bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of CD8+/FOXP3+ ratio and PD-L1 expression with survival in pT3N0M0 stage esophageal squamous cell cancer.
Authors: Zhu Yingming , Li Minghuan , Yu Jinming
Published: September 2018

e15517

Background: Data describing relationships between the tumor immune microenvironment and patient outcome are limited for esophageal squamous cell cancer (ESCC). Methods: The present study investigated the prognostic values of programmed death-ligand 1 (PD-L1) expression and CD8+ or forkhead box protein 3+ (FOXP3+) tumor-infiltrating lymphocytes (TILs) in 133 pathological T3N0M0 stage ESCC patients who underwent radical resection without neoadjuvant or adjuvant therapy. CD8+ and FOXP3+ TIL densities as well as PD-L1 levels in tumor cells and lymphocytes, were assessed through immunohistochemical staining. Results: Patient survival was not associated with CD8+ or FOXP3+ TILs alone, but PD-L1 expression and the CD8+/FOXP3+ ratio were independent predictors of both disease-free and overall survival. PD-L1 expression correlated with age (p = 0.029), tumor length (p < 0.001), tumor differentiation status (p = 0.002) and reduced intratumoral CD8+ TIL density (p < 0.001). Conclusions: Our results suggest pT3N0M0 ESCC clinical outcomes correlate with CD8+ and FOXP3+ TIL densities and PD-L1 levels. Moreover, an intrinsic mechanism for induction of PD-L1 overexpression may be occurring during early tumor oncogenesis. This information may be useful for stratifying patients and guide the application of checkpoint blockade therapy in ESCC.
Bidirectional chemotherapy in gastric cancer (GC) with peritoneal carcinomatosis (PC) combining intravenous chemotherapy with intraperitoneal chemotherapy with low-dose cisplatin and doxorubicin administered as a pressurized aerosol: An open-label, phase II study.
Authors: Khomiakov Vladimir , Ryabov Andrey , Bolotina Larisa V , Utkina Anna , Cheremisov Vadim , Kolobaev Ilya , Ivanov Andrey , Chayka Anna , Sobolev Dmitry
Published: September 2018

e15532

Background: Up to 40% of GC patients show synchronous PC at time of diagnosis and peritoneal relapse develops in 10–46% of cases after radical surgery. Systemic chemotherapy is standard method of treatment with median survival of several months. Innovative therapeutic approaches are needed to improve survival. Methods:Phase-2, open label prospective clinical trial assessing safety and efficacy of bidirectional chemotherapy for treating of gastric cancer with PC. Treatment protocol for untreated patients included initial staging laparoscopy or laparotomy, 3–4 courses of systemic chemotherapy (XELOX) followed by Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) procedures every 6 weeks until progression of disease or death. Criteria of progression included 50% and more PCI increase or distant metastases. Patients with primary or recurrent GC, who received earlier one or two lines of systemic chemotherapy, didn’t receive 4 XELOX courses before PIPAC. Primary endpoints were overall survival and histological peritoneal regression grading score after rebiopsy. Results:46 patients were included (14 men, 32 women, mean age 53.5 years), 33 patients had primary GC with PM and 13 had peritoneal relapse after surgery. 15 patients had systemic chemotherapy before inclusion to the program. About one half of patients had ascites. Mean PCI was 12.1 (min-max 3-34). Altogether, 89 PIPAC procedures were performed in the 46 patients. Complete and partial pathological response was found in 91% of the 23 patients eligible for tumor response assessment (7 and 14 patients, respectively). Median survival was 14 months and one-year overall survival was 55%. The median survival was better in patients with low PCI in compare with high PCI, but the difference was not significant. Conclusions: Bidirectional chemotherapy combining XELOX with PIPAC with cisplatin and doxorubicin can induce objective tumor regression and is associated with a promising survival in GC with PC.
CWP232291, a Wnt/β-catenin inhibitor, to suppress the growth and development of gastrointestinal cancers.
Authors: Park Jun Won , Um Hyejin , Yang Hanna , Cha Joo Young , Lee Kyoung-June , Kim Hark K.
Published: September 2018

