bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Gastric adenocarcinoma prognosis in a multiracial population.
Authors: Acoba Jared David
Published: January 2019

158

Background: Gastric adenocarcinoma is a major health issue, with a high prevalence among Asian and Pacific Islander populations. We analyzed a hospital tumor registry and demonstrated that in a multiracial population, patients who were uninsured and Filipinos with resectable disease had worse outcomes. To further investigate these findings, we performed a comprehensive analysis of the National Cancer Database. Methods: We analyzed data from 183,204 patients with gastric or gastroesophageal adenocarcinoma diagnosed between 2004 and 2015. Multivariable Cox proportional hazards regression models for survival were built adjusting for race, age at diagnosis, sex, insurance status, comorbidities, treatment facility type, histologic grade, stage, and treatment. Results: We included 86,663 patients in our analysis. Pacific Islanders presented at a younger age and higher stage. Asians had fewer comorbidities and were diagnosed at earlier stages. Older age (HR 1.97, 95% CI 1.92-2.03), lower income (HR 1.13, 1.11-1.16), more comorbidities (HR 1.59, 1.51-1.67), treatment at a community center (HR 1.22, 1.20-1.24), higher tumor grade (HR 2.00, 1.92-2.08), and advanced stage (HR 5.71, 5.57-5.85) were poor prognostic factors. Compared to whites, Asians had a more favorable prognosis (HR 0.74, 0.71-0.76). However, Filipino race was adversely associated with survival compared to other Asian races (HR 1.48, 1.29-1.69), even after adjusting for other prognostic factors. Conclusions: Asian race is an independent favorable prognostic factor. Among Asians, Filipinos did not fare as well even after adjusting for income, insurance status, comorbidities, stage and other prognostic factors. Further study in this area should be pursued. Given the differences in survival within the Asian race, studies exploring the relationship between race and cancer should consider analysis by subgroup.
Zolbetuximab combined with EOX as first-line therapy in advanced CLDN18.2+ gastric (G) and gastroesophageal junction (GEJ) adenocarcinoma: Updated results from the FAST trial.
Authors: Sahin Ugur , Tureci Özlem , Manikhas Georgy M. , Lordick Florian , Rusyn Andriy , Vynnychenko Ihor , Dudov Assen , Bazin Igor , Bondarenko Igor , Melichar Bohuslav , Dhaene Karl , Wiechen Kai , Maurus Daniel , Schuler Martin H. , Al-Batran Salah-Eddin
Published: January 2019

16

Background: Physiologically, the tight junction protein CLDN18.2 is present only in the gastric mucosa. Upon malignant transformation, CLDN18.2 epitopes are exposed on the cell surface and accessible to targeted therapy. Zolbetuximab (formerly IMAB362) is a chimeric mAb that mediates specific killing of CLDN18.2+ cancer cells through immune effector mechanisms; single-agent activity has been reported in G/GEJ cancer. Methods: Patients (pts) with advanced HER2-negative (HER–) G/GEJ cancer with CLDN18.2 expression of ≥ 2+ staining intensity with the anti-CLDN18 43-14A mAb in ≥ 40% tumor cells were eligible (NCT01630083). Patients were randomized 1:1 to receive first-line EOX ± zolbetuximab (loading dose 800 mg/m2, then 600 mg/m2) Q3W. The study was extended with an exploratory arm of 1000 mg/m2 zolbetuximab + EOX Q3W (data not presented). Primary endpoint was PFS; secondary endpoints included OS, ORR, and safety/tolerability. Results: A total of 161 pts (G, n = 128; GEJ, n = 27; esophagus n = 6) were randomized to receive zolbetuximab (800/600 mg) + EOX (n = 77) or EOX alone (n = 84). In all, 45% of pts had diffuse type histology per Lauren’s classification. Median PFS was longer with zolbetuximab + EOX (7.5 mo) versus EOX alone (5.3 mo; P < 0.0005; HR 0.44; 95% CI 0.29, 0.67). Median OS (13 vs 8.4 mo; P = 0.0008; HR 0.56; 95% CI 0.40, 0.79) and ORR (39 vs 25%; P = 0.022) were also significantly higher with zolbetuximab + EOX versus EOX alone. Increased efficacy was more pronounced in pts with high CLDN18.2 expression (≥ 2+ staining intensity in ≥ 70% tumor cells). Zolbetuximab + EOX was generally well tolerated. Most AEs considered related to zolbetuximab and EOX (ie, nausea, vomiting, neutropenia, anemia) were of grade ≤ 2 severity; there was no significant increase in grade ≥ 3 events with the addition of zolbetuximab to EOX. Conclusions: Addition of zolbetuximab to first-line chemotherapy resulted in significantly longer PFS and OS and higher ORR with manageable toxicity. A phase III trial is evaluating the combination of zolbetuximab plus mFOLFOX6 as first-line treatment of CLDN18.2+/HER2-negative, advanced/metastatic G or GEJ adenocarcinoma (NCT03504397). Clinical trial information: NCT01630083.
Efficacy of capecitabine and oxaliplatin versus S-1 as adjuvant chemotherapy in gastric cancer after D2 lymph node dissection.
Authors: Shin Kabsoo , Kim In-Ho
Published: January 2019

