bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of DNA damage response and repair, cellular signaling, tumor suppressor, and immune checkpoint gene mutations in gastrointestinal cancers.
Authors: Burke Aidan M , Prins Petra , Yeh Celine , Weinberg Benjamin Adam , Kim Sunnie S. , He Aiwu Ruth , Pishvaian Michael J. , Marshall John , Unger Keith Robert 
Published: May 2019

e15149 Background: The prevalence of genetic mutations in gastrointestinal (GI) cancers is not well characterized. Molecular targeted therapies have substantial potential to improve outcomes. As next-generation sequencing (NGS) has become more commercially available, there may be additional opportunities to find novel targets for therapy or identify predictors of response to chemotherapy and radiotherapy. Commercially available DNA sequencing was conducted on patients with GI cancers to identify novel therapeutic and prognostic factors. Methods: A total of 86 solid tumor biopsy specimens from GI cancers were submitted for molecular profiling with NGS. Tumor molecular profiles were reviewed to identify frequently occurring pathogenic mutations in DNA damage and repair (DDR), cell cycle (CC), tumor suppressor (TS) and immune checkpoint (IC) pathways. DDR genes included MGMT, MSH 2/6 and ERCC1. CC genes included cMET, EGFR and KRAS. TS genes included APC, PTEN and TP53. IC genes included PD-1 and PDL-1. The overall frequency of mutations as well as the frequency of mutations for each primary site was analyzed. Results: Samples from colorectal (CRC, n=36), gastroesophageal (GE, n=5), liver and bile duct (LBD, n=14), pancreatic (PC, n=26) and other (OC, n=5) GI cancers were analyzed. Overall 46.3% of samples had at least one DDR mutation and commonly occurred in PC (57.7%) and CRC (50.0%).The most commonly mutated DDR genes were MGMT, TOPO1 and TOP2A. 55.2% of samples had at least one CC mutation and were most common in PC (69.2%), CRC (61.1%) and LBD (42.9%). The most common CC mutations were PTEN, P53 and KRAS. 65.5% of samples had at least one TS mutation with TP52 and PTEN being the most common. TS mutations occurred commonly in CRC (80.6%) and GE (60.0%). Mutations in PD-1 and PD-L1 (IC) were present in 25.3% of samples and occurred most frequently in GE (80.0%) and LBD (28.6%). Conclusions: Mutations were commonly seen in DDR (46.3%), CC (55.2%), TS (65.5%) and IC (25.3%) genes in GI primaries, providing a path to explore the role of novel therapeutic agents and how these mutations might be used to predict clinical outcomes.
Distance from the anal verge as an indirect measure to predict response to anti-EGFR therapy in left side metastatic colon cancer.
Authors: Armentano Daniela Pezzutti DOMINGUES , Monteiro Mariana Ribeiro , Araujo Raphael , Arakelian Renata , Cardoso Paula Freire , Tsukamoto Jessica , Moreira Raphael Brandao , Picon Fernando 
Published: May 2019

e15153 Background: Right and left sided colon cancers (RC, LC) differ with respect to biology and response to therapy. Several retrospective analyses have assessed the clinical effect of epidermal growth fator receptor (EGFR) targeted agents in patients with metastatic CRC (mCRC) according to the primary tumor location. Differentiating only right from left. But can in the LC responses differ according to the distance from the anal verge (DAV)? Methods: Exploratory retrospective analyses was planned to evaluate if LC responses differ according to the DAV. LC was defined as tumors originating anywhere from the distal rectum to the left colic flexure (splenic flexure). DAV was describe in cm measured by previous to surgery or treatment, colonoscopy, CT or MRI. Patients were divided for analysis purposes in two groups: Group A (tumors above 12cm from de anal verge), Group B (tumors below 12cm from the anal verge). Results: We retrospectively evaluated 29 patients with left metastatic colorectal cancer treated with anti-EGFR therapy as part of their treatment at the Paulistano Hospital -São Paulo from 2011 to 2018. Median population age 51.8 years (48.5-62.3). Median DAV 14.5 (4.6-25 cm). Median follow-up 12.8 months. No significant difference on stable and partial response rate was detected (Group A 43.7% vs Gropup B 56.3%), p=0.211. Long-rank test with a median pFS 8,5 meses and a PFS at 6 months of 66.7 vs 78,8 (Group A and Group B respectively ), p=0.901. Two-year OS was 58.4 % in Group A and 100% in Group B, p=0.17. Conclusions: Although no significant diferences were detected, responses rates were numerically higher in patients with tumors located below 12 cm from the anal verge. Further studies are needed to evaluate the association between response and DAV.
Prospective assessment of the risk for colorectal neoplasia in a Mexican population according to risk categories.
Authors: Camargo Vanessa Rosas , Martos Armendariz Edgar Omar , Rivera Aguilar Mauricio , Hernandez-Felix Jorge Humberto , Cordon Monica Lily , Rosales Sotomayor Angela , Meneses Medina Mónica Isabel , Huitzil Melendez Fidel David 
Published: May 2019

