bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR).
Authors: Guo Songchuan , Melamed Jonathan , Eze Ogechukwu , Bowman Christopher , Ahmed Sunjida , Moore Harvey G. , Loomis Cynthia , Heguy Adriana , Brody Rachel , Morrison Debra J. , Serrano Jonathan , Du Kevin Lee , Wu Jennifer J. , Ryan Theresa , Cohen Deirdre Jill , Gu Ping , Goldberg Judith D , Snuderl Matija , Leichman Lawrence P. , Leichman Cynthia G. 
Published: February 2017

614 Background: NACR followed by total mesorectal excision (TME) is standard of care for LARC. However, only 10-20% of patients achieve complete pathologic response with associated optimal clinical outcome. No predictive biomarker is currently available. Aberrant DNA methylation is well known for its key role in the pathogenesis of colorectal cancer. Previous rectal cancer methylation studies were conducted in patients without NACR or inconclusive. We hypothesized a correlation between methylation status and pathologic outcome following NACR. Methods: This is an IRB approved, retrospective, translational study of patients with LARC who received identical NACR before TME at New York University hospitals. Ten micron sections from FFPE tissue blocks underwent laser capture microdissection (LCM) followed by genome DNA isolation. Illumina Infinium 450k methylation array was used to assess 485,000 methylation sites. Methylation profiles and copy number changes were analyzed using in-house bioinformatics. Histone H3K27me, a global methylation marker, was assessed using immunohistochemistry (IHC) and expression quantified in carcinoma cells, normal epithelium, inflammatory cells, stromal cells and endothelial cells. Results: Tumor specimens from 52 patients were collected. Analyzed specimens of stromal and cancer cells showed distinct methylation profiles pre- and post- therapy. The histone H3K27me3 mark was markedly increased in carcinoma compared to normal epithelium and strong trimethyl mark expression persisted in invasive carcinoma after the therapy including single cells. We obtained adequate DNA to demonstrate differences between pre- and post- NACR specimens and tissue sites. Full data set, including the known clinical and pathologic results, is to be presented. Conclusions: This is the first study to combine LCM and high throughput quantitative methylation profiling in rectal cancer to correlate with NACR outcome. Histone H3K27me3 IHC can be used to identify high-grade and invasive carcinoma with high specificity. Data from our annotated clinical cohort and correlative molecular results can inform a future prospective trial.
Time-course evaluation of survival and treatment in FIRE-3 (AIO KRK0306, first-line therapy of KRAS wild-type metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab).
Authors: Modest Dominik Paul , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Sobrero Alberto F. , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Seipelt Gernot , Lerchenmuller Christian A. , Kahl Christoph , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Moehler Markus H. , Jung Andreas , Kirchner Thomas , Heinemann Volker 
Published: February 2017

617 Background: FIRE-3 reported overall survival (OS) difference in favour of arm A (FOLFIRI plus cetuximab, N= 297 pts.) compared to arm B (FOLFIRI plus bevacizumab, N= 295 pts.) in the absence of significant differences in progression-free survival and response rate. Methods: We subdivided the study into six-month time intervals, starting at the time point of randomisation and evaluated OS in a time-wise fashion. Within each interval, OS was analyzed by Cox regression. Furthermore, systemic treatment and local interventions were investigated in the respective time-frames. Results: The time-course hazard ratios of OS are summarized in the Table. Pronounced differences in overall survival by time-interval analysis are observed between 24 and 30 months and between 30 and 36 months. Within the interval of 24-30 months, 24.6% (73/297) of pts in arm A and 25.1% (74/295) of pts in arm B received systemic therapy (any treatment-line). In the subsequent interval of 30-36 months, systemic anti-tumor treatment decreased to 18.9% (56/297) of pts in arm A and 16.3% (48/295) of pts in arm B. Median time on treatment was less than 2 months in the intervals of 24-30 months and 30-36 months. Updated data including RAS wild-type population will be presented at the meeting. Conclusions: The differences in OS observed in FIRE-3 are pronounced in time intervals between 24-30 months as well as 30-36 months after randomisation into the study. A small number of patients received rather short courses of anti-tumor therapy in these observation units. The significant difference in OS that manifests in time-frames between 24 and 30 months as well as between 30 and 36 months suggests that underlying effects on OS in FIRE-3 may include multiple factors and cannot be explained by the number of patients on active treatment alone. Clinical trial information: NCT00433927. [Table: see text]
The therapeutic effect of irreversible electroporation ablation in mouse model of gastrointestinal cancer.
Authors: Choi Hyuk Soon , Chun Hoon Jai , Yoo In Kyung , Lee Jae Min , Kim Seung Han , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Kim Chang Duck 
Published: February 2017