160

Background: The aim of this study is to compare capecitabine and oxaliplatin (XELOX) with S-1 based on disease-free survival, and to define the clinical impact of lymph node ratio to select a regimen. Methods: Patients who had curative resection and received either S-1 or XELOX as adjuvant chemotherapy for gastric cancer between Jan. 2011 and Dec. 2015, were analyzed using propensity score matching (PSM). Of the 412 patients enrolled, 301 received S-1 and 111 received XELOX and after PSM, the sample size of each group was 111 patients. And the groups were classified according to stage and lymph node ratio (0, > 0-0.1, > 0.1-025, > 0.25) and three-year disease-free survival (DFS) was evaluated. Results: In post-PSM analysis of all 222 patients, The three-year DFS rates in XELOX group was higher than in the S-1 group in all stage 3 (78% vs. 66.1%, p = 0.036), stage IIIC (64.1% vs. 42.0%, p = 0.038) and LNR > 0.25 (67.7.1% vs. 26.1%, p = 0.002). The hazard ratio of XELOX for recurrence compared with S-1 for stage IIIC and LNR > 0.25 was respectively 0.479 (95% CI 0.238~0.985, p = 0.046) and 0.351 (95% CI 0.162~0.758, p = 0.008). Conclusions: Adjuvant XELOX was more effective than S-1 for stage IIIC and LNR > 0.25 in gastric cancer after D2 dissection.
Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma (GEAC).
Authors: Jiang Di Maria , Suzuki Chihiro , Espin-Garcia Osvaldo , Pintilie Melania , Lim Charles Henry , Ma Lucy Xiaolu , Sun Peiran , Sim Hao-Wen , Natori Akina , Chan Bryan Anthony , Yokom Daniel , Moignard Stephanie , Chen Eric Xueyu , Liu Geoffrey , Swallow Carol Jane , Darling Gail Elizabeth , Wong Rebecca , Jang Raymond Woo-Jun , Elimova Elena
Published: January 2019

162

Background: Although commonly performed, the benefit of routine surveillance testing (SvT) following curative resection of GEAC is undefined. We aimed to determine frequency of successful salvage therapy (SST) in patients (pts) with relapsed GEAC who were surveyed post curative therapy. Methods: Between 2011 and 2016, 210 consecutive pts with locally advanced GEAC underwent curative surgery and subsequent surveillance at Princess Margaret Cancer Center. SST was defined as any potentially curative therapy for recurrence which resulted in post-recurrence survival (PRS) two years without further relapse. Time-to-event outcomes were analyzed using Kaplan-Meier and Cox regression methods. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (41%), and gastric adenocarcinomas (45%) were included. Pts received surgery alone (29%), surgery with perioperative chemotherapy (26%) or perioperative chemoradiation (45%) as primary curative therapy. At median follow-up of 33.6 months (m, range 6.0-122.4), 3- and 5-year overall survival (OS) rates were 68% (95% CI 61-75%) and 59% (95% CI 51-68%) respectively. SvT modalities included imaging (69%), endoscopy (19%), tumor markers (4%), and clinical visits only (9%). Recurrences occurred in 95 (45%) pts, 51% were surveillance-detected (SvDR), and 47% were non-SvDR. Types of recurrences included locoregional only (4%), distant (87%) or both (9%). Salvage therapy was attempted in 14 pts (7%) with SvDR and 1 with non-SvDR. In four pts with SvDR (1.9%) salvage therapy was successful with chemoradiation or surgery perioperative chemotherapy, six were unsuccessful, and 5 had immature follow-up. Compared with pts with non-SvDR, pts with SvDR had longer median OS (34.8 vs. 24.0m, p=0.03) and PRS (14.4 vs. 4.8m, p < 0.001), and similar time-to-relapse (15.6 vs. 12.0m, p = 0.67). Palliative chemotherapy was administered in 25 pts with SvDR and 18 pts with non-SvDR with similar median duration (3.5m vs. 3.3m, p=0.64). Conclusions: Following curative therapy, 96% of relapses were distant. SvT enabled SST in only 1.9% of pts, and did not extend duration of palliative chemotherapy. These data do not support the use of routine SvT in resected GEAC.
Survival benefit of gastric resection in the setting of metastatic gastric cancer.
Authors: Nguyen Trang , Vuong Brooke , Wang Mansen , Fischer Trevan D , Goldfarb Melanie , Bilchik Anton J. , Foshag Leland Jay
Published: January 2019