e15534

Background: CWP232291 (JW Pharmaceutical Corp, Seoul, Korea) is a potent β-catenin inhibitor currently tested in phase I trials for AML and MM. We evaluated the preclinical efficacy of CWP232291 for gastrointestinal cancers using xenograft and genetically-engineered mouse (GEM) models. Methods: For xenograft experiments, we intraperitoneally administered 150 mg/kg of CWP232291 twice a week to 14 heterotopic and 2 orthotopic xenografts of human gastric cancer cell lines formed in NOD/SCID mice. For GEM experiments, we intraperitoneally administered 100 mg/kg of CWP232291 (n = 19) or vehicle (n = 27) twice a week for 17 weeks to 3-week-old Villin-Cre;Smad4 F/F;Trp53F/F GEM mice that spontaneously form intestinal tumors with the β-catenin signaling activation. Results: CWP232291 exhibited in vivo activity in human gastric cancer xenografts. Activity of CWP232291 was more prominent in human gastric cancer cell lines harboring mutations in the β-catenin signaling pathway, such as APC, and in the 5-FU-resistant derivative of SNU-620, than in the other xenografts (P = 0.028, t-test). In the MKN-45 orthotopic xenograft, we noted a decrease in luciferase signal intensity after 4 weeks of CWP232291 treatment. CWP232291 demonstrated synergistic activity with paclitaxel and irinotecan in the SNU-484 heterotopic xenograft. In GEM experiments, CWP232291 treatment significantly suppressed the spontaneous development of intestinal tumors (56.3% vs. 91.3% with vehicle) in Villin-Cre;Smad4 F/F;Trp53F/F mice. Furthermore, CWP232291 treatment significantly reduced the number of mice that develop intestinal adenocarcinomas (37.5% vs. 78.3% with vehicle). Immunohistochemistry revealed CD8 T cell activation within the mouse intestinal tumors. Conclusions: CWP232291 demonstrated significant preclinical efficacy in gastrointestinal tumors, especially in cancers with the β-catenin signaling activation.
Alcohol consumption adjusted by aldehyde dehydrogenase 2 genotype: A potential risk factor for gastric cancer?
Authors: Ye Botian , Li Haojie , Wang Xuefei , He Hongyong , Zhang Heng , Min Lingqiang , Sun Yihong , Liu Fenglin
Published: September 2018

e15541

Background: The role of aldehyde dehydrogenase 2 (ALDH 2) in alcohol metabolism has been ascertained, yet the association between ALDH2 genotype and the carcinogenesis of gastric cancer remains controversy. Methods: We retrospectively collected data of 292 subjects hospitalized in Zhongshan Hospital in Shanghai during March 2016 to September 2016. All subjects were divided into case group (identified with gastric cancer by postoperative pathology) and control group. Distribution of aldehyde dehydrogenase 2 genotype, drinking status along with other clinical variables were compared. Logistic regression model included age, gender, smoking and drinking status, family history and ALDH2 genotype. Adjusted odds ratios (ORs) were calculated. Results: There was a significant elevation of alchohol consumption in case group (P = 0.033). Subjects with ALDH2 *1/*2 and *2/*2 genotype showed less inclination for drinking than ALDH2 *1/*1 (P < 0.001). The risk for gastric cancer showed no differences among subjects with ALDH2 genotype adjusted drinking status [OR 1.121, 95% confidence interval (CI) 0.555-2.263 in Never/rare drinkers; OR 3.380, 95% CI 0.232-49.240 in Light drinkers and OR 2.416, 95% CI 0.326-14.151). Further analysis indicated that high body weight index (BMI) and heavy smoking were individual risk factors for gastric cancer among Light/heavy dringkers with ALDH2 *1/*2 or *2/*2 genotype (OR 84.736, P = 0.021 for BMI and OR 3.904, P = 0.037 for smoking). Conclusions: A dose-response relationship between alchohol consumption and risk for gastric cancer was observed in primary analysis. However ALDH2 genotype failed to modify the alchohol consumption. Our findings suggested that there might be other pathways to further explain the mechanisim of the role of alchohol consumption in carcinogenisis of gastric cancer.
Clinical observation of nab-paclitaxel plus S-1 as first-line chemotherapy for advanced gastric cancer.
Authors: Hu Yi , Sun Danyang
Published: September 2018