e15158 Background: General population screening can reduce colorectal cancer (CRC) mortality. International guidelines recommend CRC screening for asymptomatic people over 50 years. There is no established national screening program in Mexico. Even in countries with low incidence of CRC such as Mexico, targeted screening of subjects at high risk could decrease resource utilization and cost. Our aim was to describe the distribution among an average-risk population based on risk for colorectal neoplasia (CRN). Methods: We performed a prospective assessment of the risk for CRN among asymptomatic people over 50 years at Instituto Nacional de Ciencias Médicas y Nutrición between 2017-2018. The inclusion was competitive consistent with our age-sex pyramid. We included workers, non-family attendants and patients (internal medicine consultation). Each subject answered a standardized questionnaire, which included information on their age, gender, family history of CRC, diabetes, body mass index (BMI), smoking status and drinking habits. In order to stratify the population according to their risk for CRN, we used the Asia-Pacific Colorectal Screening (APCS) score. Results: We included 256 subjects. Median age was 59 y/o (50-93), 52% were female. 5% had a first-degree relative with CRC. 44% were current or ex-smoker and 9% reported alcohol consumption. 21% had diabetes. The median BMI was 27.3 (17-51). According to the APCS score, 60% were assigned as average risk (AR) and 40% as high risk (HR) for CRN. We observed a higher proportion of HR compared to our previous retrospective data (Table). Conclusions: We prospectively confirmed that using basic clinical information (age, gender, smoking status, family history of CRC, BMI and diabetes), it is possible to identify a subset of asymptomatic subjects at high risk for CRN in whom screening strategies should be prioritized. In developing countries with limited resources, a focus on high risk groups could improve cost effectiveness of screening colonoscopy. Risk stratification based on APCS score. [Table: see text]
Exosomal microRNA-199b-5p as a potential circulating biomarker to predict response of preoperative chemoradiotherapy for locally advanced rectal cancer.
Authors: Baek Dong Won , Kim Kyung Hwa , Kang Byung Woog , Kim Hye Jin , Park Soo Yeon , Park Jun Seok , Choi Gyu Seog , Baek Jin Ho , Hur Keun , Kim Jong Gwang 
Published: May 2019

e15161 Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision has become the standard treatment for locally advanced rectal cancer (LARC). However, the effect of CRT varies from complete response to complete resistance, and predicting response to CRT have not been well characterized yet. Previous studies have shown the potential of micro-RNA (miRNA) based approaches to enhance tumor radiation response. Accordingly, the present study attempted to identify biomarkers to predict response for preoperative CRT using comprehensive miRNA analysis in patients with LARC. Methods: This study included 65 rectal cancer tissues and 90 serum samples from patients who diagnosed with LACR and received preoperative CRT at Kyungpook National University Chilgok Hospital. Tissue specimens and serum samples were collected before CRT to evaluate the biologic differences between the good CRT response group and the poor CRT response group. For discovery of specific miRNAs, 800 miRNAs were analyzed using NanoString in 30 rectal cancer tissues. Thereafter, a total of 65 tissues, and 90 serum samples were investigated using real-time PCR for validation. Results: The median age was 59 years (range, 30-82), and the ratio of male to female was 3.05 to 1. The pathologic stages after preoperative CRT were as follows: pathologic complete response (n=13, 14.4%), pathologic stage I (n=13, 14.4%), pathologic stage II (n=27, 30.0%), pathologic stage III (n=28, 31.1%), and pathologic stage IV (n=9, 10.0%). In the discovery set, 16 target miRNAs were detected. In the validation set with tissue specimens, expression of 3 miRNAs (miR-199a/b-3p ( p=0.032), miR-199a-5p ( p=0.023), miR-199b-5p ( p=0.005)) was significantly upregulated which was associated with better response of CRT. Moreover, among the 3 candidate miRNAs, miR-199b-5p level was significantly upregulated in serum, and it was also found to be related with better response of CRT in LARC (pathologic stage 0/I versus II/III/IV, p=0.027). Conclusions: In the present study, high level of exosomal miR-199b-5p was associated with better response, suggesting it to be a promising non-invasive biomarker to predict response of CRT in patients with LARC. Accordingly, specific miRNAs can be predictive biomarker or therapeutic target to overcome radiotherapy resistance in LARC with a functional study.
Rectal admission of chemotherapeutic drugs in neoadjuvant treatment schemes of locally advanced rectal cancer.
Authors: Korytova Luiza 
Published: May 2019

