bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of Lynch syndrome to early onset malignancy in Ireland.
Authors: Talbot Alice , Gallagher David James 
Published: January 2019

586 Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]
LINE-1 hypomethylation in colon cancer.
Authors: Vodolazhsky Dmitriy I. , Timoshkina Natalya N. , Panina Svetlana B. 
Published: January 2019

588 Background: Global hypomethylation of the genome is one of the causes of chromosomal instability and aneuploidy and is associated with an increased risk of colorectal cancer (CRC). The long interspersed nucleotide element-1 (LINE-1) is the main part of the mobile repeated elements of the genome, and the level of its methylation is concordant with genome-wide methylation. The aim of the study was to assess the methylation of LINE-1, as well as methylation of the promoter of six cancer-associated genes adjusting for the clinical and pathological characteristics in colorectal cancer (CRC). Methods: Using pyrosequencing (PyroMark Q24 analysis system, Qiagen, Germany) DNA methylation levels of LINE-1 and 6 genes ( APC, CDH13, MLH1, MGMT, P16 and RASSF1A) were measured in tumoral and normal tissues of 50 patients with CRC. Results: The level of LINE-1 methylation was 66.8 ± 0.89% in tumors, 72.5 ± 0.45% in normal tissues ( p = 0.0013). The differences in LINE-1 methylation level were not associated with age, differentiation grade, tumor localization, and the presence of activating mutation within the KRAS gene. At the same time, the MGMT methylation was positively associated with age ( p = 0.04), and the hypermethylation of the CDH13 gene was more common in tumors of the proximal colon ( p = 0.004). Methylation of the CDH13 promoter negatively correlated with methylation level of LINE1 ( r = -0.427, p < 0.05). Hypomethylation of LINE-1 was associated with progression of TNM-stages of the tumors ( r = +0.606, p < 0.001). The cancer-associated genes were hypermethylated in 70% of CRC cases when compared with normal epithelium, and hypomethylation of LINE-1 was observed in 90% of CRC cases. Conclusions: The present study demonstrated the association of LINE-1 methylation with the TNM tumor stage, which may be used as a biomarker for early diagnosis and prognosis of sporadic CRC, together with assessment of hypermethylation of tumor suppressors.
Evaluation of the sensitivity of RAS mutation detection of the Idylla platform in comparison to the OncoBEAM RAS CRC assay.
Authors: Vivancos Anna , Aranda Enrique , Benavides Manuel , Elez Elena , Gomez A. , Toledano Marta , Alvarez Martina , Parrado M Rosario Chica , García-Barberán Vanesa , Diaz-Rubio Eduardo 
Published: January 2019

592 Background: Accurate detection of RAS mutations in metastatic colorectal cancer (mCRC) patients is of high clinical importance for therapy selection as RAS detection methods lacking sensitivity may lead to poor patient outcomes. Liquid biopsy has emerged as a viable alternative to individualize the management and treatment of mCRC patients. However, there is a current need to cross-compare the performance of liquid biopsy platforms. The OncoBEAM RAS dPCR assay offers highly sensitive RAS mutation detection in clinical practice, achieving > 90% concordance when compared to results obtained by tumor mutation testing. The Idylla platform offers a highly-automated qPCR platform for RAS mutation testing of tissue samples, and has shown potential for liquid biopsy. The objective of this study was to provide a head-to-head comparison of the sensitivity of OncoBEAM and Idylla for KRAS mutation detection in plasma from mCRC patients. Methods: Plasma samples from 92 mCRC patients determined to be KRAS-positive using OncoBEAM were re-tested using Idylla. Samples with mutant allelic fractions (MAF) below 5% were selected for analysis. The positive percent agreement (PPA) of KRAS mutation results was compared for replicate samples analyzed by OncoBEAM and Idylla. Results: So far, Idylla detected KRAS mutations in 63 out of 92 (68.4%) OncoBEAM KRAS-positive plasma samples. Categorization of results based on MAF% revealed distinct differences in sensitivity between the two technologies. Conclusions: OncoBEAM demonstrated significantly greater sensitivity for plasma detection of RAS mutations than Idylla. Moreover, these data identify a “gray zone” below 1% MAF where Idylla fails to identify RAS-positivity in patient plasma samples. These findings serve as a reminder that liquid biopsy assays with diminished sensitivity may lack the dynamic range to provide accurate and timely RAS mutational status information to properly guide highly individualized anti-EGFR therapy and chemotherapy treatment decisions that may benefit patient outcomes. [Table: see text]
Molecular characterization of intestinal (IS) and diffuse subtypes (DS) of gastric adenocarcinomas.
Authors: Salem Mohamed E. , Xiu Joanne , Puccini Alberto , Philip Philip Agop , Goldberg Richard M. , Hwang Jimmy J. , Kc Birendra , Korn Wolfgang Michael , Shields Anthony Frank , Lenz Heinz-Josef , Marshall John 
Published: January 2019

