bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complement component C9 as a new biomarker for esophageal adenocarcinoma.
Authors: Joshi Virendra , Shah Alok , Brown Ian , Winterford Clay , Hill Michelle 
Published: March 2017

19 Background: Esophageal adenocarcinoma (EAC) continues an upward trend. Mortality rate and treatment costs for EAC are very high overall and significantly increase with disease stage. Diagnosis at early stage (T1) compared to advanced stage (T3) improves 5 year survival from 20% to 80-90%. Endoscopic surveillance has been ineffective in reducing EAC. Therefore the need for better diagnostic tools for early detection.Previously we reported validation of a list of serum glycoprotein biomarker candidates for EAC in an Australian cohort (Shah et al. 2015 Mol Cell Proteomics. 14:3023-39.). Here we further evaluate the serum and tissue expression of top candidate C9 in an independent cohort from the USA. Methods: Serum samples (n=38) and FFPE tissue sections (n=34) were collected from participants with IRB approved protocol, from the Ochsner Clinic undergoing endoscopic surveillance for Barrett’s and esophageal cancer. Serum glycoprotein candidates were measured using lectin magnetic bead array-coupled multiple reaction monitoring assay (Shah et al. 2015 Mol Cell Proteomics. 14:3023-39.). Immunohistochemistry was optimised for complement component C9 antibody. Initial evaluation of 2 different antibodies gave similar results, thereafter, a polyclonal antibody from Sigma Aldrich was used. Staining was assessed by a gastrointestinal pathologist. Results: Specific glycosylated forms of 3 candidate serum biomarkers were confirmed to be significantly different between EAC and benign groups (p<0.05, Kruskal-Wallis). The diagnostic value for the 3 individual markers, complement component C9, gelsolin and alpha-1-antichymotrypsin (Serpin A3) was 0.71 to 0.82 area under the receiver operating curve (AUROC). A multivariate panel consisting of 8 glycoprotein biomarkers achieved AUROC of 0.96, indicative of high diagnostic value. Immunohistochemistry of tissues detected high levels of C9 in BE and EAC compared to normal squamous epithelium. Infiltrated lymphocytes showed variable staining. Conclusions: We propose a novel candidate biomarker complement component C9 which could add to current endoscopic surveillance strategy for early detection of adenocarcinoma.
Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial.
Authors: Kang Yoon-Koo , Satoh Taroh , Ryu Min-Hee , Chao Yee , Kato Ken , Chung Hyun Cheol , Chen Jen-Shi , Muro Kei , Kang Won Ki , Yoshikawa Takaki , Oh Sang Cheul , Tamura Takao , Lee Keun-Wook , Boku Narikazu , Chen Li-Tzong 
Published: March 2017

2 Background: Recent clinical trials have established 1st and 2nd line chemotherapy as the standard treatment for advanced gastric or gastro-esophageal junction cancer (AGC). However, prognosis of AGC is still poor. Nivolumab (ONO-4538/BMS-936558) is a human monoclonal IgG4 antibody which blocks the human programmed cell death-1 (PD-1) receptor. We evaluated the efficacy and safety of nivolumab as salvage treatment after failure of the standard chemotherapy for AGC. Methods: 493 patients aged ≥ 20 years with ECOG PS 0-1 and unresectable advanced or recurrent AGC who had failed two or more previous chemotherapy regimens were randomized in a 2:1 ratio to receive 3 mg/kg nivolumab (N=330) or placebo ( N=163) every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS) in Intention-to-Treat population. This trial is registered in ClinicalTrials.gov (NCT02267343). Results: As of the data cut-off on Aug 13th2016, 5.6 months after last patient randomized, median OS was 5.32 months with nivolumab versus 4.14 months with placebo (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.78; p<0.0001), and OS rates at 6 and 12 month were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate (ORR) was 11.2% (95% CI, 7.7-15.6) with nivolumab versus 0% (95% CI, 0.0-2.8) with placebo (p<0.0001). Median progression-free survival (PFS) was 1.61 months with nivolumab versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5 % of nivolumab and 5.5 % of placebo; 2.7% and 2.5%, respectively, discontinued of study treatment due to drug-related AEs (any grade). Conclusions: Nivolumab was effective as the salvage treatment for pretreated AGC with significantly improved OS, PFS and ORR compared to placebo. Funding:Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Clinical trial information: NCT02267343.
The usefulness of Roux-en-Y reconstruction with aboral pouch following total gastrectomy for gastric cancer.
Authors: Iwagami Shirou , Hidetaka Sugihara , Mizumoto Takao , Kubota Tatsuo , Miyanari Nobutomo , Baba Hideo ,   Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University
Published: March 2017

