bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of dasatinib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib: A single arm, multicenters, phase 2 trial.
Authors: Li Jian , Zhou Ye , Zhang Xinhua , WU Xiaojun , Zhou Yongjian , Liu Xiufeng , Zhang Bo , Wu Xin , Lin Shen 
Published: January 2019

138 Background: Regorafenib is recommended to treat advanced gastrointestinal stromal tumor (GIST) refractory to imatinib and sunitinib. However, the efficacy is not satisfied, other active agents need to be explored to advanced patients. Methods: In this single arm, multi-center, phase 2 trial, we enrolled patients aged 18 years and older with advanced GIST who had received previous imatinib and sunitinib treatment. Participants were treated with oral dasatinib 50mg twice a day for 2 weeks. If patients were tolerable, then they received dasatinib 70mg twice a day treatment, to tumor progression or intolerable toxicities. The primary endpoint was RECIST-based progression-free survival (PFS) in the intention-to-treat population. The secondary endpoints included response rate, overall survival (OS) and advent events. ctDNA will be analysis in some patients to explore the sensitive biomarker to dasatinib. Results: From May 2016 to June 2018, 58 patients from nine medical centers were enrolled in this study. Two patients had partial response and disease control rate was 62.0%. The median PFS was 3.0 months (95% CI, 2.6-3.4 months). There was no statistic difference of PFS in both subgroup with different primary mutations and in subgroup with different secondary mutations. The patients with wild type GIST had a trend of longer PFS of 5.5 months. In 4 patients with PDGFRA D842V mutation, two patients had stable disease. The median OS was 14.0 months (95% CI, 10.8-17.2 months). The most frequently observed grade 3 adverse events included anemia (10.3%), diarrhea (1.7%). The analysis of ct DNA is ongoing. Conclusions: Dasatinib is an active treatment for patients with GIST who are refractory to imatinib and sunitnib. This study is registered with ClinicalTrials.gov, NCT02776878 . Clinical trial information: NCT02776878.
An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in patients with relapsed gastric cancer.
Authors: Bang Yung-Jue , Kaufman Bella , Geva Ravit , Stemmer Salomon M. , Hong Sook-Hee , Lee Jong-Seok , Domchek Susan M. , Lanasa Mark C. , Tang Mei , Gresty Christopher , Angell Helen K , Opincar Laura L.M. , Herbolsheimer Pia Maarit , Evans T.R. Jeffry 
Published: January 2019

140 Background: Olaparib is a PARP inhibitor that has shown activity in relapsed gastric cancer (GC) when combined with chemotherapy. MEDIOLA assesses the efficacy and safety of a chemo-free combination of olaparib and durvalumab, an anti-programmed cell death ligand-1 (PD-L1) agent in patients (pts) with solid tumors, including relapsed GC (NCT02734004). Methods: Eligible pts had GC that relapsed following platinum-containing therapy. Pts received olaparib 300 mg PO BID for a 4-wk run-in to allow for serial biopsies, followed by combination olaparib and durvalumab (1.5 g IV q 4 wks) until progressive disease (PD) as measured by RECIST 1.1. Tumor measurements were taken at baseline, 4 wks and q 8 wks thereafter. Primary endpoints were disease control rate (DCR) at 12 wks, safety, and tolerability. The secondary endpoints included DCR at 28 wks, objective response rate (ORR), duration of response (DoR), progression-free survival, and OS. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Bayesian predictive probability design was used for statistical analysis. Results: Forty pts were included in the safety and 39 in the efficacy analysis. Among 39 pts, median age was 57 yrs (range 28–77). Nineteen pts (48%) had a grade 3 AE; three pts (8%) a grade 4 AE. Most common AEs were anemia, lipase increase, fatigue, dysphagia, hyponatremia, and alkaline phosphatase increase. Ten pts (25%) had immune-mediated AEs, most commonly rash. The ORR was 10%; two pts had complete response; two had partial response. Median DoR was 11.1 months. DCR at 12 wks was 26%. Further efficacy and biomarker data will be presented. Conclusions: The combination of olaparib and durvalumab was tolerable, with no unexpected AEs. All responses occurred after the addition of durvalumab and were durable, suggesting synergistic treatment effect of the combination in some pts. Furthermore, several pts with early PD showed unexpectedly long survival. DCR at 12 wks was below the target (70%) due to a high rate of early PDs following the olaparib run-in. To address the early treatment failures, an upfront addition of more aggressive therapies to the combination should be explored. Clinical trial information: NCT02734004.
A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).
Authors: Yukami Hiroki , Goto Masahiro , Kii Takayuki , Terazawa Tetsuji , Yamaguchi Toshifumi , Shimamoto Fukutaro , Nishitani Hitoshi , Kawakami Hisato , Shimokawa Toshio , Matsubara Yoshihiro , Sakai Daisuke , Kurokawa Yukinori , Satoh Taroh 
Published: January 2019