e15554

Background: Gastric cancer is the third leading cause of death in the world with poor prognosis. Until recently, no standard treatment was available for patients with advanced gastric cancer in the first-line setting. Nab-paclitaxel and S-1 were both proved to have antitumor activity in many solid tumors including gastric cancer. We aimed to evaluate the efficacy and tolerance of nab-paclitaxel in combination with S-1. Methods: Patients with unresectable or recurrent gastric cancer received combination therapy of nab-paclitaxel plus S-1 every 3 weeks as one cycle. Nab-paclitaxel was administered at total dose of 260mg/ m2 on day 1 and 5 or on day 1 and 8. S-1 was given orally twice a day for 14 days, the doses were assigned according to body surface area. S-1 alone was administered as maintenance therapy after 6 to 8 cycles of combination therapy until disease progression. Results: Among the 33 patients enrolled, 28 patients (84.8%) had KPS 90, one third of patients were recurrent after gastrectomy. They received an average of 5.7 cycles of combination treatment. The median PFS was 6.6 months (95%CI, 5.557-7.716 months). The overall response rate was 51.5%, with one CR, 16 PR, 16 SD, and no PD. The median overall survival time was not obtained at the time of analysis. In safety profile, the highest incidence rate of grade 3 and grade 4 adverse events was neutropenia (12.1%). Conclusions: The combination of nab-paclitaxel plus S-1 was well tolerated and presented antitumor efficacy which may be a new therapeutic option for patients with advanced gastric cancer.
Metastatic stomach cancer: Real world scenario from a developing country.
Authors: Ganguly Sandip , Biswas Bivas , Ghosh Joydeep , E Prasad , Banerjee Sudeep , Mallath Mohandas K. , Chatterjee Suvadip , Dabkara Deepak
Published: September 2018

e15569

Background: Data on epidemiology and outcome in metastatic stomach carcinoma patients from resource poor country is scarce. We aimed to evaluate clinical features and treatment outcome in patients treated at our center. Methods: This is a single institutional review of metastatic stomach carcinoma patients treated between May’2011 and October’2016. Patients with past history of adjuvant treatment were also included when they developed metastasis. Progression-free survival (PFS) was calculated from date of diagnosis of metastasis to date of disease progression. Patients who received at least one cycle of chemotherapy were included for a modified intent-to-treat survival analysis. Results: Total 143 patients were diagnosed with metastatic stomach carcinoma with median age of 56 years (range: 29-86) and male:female ratio of 92:51. Twenty-five (17%) patients received prior adjuvant therapy before developing metastasis. Commonest symptoms were abdominal pain in 112 (78%), weight loss in 72 (50%) and gastric outlet obstruction in 33 (24%) patients. Primary sites were proximal stomach in 44 (30%), body in 81 (57%) and distal stomach-pyloric region in 18 (13%) patients. Site of metastasis was peritoneum in 86 (60%), liver in 62 (43%), lung & pleura in 22 (15%), ovary in 14 (10%), and bone in 12 (8%) patients, and 104 (75%) patients had > 1 site of metastasis. Seventy-one (50%) patients were eligible for survival analysis. Common chemotherapy regimens were capecitabine-cisplatin in 27 (38%) and EOX in 22 (31%) patients. Survival status couldn’t be assessed in 29 (41%) patients who lost to follow-up. After a median follow-up 9.7 months (range: 0.5-37.7), median PFS was 7.9 months (range: 0.5 – 23.9) and median OS was 12.2 months (range: 0.5-37.7). ECOG performance status (PS) ≥2 and presence of linitis plastica showed a trend towards inferior PFS (p = 0.052 and 0.053, respectively) only in univariate analysis. Female sex and ECOG PS≥2 predicted inferior OS in both univariate and multivariate analysis (p = 0.012, 0.02 and 0.03 & 0.05, respectively). Conclusions: Platinum based doublet chemotherapy was used in majority of patients. Overall outcome was comparable to that of the available literature. Female sex and ECOG PS≥2 predicted inferior outcome.
A phase II study of induction chemotherapy with docetaxcel, cisplatin, and S-1 (DCS) for gastric cancer with peritoneal metastasis (KUGC06): Early results.
Authors: Okabe Hiroshi , Hata Hiroaki , Ueda Shugo , Hosogi Hisahiro , Ota Shuichi , Kinjo Yousuke , Hoshino Nobuaki , Hisamori Shigeo , Tsunoda Shigeru , Obama Kazutaka , Sakai Yoshiharu
Published: September 2018