60 Background: Gastric adenocarcinomas are histologically categorized into IS and DS. TCGA categorization suggests that IS is more common in tumors arising via the chromosomal instability pathway and DS is more common in genomically stable tumors. However, molecular differences between these subtypes are not well understood. Methods: Gastric adenocarcinomas were examined using NextGen sequencing (MiSeq platform on 47 genes or NextSeq on 592 genes), protein expression, and gene amplification techniques. For tumors sequenced with NextSeq, tumor mutational load (TML) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated on known MSI loci in target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 268 gastric adenocarcinomas with annotated histology (DS [n = 144]; IS [n = 124]) were analyzed. Patients with DS were younger than those with IS (mean age: 27y [DS] vs. 65y [IS], p < 0.0001). The majority of patients with DS were female (56% [DS] vs. 35% [IS], p = 0.0004). Most frequently mutated genes in DS were TP53 (44%), ARID1A (37%) , CDH1 (14%), BAP1 (8%), and PIK3CA (5%); whereas the most frequent mutations in IS were ARID1A (57%), TP53 (51%), CDKN2A (13%), MUTYH (13%), and PIK3CA (12%). IS had a higher rate of APC mutations (10% vs. 2%, p = 0.04), whereas DS had a higher rate of CDH1 (14% vs. 2%, p = 0.01). There was no difference in PD-L1 tumor expression (DS: 4%; IS: 8%). IS, when compared to DS, exhibited higher overexpression of TOP2A (90% vs 50%, p < 0.0001), TS (58% vs 28%, p < 0.0001), RRM1 (47% vs 22%, p = 0.0006), and Her2/neu (14% vs 1%, p < 0.0001), and greater Her2 amplification (19% vs 2%, p < 0.0001). Microsatellite instability was not detected in DS, and there was a trend toward a higher frequency of MSI-high in IS (6% [IS] vs. 0% [DS], p = 0.06), as well as a higher mean TML (10.3 vs. 6.6 mutation/megabase, p = 0.01). Conclusions: Significant molecular differences between IS and DS gastric adenocarcinomas were observed, a finding that indicates different carcinogenic pathways and biology, as well as potential differences in response to therapy. Low frequency mutations in several druggable genes may provide therapeutic options.
Impact of age on clinical and pathological features as well as outcome in Egyptian patients with colorectal cancer (CRC).
Authors: Rashad Noha , Heeke Arielle Lutterman , Khaled Hussein Mustafa , Ali El din Nelly , Abd El Motaal Gamal , Wang Hongkun , Salem Mohamed E. 
Published: January 2019

600 Background: The incidence of early onset CRC is rising. Little is known about the clinicopathological differences between younger and older Egyptian (EGY) adults with CRC. Herein we explore these differences. Methods: A retrospective review of younger EGY adult (YA; ≤ 46 years) and older EGY adult (OA; > 65 years) patients (pts) with CRC was performed. T and Fisher’s exact tests were used for comparative analyses. Kaplan-Meier methodology estimated survival. Results: In total, 997 EGY pts with CRC were studied, including 443 YA (median age 35 years; range 15-46) and 153 OA pts (median 70 years range 65-84).There were no statistically significant differences with respect to gender, degree of tumor differentiation, extracolonic extension, stage at presentation, or patterns of metastasis between the two groups. YA pts had more rectal primaries compared with OA pts (49% vs. 31%, p < 0.001), whereas older pts had more colon primaries (69% vs. 51%, p < 0.001). Additionally YA pts had more left-sided tumors (78% vs. 62%, p < 0.001) compared with OA pts, whereas older pts had more right-sided tumors (32% vs. 17%, p < 0.001). YA pts were more likely to have mucin-producing tumors (40% vs. 23%, p = 0.003). Although there were no differences in the proportion of pts presenting with metastatic disease (28% [YA] vs. 32% [OA], p = 0.615), or the pattern of metastasis to the liver, lung, or peritoneum (40% vs. 50%, p = 0.288; 5% vs. 6%, p = 1.00, 16% vs. 17%, p = 1.00), YA were more likely to have CRC-related lymph node (LN) involvement (mean: 3.2 vs. 1.6, p = 0.006). There were no differences in PFS (Median: 12 months for YA vs. 13 months for OA) or OS (median: 76 months for YA vs. not reached for OA) between the two groups. However male YA pts had a better OS that female pts (median OS not reached in males, 72 months in females). Conclusions: Significant differences were evident between YA and OA pts with CRC, notably locations of primary tumors. Male had improved outcome compared to female YA patients. Additional evaluation of the molecular features of CRC in young and older patients in Egypt is warranted.
Racial/ethnic variation in incidence rates for anal cancer in New Mexico.
Authors: Osman Diaa , Fahy Bridget N. , Belmonte Jessica , Meisner Angela W. , Wiggins Charles 
Published: January 2019