166

Background: Prognosis remains poor for metastatic gastric cancer. Gastrectomy in the setting of stage IV disease is typically reserved for palliation of symptoms such as bleeding or obstruction. The potential survival benefit of resection on survival is controversial. The objective of this study is to determine using the National Cancer Database (NCDB) whether there was an increase in overall survival in patients diagnosed with metastatic cancer who underwent a gastrectomy in addition to chemotherapy. Methods: The NCDB was queried between 2004-2014 for patients with metastatic gastric cancer (adenocarcinoma, mucinous adenocarcinoma, or signet ring carcinoma) who received chemotherapy. Kaplan-Meier analysis and multivariate Cox proportional hazards regression analysis was done using SAS software. Results: A total of 20,599 patients met inclusion criteria. A minority of these patients (2,508; 12.2%) underwent gastric resection in addition to chemotherapy. The median overall survival for those who underwent gastrectomy was 14.1 months compared to 8.6 months for chemotherapy alone (p < 0.0001). Other factors influencing survival included age, race, Charlson-Deyo co-morbidity index, year of diagnosis, primary tumor site, grade, and metastasis to multiple organs. Following multivariate analysis, patients who underwent gastrectomy and chemotherapy had a 36% lower risk of death compared to patients that had received chemotherapy alone (HR 0.64, 95% CI 0.48–0.80, P < 0.0001). Conclusions: In this population analysis, the addition of gastrectomy to chemotherapy was associated with improved overall survival for patients with stage IV gastric cancer and should be considered for patients that are surgical candidates. Patients who underwent gastrectomy had a 36% decreased risk of death compared to those who had chemotherapy alone. However, only a small proportion of patients in the United States received multimodality treatment.
Prognostic significance of malnutrition in metastatic esophageal squamous cell carcinoma.
Authors: Taylor Kirsty , Espin-Garcia Osvaldo , Jiang Di Maria , Yokom Daniel , Ma Lucy Xiaolu , Lim Charles Henry , Chan Bryan Anthony , Sun Peiran , Sim Hao-Wen , Natori Akina , Liu Geoffrey , Darling Gail Elizabeth , Wong Rebecca , Chen Eric Xueyu , Jang Raymond Woo-Jun , Veit-Haibach Patrick , Rozenberg Dmitry , Elimova Elena
Published: January 2019

171

Background: Disease related symptoms including anorexia, nausea and dysphagia lead patients with esophageal cancer to become malnourished. Malnourishment can result in systemic inflammation, reduced treatment tolerance, poorer quality of life and decreased overall survival. Currently weight loss is the main clinical measure of malnutrition, and thus we set out to evaluate the prognostic utility of alternative screening tools of malnutrition. Methods: Patients with metastatic esophageal squamous cell cancer (MESCC) attending the Princess Margaret Cancer Centre, between January 2011 and December 2016, were identified from the institutional gastroesophageal database. Nutritional Risk Score (NRS), Nutritional Risk Index (NRI) and Neutrophil Lymphocyte Ratio (NLR) were calculated and correlated with clinical-pathological variables and survival. Malnutrition was defined as NRS ≥ 3, NRI < 97.5 and NLR ≥ 3. Results: Of the 64 consecutive patients, 30 (47%) presented with de novo metastatic disease and 34 (53%) with recurrence. The median age was 62 years (range 40-85), 47 patients were ECOG PS ≤ 2 and 29 (45%) received systemic chemotherapy. 90% of patients experienced weight loss > 5% prior to diagnosis and median BMI was 20.1 (range 14.3-34.9). NRI identified 37 (58%) and NRS 45 (70%) patients as malnourished. Both were associated with poorer ECOG PS (p = 0.012 and p = 0.027 respectively). No difference was identified with sex, smoking status or albumin with univariate analysis. NRI did not associate significantly with age. Median overall survival was 5months; 8.1-9 months with normal nutrition and 2.8-3.2 months in malnourished patients. Kaplan Meier analysis revealed significant difference in overall survival (malnutrition vs. normal nutrition) using NRS (p = 0.029) and NRI (p = 0.001) but not weight (p = 0.509) or NLR (p = 0.69). Conclusions: Patients with MESCC identified as malnourished at the time of diagnosis have inferior survival outcomes. Malnutrition tools are superior to weight alone with respect to discriminating outcomes in this patient population. Further investigation is needed in larger patient cohorts; to identify those at risk, initiate early supportive interventions and improve patient outcomes.
Utility of radiation after neoadjuvant chemotherapy for surgically resectable esophageal cancer.
Authors: Macedo Francis Igor , Kelly Kristin , Yakoub Danny , Franceschi Dido , Livingstone Alan S , Merchant Nipun B.
Published: January 2019

