bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase II trial of first-line FOLFIRINOX for advanced gastroesophageal cancers.
Authors: Jin Ramon , Park Haeseong , Wang-Gillam Andrea , Suresh Rama , Rigden Caron E. , Amin Manik A. , Tan Benjamin R. , Pedersen Katrina , Lim Kian-Huat , Trikalinos Nikolaos , Acharya Abhi , Copsey Megan , Navo Katie , Morton Ashley , Gao Feng , Lockhart A. Craig 
Published: May 2020

4532 Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have moderate clinical benefit with objective response rates (ORR) of approximately 40-50%. FOLFIRINOX has been shown to be an effective and well-tolerated first line therapy in other GI cancers. In this open-label, single-arm phase II study of patients with advanced gastroesophageal adenocarcinomas, we sought to evaluate the safety and clinical activity of FOLFIRINOX. Methods: The primary endpoint was ORR, and secondary endpoints included safety profile, progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Estimated sample size included 41 patients with HER2 negative disease with 90% power to detect an ORR≥60% with alpha of 0.10. No enrollment goal was planned for HER2 positive patients, but they were allowed participation to receive study treatment in combination with trastuzumab. Treatment consisted of 400mg/m2 5-FU bolus, 400 mg/m2 leucovorin, 2400 mg/m2 5-FU infusion over 46 hours, 180 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin. Trastuzumab was administered intravenously as a 6 mg/kg loading dose then given 4 mg/kg every 14 days for HER2 positive patients. This trial is registered with ClinicalTrials.gov, NCT01928290. Results: From November 2013 to May 2019, 67 patients were enrolled, of which 26 (39%) had HER2 positive disease. Median follow-up was 16.1 months. ORR was 61% (25/41) for HER2 negative and 85% (22/26) for HER2 positive groups. Overall, one patient (2%) had a complete response, 36 patients (69%) had partial responses, and 13 patients (19%) had stable disease for >6 months; therefore, CBR was 96%. Median PFS was 11.9 months, median OS was 17.4 months. 41 patients (83.7%) had dose modification or treatment delay with the most common toxicities being neutropenia, diarrhea, peripheral sensory neuropathy, and nausea with no unexpected toxicities. Conclusions: FOLFIRINOX is a highly effective three-drug regimen for first-line treatment of advanced gastroesophageal cancer with expected, tolerable toxicities. Clinical trial information: NCT01928290 .
Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) mobilize specific therapeutic immunity for high-risk resected gastric cancer.
Authors: Liu Qin , Qian Hanqing , Shao Jie , Xu Qiuping , Sha Huizi , Yang Yang , Wang Weifeng , Yu Lixia , Liu Baorui , Wei Jia 
Published: May 2020

4535 Background: 35% of stage IIIB/C Gastric cancer patients will recurrent after D2 gastrectomy within one year. Mutation-derived epitopes (neoantigens) has been demonstrated to induce tumor cell specific immune responses controlling the tumor growth. Nanovaccine can increase antigen presentation efficiency and elicit potent antitumor T cell responses with robust therapeutic efficacy. We hypothesized that vaccination with neoantigens/cancer testis (CT) antigens could expand pre-existing and induce antigen-specific T-cells populations, favouring of tumor control enhancement. Here, we report the first-in-human application of this concept in gastric cancer. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. PVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens/cancer testis antigens designed to induce antigen specific T cells and associated antitumor responses. PVAC will be administrated to stage IIIB/IIIC gastric carcinoma after six cycles of adjuvant chemotherapy (S-1/Oxaliplatin or S-1/docetaxel). Each patient received PVAC by subcutaneous injection on Days 1, 4, 8, 15, 22, 43, 64, 85, 169, administrated with the adjuvant montanide ISA 51 VG. Safety, immunogenicity and clinical efficacy will be evaluated. Results: 25 stage IIIB or IIIC gastric cancer patients were enrolled in this study. Mean age was 54.3 years old (range: 34-70), and ECOG performance scores were 0 or 1. Repeated dosing has been well tolerated with mild local discomfort and no DLTs. Three patients were observed grade 2 local skin reactions in the injection sites. No SAEs related to PVAC have been observed. Among median follow up time of 12.6 months (range: 8.5-25.0 months), only two patients had local recurrence at 24.0 months and 10.5 months after surgery, respectivelt. The rest 23 patients remain disease free on study. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is a multiple neoantigen/CT antigens nanovaccine that personalizes tumor specific antigens and the individual patient’s capacity to respond. Addition of PVAC may prolong progression-free survival (PFS) after the standard of care chemotherapy. Clinical trial information: ChiCTR1800017319 .
Translational analysis of esophageal adenocarcinoma (EAC) patients treated with oxaliplatin and capecitabine (Xelox) +/- the dual ErbB inhibitor AZD8931 in the DEBIOC study.
Authors: Lavery Anita , Stevenson Leanne , McManus Damian , Logan Gemma E. , Walker Steven M. , Jellema Gera L. , Van Schaeybroeck Sandra , Virdee Pradeep Singh , Elhussein Leena , Turbitt Julie , Colinson Diane , Miedzybrodzka Zofia , Petty Russell D. , Harkin Paul D. , Kennedy Richard D. , Eatock Martin McKinlay , Middleton Mark R. , Thomas Anne L. , Turkington Richard C. 
Published: May 2020

