bluuebunny/crossref_metadata_2025_split huggingface dataset:
A unique ex vivo tumor model: 3D cocultured system with cancer and stromal cells including blood microvessels.
Authors: Takahashi Yuki , Tsukamoto Kei , Morimura Rii , Nada Isana , Shimizu Yuki , Katayama Ryohei , Shinozaki Eiji , Nagayama Satoshi , Matsusaki Michiya , Kitano Shiro , Yamaguchi Kensei , Fujita Naoya 
Published: February 2020

211 Background: Importance of interaction between cancer and stromal cells has been widely recognized in tumor progression and tolerance against treatment. Although 2D culture and spheroid consisting only cancer cells still remains the preferred platform for most laboratory preclinical studies while these provide only limited information about tumor microenvironment. In order to mimic the patient tumor tissue, ex vivo model which recaptures the tumor microenvironment is required. Methods: Layered 3D stromal tissues comprising microvascular network were produced by culturing fibroblasts and endothelial cells coated with the extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin. The layered 3D stromal tissues and co-cultured tumor were morphologically evaluated by HE stain, immunohistochemistry and immunofluorescence (IF). Their gene expression and secretome profile were characterized by RNA-sequencing and bio-plex suspension array technologies. Furthermore, drug sensitivity assay were conducted using popular colorectal cancer cell lines, and patient-derived cell lines (PDCs) established in the laboratory of JFCR. Remaining cancer cells post drug treatment were quantified by IF and imaging analysis. Results: The 3D stromal tissues including CD31 positive luminal structure were multi-layered (approximately 20 layers), and the tendency that dense microvascular network was formed nearby cancer cells was observed. In comparison with 2D culture or 3D mono-cultured spheroid model, decreased drug sensitivities were represented in the layered 3D co-cultured model. Omics profiles difference among models suggest that our 3D model has some similarity to in vivo tumor. Conclusions: We developed the layered 3D stromal tissue culture system including blood micro-vessels. Drug sensitivity in the co-cultured tumors may reflect the response of cancer cells in in vivo. Our unique 3D ex vivo model appear to be a valuable tool for drug evaluation, and thus testing approved and/or developing compounds with patient-derived cells would enable better prediction their efficacy.
Post hoc safety and effectiveness analysis of aflibercept + FOLFIRI for patients with metastatic colorectal cancer (mCRC) previously treated with antiepidermal growth factor receptor (EGFR) therapy in OZONE.
Authors: Cartwright Thomas H. , Fakih Marwan , Garcia-Alfonso Pilar , Linke Zdenĕk , Ruíz Casado Ana , Polo Marques Eduardo , Picard Pascaline , Celanovic Marina , Singh Arvind Rup , Salinardi Taylor , Chau Ian 
Published: February 2020

212 Background: Anti-EGFR therapies are frequently given as first-line therapy for patients with mCRC, while anti-angiogenic therapies may be suitable at any line. Despite improving outcomes for patients with mCRC, there is still an unmet need regarding the optimal treatment sequence. In this post hoc analysis, the safety and effectiveness of aflibercept + FOLFIRI was evaluated for patients with mCRC based on their prior anti-EGFR therapy use. Methods: OZONE is a prospective, multicenter, observational, non-comparative study evaluating patients receiving aflibercept + FOLFIRI in the clinical setting, for 24 months from aflibercept initiation or until death. Patients were retrospectively assessed according to prior use of anti-EGFR therapy (defined as patients who received cetuximab and/or panitumumab as previous anti-cancer therapy). Overall survival (OS) and progression-free survival (PFS) were analyzed by hazard ratios (HR) and 95% confidence intervals (CI); overall response rate (ORR) was analyzed by odds ratios (OR) and 95% CI. Results: Among the overall treated population (N = 766), 19.2% (n = 147) received prior anti-EGFR therapy. Prior anti-EGFR therapy had no significant impact on the median OS (11.47 vs 12.58 months; HR [95% CI] 1.112 [0.889–1.390]), median PFS (5.29 vs 6.24 months; HR [95% CI] 1.022 [0.830–1.260]), or ORR (14.96% vs 18.75%; OR [95% CI] 0.597 [0.332–1.071]) of patients vs those who did not receive prior anti-EGFR therapy. Rates of grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar between patients who did vs did not receive prior anti-EGFR therapy (70.7% vs 67.7%). The most frequently reported grade ≥ 3 TEAEs for patients who did vs did not receive prior anti-EGFR therapy were neutropenia (12.2% vs 15.0%), hypertension (8.8% vs 10.3%), and diarrhea (10.2% vs 9.4%). Conclusions: This post hoc analysis of the OZONE study did not reveal major differences in safety and effectiveness according to prior anti-EGFR therapy. Clinical trial information: ENCEPP/SDPP/4836.