209 Background: Patients with gastric cancer that involves the upper part of the stomach should undergo total gastrectomy for their curative resection. Roux-en-Y reconstruction is the most common procedure followingtotal gastrectomy. However, this reconstruction causes them various postgastrectomy symptoms and problems of their nutritional status and QOL. Although the development of the new reconstruction to prevent these symptoms have being carried out, we have not generally established procedures. Methods: To compare the feasibility and the nutritional parameters of the patients with Roux-en-Y reconstruction with aboral pouch following total gastrectomy to the simple Roux-en-Y. From February 2011 to June 2014, sixty three patients with gastric cancer underwent total gastrectomy. We analyzed the short-term outcome of surgery and the nutritional parameters in two groups. Results: The aboral pouch was created as a side to side anastomosis approximately 50 cms distal to the esophagojejunostomy, 12 cm in length. Most nutritional parameters after surgery were similar in two groups. However, lymphocyte, serum albumin and prognostic nutritional index in aboral pouch group one year later were good tendency compared with simple Roux-en-Y group. Conclusions: Roux-en-Y reconstruction with aboral pouch might become one of the standard methods after total gastrectomy for gastric cancer.
Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Sahai Vaibhav , Bendell Johanna C. , Bullock Andrea J. , LoConte Noelle K. , Hatoum Hassan , Ritch Paul S. , Hool Hugo , Leach Joseph W. , Sanchez James , Sohal Davendra , Strickler John H. , Patel Ravindranath , Wang-Gillam Andrea , Firdaus Irfan , Kapoun Ann M. , Holmgren Eric , Zhou Lei , Dupont Jakob , Picozzi Vincent J. 
Published: March 2017

279 Background: Tarextumab (TRXT), fully human IgG2 antibody inhibits signaling of Notch2/ 3 receptors. Tumor regression seen in Notch3 (N3) expressing pt-derived pancreatic cancer xenografts when TRXT combined with Nab-P+Gem. Phase 2, randomized, placebo-controlled trial conducted to evaluate efficacy, safety of combination in mPC. Methods: Pts randomized 1:1 to TRXT or placebo (PL). TRXT given IV at 15 mg/kg q 2wks (D 1, 15), nab-P 125 mg/m2, GEM 1000mg/m2 on D1, 8, 15 q 28 days. Tissue for N3 gene expression determination was required. Primary endpoints: overall survival (OS) in all and in 3 subgroups determined by Notch 3 gene expression. Secondary: safety, progression-free survival (PFS) and overall response rate (ORR). Results: N = 177 pts randomized. Performance status (0 or 1), CA19-9 stratum (0 – ULN, > ULN – 59ULN, ≥ 59ULN) balanced. Clinical trial information: NCT01647828. . Conclusions: Addition of TRXT to Nab-P+Gem did not improve OS in 1st line mPC. A potential detrimental effect on PFS and ORR was seen in subjects with N3 < 25%ile.[Table: see text]
Genomic profiling of ampullary adenocarcinoma (AA): Insights from a comparative analysis of pancreatic and intestinal adenocarcinoma and opportunities for targeted therapies use.
Authors: Perkins Geraldine , Bouchet-Doumenq Cecile , Svrcek Magali , Colussi Orianne , Voron Thibault , Sauvanet Alain , Hammel Pascal , Cros Jerome , Paye Francois , Andre Thierry , Vaillant Jean-Christophe , Bachet Jean Baptiste , Bardier Armelle , Berger Anne , Meatchi Tchao , Nordlinger Bernard , Emile Jean-Francois , Cojean-Zelek Isabelle , Taieb Julien , Laurent-Puig Pierre 
Published: March 2017