62 Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. IRE has an advantage over other ablation technique in its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Studies regarding the clinical application of IRE have been performed in humans, as well as in animals, for organs such as the liver, kidney, prostate, etc. and IRE is now accepted as a novel anti-cancer ablation modality. The aim of this study was to evaluate the therapeutic effect of IRE in mouse model of gastrointestinal cancer for the first time. Methods: The Caco2 cells (ATCC) were cultured in petri-dishes. Male nude mice (Immunodeficient (CAnN.Cg-Foxn1 nu/CrljBgi) 6 weeks old, Orient Inc., Korea) were introduced. Caco2 cells were each visually injected at 1.0 x 107cells/ml into both flakes (one for control, the other for IRE). We performed in vivo IRE procedures in the tumors of nude mouse model. Electrical pulses were applied to the tumor of nude mouse using a DC generator at 1~2kV/cm amplitude, 20~50 pulses, 100 µA length, with 1mm separation between two needle type electrodes. We analyzed the tissues with H&E staining and TUNEL assay immediately afterwards, and then 10 hours, 24 hours. Results: All mice were preserved during the experiment without significant complications. There was complete cell death within the IRE lesions without intervening live cells in 2KV after 24 hours. H& E statin and Tunnel stain at 10hr after 2KV IRE ablation revealed more severe apoptotic cell death comparing with control group. Apoptotic index peaks at 10 hours after IRE ablation, and decreases in 24hours. The framework of extracellular matrix and blood vessels were not affected by IRE. Conclusions: The present study demonstrated that IRE ablated colon cancer tissue very effectively through the induction of cellular apoptosis. This study suggests that IRE has the potentiality in treatment of gastrointestinal cancer patients.
Translational investigations of gastrointestinal malignancies using spheroid cultures.
Authors: Carchman Evie , Payne Susan , Pasch Cheri , Matkowskyj Kristina , Lubner Sam Joseph , Bassetti Michael F. , LoConte Noelle K. , Mulkerin Daniel , Deming Dustin A. 
Published: February 2017

620 Background: Spheroid cultures are now being used to investigate the biology of multiple types of cancer. This technique allows for a cost-effective, efficient and reliable means to culture tissues of interest. Recent investigations have demonstrated that spheroids maintain high mutational concordance with the cancers they are derived. We sought to determine if spheroid techniques could be utilized to perform translational investigations into subtypes of gastrointestinal malignancies. Methods: Transgenic mice carrying conditional mutations in key genes known to have important roles in colorectal cancer (CRC) tumorigenesis and progression were treated with a Cre-expressing adenovirus to initiate tumorigenesis. The mutant genes of interest included Apc, Trp53, KRAS, Pik3ca, and/or BRAF. Biopsies of these cancers were obtained with the murine endoscope and the tissue processed for spheroid culture. In addition, transgenic E6 and E7 mice were treated with DMBA and the resulting anal squamous cell carcinomas were harvested for spheroid culture. Cultured spheroids were imaged to characterize growth rate and changes in architecture. In addition, studies assessing response to therapeutics were performed and correlated with in vivo response. Human operative specimens were also obtained for culturing. Results: Multiple lines of murine CRC spheroids were able to be generated with a greater than 90% efficiency rate. These cultures maintained phenotypic characteristics of the cancers from which they were derived. Bright field imaging pre- and post-treatment was able to be utilized for quantification of treatment response. The median relative change in spheroid diameter was compared across treatment groups and correlated with response in vivo. Heterogeneity in the response of individual spheroids to treatment strategies was detected with this method. Murine squamous cell anal carcinoma was spheroid lines were generated similarly. Human CRC and anal cancers were also generated with high efficiency. Conclusions: Spheroid cultures from CRC and anal cancers can be generated with high efficiency and hold great promise for furthering treatment options for patients with cancer.
Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.
Authors: Kawazoe Akihito , Shitara Kohei , Noguchi Masaaki , Fukuoka Shota , Kuboki Yasutoshi , Bando Hideaki , Okamoto Wataru , Kojima Takashi , Doi Toshihiko , Ohtsu Atsushi , Yoshino Takayuki 
Published: February 2017