e15168 Background: High incidence and steady rise of rectal cancer morbidity, unsatisfactory treatment results, amount of disabling surgery, high rate of local recurrents advocate for searching for new methods of combined treatment of locally advanced rectal cancer. Methods: We had suggested to rectally install sterile hydrogel material based on sodium alginate with incorporated 5-FU for radio modification purposes during neoadjuvant chemo radiotherapy. 39 patients with histologically confirmed diagnosis were included into our study. 19 patients received preoperative radiotherapy with summary dose of 50-56 Gy and systemic chemotherapy with fluorpirimidines and rectally admitted hydrogel material with incorporated 5-FU twice per day. Control group consisted of 20 patients who had similar treatment, excluding rectal hydrogel installations. Results: There was no increase in early radiotherapy complications noticed. Three study group patients had complete response, 16 had partial response (versus 1 CR, 15 PR, 3 stabilization and 1 progression in control group). This allowed reduction of surgical assistance volume in seven patients - sphincter-preserving operations were performed. Grade 3-4 pathomorphosis by Dworak’s scale was identified in 17 out of 19 patients (13 out of 20 in control group). Conclusions: Use of hydrogel material based on sodium alginate with incorporated 5-FU does not increase amount and intensity of radiation induced complications, allows to improve patients quality of life and treatment results.
Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502).
Authors: Sinicrope Frank A. , Ou Fang-Shu , Zemla Tyler , Nixon Andrew B. , Mody Kabir , Levasseur Alexandra , Dueck Amylou C. , Dhanarajan Asha R. , Lieu Christopher Hanyoung , Cohen Deirdre Jill , Innocenti Federico , Behrens Robert J. , Peters Walter , Sommer Nicolas , O'Reilly Eileen Mary , Meyerhardt Jeffrey A. 
Published: May 2019

e15169 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (dMMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for cancers with proficient MMR. In an ongoing phase III randomized trial, we will determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR. By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that could serve as ‘immune priming'. Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR are randomized to modified FOLFOX6 for 6 months (12 cycles) alone (control arm) or combined with atezolizumab (840 mg IV q2 wk) with continuation of the antibody as monotherapy for an additional 6 months (total duration of 12 months) [experimental arm]. Patients will be stratified by T, N stage and tumor sidedness. Local testing for MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. One cycle of FOLFOX is allowed pre-registration. The targeted accrual goal of 700 patients and 165 disease-free survival (DFS) events will provide 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint of DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. Results: This study is being conducted by the Alliance for Clinical Trials in Oncology, was approved by NCI CTEP and activated in 09/2017. The study is actively accruing and, as of 02/11/2019, 152 patients are enrolled. We are actively exploring an international collaboration. Conclusions: This is a current clinical trial in progress. Clinical trial information: NCT02912559.
Patient reported outcome measures (PROMs) in patients (pts) with locally advanced rectal cancer (LARC) managed with a watch and wait (W&W) approach after a clinical complete response to chemoradiotherapy (CRT).
Authors: Vatandoust Sina , Chen Gang , Sposato Luigi , Wattchow David , Roy Amitesh Chandra , Klevansky Myron , de Fontgalland Dayan , Leung John , Koczwara Bogda , Hollington Paul , Wilson Carlene , Flight Ingrid , Ruminski-Smith Dania , Karapetis Christos Stelios 
Published: May 2019

e15173 Background: PROMs have not been adequately studied in LARC pts who are managed with W&W after a clinical complete response to CRT. The objectives of this study were to evaluate: quality of life measures, bowel function, Fear of Cancer Recurrence (FCR) and survivors’ needs, in this population. Methods: Data were collected from the Flinders Medical Centre W&W prospective database. Questionnaires including Self-Administered Comorbidity (SCQ), EORTC QLQ-C30 and -CR29, EQ-5D-5L, MSKCC Bowel Function Instrument (MBFI), Low Anterior Resection Syndrome (LARS) score, Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF), Cancer Survivors’ Unmet Needs (CaSUN) and Response Efficacy Score (RES) were sent via mail to eligible pts according to a Tailored Design Method. Descriptive statistical analyses were conducted. Results: Of 40 eligible pts, 21 (52.5%) responded: 15 (71%) were male, median age at diagnosis was 66 years (34-81). 5 developed local re-growth (1 had local excision and 4 had ultra-low anterior resection). Median time from end of CRT to data collection was 39.8 months (6.0-77.5). The mean SCQ score was 5.7 (SD 5.5). Mean EQ-5D-5L utility score was 0.84 (SD 0.13), mean EQ-VAS score was 81.9 (SD 12.7) and mean EORTC QLQ global health status score was 76.2 (SD 19.2). The most common symptoms were fatigue (90%), pain (67%) and flatulence (67%). In pts without a re-growth (n = 16), the mean MBFI total score was 27.9 (SD 7.7); based on LARS score: 6 (38%) had no LARS, 5 (31%) had minor LARS and 5 (31%) had major LARS. Mean FCRI-SF score was 11.8 (SD 6.1), clinical level FCR was reported by 2 (9.5%) [cut-off 22] and 4 (19%) pts [cut-off 16]. 10 (47%) reported unmet needs: the most common area was Comprehensive Cancer Care n = 9 (42%). On RES, of 20 responders, 19 (95%) believed W&W was a worthwhile and effective strategy. Conclusions: The most commonly reported symptoms included fatigue, pain and flatulence. LARS was common: in the absence of surgery, LARS is due to CRT. Clinical FCR was uncommon. The majority believed W&W was worthwhile and effective. Larger comparative studies are needed in this group of pts.
Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.
Authors: Abdalla Ahmed , Aref Amr M. , Alame Amer , Ma Danny , Barawi Mohammed , Szpunar Susan , Lambert Karrah , Kafri Zyad 
Published: May 2019