172

Background: Neoadjuvant chemotherapy (NAC) is the gold standard approach for locally advanced esophageal cancer (EC), however the addition of radiation remains largely controversial. We sought to investigate the role of neoadjuvant radiation in resectable EC by comparing outcomes of patients who underwent neoadjuvant chemotherapy with (NACR) or without radiation (NAC) using a large nationwide cohort. Methods: National Cancer Data Base (NCDB) was queried for patients with non-metastatic EC between 2010 and 2014. Kaplan-Meier, log-rank and Cox multivariable regression analysis were performed to calculate overall survival (OS). Logistic regression was used to identify factors associated with 90-day mortality and complete pathological response (pCR). Results: A total of 12,546 EC patients who underwent neoadjuvant therapy were included: the majority were males (84%), Caucasians (90.3%), and had adenocarcinoma (81.1%), cT3 (60.6%) and cN1 (49.1%). 11,269 (89.8%) patients had NACR, whereas 969 (7.7%), NAC alone. pCR rate was 14.1% (19.2%, NACR vs. 6.3%, NAC, p < 0.001). Neoadjuvant radiation was an independent predictor for improved pCR [HR 0.305, 95% CI 0.205-0.454, p < 0.001], however OS was similar in patients undergoing NAC with or without radiation (35.9 vs. 37.6 months, respectively, p = 0.393). This persisted regardless of tumor staging. There was a trend towards worse 90-day mortality after radiation (8.2%, NACR vs. 7.7%, NAC; HR 1.410, 95% CI 0.975-2.038, p = 0.068). In Cox regression, controlling for patient and disease-related factors, neoadjuvant radiation was an independent predictor of worse OS (HR 1.322, 965% CI 1.177-1.485, p < 0.001). Conclusions: This is the largest study comparing NACR versus NAC in resected EC. The addition of radiation to neoadjuvant chemotherapy is associated with improved pathological response rates, however it had deleterious effects in long-term and possibly, short-term survival. Our findings suggest that NAC without radiation may be the optimal neoadjuvant therapy in resectable EC, however further evidence with randomized clinical trials is warranted.
Incidence and prognosis of multiple organ involvement at gastric MALT lymphoma.
Authors: Kwon Tae Hun , Lee In Seok
Published: January 2019

18

Background: MALT (mucosa-associated lymphoid tissue) lymphoma usually occurs in stomach but various MALT organs can be afflicted including salivary glands, ocular adnexa, lung, intestine and thyroid. In this study, we aimed to evaluate the prevalence and characteristics of gastric MALT lymphoma with multi-organ involvement. Methods: We retrospectively analyzed a total of 174 consecutive patients who had been diagnosed with gastric MALT lymphoma at Seoul St. Mary’s Hospital from January 2009 to May 2018. Clinical data were obtained from the medical records. At the time of diagnosis, neck, chest, abdominal CT, PET-CT and bone marrow biopsy were performed for the purpose of staging work-up. Organ involvement was identified by biopsy. Results: Nine out of 174 (5.2%) gastric MALT lymphoma patients were found to have multi-organ involvement. Three patients had biopsy proven lymphoma at lung, two patients had colon involvement, and two patients had ocular involvement. A patient with involvement at small bowel and duodenum were found, respectively. Seven patients were examined for Helicobacter infection. Two of them were positive for H. pylori infection and received eradication treatment. Except one patient treated with palliative care, eight patients underwent chemotherapy, in which two of them received additional radiation therapy and other two patients underwent bone marrow transplantation. Except one patient died of pneumonia during chemotherapy and one patient underwent palliative treatment, 7 patients had maintained complete remission. Conclusions: The overall prevalence of gastric MALT lymphoma with multi-organ involvement was 5.2%. The result suggests that the gastric MALT lymphoma patients require a careful investigation of other MALT organs. [Table: see text]
Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated biliary tract cancer (BTC): A cohort of the ROAR basket trial.
Authors: Wainberg Zev A. , Lassen Ulrik Niels , Elez Elena , Italiano Antoine , Curigliano Giuseppe , De Braud Filippo G. , Prager Gerald , Greil Richard , Stein Alexander , Fasolo Angelica , Schellens Jan H. M. , Wen Patrick Y. , Boran Aislyn D. , Burgess Paul , Gasal Eduard , Ilankumaran Palanichamy , Subbiah Vivek
Published: January 2019