629 Background: Recently, anti-programmed death 1 (PD-1) antibody has shown promising efficacy in a phase II trial for patients with microsatellite instability-high (MSI-H) tumors, especially in those with metastatic colorectal cancer (mCRC). Currently, several clinical trials of anti-PD-1 antibody for patients with MSI-H mCRC are ongoing. However, little is known about the frequencies and clinicopathological features of MSI-H mCRC in Japanese patients. Methods: Patients with histologically confirmed adenocarcinoma of mCRC were eligible for this observational study. MSI status was analyzed in tumors using the MSI Analysis System (Promega) composed of 5 mononucleotide markers. KRAS, NRAS, BRAF and PIK3CA mutations were also evaluated using the multiplex kit. Results: A total of 232 patients were enrolled until August 31, 2015, of which MSI-H was detected in 5 patients (2.1%). Among five patients with MSI-H mCRC, median age was 45 years (28-75), four had tumors on right-sided colon, five had moderately differentiated adenocarcinoma, one had poorly differentiated adenocarcinoma, and three had stage IV disease at presentation. Overall survival for patients with MSI-H mCRC from the start of first-line systemic chemotherapy ranged from 8.1 to 62.0 month. All five patients with MSI-H mCRC had RAS wild-type tumors and two had BRAF V600E mutation. One patient with MSI-H mCRC was enrolled in a phase II trial of anti-PD-1 antibody. Conclusions: MSI-H mCRC is rare in Japanese patients. A large scale nationwide cancer genome screening project together with MSI status is required to evaluate more detailed clinicopathological features and facilitate the enrollment of patients with MSI-H mCRC for clinical trials with anti-PD-1 antibody.
Prognostic impact of tumor-associated B-cells and plasma cells in esophageal and gastric adenocarcinoma.
Authors: Fristedt Richard , Hedner Charlotta , Borg David , Nodin Bjorn , Eberhard Jakob , Micke Patrick , Jirstrom Karin 
Published: February 2017

63 Background: Tumor immune cell infiltration has been shown to influence the prognosis and treatment prediction in several types of cancer and the focus has largely been on the innate immune system as well as the cell-mediated immune response. There are, however, recent findings suggesting an important role for the humoral immune system in stemming cancer progression. The aim of this study was therefore to investigate the prognostic impact of B cell and plasma cell infiltration in esophageal and gastric cancer. Methods: Immunohistochemical expression of the pan B-cell marker CD20 and plasma cell markers CD138 and immunoglobulin kappa C (IGKC), were analyzed in tissue microarrays (TMA) from primary tumors in a cohort of 174 consecutive, surgically treated cases of gastro-esophageal adenocarcinoma. A multiplier of intensity and fraction was calculated, and the median value was used for prognostic cut-off. Kaplan-Meier analysis, univariable and multivariable Cox regression analysis, adjusted for age, TNM-stage, resection margins and adjuvant chemotherapy, were used to determine the impact of IGKC, CD20 and CD138 expression on overall survival (OS). Results: A high density of IGKC+ plasma cells was significantly associated with a prolonged survival in esophageal (HR 0.41, 95% CI 0.21-0.78) and gastric adenocarcinoma (HR 0.50, 95% CI 0.28-0.88). A high density of CD138+ plasma cells was also significantly associated with prolonged survival but only in gastric adenocarcinoma (univariable HR 0.48, 95% CI 0.27-0.86, multivariable HR 0.51; 95% CI 0.27-0.97)). IGKC+ plasma cell expression remained significant in multivariable analysis, for esophageal (HR 0.50, 95% CI 0.26-0.97) and gastric adenocarcinoma (HR 0.50, 95% CI 0.27-0.94). There was no significant association between the density of CD20+ cells and survival. Conclusions: Our findings show, for the first time, that a higher density of stromal plasma cells correlates with a prolonged survival in both esophageal and gastric adenocarcinoma. These are new and encouraging findings that warrant further evaluation in additional patient cohorts.
Effects of a structured exercise program on physical activity and health-related fitness in colon cancer survivors: One year feasibility results from the NCIC CTG CO.21 (CHALLENGE) trial.
Authors: O'Callaghan Christopher J. , Courneya Kerry S. , Vardy Janette L. , Friedenreich Christine , Campbell Kristin L. , Prapavessis Harry , Crawford Jennifer J , O'Brien Patti , Dhillon Haryana M. , Jonker Derek J. , Chua Neil Sun , Lupichuk Sasha M. , Sanatani Michael Susmoy , Gill Sharlene , Meyer Ralph M. , Begbie Stephen , Bonaventura Antonino , Burge Matthew E. , Tu Dongsheng , Booth Christopher M. 
Published: February 2017