4539 Background: The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant Xelox +/- AZD8931 but limited efficacy. We utilized EAC patient samples from DEBIOC to evaluate the impact of neoadjuvant Xelox +/-AZD8931 on biological pathways using a unique software driven solution. Methods: 24 pre-treatment FFPE EAC biopsies and 17 matched surgical resection specimens were transcriptionally profiled using the Almac Diagnostics Xcel Array. Gene expression data was analyzed using the Almac claraT total mRNA report V3.0.0, reporting on 92 gene expression signatures and 7337 single genes associated with 10 key biologies. Paired Wilcoxon tests (5% significance level) were used to evaluate changes in claraT scores pre- and post-treatment. EGFR and Her2 expression were assessed by IHC and FISH. Results: 15 patients received Xelox+AZD8931 and 9 Xelox alone. Hierarchical clustering of biopsies identified 4 major clusters: Inflammation active, Genomic Instability active, EGFR & MAPK active, and EMT & Angiogenesis active. Comparison of signature scores pre- and post- neoadjuvant treatment demonstrated a significant reduction in scores relating to DNA damage repair (DDR) deficiency (Almac DNA Damage assay, p< 0.0001; BRCAness Profile, p= 0.0025; HRD Gene Signature, p< 0.0001; BRCA1ness Signature, p= 0.0004) and a significant increase in angiogenesis signatures (Almac Angiogenesis Assay, p= 0.0002; Angio Predictive G model, p= 0.0228; Angiogenesis Signature A, p= 0.0034) and EMT signatures (EMT Signature, p= 0.0031, EMT Enrichment Score, p= 0.0013, Pan-Can EMT Signature B, p= 0.0001). Comparing pre- and post-treatment signature scores in patients treated with Xelox +/-AZD8931 revealed a significant reduction in EGFR Sensitivity Signature ( p= 0.0088), ERBB2-specific Gene Expression Signature ( p= 0.0127) and Hallmark PI3K-AKT-MTOR Signaling ( p= 0.0195) in those treated with Xelox + AZD8931 in keeping with the mechanism of action of AZD8931. Downregulation of AKT signaling was confirmed in AZD8931 treated and resistant cell lines. Conclusions: We report the use of a novel software tool to apply 92 gene expression signatures to EAC biopsy and resection specimens from the DEBIOC trial to provide insight into mechanisms of action. Neoadjuvant treatment was associated with a reduction in DDR deficiency and an increase in angiogenesis and EMT signatures whilst a reduction in EGFR, Her2 and AKT pathways was noted with AZD8931 treatment.
Interim safety analysis of the DANTE trial: Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma—A randomized, open-label phase II trial of the German Gastric Group at the AIO and SAKK.
Authors: Homann Nils , Lorenzen Sylvie , Schenk Michael , Thuss-Patience Peter C. , Goekkurt Eray , Hofheinz Ralf Dieter , Kretzschmar Albrecht , Bolling Claus , Angermeier Stefan , Wicki Andreas , Siebenhuener Alexander Rheinhard , Lindig Udo , Pink Daniel , Ettrich Thomas Jens , Schmalenberg Harald , Waberer Lisa , Talbot Jonathan , Pauligk Claudia , Goetze Thorsten Oliver , Al-Batran Salah-Eddin 
Published: May 2020