187

Background: BTCs are rare, aggressive malignancies with poor prognoses. Treatment options and outcomes after first-line therapy are not well defined. Median progression-free survival (PFS) in second-line BTC is < 5 mo. Combined BRAF + MEK inhibition is efficacious in BRAF V600–mutated anaplastic thyroid cancer, melanoma, and lung cancer, but less so in BRAF V600E-mutated colorectal cancer. Activating BRAF V600E mutations have been reported in 0% to 20% of BTCs; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated BTC in the ROAR basket trial. Methods: In this phase II, open-label trial, pts with BRAF V600E mutations in 9 rare tumor types, including BTC, received D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer and had been treated with ≥ 1 prior systemic therapy. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), PFS, overall survival (OS), biomarker correlates, and safety. Results: Thirty-three pts with BTC had enrolled at data cutoff (January 3, 2018). BRAF V600E mutations were centrally confirmed in 30 of 33 pts with BTC (91%). Median age was 58 y, and 78% had received ≥ 2 prior lines of systemic therapy. 32 of 33 pts with BTC were evaluable. Investigator-assessed ORR was 41% (13/32; 95% CI, 24%-59%), with 6 of 13 responses ongoing at data cutoff, 7 of 13 pts (54%) had a DOR ≥ 6 mo. Median PFS was 7.2 mo (95% CI, 4.6-10.1 mo), and median OS was 11.3 mo (95% CI, 7.3-17.6 mo). Grade 3/4 adverse events in ≥ 3 pts were increased γ-glutamyltransferase (n = 3 [9%]) and decreased white blood cell count (n = 3 pts [9%]). Biomarker analyses demonstrate a heterogeneous genetic landscape, and suggest a higher baseline expression of MAPK pathway genes in the pts who did not respond to D + T. Conclusions: D + T demonstrated promising efficacy in pts with BTC, with a favorable safety profile. These pts should be considered for BRAF mutation analysis, and D + T should be considered for pts with BRAF V600E-mutated BTC. Clinical trial information: NCT02034110.
Impact of intramuscular fat accumulation on survival in stage II/III gastric cancer.
Authors: Waki Yuhei , Makuuchi Rie , Irino Tomoyuki , Kamiya Satoshi , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Terashima Masanori
Published: January 2019

19

Background: Intramuscular fat accumulation of skeletal muscle has been reported to be a prognostic factor in various cancers. To evaluate the intramuscular steatosis, intramuscular adipose tissue content (IMAC) measured by CT scan is thought to be an ideal method. However, this kind of study is very limited in curatively resected gastric cancer. So, this study was aimed to clarify the impact of IMAC on survival in stage II/III gastric cancer (GC). Methods: A total of 383 patients with pathological stage II/III GC after curative gastrectomy between January 2009 and December 2013 were included. IMAC was calculated by dividing the CT value of the multifidus muscles with that of the subcutaneous fat at the level of third lumbar vertebra. The IMAC cut-off values associated with cancer-specific survival (CSS) were separated by sex based on the maximum values of Youden index (sensitivity + specificity -1). Patients were classified into normal or high IMAC group according to this cut-off value. Clinicopathological factors and survival outcomes were compared between the two groups. Results: The median values of IMAC were -0.327 (IQR: -0.404- -0.250) in male and -0.239 (IQR: -0.335- -0.114) in female. The cut-off values of IMAC were -0.345 in male and -0.126 in female. Patients were classified into normal IMAC group (n = 204) and high IMAC group (n = 179). Patients in the high IMAC group were elderly, male, obese, having many comorbidities and with poor ECOG-PS compared to those in the normal IMAC group. Interestingly, despite the fact that no significant differences were observed in the pathological findings between the groups, the overall survival and CSS were significantly worse in the high IMAC group than in the normal IMAC group (p < 0.001 and p = 0.035). Moreover, the high IMAC was identified as an independent prognostic factor not only for overall survival but also for CSS (HR: 1.440, p = 0.021, HR: 1.646, p = 0.008, respectively). Conclusions: The high IMAC was significantly associated with worse survival, suggesting that IMAC represents certain oncological implications in patients with GC. Therefore, IMAC could be used as a new prognostic factor in curatively resected GC.
Peritoneal carcinomatosis (PC) in well-differentiated (WD) small-intestinal neuroendocrine tumor (SI-NET) patients (Pts) with mesenteric tumor deposits (MTDs).
Authors: Das Satya , Shi Chanjuan , Koyama Tatsuki , Huang Yi , Gonzalez Raul S. , Idrees Kamran , Bailey Christina Edwards , Berlin Jordan
Published: January 2019