Effect of phenotype on outcome in synchronously resected primary colorectal cancer and matched liver metastases.
Authors: Pennel Kathryn AF , Steele Colin William , Quinn Jean A. , Roseweir Antonia K. , Jackstadt Rene , Nixon Colin , Cortes-Lavaud Xabier , Roxburgh Campbell SD , Van Wyk Hester Catharina , McMillan Donald C. , Horgan Paul G. , Sansom Owen , Edwards Joanne 
Published: February 2020

221 Background: 5-year survival of patients with resectable colorectal liver metastases is 25-40%. Mechanisms of disease progression are heterogenous and do not follow a clearly defined pathway from genotype to phenotype. In stage I-III colorectal cancer (CRC), patients with high tumor stroma exhibit poor prognosis, while those with high immune cell infiltrate do well following resection. We hypothesise that stromally-dense phenotypes lead to T cell exclusion, myeloid cell accumulation and aggressive metastatic progression. Here, we examine relationships between histological tumor phenotype, cellular infiltrate and outcomes in metastatic CRC. Methods: A unique cohort of synchronously resected primary CRC and matched liver metastases (n = 46) were assessed for immune cell infiltration (CD3, CD4, CD8, CD68, CD66b), inflammatory signalling (CXCR2, PDL-1, MMP9) and hypoxia (CAIX) using immunohistochemistry. Tumors were phenotypically subtyped using immune infiltrate (Klintrup-Makinen Grade (KM)), stromal invasion (tumor-stroma percentage (TSP)) and proliferation (Ki67). Results: Phenotypic subtype of primary tumors was predictive of metastatic subtype (rho = 0.522, p = 0.003). Immune phenotypes were associated with good prognosis and stromal phenotypes with poor prognosis (p = 0.004). Infiltration of macrophages and granulocytes associated with poor outcomes (p = 0.018) and increased CXCR2 expression (p = 0.03) at both sites. Increased CXCR2+ cells and macrophages at both sites associated with stromal phenotype (p = 0.02), tumour budding (p = 0.002), low KM grade (p = 0.05) and poor prognosis (p = 0.002). Macrophage and MMP9 levels increased in metastases compared to primary tumour, but no changes were seen in lymphocyte infiltration, CXCR2 and CD66b. Conclusions: Density of immune cell infiltrate, in the primary and metastatic niche, conferred good prognosis. In contrast, stromal, myeloid rich tumors convey poor prognosis. This clinically relevant and histologically efficient process permits segregation of disease and supports further study of relationships in the tumour microenvironment of CRC in the context of chemotherapy to better target therapeutics to individual patients.
The pretreatment lymphocyte-to-monocyte ratio (LMR) to predict treatment efficacy and prognosis in metastatic colorectal cancer treated with the combination of TAS-102 and bevacizumab (TAS-CC3 Study).