e15574

Background: Although the prognosis of gastric cancer with peritoneal metastasis is extremely poor, we previously showed the significant efficacy of S-1 plus cisplatin for limited peritoneal dissemination, and favorable outcome following curative resection. We conducted a phase II study to evaluate the safety and efficacy of induction chemotherapy with docetaxel, cisplatin, and S-1 (DCS) triplet regimen for patients (pts) with gastric cancer with peritoneal metastasis. Methods: The key eligibility criteria were gastric cancer with peritoneal metastasis or positive peritoneal cytology, without any other distant metastases, age between 20 and 75 years old, PS 0 or 1, capable of oral administration, and adequate hematologic, hepatic, and renal function. Pts received three 28-day cycles of DCS (cisplatin of 60 mg/m2, docetaxel of 40mg/m2 on day 1, and S-1 of 80 mg/m2 from day 1 to 14). Following evaluation for resectability, pts received D2 gastrectomy if R0 was possible. Primary endpoint was R0 resection rate. Secondary endpoints were clinical response of peritoneal metastasis, overall response, pathological response, adverse events, progression free survival, and overall survival. Sample size was determined to have 80% power for detecting 20% improvement of R0 resection rate over 45% baseline at one-sided alpha of 0.1. Results: Between June 2011 and April 2015, 30 pts were enrolled. All pts started DCS and were included in the analysis. Three cycles of DCS (80%) were completed in 24 pts (80%). The most frequent grade 3/4 toxicity was neutropenia (60%). Complete response of peritoneal metastasis was observed in 16 pts (53%), 21 pts underwent surgery, and 14 pts achieved R0 resection (47%; 95%CI, 28-66%). When the extent of peritoneal metastasis was classified as P0CY1, P1, P2, and P3 according to the Japanese classification, R0 resection rate for each group was 63%, 60%, 46%, or 0%, respectively. Conclusions: Induction chemotherapy with DCS is safe, and could achieve R0 resection in some patients with limited peritoneal metastasis or positive peritoneal cytology. However, the efficacy seems to be similar to the conventional S-1 plus cisplatin. Clinical trial information: UMIN000004932.
Tongue image information for prediction esophageal precancerous lesion: A multi-centric logistic regression analysis of esophageal cancer high risk population in China.
Authors: Deng Bo , Chen Zhifeng , Wang Xinzheng , Song Guohui , Duan Jinlong , Jia Liqun
Published: September 2018