648 Background: There is strong interest in testing lifestyle interventions to improve cancer outcomes, however, the optimal methods for achieving behaviour change in large scale pragmatic trials are unknown. We report the 1 year feasibility results for behaviour change in NCIC CTG CO.21 Colon Health and Life-Long Exercise Change (CHALLENGE) Trial. Methods: Between 2009 and 2014, 273 high risk stage II and III colon cancer survivors who had recently completed chemotherapy at 50 centers in Canada and Australia were randomized to a structured exercise program (SEP n = 136) or health education materials (HEM n = 137). The primary feasibility outcome in an a priordefined interim analysis was a difference between groups of ≥ 5 metabolic equivalent task (MET) hours/week in self-reported physical activity (PA) after at least 250 participants had reached 1 year. Secondary feasibility outcomes included cardiorespiratory fitness, body weight and circumferences, and objective physical functioning. Results: The SEP group reported a mean increase from baseline to 1 year PA of 15.6 MET hours/week vs a mean increase of 5.1 in the HEM group (+10.5 hrs/wk [95% CI = +3.1 to +17.9]; p = 0.002). SEP also improved relative to HEM in mean differences for predicted VO2max (+2.2ml/kg/min; p = 0.068), 6 minute walk (+29m; p < 0.001), 30 second chair stand (+1.6reps; p < 0.001), 8 foot up and go (-0.4s; p = 0.004), and the sit and reach (+2.1cm; p = 0.08). Conclusions: The behaviour change intervention in the CO.21 Trial produced an increase in self-reported PA that exceeded the feasibility criterion for trial continuation, resulted in objective fitness improvements, and is consistent with the amount of PA associated with improved colorectal cancer outcomes in observational studies. Recruitment to CO.21 remains ongoing. Clinical trial information: NCT00819208.
Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin).
Authors: Kim Seung , Won Young-Woong , Kim Jung Hoon , Park Joon Ho 
Published: February 2017

65 Background: The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin). Methods: We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8%). Results: Among 54 patients, the median age was 51.5 years (range, 23–72 years). Most patients were men (59.3%). Seven patients (13.5%) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among 7 patients with tumors with FGFR2 expression, 6 achieved partial response (PR) with a 85.7% response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5%). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, p = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS. Conclusions: FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx.
Impact of anti-VEGF therapy in metastatic colorectal cancer with an intact primary tumour.
Authors: Lee Belinda , Wong Hui-Li , Tie Jeanne , Wong Rachel , Lee Margaret , Nott Louise M. , Shapiro Jeremy David , Jennens Ross , Turner Natalie Heather , Tran Ben , Ananda Sumitra , Yip Desmond , Richardson Gary Edward , Parente Phillip , Lim Lionel , Stefanou Greg , Burge Matthew E. , Iddawela Mahesh Y. , Gibbs Peter 
Published: February 2017