Authors: Matsuda Akihisa , Yoshida Yoichiro , Kamiyama Hirohiko , Kosugi Chihiro , Yoshida Hiroshi , Ishibashi Keiichiro , Ihara Keisuke , Takahashi Makoto , Kuramochi Hidekazu , Fukazawa Atsuko , Sonoda Hiromichi , Yoshimatsu Kazuhiko , Yamaguchi Satoru , Ishida Hideyuki , Hasegawa Suguru , Yamada Takeshi , Sakamoto Kazuhiro , Koda Keiji ,   TAS-CC3 Study Group
Published: February 2020

224 Background: The combination regimen of TAS-102 and bevacizumab as salvage-line therapy for metastatic colorectal cancer (mCRC) was established based on its high clinical effectiveness (C-TASK FORCE). Recently, our current phase II TAS-CC3 study demonstrated comparable median progression-free survival (PFS: 4.5m) and overall survival (OS: 9.2m) with exclusive inclusion of 3rd line therapy patients. However, practical predictors for its efficacy are lacking. This study evaluated inflammation-based scores as potential predictors for this combination therapy. Methods: This is a post hoc analysis of investigator-initiated, open-label, single-arm, multicentered phase II study (TAS-CC3) in Japan with 32 mCRC patients treated with the combination therapy. We investigated the predictive and prognostic values of pretreatment blood inflammation-based scores, including neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-monocyte ratios (LMR), on disease-control (DC), PFS and OS. These were divided into two groups (high and low) using cut-off of each median values. This study was registered at the University Hospital Medical Information Network, as UMIN#000022438. Results: ROC curve analyses of 3 inflammation-based scores versus DC showed a best predictive performance in LMR, followed by NLR and PLR (AUC: 0.89, 0.85, and 0.68, respectively). The high LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%, P= 0.023). Two patients showing partial responses were in the high group. The high LMR group showed significantly longer survivals compared with the low group (4.9 vs. 2.3m, respectively for median PFS, P= 0.014) (20.5 vs. 5.1m, respectively for median OS, P< 0.001). The values of LMR were significantly correlated with PFS and OS (r = 0.56: P< 0.001 and 0.62: P< 0.001, respectively). Conclusions: Pretreatment LMR is a valid predictive and prognostic biomarker for mCRC patients with TAS-102 and bevacizumab treatment and might be clinically useful for selecting patients of the responder. Clinical trial information: 000022438.
Racial variation in molecular profile of advanced gastrointestinal cancers.
Authors: Macherla Shravanti , Nandimandalam Sujitha , Jayananda Sriraksha , Appah Ebenezer Ofori , Bulumulle Anushi , Baig Sameer , Patel Anokhi , Polsani Shanker , Muzaffar Mahvish 
Published: February 2020

236 Background: Heterogeneity in the tumor molecular profile based on race is poorly understood. We sought to review the utilization of next generation sequencing (NGS) in patients with advanced gastrointestinal (GI) malignancies treated at a rural academic center and analyze inter racial variations in the molecular tumor profile. Methods: We conducted a retrospective review of patients with advanced GI malignancies that underwent NGS between 2015 to 2018 at East Carolina University.104 patients met eligibility criteria but 8 patients were excluded due to insufficient tissue sampling. Patients with colorectal, gastric, pancreatic, biliary, small intestinal and esophageal cancers were included. Targeted NGS using Caris Life Sciences¨ platform was performed to obtain molecular analysis. We conducted descriptive univariate analysis, cox regression and Kaplan-Meier survival curve analysis. Results: Median age at diagnosis was 64yrs and 64% of patients were black. The study cohort had 41% (n=39) with colon cancer, 18%(17) gastric cancer, 30% (29) pancreatic cancer, 6%(6) biliary cancer, 4%(4) small intestinal cancer and 1%(1) esophageal cancer. 60% (55) had de novo Stage IV disease. Median overall survival (OS) was 25 months (mo), 30 mo in blacks and 32 mo in whites (p value =0.46). Microsatellite stability was seen in 94% (87) and instability in 3% (3). Overall cohort had mutations (mut) in KRAS (50%), TP53 (64%), BRAF (4%), and ERBB amplification (3%). On the cox regression model APC mutation was associated with worse outcome. Black patients had more alterations in KRAS, TP53 (both not significant), and APC (p=0.02). Conclusions: In our analysis we observed inter racial variations in molecular profile of advanced GI malignancies. Black patients had increased rates of APC, KRAS and TP 53 mut. Further studies are required to analyze the impact of these molecular variations on outcomes. Results. [Table: see text]
Exploratory analysis of trifluridine/tipiracil in late-stage metastatic colorectal cancer (mCRC): Prognostic factors.