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.
Clinical impact of newly developed sarcopenia after surgical resection for gastric cancer.
Authors: Kim Beom Jin , Lee Eun Sun , Park Jae Yong , Kim Jae Gyu 
Published: January 2019

145 Background: The purpose of this study was to investigate the risk factors and the clinical impact of of newly developed sarcopenia after surgical resection on the prognosis in patients undergoing radical gastrectomy for gastric cancer. Methods: We retrospectively reviewed clinicopathological data from 430 consecutive GC patients who underwent surgical resection at Chung-Ang University Hospital between January 2011 and December 2015. Their skeletal muscle mass and abdominal fat volume were measured by abdominal CT imaging. Results: A total of 425 patients were analyzed in the study. The mean age was 62 years old and male were 301 (70.8%). Of these, 42 patients (9.9%) were diagnosed as pre-operative sarcopenia. Compared with non-sarcopenic group, pre-operative sarcopenia groups showed more female, higher BMI, less alcoholic, and less smoking. However, there was no significant difference in 5-year overall survival and disease free survival between the groups (p=0.836 and p=0.638, respectively). Among 381 non-sarcopenic patients, 48 patients (12.6%) were diagnosed as newly developed sarcopenia in one year after gastric resection. Compared with non-sarcopenic group, the newly developed sarcopenic group showed more male, more undifferentiated tumor, lower hemoglobin level, less alcoholic, less smoking, and presence of diabetes mellitus. Furthermore, newly developed sarcopenic group showed more total fat area, especially more subcutaneous fat area and lower VFA / SFA ratio in the abdominal CT imaging. However, there was no significant difference in the 5-year overall survival and disease free survival among non-sarcopenic, sarcopenic, and newly developed sarcopenic groups (p=0.521 and p=0.534, respectively). The relationship between preoperative body fat volume and postoperative muscle mass showed a significant correlation (rho = 0.296, p <0.001), but only BMI was significantly associated with long term survival. Conclusions: Although newly developed sarcopenia after surgery did not affect the survival rate, patients with nutritional risk of sarcopenia after surgical resection may require early evaluation of nutritional status and nutritional support.
Evaluation of safety and tolerability of durvalumab (D) and tremelimumab (T) in combination with first-line chemotherapy in patients (pts) with esophageal squamous-cell carcinoma (ESCC).
Authors: Lee Dae Ho , Kim HyeRyun , Keam Bhumsuk , Kato Ken , Kuboki Yasutoshi , Vlahovic Gordana , Takahashi Osamu , Fitts David , Ahn Myung-Ju 
Published: January 2019