e15178 Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.
Utilization of surgery and its impact on survival in elderly patients with localized colon cancer in the United States.
Authors: Arjyal Lubina , Bista Amir , Ojelabi Michael Olayiwola 
Published: May 2019

e15179 Background: For patients with localized colon cancer, surgical resection is the only curative treatment modality. Old age may be an independent factor associated with decreased receipt of surgery. We conducted this study to evaluate the utilization of surgery and its impact on survival in older patients with colon cancer in the United States. Methods: Surveillance, Epidemiology and End Results Database (SEER-18) was utilized to identify elderly patients (≥65 years) diagnosed from 2004-2013 with non-metastatic colon cancer (stage≤ III). Study population was divided into various cohorts based on race (Caucasian, African Americans, others), sex and age (< 80 years and ≥80 years), histology grade, tumor side, and stage. Multivariate logistic regression model was utilized to assess factors associated with receipt of surgery. Kaplan-Meier estimators with the log rank test was used to compare median overall survival (Md OS) between the surgery arm and non-surgery arm. Statistical significance was defined for p < 0.05. Results: Database identified 89,467 patients (54.7% female, 82.7% Caucasian; Median age 77 years). 94.6% (n = 84,656) of patients received surgery. On multivariate-analysis, left sided disease, lower grade tumor, lower stage, female gender, residents of lower median household income county, African Americans and age ≥80 years were less likely to receive surgery. The Md OS in the surgery arm was 87 months vs 69 months for non-surgery arm, p < 0.001. This benefit was seen in all the three stages (stage I: Md OS 104 vs 75 months; stage II: Md OS 88 vs 50 months; stage III: Md OS 74 vs 37 months, p < 0.001 for all comparisons). Additional analysis for octogenarians (age≥ 80 years) showed Md OS of 68 months in the surgery arm vs 48 months in the non-surgery arm, p < 0.001). Conclusions: Our study showed significant utilization of surgery (94.6%) in elderly patients with localized colon cancer. There is a clear survival benefit to surgery even in patients with age≥ 80 years. Surgical resection with curative intent should be strongly considered in patients with good performance status irrespective of age.
Role of tropomyosin 4 gene misregulation in colon epithelial cell tumorigenesis.
Authors: Son Mony Pheachnak , Papetti Michael 
Published: May 2019

e15184 Background: Ordered migration of colon epithelial cells from the bottom to the top of the crypt is required for their differentiation. Because aberrant colon cell migration may contribute to early stages of colon tumorigenesis, elucidation of how this migration is regulated provides insight into how colon cancer can be prevented and treated before malignancy. Certain actin-binding tropomyosins, including tropomyosin 4 (TPM4), regulate cytoskeletal contractility and migration in many different cell types. Methods: To determine whether aberrant TPM4 regulation may be an early event in colon cell tumorigenesis, we measured TPM4 RNA expression in uninvolved, grossly normal colon tissue from 10 human familial adenomatous polyposis (FAP) patients genetically predisposed to colon cancer versus 7 patients not genetically predisposed (normal). We also examined TPM4 expression in a colon adenocarcinoma cell line (Caco2). These are highly proliferative, undifferentiated cells but can be induced to growth arrest and differentiate, thus acquiring many characteristics of normal absorptive colon epithelial cells. Reporter assays were used to identify sequences that regulate TPM4 gene expression in Caco2 cells. Results: Average TPM4 RNA expression is 2.59 fold higher in the FAP versus normal tissue. TPM4 RNA and protein are highly expressed in proliferating, undifferentiated Caco2 cells but are severely reduced in growth arrested, differentiated cells. Reporter assays have identified genetic regions, near the TPM4 transcriptional start site, that may regulate TPM4 gene expression in proliferating Caco2 cells. Conclusions: This data suggests that aberrantly upregulated TPM4 may be an early event in colon tumorigenesis and that normal TPM4 expression, by fostering ordered colon epithelial cell migration, may promote normal cell differentiation and mitigate adoption of a premalignant state.