M-R:NLR ≥5). There are other variables to be considered that affect the OS, as: sex, histologic grade and lymph node involvement, sidedness, histologic grade, LVI and metastasectomy performed.
The Idylla MSI Test (CE-IVD) multi-center concordance study: Microsatellite instability detection in colorectal cancer samples.
Authors: Pauwels Patrick , Steiniche Torben , Gazin Muriel , Van de Velde Jan , Bellon Ellen , Rondelez Evelien , Vandenbroeck Liesbeth , Zwaenepoel Karen , De Winne Koen , Meyer Tine , Mejer Julie , Stougaard Magnus , Decanniere Klaas , Devogelaere Benoit , Maertens Geert G. , De Craene Bram 
Published: May 2019

e15112 Background: To validate the Idylla MSI Test to detect microsatellite instability (MSI) in colorectal cancer (CRC) samples in comparison with Promega MSI Analysis System v1.2 (Promega MSI) and in conditions similar to normal use. Methods: The study was performed on residual formalin-fixed and paraffin-embedded (FFPE) samples obtained from routine diagnostics by two centers, University Hospital Aarhus and University Hospital Antwerp. Samples originated from CRC patients (all stages). Both centers performed the Idylla MSI Test (with 7 novel homopolymer deletion markers) at their premises on 150 and 180 samples, respectively. The comparator method, Promega MSI, was performed for all 330 samples by University Hospital Antwerp. Results: Seven (n=7) of 330 samples were excluded from the concordance analysis due to invalid or error (failed) results for Idylla MSI Test and/or Promega MSI. For the 323 valid results, overall, positive and negative percentage agreement were 99.7% (98.3%-100%;), 98.7% (92.9%-99.8%) and 100% (98.5%-100%), respectively. A higher number of invalids was observed for Promega MSI (2.1%) compared to the Idylla MSI Test (0.6%) taking into account per protocol retesting (18 retests for Promega MSI (6%) and 3 for Idylla MSI Test (1%)). Conclusions: This study validated the Idylla MSI Test with high performance and low invalid rate to discriminate MSI-H from MSS status on a clinical routine set of CRC samples.