146 Background: Platinum-doublet chemotherapy in first-line (1L) ESCC pts has reached a therapeutic plateau, and new therapeutic strategies are needed. Adding D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) to 1L platinum-based chemotherapy may improve outcome in pts with advanced/metastatic ESCC. Methods: In Part A of this Phase 1b study (NCT02658214), dose-limiting toxicities (DLTs) for D+T (D 1.5 g + T 75 mg on d1, q4w) plus 5-FU+cisplatin (5-FU 800 mg/m2 + cisplatin 80 mg/m2 d1-5, q4w) were evaluated for the first 4 cycles in pts with advanced/metastatic ESCC who were eligible for 1L chemotherapy. The primary objective was safety and tolerability and exploratory objectives included antitumor activity and biomarker analysis. Results: Pts (N = 6) were enrolled to receive D+T + 5-FU+cisplatin between November 13, 2017, and February 14, 2018. Median age was 56 years, 83% were male, and all were ECOG PS 1. Four pts had recurrent disease and 2 were newly diagnosed with advanced/metastatic disease. All 6 pts had ≥1 treatment-related adverse event (trAE), 3 pts had grade ≥3 trAEs. All pts experienced 5-FU+cisplatin-related AEs. All grade ≥3 trAEs were neutropenia and considered due to 5-FU+cisplatin treatment; 2 were grade 3 and 1 was grade 4, which was the only serious trAE reported. Two pts had D- and/or T-related trAEs. Immune-mediated AEs were grade 1 or 2 and included diarrhea (n = 1), pruritus (n = 1), rash (n = 1), and increased AST (n = 1). There were no trAEs that led to discontinuation or death. Two of the 6 pts had a confirmed partial response that was ongoing at data cutoff (June 29, 2018). Conclusions: For patients in the ESCC DLT evaluation cohort, D+T + 5-FU+cisplatin was tolerable, and no unexpected toxicities occurred. No DLTs were observed for this regimen. The majority of trAEs and all trAEs grade ≥3 were attributed to 5-FU+cisplatin, and all were manageable. AEs related to D and/or T were all grade 1 or 2. No treatment discontinuation or death was attributed to trAEs. The study has been expanded to further evaluate this regimen in additional patients for efficacy, safety, and biomarkers. Clinical trial information: NCT02658214.
Exploratory evaluation of baseline tumor biomarkers and their association with response and survival in patients with previously treated advanced gastric cancer treated with andecaliximab combined with nivolumab versus nivolumab.
Authors: Metges Jean-Philippe , Elboudwarej Emon , Cunningham David , Catenacci Daniel V.T. , Van Cutsem Eric , Wainberg Zev A. , Zhang Yafeng , Turner Scott , Thai Dung , Bhargava Pankaj , Shah Manish A. , Brachmann Carrie 
Published: January 2019

148 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T cell infiltration to potentiate checkpoint blockade. In the phase 2 study combining ADX with nivolumab (N) versus N monotherapy (NCT02864381), addition of ADX to N did not improve objective response rate, progression-free survival (PFS), or overall survival (OS). Methods: Archival tumor samples were collected from all patients (n = 141). CD8 and PD-L1 (28-8 DAKO) were assessed by immunohistochemistry. CD8+ cell density was measured in the tumor area. PD-L1 was prospectively scored by a pathologist for tumor cell (TC) and associated immune cell (IC) positivity. IFNg, Teffector (Teff), and activated CD8+ T cell (ActT) gene signatures were assessed by RNA sequencing. Due to a small number of responders, treatment arms were combined to evaluate response. Cox proportional hazards models were used for survival analyses. Nominal p-values are reported. Results: Baseline biomarkers of T cell infiltration and activation did not differentiate responders from non-responders (IFNg, Teff, ActT, CD8+; p > .10). None of the evaluated biomarkers were associated with PFS or OS for all treated patients or per treatment arm (IFNg, Teff, ActT; p > .10), with the exception of CD8+ (PFS HR = .43, p = .02). The majority of baseline samples were positive for IC PD-L1 (< 1%, n = 36; 1-10%, n = 50; > 10-25%, n = 32; > 25%, n = 20) and negative for TC PD-L1 (H = 0, n = 88; H < 1, n = 27; H > 1; n = 27). Comparing ADX/N to N, there was a trend toward longer OS for the PD-L1+ (TC + IC ≥ 1%) population (n = 102, HR = .621, p = .098), the TC H < 1 group (HR = .464, p = .08) and the IC > 10-25% (HR = .466, p = .08). Conclusions: Neither CD8+ cell density nor IFNg, Teff or ActT gene signatures were associated with response or survival to checkpoint blockade. While TC was low, IC intermediate and TC + IC ≥ 1% PD-L1+ groups trended toward better survival for the ADX+N arm, consistent with the hypothesis that ADX potentiates N activity; this did not translate into better outcome. Clinical trial information: NCT02864381.
The combination of the changes and the value of neutrophil-to-lymphocyte ratio is useful for prediction of response for advanced gastric cancer treated with nivolumab: A multicenter retrospective study.
Authors: Ogata Takatsugu , Satake Hironaga , Ogata Misato , Inoue Kentaro , Hamada Madoka , Yasui Hisateru , Hatachi Yukimasa 
Published: January 2019