650 Background: The management of metastatic colorectal cancer (mCRC) with anti-VEGF therapy and a fluoropyrimidine-containing chemotherapy is well established in first and second line therapy. However the role, safety and benefits of anti-VEGF therapy (Bevacizumab) in specific subgroups including those with an intact primary tumour (IPT), are not well described. Methods: Consecutive mCRC pts enrolled from January 2009 were identified from a prospective multi-site Australian registry. Survival and key safety endpoints were explored for pts with an IPT versus pts with a resected primary (RPT). Differences in outcomes were compared using log-rank test and Kaplan-Meier curves. Results: Of 1,204 pts with mCRC, 826 (69%) eligible pts were identified. Anti-VEGF therapy use in the first-line setting was similar in pts with an IPT [200/313 (64%)] vs. a RPT [357/513 (70%)]. In both groups the addition of anti-VEGF therapy was associated with greater PFS; IPT 8.5 vs. 4.7 months (HR 0.73, p=0.017) and RPT 10.8 vs. 5.8 months (HR 0.67, p=0.0002). OS was longer in anti-VEGF treated pts; IPT 20 vs. 14.8 months (HR 0.66, p=0.0046) and RPT 24.4 vs. 17.3 months (HR 0.71, p=0.0039). A trend for more GI perforations with anti-VEGF therapy use was seen in pts with IPT (4.5% vs. 1.8%, p=0.33), but not RPT (1.7% vs. 1.9%). The rate of bleeding and thrombosis was lower in the IPT group treated with bev: 1.5% vs. 5.3%, p=0.05 and 1.5% vs. 2.7%, p=0.47 respectively. In comparison, RPT pts treated with and without anti-VEGF therapy had a bleeding rate of 3.4% vs. 0.6%, p=0.07, and a thrombosis rate of 5.9% vs. 0.6%, p=0.007. Conclusions: In routine clinical practice clinicians appear comfortable using anti-VEGF therapy in pts with an IPT. Superior PFS and OS outcomes were seen with addition of anti-VEGF therapy, with no evident impact of primary tumor status. There was a trend for a higher GI perforation rate in anti-VEGF treated IPT pts, but a lower rate of other adverse events. This may reflect clinicians avoiding anti-VEGF therapy in pts considered at increased risk of these complications. Further analysis is underway to explore this possibility.
Impact of comorbidities using Adult Comorbidity Evaluation-27 (ACE-27) score on survival in stage II colon cancer: Age, TNM staging, and pathological high risk-disease.
Authors: Amin Manik A. , Wang-Gillam Andrea , Tan Benjamin R. , Suresh Rama , Picus Joel , Singh Preet Paul , Lim Kian-Huat , Masood Ashiq , Lockhart Albert C. 
Published: February 2017

659 Background: Impact of comorbidities is identified in stage III colon cancer patients (CCPs) receiving adjuvant chemotherapy (Wildes et al, PMID 21113435) but is not well defined in predicting overall survival (OS) in stage II CCPs undergoing either adjuvant treatment or observation depending upon high-risk disease. The goal of this study was to identify impact of comorbidities on OS in this potentially curable disease using ACE-27 score, which uses 27 different patient comorbid conditions has been developed and validated by Piccirrillo et al at Barnes Jewish Hospital (BJH) (PMID: 24933715). Methods: We identified stage II CCPs treated at BJH, Siteman cancer center from January 1, 1996 to October 31st, 2013 from BJH oncology data cancer registry. The primary outcome was OS, defined as the time from date of surgery to death from any cause, censored at the time of last follow-up. Patient comorbidities at diagnosis were recorded using ACE-27 score, assigning a comorbidity score of none, mild, moderate and severe to the patients. Survival analysis was done using Cox proportional hazard modelling using STATA/SE 11.2 software. Pathological high risk features such as T4 lesions, < 12 LN, perineural, lymphovascular invasion, positive margins & perforation/obstruction were identified. Results: Out of 579 stage II CCPs, 48% male and 51% were females. High risk features were identified in 45% of patients. ACE-27 comorbidity score of none (n = 146), mild (n = 229), moderate (n = 132) and severe (n = 72) was calculated. 497 patients had T3N0M0 and 82 had T4N0M0 staging. Cox regression hazard model using histological prognostic factors, age at surgery, sex, race, prior cancer history and TNM staging showed that ACE-27 score of moderate and severe were independent predictors of OS with a hazard ratio of 1.6 (95% CI 1.0-2.4), P = 0.036 and 2.5 (95% CI 1.5-4.0), P = 0.00 respectively. Conclusions: Highest commodity burden using ACE-27 comorbidity score was associated with poor OS in stage II CCPs and was independent of other prognostic risk factors including high-risk features. Treatment related mortality will be calculated in patients with high risk disease.