194

Background: Although WD SI-NETs are typically biologically indolent, they tend to metastasize. PC is a dreaded regional metastatic complication in pts with SI-NETs and contributes to significant morbidity and mortality. Risk factors for PC development in these pts are not well studied, however one factor may be MTD presence. Our analysis is the first to suggest an association between MTD presence and PC in this pt subgroup. Methods: We performed a retrospective analysis on 191 WD SI-NET samples from Vanderbilt University Medical Center with mesenteric masses identified on gross pathology or radiographic review. Of 138 samples with suspected MTDs, 79 were confirmed definitively by detailed pathologic review and 59 were considered likely based on descriptions from surgical pathology reports. We assessed whether pts in our cohort with MTDs had greater rates of PC compared to those without MTDs. We also assessed what other patient determinants were associated with PC and the prognostic role of these determinants. Results: Pts with suspected MTDs had an odds ratio (OR) of 3.9 for PC compared to pts without MTDs. Rates of PC in pts with definitive MTDs and those with likely MTDs were not significantly different (OR 1, p = 1.00). Although suspected MTD presence was not associated with poorer OS (p = 0.97), pts with confirmed MTDs had a trend toward poorer overall survival (OS) than pts with likely MTDs (p = 0.05). PC was a negative prognostic factor in all pts with regards to OS (p = 0.044). Conclusions: SI-NET pts with MTDs appear to have significantly increased rates of PC compared to those without mesenteric deposits. We believe this observation merits prospective evaluation given its potential therapeutic implications. If confirmed prospectively, pts with MTDs could benefit from earlier use of cytoreductive therapies to hinder development of PC. [Table: see text]
Predictive factors for major complications after pancreaticoduodenectomy in patients aged 80 years or older.
Authors: Takeda Naoya , Sawada Shigeaki , Yoshioka Isaku , Shibuya Kazuto , Tazawa Kenichi , Fukuda Takuma , Mori Kosuke , Hirano Katsuhisa , Okumura Tomoyuki , Nagata Takuya , Yamagishi Fuminori , Fujii Tsutomu
Published: January 2019

199

Background: As the population ages, elderly patients are being diagnosed with periampullary tumors, and hence, it has been suggested that surgeons should consider the indications for pancreaticoduodenectomy (PD) in elderly patients. The aim of this study is to reveal risks and benefits of PD, and is to identify prognostic inflammatory biomarkers for major complications after PD in patients aged 80 years or older. Methods: We retrospectively analyzed the cases of 161 consecutive patients who underwent PD between January 2000 and December 2015, and compared the patients aged ≥ 80 years (n = 22) with those aged < 80 years (n = 139). Postoperative results and preoperative conditions such as nutrition status using controlling nutritional status (CONUT) score, hemoglobin level and comorbidity were assessed. Correlations were evaluated between major postoperative complications (Clavien-Dindo grade III or higher) and 6 systemic inflammation–based prognostic score such as Glasgow prognostic score (GPS), modified-GPS, High sensitive-mGPS, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio (PLR), and prognostic nutritional index in elderly patients. Results: There was no operative mortality. In elderly patients, preoperative hemoglobin level was lower and CONUT score was higher than in younger patients. The complication rates and the disease-specific survival did not differ significantly between the two groups. Ten patients (45%) experienced major complications in the elderly group. Among 6 systemic inflammation–based prognostic score, only PLR was revealed as predictor of major complications (p = 0.012) and optimal cutoff value was determined to be 145.3 (sensitivity = 33%, specificity = 100%, AUC = 0.842). Conclusions: PD could be performed safely in patients aged 80 years or older. The preoperative PLR was a simple and useful predictor of major complications after PD in elderly patients.
Incidence of metachronous gastric neoplasia after endoscopic submucosal dissection for gastric dysplasia.
Authors: Kim Jae Gyu , Park Jae Yong , Kim Young-Il
Published: January 2019