Authors: Karthaus Meinolf , Hoell B , Zaun G , Guyot M , Schuler Martin H. , Kasper Stefan 
Published: February 2020

24 Background: Trifluridine/Tipiracil (FTD/TPI) is effective in pts with refractory mCRC. Enrollment into in the RECOURSE trial was allowed only for pts with ECOG < 1 pts, while real world pts may have a lower ECOG. In addition, predictive markers for the efficacy of FTD/TPI at late stage are open. This exploratory analysis assessed outcome of mCRC pts (including ECOG PS ≥ 2) upon FTD/TPI treatment by prognostic factors in the real world setting. Methods: This cohort included mCRC pts who were treated with FTD/TPI from 01/2016 until 08/2019 at two large volume CRC centers in Germany. Pts were classified with good prognosis characteristics (GPC) according to Tabernero et al. (abstract 677, ASCO-GI 2019) defined by 1 or 2 metastatic sites and time since diagnosis of first metastases ≥ 18 mo. Pts of this group without liver metastases had the best prognostic characteristics. Pts with poor prognostic characteristics (PPC) were characterized by ≥ 3 metastases sites and time since diagnosis of first metastases ≤ 18 mo. Results: A total of 44 mCRC pts were included in this analysis (mean age 62.5 yrs; 22 males and 22 females). Within the GPC population (n=28; median age 67 yrs; KRAS wt n= 21; KRAS mt n= 7; ECOG 0-1 n= 23; ECOG ≥ 2n=7) 6 pts were alive up to 08/2019 and 4 were lost to FU. Four pts of the GPC were without liver metastases. Within the PPC group (n=16; median age 59 yrs; KRAS wt n= 6; KRAS mt n= 10; ECOG 0-1 n= 15; ECOG ≥ 2 n=1) 2 pts were alive and 2 were lost to FU. The mPFS and mOS of the GPC group (n=18) were 2,15 mo (range 0,62-10,13) and 4,63 mo (range 0,95-14,39), respectively. The mPFS and mOS of the PPC group (n=12) were 1,31 mo (range 0,76-9,72) and 4,72 mo (range 0,76-16,61), respectively. Pts with an ECOG ≥ 2 had a mOS of 2,76 mo (range 0,95-6,92), and a mPFS 1,67 mo (range 0,53-1,77). Conclusions: GPC and PPC group pts treated with FTD/TPI differed with respect to mPFS, but these pts had a comparable mOS in the real world setting. PFS and OS were lower when compared to the Tabernero analysis of the RECOURSE trial, which may reflect the real world setting. Inclusion of pts with an ECOG of ≥ 2 was feasible but showed poor survival data in the third line. Nevertheless, all pts with mCRC benefited from FTD/TPI treatment.
Systematic review of gastrointestinal cancer studies of concordance with expert opinion for a clinical decision support system (CDSS).
Authors: Arriaga Yull Edwin , Draulis Karlis , Hekmat Rezzan , Wang Suwei , Felix Winnie , Dankwa-Mullan Irene , Rhee Kyu , Jackson Gretchen 
Published: February 2020

250 Background: Watson for Oncology (WfO), a cognitive CDSS, provides therapeutic options to cancer-treating physicians. We reviewed the concordance of WfO therapeutic options in gastrointestinal cancers with experts’ treatment decisions. Methods: Systematic review to identify WfO concordance studies in gastrointestinal cancers, published from June 2015 to June 2019. Concordance was defined as agreement between WfO “Recommended” and “For Consideration” treatment options and decisions made by experts. Mean concordance rates were calculated as an average, weighted by the number of patients in each study. Results: 2,407 patients were identified (Table). Overall treatment decision concordance was 67.2% (SD 25.7%). Concordance for rectal, colon, hepatocellular, and gastric cancers were 90.5% (SD 9.4%), 80.9% (SD 24.3%), 58.5%, and 47.5% (SD 33.9%), respectively. Concordance with WfO were significantly higher for rectal versus colon cancer ( p = .001), rectal versus gastric cancer ( p < .0001) and for colon versus gastric cancer ( p <.0001). Conclusions: Concordance between WfO and treatment decisions by experts for rectal and colon cancers were high. Concordance for HCC and gastric cancer were the lowest. A higher discordance in gastric cancer is likely related to disease-specific and management differences compared to United States practice. Variable concordance between expert clinical decisions and CDSS suggestions and can be minimized by localization efforts. [Table: see text]
A randomized controlled phase III multicenter study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer: ARTDECO study.