e15579

Background: More than 50% esophageal cancer cases of the world are in China. The main causative factors that contribute to extremely high incidence of esophageal cancer (9.15/ million) in certain rural areas of China has not yet been elucidated. Screening and diagnosis of precancerous lesions and early stage cancer are main neasures of decreasing incidence rate and mortality rate. Methods: High-risk population (40-69 years old) in high risk areas of esophageal cancer, Cixian and Yangcheng were screened, and 4742 cases were included. They were divided into 4 groups: normal group, esophagitis/gastritis, esophageal neoplasia low-level group and esophageal neoplasia high-level group, according to pathology and electronic gastroscope diagnosis. Diagnostic testing lingual information collection system (DS01-B) was used and tongue image were collected, including tongue color, coating color, fur character, tongue shape, local ecchymosis, et al. Difference of tongue image information was analyzed by multi-factor logistic regression using SPSS and R statistical software. Results: Logistic regression analysis showed that dark purplish tongue colour, and tongue local ecchymosis were correlated to precancerous lesions and early stage cancer (P < 0.01 or P < 0.05). Red and crimson tongue, yellow and white coated tongue, spotted tongue and tongue local ecchymosis were correlated to esophagitis and gastritis(P < 0.01 or P < 0.05). Logistic regression model had diagnostic total coincidence rate (69.4%) for early esophageal cancer screening. Conclusions: Multi-factor logistic regression model based on tongue image information has clinical value of prediction esophageal precancerous lesion.
Cancer-related distress and cost of care concerns among gastric cancer patients.
Authors: House Linda S. , Miller Melissa F , Zaleta Alexandra K , Johnson Jamese , Denlinger Crystal Shereen , Buzaglo Joanne S
Published: September 2018

e15583

Background: Individuals with gastric cancer (GC) are at risk for significant physical, psychological, and financial burden related to their illness and cost of care. This study characterizes cancer-related distress and concerns among survivors of GC and related cancers and the support survivors receive from their health care team for these concerns. Methods: Of 110 GC survivors enrolled in the Cancer Support Community’s online Cancer Experience Registry, 30 (43% stomach, 37% esophageal, 20% GIST) rated their level of concern (0 = not at all; 4 = very seriously) about psychological, emotional, physical and practical concerns (27 items). Risk for clinically significant distress was identified via a 4-item subscale (α = 0.86, cutoff score = 6.) Participants also completed the Impact of Events (IES) intrusion subscale and questions about their healthcare team’s involvement in addressing concerns. Results: Participant median age was 61 years; median time since diagnosis was 3 years. 23% experienced recurrence; 37% had metastatic disease.The highest ranked concerns (rated moderately to very seriously) included: eating and nutrition (62%); fatigue (62%); health insurance or money worries (59%); worry about the future (59%); feeling sad or depressed (50%); changes or disruptions to work, school, or home life (48%); sleep problems (48%); and worry about family (48%). Half of respondents (50%) were at risk for clinically significant emotional distress; 39% reported intrusive thoughts about the cost of cancer care. Fewer than half indicated their health care team asked about emotional distress (43%), lifestyle (43%), work (40%), finances (37%), or family (33%). Participants wished for more help with emotions related to cancer (57%), long-term side effects (55%), and financial advice/assistance (52%). Conclusions: Substantial proportions of gastric cancer survivors express concern about physical symptoms, emotional distress, and financial burden, yet many report they are not counseled about these concerns. Efforts are needed to reduce distress and the financial burden associated with gastric cancer to reduce their potential impact on quality of life, treatment adherence, and other illness outcomes.
Prognostic factors associated with survival and recurrence in resectable gastroesophageal adenocarcinoma: retrospective analysis of 497 patients operated at two Italian centers.
Authors: Ghidini Michele , Botticelli Andrea , Donida Bianca Maria , Strigari Lidia , Onesti Concetta Elisa , Ratti Margherita , Pizzo Claudio , Aldighieri Federico , Toppo Laura , Ranieri Valerio , Occhipinti Mario , Senti Chiara , Tanzi Giulia , Mazzuca Federica , Marchetti Paolo , Martinotti Mario , Passalacqua Rodolfo , Tomasello Gianluca , Rovatti Massimo
Published: September 2018