601 Background: Anal cancer comprises only 2.5% of all digestive system malignancies in the United States; only 8200 new cases are diagnosed annually, nevertheless, an increasing incidence rate has been noted. The goal of this study is to describe the incidence rates of anal cancer in New Mexico. New Mexico is a unique, mainly rural state, with unique demographics consisting of a large mix of patients being primarily Non-Hispanic White, Hispanics or Native Americans. Methods: All incident cases of anal cancer diagnosed among New Mexico residents during the twenty-year period 1995-2014 were identified from the population-based New Mexico Tumor Registry. Average annual age-adjusted incidence rates (US 2000 standard) were calculated by the direct method for non-Hispanic whites, Hispanics and American Indians. Incidence rates for non-Hispanic whites in nine core areas of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program served as the comparison. Results: A total of 556 anal cancers were diagnosed among New Mexico residents during the study period, an average of approximate 28 cancers annually. Anal cancer incidence rates per 100,000 were highest for non-Hispanic whites (1.80, 95% Confidence Interval (CI) 1.62-1.98) in New Mexico, which were similar to rates for non-Hispanic whites (1.70, 95% CI 1.66-1.74) in nine core areas of the SEER Program. Statistically significant lower rates were observed in New Mexico Hispanics (0.92, 95% CI 0.76-1.11) and American Indians (0.75, 95% CI 0.45-1.16). Females had higher rates than males in each of these three racial/ethnic groups. Incidence rates increased from 1995-2004 to 2005-2014 for all race/ethnic groups, with the largest increase observed in Hispanic females. Conclusions: Anal cancer incidence rates vary by race/ethnicity and sex in New Mexico. Further research is needed to characterize time trends in incidence and to identify factors that may account for observed differences in incidence rates by race/ethnicity and sex in New Mexico.
Peritoneal carcinomatosis of colorectal origin: Impact of ovarian metastases.
Authors: Ghouti Laurent , Pinto Amandine , Kirzin Sylvain 
Published: January 2019

604 Background: To compare survival and morbidity in women treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for colorectal peritoneal carcinomatosis with or without ovarian metastases (OM). Methods: A prospectively maintained database was analyzed to identify women treated by CRS- HIPEC between 2009 and 2015. Results: Among 62 included women, 39 had ovarian metastasis (63%) with comparable PCI (10 vs. 7 p=0.15). OM patients experienced more frequent grade III/IV postoperative morbidity (56.4% vs. 30% p=0.04), and postoperative haemoperitoneum (23.1% vs 4.3% p=0.07) leading to more frequent reoperation (36 vs. 21.7% p=0.2). Among OM patients, 20 (52 %) had undergone ovariectomy previously to CRS-HIPEC procedure. Haemoperitoneum (30% vs 15% p=0.4) and reoperation (45% vs. 26% p=0.2) were more frequent if previous OM resection had been performed as compared to synchronous. The 36-month survival (94.7 % vs 61.7 %) was significantly impaired by OM (p=0.007) and 36- month survival without recurrence was better when ovariectomy was performed during CRS- HIPEC (24 % vs. 5.5%, p=0.4). Conclusions: Survival and morbidity of patients with CRS-HIPEC for colorectal peritoneal carcinomatosis were impaired by the presence of OM and previous OM resection.
HER2 positivity in brain metastases from gastrointestinal primary malignancies.
Authors: Mitra Devarati , Shih Helen Alice , Oh Kevin , Brastianos Priscilla , Wo Jennifer Y , Curry William , Clark Jeffrey W. , Parikh Aparna , Corcoran Ryan Bruce , Ryan David P. , Lennerz Jochen K , Hong Theodore Sunki 
Published: January 2019