Authors: Hulshof Maarten C.C.M. , Geijsen Debby , Rozema Tom , Oppedijk Vera , Buijsen Jeroen , Neelis Karen J. , Nuyttens Joost , Van Der Sangen Maurice , Jeene Paul , Reinders Janny , van Berge Henegouwen Mark I. , van Hooft Jeanin E. , Van Laarhoven Hanneke W.M. , Gaast Ate Van Der 
Published: February 2020

281 Background: To analyze the effect of radiation dose escalation to the primary tumor on local control, locoregional control, survival and toxicity in definitive chemoradiation for esophageal cancer. Methods: Patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus were randomized between a standard dose of 50.4 Gy/1.8 Gy/5,5 weeks to the tumor and regional lymph nodes (SD) versus the same dose combined with an integrated boost of 0,4 Gy per fraction (total 61,6 Gy) to the primary tumor (HD). Chemotherapy consisted of 6 weekly concurrent carboplatin (AUC 2) and paclitaxel (50 mg/m2) in both arms. The primary endpoint was local progression free survival (LPFS) and 260 patients were needed to detect a difference of 15% (power: 80%). Secondary endpoints were locoregional progression free survival (LRPFS), overall survival (OS) and toxicity. Patients were stratified for histological subtype. Results: Between September 2012 and June 2018, 260 patients were included. Reasons for inoperability were proximal localization and patient preference (44%), comorbidity (30%), unresectable lymph nodes (11%), T4 (5%), local recurrence 2% and combinations (7%). 61% of the patients had a squamous cell carcinoma (SCC) and 39% had an adenocarcinoma (AC). 94% completed radiation treatment and 85% had at least 5 courses chemotherapy. Median follow up time was 45 months. 3-year LPFS was 70% in the SD arm versus 76% in the HD arm (ns). LPFS for SCC and AC was 74% versus 81% and 62% versus 65% for SD and HD, resp. (ns). 3-year LRPFS was 53% and 63% for the SD and HD arm resp. (p = 0.08). 1 year any progression free survival was 60% for SCC and 50% for AC, without a significant difference between SD and HD (p = 0,5). 3-year OS was 41% versus 40% for SD and HD resp. Overall grade 4 and 5 CTC toxicity was 12% and 4% in the SD arm versus 14% and 10% in the HD arm, resp. Conclusions: In definitive chemoradiation for esophageal cancer, radiation dose escalation up to 61,6 Gy to the primary tumor did not result in a significant increase in local control over 50,4 Gy. Numerical improvement of locoregional control after HD was observed with an increase in toxicity and without improving OS. Clinical trial information: NL38343.018.11.
Usefulness of laparoscopic narrow-band imaging for the evaluation of therapeutic effects on peritoneal metastasis in gastric cancer.