e15588

Background: Chemotherapy (CT) and chemoradiotherapy (CTRT) both in neoadjuvant (neoadj) or adjuvant (adj) setting are associated with better overall survival (OS) over surgery alone in patients (pts) with resectable gastroesophageal (GE) adenocarcinoma (ADK). The best sequence and timing of treatments have still not been defined. A large cohort of GE ADKs derived from 2 high-volume Italian centers was analyzed to describe clinical outcomes and prognostic factors. Methods: 497 patients (pts) diagnosed with GE ADK who underwent surgery with curative intent from 2007 to 2016 were considered. Variables analyzed were: age, sex, tumor location, histology, T, N, M, R, G, HER-2, Helicobacter Pylori (HP) infection, (neo)adj CT, and adj CTRT. Analysis was performed according to ITT principle. Results: Median age at diagnosis was 71 years (range 35-92). At 26.7 months (mo) median follow-up, median OS was 27.6 mo (range 1-127) and median time to recurrence (TTR) 10.8 mo (range 7.8-13.1). Adj CT was administered in 203 cases (41%); 116 pts (23%) had adj CTRT and 47 (9%) neoadj CT. Statistically significant variables for OS and/or TTR at 12 months at univariate analysis were: age, T, N, M, R, G, adj CTRT, neoadj CT and adj CT. Results of multivariate analysis (MVA) are shown in Table 1. Conclusions: Despite a short follow-up, our analysis performed on a very large cohort of consecutive pts confirms the prognostic value of T and N for both OS and TTR. Adj CT and CTRT had a significant impact on 1 year OS, while neoadj CT gave only a 12 months TTR significant benefit. Based on these results, perioperative treatment strategies should always be considered in the management of resectable GE cancer. [Table: see text]
Association of intratumoral PD-L1 expression with survival of patients with Epstein-Barr virus-associated gastric cancer.
Authors: Kim Jong Gwang , Kang Byung Woog , Chae Yee Soo , Lee Soo Jung , Lee In Hee , Baek Dong Won , Seo An Na
Published: September 2018

e15590

Background: The present study analyzed the expression of tumoral (t-) PD-L1/L2 and stromal (str-) PD-L1/L2, and their impacts on the survival of a relatively large group of Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). Methods: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. Immunohistochemistry of PD-L1 and PD-L2 was carried out and the intensity was scored as an intensity score 0 (no staining), 1 (weak intensity), 2 (intermediate intensity), and 3 (high intensity). The expression was also evaluated in tumor tissues and stromal immune cells and divided into two groups (2 and 3 were interpreted as a positive result). Results: Among the 120 patients, 57 patients (47.5%) and 66 patients (55.0%) were determined as t-PD-L1-positive and str-PD-L1 positive, while 23 patients (19.2%) and 41 patients (34.2%) were determined as t-PD-L2-positive and str-PD-L2 positive. In a univariate analysis, t-PD-L1-positive was significantly associated shorter disease-free survival (DFS, P = 0.032), yet not overall survival (P = 0.482). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, gender, WHO classification, and tumor-infiltrating lymphocytes, t-PD-L1 positivity was independently associated with poor DFS (Hazard ratio = 4.183, P = 0.044). Meanwhile, in the univariate analysis, t-PD-L2-positive and str-PD-L2-positive showed a better DFS trend than t-PD-L2-negative and str-PD-L2-negative, respectively (P = 0.071 and P = 0.092). However, t-PD-L2 and str-PD-L2 expressions showed no prognostic significance on DFS in the multivariate analysis. Conclusions: The level of t-PD-L1 expression represents a significant difference for DFS in patients with EBVaGC. The current findings support the concept that PD-L1 may be a prognostic parameter for predicting patient outcome and act as a therapeutic target in EBVaGC.
Genomic profiling using a 435-gene panel provides a vision for precision medicine in Japanese gastric cancer.
Authors: Ichikawa Hiroshi , Nagahashi Masayuki , Kitagawa Yuko , Yoshida Kazuhiro , Oki Eiji , Yabusaki Hiroshi , Nakagawa Satoru , Sato Nobuaki , Hanyu Takaaki , Ishikawa Takashi , Muneoka Yusuke , Yuza Kizuki , Shimada Yoshifumi , Ring Jennifer E. , Protopopov Alexei , Lyle Stephen , Ling Yiwei , Okuda Shujiro , Takabe Kazuaki , Wakai Toshifumi ,   NGST-Japan
Published: September 2018