300 Background: Ampullary adenocarcinoma (AA) is a rare entity. AA can originate from either intestinal or pancreaticobiliary ductal epithelium, and patients are often managed as those with pancreaticobiliary carcinomas. The study objectives were the genetic profiling of AA and the identification of specific molecular profiles according to these 2 pathological types. Methods: AA patients included in the AGEO retrospective multicenter cohort who underwent surgical resection of their tumor between 1999 and 2010 were selected. Formalin-fixed, paraffin-embedded (FFPE) archival tissue blocks were collected. Next generation sequencing (NGS) using a 50 gene panel (Ion AmpliSeq Cancer panel) on tumor DNA, and immunohistochemistry (IHC) panel including CK7, CK20, MUC1, MUC2 and CDX2, on tumor sections, were performed. Results: NGS was performed on 101 tumors from 6 hospitals, with 1 technical failure. In total, the most frequent gene mutations were: KRAS (45%), TP53 (40%), APC (15%), PIK3CA (12%), SMAD4 (9%), BRAF (8%), CDKN2A (6%). No mutation was found in 21% of tumors. According to IHC, the most common histological type was intestinal (51%), followed by pancreaticobiliary type (42%) and undetermined (7%). BRAF mutation was significantly associated with intestinal type (8 vs 0, p = 0.017). According to Cosmic database, similarities of molecular profiles exist between AA with intestinal type and colorectal adenocarcinoma, and between AA with pancreaticobiliary type and pancreas adenocarcinoma, respectively. Conclusions: This study shows that AA is a heterogeneous entity and that a large proportion of AA presents a molecular profile that is more similar to that of colorectal adenocarcinoma, compared to pancreatic adenocarcinoma. This important information could be interesting to guide treatment decision in patients with this rare disease.
Interim analysis of a phase 2 study of lenvatinib (LEN) monotherapy as second-line treatment in unresectable biliary tract cancer (BTC).
Authors: Morizane Chigusa , Ueno Makoto , Sasaki Takashi , Nagashima Fumio , Mizuno Nobumasa , Shimizu Satoshi , Hayata Nozomi , Ikezawa Hiroki , Suzuki Takuya , Nakajima Ryo , Dutcus Corina E. , Ikeda Masafumi 
Published: March 2017

310 Background: LEN inhibits the activity of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor–α. These targets have been shown to be expressed in patients (pts) with BTC. The objective of this study is to evaluate LEN as a potential treatment option for these pts. Methods: This is an open-label, phase 2 study conducted in Japan. Pts aged ≥ 20 years with confirmed diagnosis of unresectable BTC, measureable disease per Response Evaluation Criteria in Solid Tumors v1.1, and 1 prior gemcitabine-based doublet chemotherapy, will receive LEN 24 mg/d. The primary endpoint is objective response rate. Secondary objectives include disease control rate (DCR), safety, and pharmacokinetics. Enrollment of 25 pts is planned. The study includes an interim evaluation for futility. If there is no objective response and disease control is achieved in < 5 pts of 15‒17 pts, the study will end. Results: An interim evaluation was performed with 17 pts enrolled (data cutoff: 25 July 2016). Ten (59%) pts were aged < 65 years, 10 (59%) were male, 2 (12%) had prior surgery, and 13 (76%) received prior gemcitabine + cisplatin therapy. Efficacy results appear in the table. One pt had a partial response (PR) and 13 had stable disease (SD). The DCR was 82%. All pts experienced treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 11 (65%) and serious AEs (SAEs) occurred in 7 (41%) pts. There were no fatal SAEs. TEAEs leading to LEN discontinuation, dose reduction, and dose interruption occurred in 1 (6%), 12 (71%), and 9 (53%) pts, respectively. Analysis of trough plasma concentration in 13 pts from this study showed no difference versus that observed in a previous phase 3 study of LEN in differentiated thyroid cancer. Conclusions: Because results of this interim evaluation did not meet futility criteria, the study was continued, with findings suggesting possible activity of LEN in pts with unresectable BTC who failed gemcitabine-based doublet chemotherapy. Toxicities were generally manageable with dose modifications as only 1 pt required discontinuation from LEN. Clinical trial information: NCT02579616. [Table: see text]
A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer.
Authors: Jameson Gayle S. , Borazanci Erkut Hasan , Babiker Hani M. , Poplin Elizabeth , Niewiarowska Anna A. , Gordon Michael S. , Barrett Michael T , Ansaldo Karen , Lebron Leticia , Stoll Amy C. , Rosenthal Adam , Shemanski Lynn R. , Korn Ronald Lee , Ramanathan Ramesh K. , Von Hoff Daniel D. 
Published: March 2017