Authors: Kikuchi Hirotoshi , Soneda Wataru , Kawata Sanshiro , Hirotsu Amane , Matsumoto Tomohiro , Hiramatsu Yoshihiro , Kamiya Kinji , Morita Yoshifumi , Sakaguchi Takanori , TAKEUCHI HIROYA 
Published: February 2020

287 Background: As recent advances in chemotherapy improved prognosis of gastric cancer (GC) patients with peritoneal metastasis (PM), accurate diagnosis of PM has become more important. However, the sensitivity of conventional imaging modalities such as CT or PET is not satisfactory. Staging laparoscopy (SL) is often used to diagnose PM in advanced GC patients, but accurate detection of PM can be difficult. In this study, we evaluate the usefulness of laparoscopic narrow-band imaging (NBI) versus conventional laparoscopic white-light imaging (WLI) for the diagnosis of PM and for the evaluation of therapeutic effect of chemotherapy. Methods: We excised 54 white nodules from the parietal peritoneum of 40 GC patients. Among them, 9 patients received chemotherapy for advanced or recurrent GC before SL, and 31 did not receive chemotherapy except for adjuvant chemotherapy with S-1. The WLI and NBI findings were compared with the pathological findings. Results: Intranodular vessels were evaluated by WLI and NBI for dilatation, tortuousness, heterogeneity, and brown spots. Detection of any one abnormal finding on NBI plus clear demarcation of the peritoneal nodules on WLI more properly diagnosed 42 peritoneal nodules of 31 patients who did not receive chemotherapy (sensitivity, 100%; specificity, 88.9%; accuracy, 95.2%). In contrast, diagnosis ability was poor for 12 peritoneal nodules of 9 patients who received chemotherapy before SL (sensitivity, 66.7%; specificity, 33.3%; accuracy, 58.3%). Conclusions: Laparoscopic NBI is a useful tool for the diagnosis of PM in advanced GC before chemotherapy, and disappearance of dilated vessels on laparoscopic NBI could be useful to evaluate the therapeutic effect.
The impact of single-hetero UGT1A1 on clinical outcomes of irinotecan monotherapy in gastric cancer after fluoropyrimidine, platinum, and taxanes: Multicenter retrospective study.
Authors: Ito Ken , Komatsu Yoshito , Yuki Satoshi , Nakano Shintaro , Nakatsumi Hiroshi , Kawamoto Yasuyuki , Muranaka Tetsuhito , Sawada Kentaro , Ando Takayuki , Kajiura Shinya , Miyagishima Takuto , Harada Kazuaki , Kobayashi Yoshimitsu , Hatanaka Kazuteru , Ishiguro Atsushi , Honda Takuya , Dazai Masayoshi , Sasaki Takahide , Sakamoto Naoya 
Published: February 2020

296 Background: Japanese gastric cancer treatment guidelines (5th edition) recommend irinotecan (IRI) after fluoropyrimidine, platinum and taxanes as a third line chemotherapy. We previously reported that patients with UGT1A1 single heterozygous (SH) had significantly high frequency of severe hematological adverse events (AEs) compared to patients with UGT1A1 wild type (WT) in IRI monotherapy for advanced gastric cancer (AGC). However, it remains unclear that UGT1A1 SH affect efficacy and safety of IRI after fluoropyrimidine, platinum and taxanes compared to WT as a salvage line. Methods: We retrospectively analyzed the clinical data of patients who received IRI monotherapy after fluoropyrimidine, platinum and taxanes in the multi-institutional retrospective study. From January 2010 to December 2017, 69 eligible patients were registered from 8 centers in Japan. Results: Forty one patients with UGT1A1 WT and 28 patients with UGT1A1 SH were included in this study. In WT/SH patients, performance status 0/1/≥2 was 12/25/4 and 5/17/6, treatment line 3rd/4th or later was 33/8 and 26/2, HER2 status positive/negative was 12/29 and 5/23, respectively. In WT/SH patients, rate of initial dose reduction was 22 and 28% (P = 0.363), median relative dose intensity (RDI) was 82% and 80% (P = 0.309). Of 88 patients who have measurable lesions, the overall response rate (ORR) was 5.7% and 4.2% (P = 1.000), disease control rate (DCR) was 54% and 38% (P = 0.289). Median progression free survival was 3.2 and 2.1 months (HR 0.607, P = 0.058) and median overall survival from initial day of IRI monotherapy was 10.0 and 7.0 months (HR 0.618 P = 0.086). In WT/SH patients, severe hematological AEs (≥G3) were observed more frequently in patients with UGT1A1 SH (WT: 43% and SH: 68%, P = 0.050), although frequency of severe non-hematological AEs (≥G3) were not significantly different in both groups (13% and 25%, P = 0.211). Conclusions: Compared to UGT1A1 WT, UGT1A1 SH status may be associated with poor efficacy and be a risk factor of higher frequency of severe hematological AEs.