e15592

Background: Molecular heterogeneity represents a significant hurdle in realizing precision medicine for gastric cancer (GC). Large-scale whole exome sequencing projects have identified distinct molecular subtypes to help define the heterogeneity of GC. However, it remains unclear whether the targeted gene panel-based sequencing can provide optimum targeted therapies and clinical utility in GC. The aim of this study is to generate comprehensive genomic profiling data and classify Japanese GC into actionable clusters associated with targeted therapies. Methods: FFPE tumor tissues were obtained from surgical or biopsy specimens of 207 Japanese patients with GC. Extracted DNA was subjected to genomic sequencing for 435 cancer related genes including 69 druggable genes with FDA approved targeted therapies. Somatic mutations, copy number alterations (SCNA), microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection were evaluated using sequencing data. Results: Genomic sequencing identified at least one alteration of 435 genes in 194 pts (94%), and that of 69 druggable genes in 141 pts (68%). The most frequently altered druggable gene was ERBB2 (14%), following BRCA2 (11%) and ATM (10%). We successfully classified 207 tumors into four molecular subtypes, similar to the previously report; EBV (4%), MSI (8%), chromosomal instability (58%) and genomically stable subtype (30%). Frequent alterations of druggable genes ( > 5%) were widely observed through these subtypes. To discover the novel classifications associated with targeted therapies, we classified 207 tumors using mutation rate and hierarchical clustering. We identified a hypermutated group (n = 32), and a remaining non-hypermutated group (n = 175) which were sub-divided into six clusters including five actionable ones; ERBB2 (n = 25), CDKN2A and CDKN2B (n = 10), KRAS (n = 10), BRCA2 (n = 9) and ATM cluster (n = 12). Interestingly, we experienced a case of unresectable GC with a remarkable response for anti-HER2 therapy in the ERBB2 cluster. Conclusions: Genomic sequencing using a 435-gene panel has the potential to provide the information of optimum targeted therapies for upcoming precision medicine in Japanese GC.
Prognostic and predictive value of immunoscore signature in gastric cancer.
Authors: Qi Xiaolong , Jiang Yuming , Zhang Qi , Hu Yanfeng , Li Tuanjie , Yu Jiang , Zhao Liying , Ye Gengtai , Deng Haijun , Mou Tingyu , Liu Hao , Cai Shirong , Zhou Zhiwei , Chen Guihua , Li Guoxin
Published: September 2018

e15594

Background: TNM staging system is not adequate to define the prognosis of patients with gastric cancer (GC). This system is also unable to predict whether the GC patients are likely to benefit from adjuvant chemotherapy. We postulated that ImmunoScore of GC (ISGC) could markedly improve the prediction of postsurgical survival and adjuvant chemotherapeutic benefits. Methods: 125 GC patients were enrolled as a training cohort to detect the expression of 27 immune features using immunohistochemistry and then constructed a five-feature-based ISGC using the LASSO Cox regression model. Internal validation cohort (126 specimens) and two external validation cohorts (628 specimens) were utilized to validate the prognostic and predictive value of ISGC. Results: We established the ISGC classifier based on the five features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. The ISGC classifier could distinguish GC patients with high-ISGC from those with low-ISGC with significant differences in 5-year disease-free survival (45.0% v.s. 4.4%, p < 0.001) and 5-year overall survival (48.8% v.s. 6.7%, p < 0.001). According to the multivariate analysis, the ISGC classifier was proved to be an independent prognostic factor. A combination of ISGC and TNM had better prognostic value than TNM stage alone. In a further analysis, stage II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. To provide a quantitative method to predict stage II and III GC patients’ probability of 3- and 5-year overall survival, we constructed two nomograms that integrated the ISGC and clinicopathological risk factors. Calibration plots showed that the nomograms performed well compared with an ideal model. The predictive accuracy and clinical usefulness of the nomograms were also demonstrated. Conclusions: The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value to TNM system. Moreover, the classifier might be a useful predictive tool to identify candidates with stage II and III GC who would benefit from adjuvant chemotherapy. Therefore, the ISGC might facilitate the counseling and personalize the postoperative management of GC patients.
Prognostic significance of the lymphocyte‐to‐monocyte ratio and the tumor‐infiltrating lymphocyte to tumor‐associated macrophage ratio in patients with stage T3N0M0 esophageal squamous cell carcinoma.
Authors: Zhu Yingming , Yu Jinming , Li Minghuan
Published: September 2018