341 Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.
A randomized phase II trial comparing different schedules of nab-paclitaxel (nabP) combined with gemcitabine (GEM) as first line treatment for metastatic pancreatic adenocarcinoma (PDAC).
Authors: Corrie Philippa , Qian Wendi , Basu Bristi , Jodrell Duncan Ian , Falk Stephen , Iwuji Chinenyu , Wasan Harpreet , Palmer Daniel H. , Scott-Brown Martin , Wadsley Jonathan , Arif Seema Safia , Babaoglan A. Burcu , Dalchau Katy Marie , Gopinathan Aarthi , Chhabra Anita , Machin Andrea , Neesse Albrecht , Tuveson David A. , Valle Juan W. ,   SIEGE Trial Investigators
Published: March 2017

342 Background: NabP+GEM chemotherapy improves survival compared with standard GEM monotherapy as treatment for advanced PDAC. A PDAC mouse model showed that delivery of nabP prior to GEM generated a higher intratumoural dFdC:dFdU ratio, which correlated with improved outcome. Therefore, scheduling may be critical to optimise clinical benefit. Methods: Patients were randomised to receive nabP+GEM, either concomitantly (CON) or sequentially (SEQ), 24 hours apart. After 6 cycles, patients benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) assessed by 8-weekly CT scanning; secondary endpoints included safety, response rate, overall survival (OS) and quality of life (QoL). Results: Between March 2014 and 2016, 146 patients (71 SEQ, 75 CON) from 19 UK sites were randomly assigned. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% of patients), 80 (27%), 90 (38%) or 100 (24%); 47% of primary tumours were situated in the pancreatic head; 84% had liver metastases. Median number of cycles was 4 SEQ, 3 CON; 50 patients (34%) received ≥ 6 cycles of treatment (41% SEQ, 28% CON). A 24+2hr interval was achieved in over 90% SEQ administrations. Most patients stopped treatment prior to 6 cycles due to disease progression/death (42%) or toxicity (41%). Grade ≥ 3 adverse events experienced by ≥ 10% patients (SEQ, CON) were neutropaenia (54%, 30%), febrile neutropaenia (12%, 12%), fatigue (22%, 16%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered to 35 patients (23 SEQ, 12 CON). To date, 109 patients have died. 6-month PFS by SEQ and CON arms was 46.7% and 33.8%; median PFS was 5.8 and 4.3 months. 12-month OS by SEQ and CON arms was 29.1% and 20.1%; median OS was 10.1 and 7.9 months. The objective response rate was 44% SEQ and 30% CON. Mean baseline QoL Global health status was 60.6 SEQ and 63.4 CON. The change from baseline (mean) at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP and GEM improves progression-free and overall survival. Although more myelosuppressive, QoL was maintained. Clinical trial information: ISRCTN71070888.
Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): Results of the international, randomized phase 3 RESORCE trial.
Authors: Finn Richard S. , Merle Philippe , Granito Alessandro , Huang Yi-Hsiang , Bodoky Gyorgy , Pracht Marc , Yokosuka Osamu , Rosmorduc Olivier , Gerolami René , Caparello Chiara , Cabrera Roniel , Chang Charissa , Sun Weijing , Han Guohong , Le Berre Marie-Aude , Baumhauer Annette , Meinhardt Gerold , Bruix Jordi ,   On Behalf of the RESORCE Investigators
Published: March 2017