150 Background: The ATTRACTION-2 study showed that nivolumab is effective in treating advanced gastric cancer (AGC). Many studies have examined the effectiveness of predictive factors. We previously suggested that neutrophil-to-lymphocyte ratio (NLR) was associated with progression-free survival (PFS) and overall survival. The objective of this study was to determine the effectiveness of the changes of NLR for AGC treated with nivolumab. Methods: Data on patients with AGC treated with nivolumab from November 2014 to December 2017 were collected at two centers. NLRs were calculated before the first cycle (NLRpre) and 2 weeks after the first cycle (NLRpost) of nivolumab, and the changes in NLR (cNLR) was calculated by NLRpost/NLRpre. The association of NLRpre and cNLR with the disease control rate (DCR) and PFS were assessed. Results: Forty-one patients (pts), with the median age of 64 years, were enrolled. Twenty-seven pts were men and 14 were women. Regarding ECOG PS, 34 pts had scores of 0-1 and 7 had a score of 2. The median NLRpre, NLRpost, and cNLR were 2.01 (range, 0.79–18.4), 2.76 (1.27–12.3), and 1.22 (0.16–5.20), respectively. With a median follow-up period of 6.1 months, DCR was 34.1% (complete response [CR], 1 pt; partial response [PR] 3 pts, stable disease [SD], 10 pts). Patients were divided into 3 classes: 8 in Class I (NLRpre≤5 and cNLR≤ 1); 17 in Class II (NLRpre ≤ 5 and 1 < cNLR≤ 2); and 16 in Class III (NLRpre> 5 or cNLR > 2). There were 8 pts, 17 pts, and 16 pts in Class I, II, and III, respectively. DCRs of Class I, II, and III was 87.5% (CR, 1 pt; PR, 2 pts; SD 4 pts), 29.4% (PR, 1 pts; SD 4 pts), and 12.5% (SD 2 pts), respectively. The median PFS was 2.0 months (mo), and it was longer in Class I than in Classes II+III (5.6 vs. 1.4 mo; p = 0.017) and shorter in Class III than in Classes I+II (3.1 vs. 1.3 mo; p = 0.008). The median PFS was 2.0 months (mo). The median PFS was longer in Class I compared with in Class II+III (5.6 vs 1.4 mo; p = 0.017). The median PFS was shorter in Class III compared with in Class I+II (3.1 vs 1.3 mo; p = 0.008). Conclusions: The combined use of NLRpre and cNLR seemed to be effective in predicting the response of AGC to nivolumab.
Simulation study on regionalization of esophagectomy using data of 27,576 patients with esophageal malignant tumor.
Authors: Nishigori Tatsuto , Takahashi Arata , Ichihara Nao , Tsunoda Shigeru , Toh Yasushi , Watanabe Masayuki , Matsubara Hisahiro , Kakeji Yoshihiro , Seto Yasuyuki , Miyata Hiroaki , Sakai Yoshiharu 
Published: January 2019

151 Background: The culture of evidence-based policy making in the field of cancer surgery is still at a developing stage. Although the volume-outcome relationship with esophagectomy has been recently recognized in Japan, there is no regionalization policy. This study was aimed to simulate regionalization of esophagectomy in Japan using data registered in a nationwide clinical database. Methods: The National Clinical Database (NCD) covers more than 95 per cent of all surgical procedures in Japan. The study used data of 27,476 patients with esophageal malignant tumor registered in the NCD as having undergone esophagectomy at 1040 hospitals between 2012 and 2016. The following four scenarios were tested; in scenario 1, 2, 3, and 4, a minimum volume standard was set as 2, 5, 10 and 15 cases per year. The risk-adjusted operative mortality rates after regionalization and travel distances according to patients’ place of residence were estimated for each scenario. Results: Current operative mortality rates according to hospital volume were < 2 cases: 4.8%, 2-4: 3.7%, 5-9: 2.4%, 10-14: 2.1%, and ≥15: 1.6%. In scenario 1 to 4, 598, 791, 896, and 939 hospitals, and 1,982, 4,740, 7,996, and 10,419 patients were affected by regionalization. The risk-adjusted operative mortality rates after regionalization in target patients were estimated to decrease to 2.7, 2.1, 1.8, and 1.7% in each scenario. The median travel distances after regionalization in metropolitan areas were calculated as 4 kilometer (km) in scenario 1 and 7 km in scenario 4. However, those in provincial cities and depopulated areas were 8 and 36 km in scenario 1, and 28 and 65 km in scenario 4. Conclusions: Regionalization of cancer surgery services could be simulated using the comprehensive clinical database covering almost all surgeries in the nation. The simulation showed that operative mortality rate could decrease to less than 2 % by regionalization but a minimum volume standard should be determined considering regional characteristics.
Three different chemotherapeutic regimens as a postoperative adjuvant chemotherapy for curatively resected gastric cancer: A retrospective analysis.
Authors: Zhao Shen , ZHAO SHEN 
Published: January 2019