4549 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sep 2018; by Feb 2020, a total of 175 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 5% of the 40 patients (overall 7.4% of 175 pts enrolled) showed microsatellite instability. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: Perioperative atezolizumab plus FLOT is feasible and safe. The study continues recruitment. Clinical trial information: NCT03421288 .
A population-based study on gender differences in tumor and treatment characteristics and survival of curable gastroesophageal cancer.
Authors: Kalff Marianne C. , Dijksterhuis Willemieke P.M. , Verhoeven Rob H.A. , Wagner Anna Dorothea , Lemmens Valery E.P.P. , Van Laarhoven Hanneke W.M. , Gisbertz Suzanne S. , van Berge Henegouwen Mark I. 
Published: May 2020

4550 Background: Although curative treatment options for gastroesophageal cancer are identical for men and women, outcomes may vary. This study examined differences in tumor and treatment characteristics and survival between men and women with potentially curable gastroesophageal cancer. Methods: Nationwide data was acquired from the Netherlands Cancer Registry. Patients with a potentially curable gastroesophageal carcinoma (cT1-T4a or cTx, any cN, cM0 or cMx) diagnosed between 2006 and 2017 were selected. Patient stratification was performed for tumor location and histology. The primary endpoint, relative survival, was compared between men and women with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC) and gastric adenocarcinoma (GAC), adjusted for the normal life expectancy for men and women separately. Results: In total, 13,391 patients with an EAC (79.1% men), 5,103 patients with an ESCC (54.7% men), and 8,149 patients with a GAC (60.1% men) were included. Women with gastroesophageal cancer were older than men. Lower cT-stages were observed in women with EAC and ESCC (both p < 0.001) and lower cN-stages were observed in women in all groups, although clinical T- and N-stage were more frequently graded as cTx and cNx in women. In women, EAC tumors were less frequently located in the distal esophagus (70.4% vs. 58.6%, p < 0.001), ESCC tumors had a more proximal tumor location (p < 0.001), and GAC tumors were more frequently located at the antrum (32.3% vs. 37.2%, p < 0.001). For EAC and GAC, but not for ESCC, men were more frequently allocated to a potentially curative treatment; endoscopic resection, surgical resection or definitive chemoradiotherapy (EAC: 74.6% vs. 60.1%, p < 0.001; GAC: 69.0% vs. 65.4%, p 0.001; ESCC: p 0.117). An inferior 5-year relative survival was observed in women with EAC (34.3% vs. 30.1%, p < 0.001) and GAC (36.1% vs. 33.2%, p 0.016). In women with ESCC a superior 5-year relative survival was observed (24.4% vs 28.5%, p 0.001). Conclusions: Remarkable differences in 5-year relative survival were observed between men and women with gastroesophageal cancer, in addition to important differences in tumor stage, tumor location and treatment. Strikingly, men with esophageal and gastric adenocarcinoma were more frequently allocated to a potentially curative treatment compared to women. These findings illustrate the need for further exploration and consideration of gender differences in gastroesophageal cancer treatment.
Diagnostic accuracy of CT-staging of advanced gastric cancer following neoadjuvant chemotherapy.
Authors: Jang Jong Keon , Lee Jong Seok , Ryu Min-hee , Yook Jeong Hwan , Park Young-Kyu , Kim Young Woo , Kim Jin Young , Rha Sun Young , Chung Ik-Joo , Kim In-Ho , Oh Sang Cheul , Yoo Chang Hak , Choi Jin-Hyuk , Zang Dae Young , Kim Gyunji , Lee YeonJu , Noh Sung Hoon , Kang Yoon-Koo 
Published: May 2020