344 Background: SOR is standard first-line systemic treatment for HCC unsuitable for locoregional therapy. RESORCE showed that REG improves overall survival (OS) in patients who progressed during SOR treatment (HR 0.63, 95% CI 0.50, 0.79; P < 0.001). This exploratory analysis describes outcomes for the sequence of SOR followed by REG. Methods: 573 patients were randomized 2:1 to receive REG 160 mg/day (d), 3 wks on/1 wk off or PBO. Data on prior SOR treatment and radiologic progression were prospectively collected. Efficacy and safety were evaluated by the last SOR dose. Time from the start of SOR to death was assessed. Results: Baseline characteristics were balanced. Times from the start of SOR to progression on SOR and times from progression on SOR to start of study drug were similar (Table). When analyzed based on last SOR dose 800 mg/d vs < 800 mg/d, rates of all grade treatment-emergent adverse events (TEAEs) on study were similar (REG: 100% vs 100%; PBO: 92% vs 93%). TEAE grades 3/4/5 by last SOR dose 800 mg/d vs < 800 mg/d were 52/11/15% vs 61/10/12%, respectively, with REG and 30/8/24% vs 32/7/14% with PBO. HRs (95% CI) REG/PBO for OS by last SOR dose were similar: 0.67 (0.51, 0.87) for 800 mg/d and 0.68 (0.48, 0.97) for < 800 mg/d. Median OS (95% CI) from the start of SOR was 26.0 months (22.6, 28.1) for REG and 19.2 months (16.3, 22.8) for PBO. Clinical trial information: NCT01774344. Conclusions: This exploratory subgroup analysis by prior SOR dose demonstrates a consistent survival benefit for REG. In addition, the safety profile of REG was not remarkably different when analyzed by the last SOR dose.[Table: see text]
Histologic classification and grading enhances gallbladder cancer staging: A population-based prognostic score validated by the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Tran Thuy , Ethun Cecilia Grace , Pawlik Timothy M. , Buettner Stefan , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Krasnick Bradley , Weber Sharon M. , Salem Ahmed , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar , Poultsides George A. 
Published: March 2017

356 Background: Beyond the most common adenocarcinoma type, several gallbladder cancer (GBC) histologies have been described as being associated with more favorable (papillary) or less favorable outcome (adenosquamous, mucinous, signet ring). We sought to examine the added value of histologic type and grade on the existing AJCC staging system for resected GBC. Methods: Patients who underwent resection of GBC from 1988-2013 were identified using the Surveillance Epidemiology End Results (SEER) registry. A prognostic score was created by assigning points for T stage, N stage, grade and histology based on the regression coefficient in multivariate analysis. The score was externally validated using the US Extrahepatic Biliary Malignancy Consortium (USEBMC) database (2000-2015) and compared with the AJCC staging system. Results: Of 7,915 patients identified in SEER, 83% had adenocarcinoma, 7% papillary, 4% adenosquamous, 4% mucinous, and 2% signet ring. In the USEBMC database, the frequencies of the respective histologies were 86, 9, 2, 1 and 2%. Median survival per histologic type, for SEER and USEBMC respectively, were 45 and 110 mos for papillary, 16 and 24 mos for adenocarcinoma, 14 and 12mos for mucinous, 8 and 4mos for adenosquamous, and 9 and 15mos for signet ring (P between histologies < 0.001 for both cohorts). On multivariate analysis, T stage, N stage, grade and histology were independent predictors of survival. The developed prognostic score, based on points for each of these 4 variables, showed excellent discriminatory ability both in the SEER and USEBMC cohorts. The AUC for the prognostic score was significantly improved compared with the AJCC system (0.69 vs. 0.64,both P < 0.001 using SEER, and 0.76 vs. 0.66,both P < 0.001 using USEBMC). Conclusions: The incorporation of histology and grade into the TNM system allows for a simple and accurate tool to determine prognosis following resection of GBC. [Table: see text]