154 Background: Two double regimens, CAPEOX (CLASSIC trial) and docetaxel/S-1 (JACCRO GC-07), were standard treatment for curatively resected gastric cancer (GC) in Asia. However, the outcome of double regimens as postoperative adjuvant treatment remains unsatisfactory and the efficacy between oxaliplatin-based or taxane-based doublets is unknown. This study aimed to investigate if triplet improve survival compared with doublets and difference between oxaliplatin-based or taxane-based doublets. Methods: We found the patients with gastric cancer who received FOLFOX or POF or TF as adjuvant chemotherapy after curatively resection between 2002 and 2015 from our hospital. The POF consisted of a three-hour infusion of paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-Fu bolus. The TF is a substitution of paclitaxel 135 mg/m2 for oxaliplatin of FOLFOX. We checked the overall survival rate and the frequency of adverse reaction among the three groups. Results: We retrospectively studied 275 patients (POF 26, FOLFOX 172, TF 67). One, two, and three years OS rate were shown in table. POF was the worst survival among three regimens (p = 0.04). The patients with POF were shown more grade ¾ toxicity than two doublets. The patients with TF was more grade ¾ neutropenia, FOLFOX was more grade ¾ neuropathy. Conclusions: FOLFOX and TF which were similar in term of survival were recommended as adjuvant chemotherapy after curatively resection in the patients with gastric cancer. POF was less likely to improved survival than two doublets, which was not recommended. [Table: see text]
Surgical outcomes of laparoscopic transhiatal lower mediastinal lymphadenectomy for seiwert type II adenocarcinoma of the esophagogastric junction.
Authors: Tokunaga Masanori , Akimoto Eigo , Sato Reo , Kaito Akio , Kinoshita Takahiro 
Published: January 2019

155 Background: Optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG-II) has not yet been determined, presumably due to complex anatomical structures and the limited number of reports regarding this aspect. The transhiatal approach is preferred in East Asia in cases with 30 mm or less esophageal invasion, and laparoscopic surgery is increasingly performed. However, the feasibility of the laparoscopic transhiatal approach for AEG-II is still unclear, and thus was investigated in this study. Methods: A total of 51 consecutive patients who underwent total/proximal gastrectomy with lower mediastinal lymphadenectomy by laparoscopic transhiatal approach between January 2008 and May 2018 were included. Patients with greater than 30 mm esophageal invasion, and those who received preoperative chemotherapy, were excluded. Results: The male/female ratio was 38:13, and the median age (range) was 69 (37-81) years. Total gastrectomy and proximal gastrectomy were performed in 10 and 41 patients, respectively. All surgeries were performed by experienced surgical teams. Median operation time and intra-operative blood loss were 300 (141-511) minutes and 21 (0-267) g, respectively. Pathological tumor depth was T2 or deeper in 28 patients (55%), and nodal status was negative in 20 patients (39%). Clavien-Dindo grade IIIa or higher complications were observed in eight patients (16%), which included two anastomotic leakages and one pancreas fistula, and the mortality rate was 0%. The 5-year overall survival rate of all patients was 97% with a median observational period of 30 months. Conclusions: Laparoscopic transhiatal approach with lower mediastinal lymphadenectomy seems to be a technically feasible procedure, provided an experienced surgical team performs the surgeries. However, oncological safety for advanced disease needs to be confirmed, considering that the proportion of advanced stage cancer included in this study was limited.