61 Background: HER2 amplification in gastrointestinal (GI) cancers, beyond gastric cancer, is uncommon and as a result infrequently tested. In breast cancer, HER2 amplification has been associated with brain metastases (BM) with associated prognostic value and therapeutic opportunity. The purpose of this project was to determine if HER2 amplification is more frequent in GI cancer patients with brain metastases. Methods: Retrospective review of our institution’s medical record system identified all patients with GI primary malignancies who had resection of BM between 1999-2015 with tissue available. Fluorescence in-situ hybridization for HER2 amplification and immunohistochemistry for HER2 expression was performed on each sample and quantified by a board-certified pathologist. Results: Twenty-five GI cancer patients with BM were identified: 40% esophageal adenocarcinoma (AC), 12% esophageal squamous cell carcinoma (SCC), 44% colorectal AC and 4% pancreatic AC. At diagnosis 36% had metastatic disease. A BM was the isolated first site of metastasis in: 11/13 esophageal cancers, 1/11 colorectal cancers and 1/1 pancreatic cancer. Two esophageal cancer patients and one colon cancer patient had BM at diagnosis but otherwise median time to BM was 30 months (range 4-127 months). There was a median of 1 BM with a maximum of 4 lesions per patient. The most common intracranial site was the cerebellum (40%) with a median metastasis size of 27 mm (range 5-55 mm). Overall, HER2 was amplified in 24% (n=6) with 4 of these patients having paired primary tumor tissue available. None of the primary tumor tissue was HER2 amplified. No colorectal cancer patients had HER2 amplification but 67% of esophageal SCC, 30% of esophageal AC and the only pancreatic AC patient had Her2 amplified and overexpressed brain metastases. Conclusions: HER2 amplification was enriched in esophageal SCC and AC patients who developed resectable BM despite none of these patients having HER2 amplification in their primary tissue. HER2 amplification testing in esophageal cancer patients with BM (regardless of histology) may lead to additional therapeutic options, even if primary tissue was negative for HER2 amplification.
Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)â€“An ACCRU Network study.
Authors: Bekaii-Saab Tanios S. , Ou Fang-Shu , Anderson Daniel M. , Ahn Daniel H. , Boland Patrick McKay , Ciombor Kristen Keon , Jacobs Nisha Lassi , Desnoyers Rodwige J. , Cleary James M. , Meyers Jeffrey P. , Chiorean E. Gabriela , Pedersen Katrina , Barzi Afsaneh , Sloan Jeffrey , McCune Jeannine S. , Lacouture Mario E. , Lenz Heinz Josef , Grothey Axel 
Published: January 2019

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.
The 12-gene Oncotype DX Colon Recurrence Score (RS) test: Experience with > 20,000 stage 2 patients (pts).
Authors: Bailey Helen , Turner Michelle , Stoppler Melissa C , Chao Calvin 
Published: January 2019

618 Background: Genomic assays can provide information beyond the traditional methods used to assess risk of recurrence. The 12-gene Oncotype DX Colon RS test is clinically validated to predict recurrence risk after surgical resection in pts with stage 2 colon cancer (CC). The test measures expression of 12 genes (7 cancer-related; 5 reference) to give an RS result (scale 0-100) that estimates the risk of recurrence based on individual tumor biology in MMR-proficient tumors. Here, we report the Genomic Health Clinical Laboratory experience with stage 2 CC since its commercially availability. Methods: Over 20,000 samples from stage 2 CC pts submitted from 4/2010 to 8/2017 were analyzed. Descriptive statistics for the clinical characteristics of pts and RS results were calculated. Standard low (RS < 30), intermediate (RS 30-40), and high (RS ≥41) RS subgroups were used. Results: In 20,406 samples, 92.4% were adenocarcinoma and 7.6% were mucinous carcinoma. Median age was 64 y; 51% were men. Samples were received from 42 countries. The median RS result was 24 (range 0-77); 72% had low, 20% had intermediate, and 8% had high RS results. Mucinous carcinoma had a significantly higher median RS result than adenocarcinoma (34 vs. 23; p < 0.001). Of adenocarcinoma pts, 74% had low, 20% intermediate, and 6% had high RS results. Of mucinous carcinoma pts, 35% had low, 35% had intermediate, and 30% had high RS results. Conclusions: More than 20,000 samples from stage 2 CC pts were submitted over a 7-year period for Colon RS testing. Compared with adenocarcinoma, mucinous carcinoma had a higher median RS result and more high RS results. Overall, there was a wide range of RS results (0-77), indicating that risk of recurrence is continuous and not simply dichotomous. Traditional methods for assessing risk do not reveal the full picture. Because the 12-gene Colon RS result provides a quantitative and more individualized risk assessment for stage 2 CC pts beyond T-stage and MMR status, the test greatly improves the ability of clinicians to personalize care and treatment decisions for these pts.