20

Background: Endoscopic submucosal dissection (ESD) has been usually performed to treat gastric high-grade dysplasia (HGD) and selected lesions of low-grade dysplasia (LGD). However, HGD was classified into the same category of non-invasive carcinoma which were different from LGD in the Vienna classification of gastrointestinal epithelial neoplasia. We investigated whether the incidence of metachonous gastric neoplasia after ESD for gastric dysplasia is different between patients with LGD and HGD. Methods: Between March 2011 and December 2016, 508 patients underwent ESD for 545 gastric dysplasias or cancers at the Chung-Ang University Hospital. Of them, 198 patients with LGD (LGD group) and 46 with HGD (HGD group) who had been followed up for at least one year were included. The primary outcome was the incidence of gastric neoplasia occurred at 1-year follow-up or later after ESD. The secondary outcome was the composite incidence of metachronous HGD and gastric cancers. Results: During a median follow-up of 2.5 years, overall cumulative incidence of metachronous gastric neoplasm was 33.2 cases/1000 person-years. The metachronous neoplasms developed in 17 patients (8.6%; 11 LGD, 2 HGD and 4 gastric cancers) in the LGD group and in 6 patients (13.0%; 3 LGD, 1 HGD and 3 gastric cancers) in the HGD group. The incidence of metachronous gastric neoplasia in LGD group was not significantly different from that in HGD group (hazard ratio [HR] in the LGD group, 0.56; 95% confidence interval [CI], 0.22-1.43; P = 0.229). The composite incidences of metachronous HGD and gastric cancers were not also different between the two groups (HR for the composite incidences in the LGD group, 0.42; 95% CI, 0.10-1.68; P = 0.218). Conclusions: After ESD for gastric LGD, the incidence of metachronous gastric neoplasia was not different from that after ESD for HGD. Thus, similar surveillance strategies are needed for patients who underwent ESD for LGD and HGD.
Role of central hypovascularity in the hepatic arterial phase of dynamic CT on mass-forming intrahepatic cholangiocarcinoma.
Authors: Shimada Mitsuo , Teraoku Hiroki , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Iwahashi Shuichi , Saito Yu , Takasu Chie , Yamada Shinichiro
Published: January 2019

205

Background: Intrahepatic cholangiocarcinoma (IHCC) is known as one of most malignant cancers. Recently, the vascularity in the hepatic arterial phase (HAP) of dynamic CT has been reported as a possible prognostic marker in IHCC. The aim of this study is to elucidate the role of central hypovascularity in the HAP on mass-forming IHCC. Methods: Forty patients who underwent initially hepatic resection for mass-forming IHCC were enrolled. The HAP was scanned 40 seconds after the injection of contrast agent. Vascular pattern was classified into three groups; hypervascularity (Hyper) group (n = 8), rim-enhancement (Rim) group (n = 7) and hypovascularity (Hypo) group (n = 25) by a radiologist in reference to Fujita, et al (Eur Radiol 2017). Hypoxia-inducible factor-1 (HIF-1) expression in the surgical specimen was evaluated by immunohistochemistry. The clinicopathological findings were compared among the groups. Results: The advanced stage tended to be more frequent in Hypo group, however, no difference of tumor location (hilar or peripheral) was observed. Overall survival (OS) in Hypo group was worse than that in Hyper group. The OS in Rim+Hypo group, that means central hypovascularity in the tumor, was worse than that in Hyper group. Furthermore, Rim+Hypo group was an independent prognostic factor in OS (HR: 5.44). Regarding the HIF-1 expression, high HIF-1 expression in the central part of the tumor correlated with central hypovascularity in the HAP (25% in Hyper-group and 72% in Rim+Hypo group, respectively). Conclusions: The central hypovascularity (Rim+Hypo group) was an independent prognostic factor, furthermore, high malignant potential of the tumor with central hypovascularity might be related to HIF-1 upregulation.
Investigating disparities: The effect of social environment on pancreatic cancer survival.
Authors: Madnick David , Sorice Kristen , Yin Yinuo , Handorf Elizabeth A. , Nagappan Lavanya , Moccia Matthew , Cheema Khadija , Vijayvergia Namrata , Dotan Efrat , Lynch Shannon M.
Published: January 2019