4551 Background: Neoadjuvant or perioperative chemotherapy has been accepted as a standard treatment globally in patients (pts) with locally advanced gastric cancer (LAGC). In PRODIGY phase III study (n = 530), we have demonstrated that neoadjuvant chemotherapy with DOS regimen (docetaxel, oxaliplatin, S-1) led to significant tumor downstaging and improved PFS in Korean LAGC pts (Kang, et al. ESMO 2019). Although CT has been performed to re-stage the tumor after neoadjuvant chemotherapy, there has been a relative paucity of diagnostic accuracy data. This study is to evaluate the diagnostic performance of restaging of LAGC after neoadjuvant chemotherapy using CT in PRODIGY study population. Methods: Of 266 pts, who had been diagnosed LAGC of T2-4 or N+ stage as assessed with CT and randomized to neoadjuvant chemotherapy arm (CSC) in PRODIGY study, 214 pts underwent gastrectomy were included in this analysis. The post-chemotherapy T- and N- stage was determined based on CT scan taken just prior to surgery and compared with the pathologic stage (AJCC 7th edition). Two experienced radiologists independently evaluated depth of primary tumor and reached consensus if any discrepancy between two readers. Diameter of short axis of the largest regional lymph node was measured to predict metastatic lymph node. Result of histopathologic T- and N-staging using surgical specimen was used as reference standard. Results: The study cohort consisted of pathologic T0 (n = 22), T1(n = 39), T2(n = 31), T3(n = 79), and T4(n = 43). The overall diagnostic accuracy of CT was 45%. For each T-stage, accuracy of T0,T1,T2,T3, and T4 was 0%, 26%, 29%, 55% and 79%, respectively. Rate of over- and under- staging was 47% and 8%, respectively. Accuracy for prediction of downstaging to early gastric cancer (T0-T1) was 83%. Interobserver agreement of T-staging was moderate (k = 0.41). There were 98 patients of N+ and 116 patients of N- at histopathology. Area under the curve of receiver operating characteristics to differentiate lymph node metastasis was 0.63. Sensitivity and specificity of size criteria of the largest lymph node (cut off value: > 6mm, > 7mm, and > 8mm) to predict pathologic N+ were 90% and 17%, 78% and 34%, and 68% and 51%, respectively. Conclusions: Re-staging using CT after neoadjuvant chemotherapy showed suboptimal accuracy and over-staged residual tumor. However, it predicted downstaging of gastric cancer with high accuracy.
Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.
Authors: Wang Jingyuan , Xiu Joanne , Shields Anthony Frank , Grothey Axel , Weinberg Benjamin Adam , Marshall John , Lou Emil , Khushman Moh'd M. , Sohal Davendra , Hall Michael J. , Battaglin Francesca , Arai Hiroyuki , Soni Shivani , Zhang Wu , Korn Wolfgang Michael , Lenz Heinz-Josef 
Published: May 2020

4558 Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p < .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p < .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p < .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p < .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p < .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).
Health-related quality-of-life assessment in accordance with reconstruction procedures for distal gastrectomy for stage I gastric cancer using data from JCOG0912.
Authors: Fujiya Keiichi , Ando Masahiko , Mizusawa Junki , Katai Hitoshi , Yamada Takanobu , Ito Seiji , Fukagawa Takeo , Bando Etsuro , Misawa Kazunari , Tanizawa Yutaka , Morita Shinji , Katayama Hiroshi , Yoshikawa Takaki , Terashima Masanori , Sasako Mitsuru ,   Stomach Cancer Study Group, Japan Clinical Oncology Group
Published: May 2020

4562 Background: There are three major reconstruction methods after gastrectomy for distal gastric cancer; Billroth-I (B-I), Roux-en-Y (RY) and pylorus-preserving gastrectomy (PPG). These procedures can affect postoperative health-related quality-of-life (HRQoL), but the method is often selected due to physician’s preference or each institutional policy without solid evidence. We aimed to explore differences in HRQoL after each reconstruction procedure selected in JCOG0912, a phase III noninferiority trial comparing open and laparoscopic distal gastrectomies for stage I gastric cancer. Methods: Among 33 institutions participated in JCOG0912, 4 major cancer centers were selected for HRQoL assessment. HRQoL was assessed using the EORTC QLQ-C30 and STO22 before (baseline) and at 1, 3, 12, and 36 months after surgery as preplanned exploratory analysis. Results: Excluding 2 patients who didn’t answer the questionnaire, 590 patients were analyzed in this study. For reconstruction, B-I was performed for 222 patients (37.7%), RY for 178 (30.2%) and PPG for 189 (32.1%). Proportion of the opted reconstruction procedures was not different in open and laparoscopic gastrectomies. Global health status (GHS) scores of QLQ-C30 were not different among 3 groups at any time point. In comparison of B-I and RY, B-I was better than RY in constipation, while RY was better than B-I in diarrhea and reflux symptoms. In comparison of B-I and PPG, B-I was better than PPG in constipation and reflux symptoms, while PPG was better than B-I in diarrhea. When comparing RY and PPG, RY was better than PPG in constipation and reflux symptoms, while PPG was better than RY in taste (table). Conclusions: GHS scores were similar regardless of the reconstruction procedure, however postoperative symptoms including reflux, constipation, and diarrhea were various according to reconstruction methods. [Table: see text]