208

Background: Incidence rates of pancreatic adenocarcinoma (PAC) are higher in Black compared to White patients (pts). Beyond race, exposure to poor neighborhoods or social environments also contribute to cancer disparities. However, social environmental effects on PAC are not well-studied. Social environment is defined as: 1) a neighborhood’s socioeconomic conditions (SES; i.e. a combination of education, income, poverty and employment levels); 2) racial segregation (RS) or the degree of isolation/separation of race/ethnic groups in a neighborhood. The goal of our study is to investigate whether poor social environments impact survival in a clinic population with metastatic PAC. Methods: Neighborhood SES and RS measures were derived from US census data (2011-2015) at the census tract level, which is a smaller geographic area than a county. Patient (pt) addresses were used to generate a geocode that identifies the census tract or neighborhood in which a pt lives. We joined medical records of PAC pts (n = 374; diagnosed 2010-2016 at Fox Chase Cancer Center) to neighborhood measures via the geocode. Pt variables included in the analysis were: age, sex, race, marital status, treatment, PAC family history, stage, Jewish ancestry, tobacco use and Charlson comorbidity index. Multivariable cox proportional hazards models with cluster adjustments were used and variables with p-values < 0.05 were considered significant. Results: 342 PAC deaths occurred and median survival was 12m. 81% of pts were White; < 40% resided in poor social environments (i.e. low SES or high RS). In multivariable analyses stratified by RS, median survival was lower in pts from high RS (11m) vs low RS areas (13m); however, this difference was not significant (p = 0.27). Variable effects differed by high/low RS. In high RS areas, sex, surgery, chemo, diabetes and neighborhood SES were significant predictors of survival; in low RS areas, surgery, chemo, radiation, PAC family history, tobacco use, Jewish ancestry and race were significant. Conclusions: While social environment did not appear to significantly affect survival time in metastatic pts, its potential moderating (interaction) effects on variable associations with PAC warrant further investigation.
Measurement of urinary kininogen (KNG) fragments as a noninvasive tool for early diagnosis of pancreatic cancer (PaCa).
Authors: Ohno Izumi , Mitsunaga Shuichi , Kan Motoyasu , Ikeda Masafumi , Tsubouchi Hironobu , Yanagi Shigehisa , Matsumoto Nobuhiro , Okumura Nobuaki , Takao Toshifumi , Nakazato Masamitsu
Published: January 2019

209

Background: There is a clear need to identify a non-invasive biomarker for early diagnosis of PaCa, in order to improve the overall survival of PaCa patients. Secretion of large amounts of proteases is a hallmark of PaCa, which results in an abundance of protease-induced cleavage products being excreted in the urine. This has led to speculation that measurement of PaCa-specific fragments in the urine might be useful as a tool for discrimination between PaCa patients and healthy controls. Herein, we introduce urinary KNG fragments as a promising biomarker for early diagnosis of PaCa. Methods: Urine samples were collected from PaCa patients and healthy volunteers, with the written informed consent, from January 2014 to July 2016. Urinary protein tryptic fragments derived from protein C-termini were measured using isobaric tags (iTRAQ) for their relative quantitation, and the diagnostic ability of the urinary levels of these fragments was evaluated by receiver operating characteristic (ROC) curve analysis. The fragments which showed an area-under-the-curve (AUC) of over 0.8 were selected as candidate fragments for further validation by the multiple-reaction-monitoring technique (MRM) combined with high-speed liquid chromatography. The urinary level of each candidate fragment was quantified by MRM, and the diagnostic capability of each for discriminating PaCa patients from healthy controls was evaluated by ROC curve analysis. Results: Urine samples of 39 PaCa patients (7 resectable, 32 unresectable) and 42 healthy controls were examined by iTRAQ to find 12,783 fragments. ROC curve analysis was carried out to select two candidate fragments (fragments A, B), both of which turned out to be KNG cleavage products. The urinary levels of the two fragments were measured in 23 resectable PaCa, 118 unresectable PaCa patients, and 42 healthy volunteers using high-speed-LC-/MRM. The AUCs of serum CA19-9 and urinary levels of fragments A and B for discriminating patients of PaCa from healthy controls were 0.89, 0.81 and 0.70, respectively. Conclusions: Urinary KNG fragments showed favorable diagnostic capability and were considered as promising, noninvasively measurable biomarkers of PaCa.