e15602

Background: We assessed the prognostic signi cance of, and the relationship between, the pretreatment lymphocyte- to-monocyte ratio (LMR) and the TILs/tumor-associated macrophages (TAMs) ratio, in patients with esophageal squamous cell carcinoma (ESCC) of pathological stage T3N0M0 (pT3N0M0). Methods: A total of 220 newly diagnosed ESCC patients of stage pT3N0M0 who had not undergone neoadjuvant therapy were included. Densities of CD8+ TILs, CD4+ TILs, CD45RO+ TILs, and CD68+ TAMs were assessed by immunohistochemical staining of tissue microarray cores from all 220 pT3N0M0 ESCC patients (who underwent radical resection). Hematological biomarkers including lymphocyte and monocyte counts were obtained from routine preoperative blood test data, and the LMR and TILs/ TAMs ratios calculated. Cutoff nder for survival predic- tion was plotted to nd out the optimal cutoff point for each parameter. Results: The LMR and TILs/TAMs ratios were interrelated. On univariate analyses of data from the entire cohort, the LMR, CD45RO/CD68 ratio, and CD8/CD68 ratio were significantly associated with both OS and disease-free survival. Only the CD45RO/CD68 ratio was independently prognostic of survival on multivariate analysis. Conclusions: The prognostic significance of the CD45RO/ CD68 ratio was higher than that of the LMR. The CD45RO/ CD68 ratio is a useful independent prognostic marker in patients with pT3N0M0 ESCC who have undergone complete resection without neoadjuvant therapy.
Comparison of fluoropyrimidine based (FP)and taxane based platinum doublets (TP) in frontline treatment of patients with metastatic gastroesophageal adenocarcinomas (mGEAC): A retrospective analysis.
Authors: Ismail Hibah , Mohamed AMR , Song Yeohan , Abdallah Nadine , Surapaneni Malini , Kim Seongho , Mandana Kamgar , Mettu Jayadev , Akhras Alaa , Ahmed Abdelrahman , Philip Philip Agop , Shields Anthony Frank , Tesfaye Anteneh A.
Published: September 2018

e15604

Background: Although, fluoropyrimidine (FP) and taxane based platinum doublet (TP) chemotherapy have demonstrated efficacy against advanced gastroesophageal cancer, these two regimens have not been compared in prospective trials. We retrospectively compared fluoropyrimidine based (FP)and taxane based platinum doublet (TP)chemotherapy in the frontline setting in patients with mGEAC. Methods: Patients with mGEAC treated at Karmanos Cancer Institute between 2000-2014 were reviewed. We compared progression free survival (PFS), Response rate (RR), and toxicity profile of the two regimens. Outcomes were analyzed using weighted estimates. Fisher’s exact tests and Kruskal-Wallis tests were used for categorical and continuous variables, respectively. Survival differences were assessed by a log-rank test. Results: Of the total136 patients, 39% (53) received FP and 61% (83) received TP chemotherapy. Males were 68% (94) of the patients. Gastric, esophageal and gastroesophageal adenocarcinomas contributed to 47% (64), 26.5% (36) and 26.5% (36) of the cases respectively. FOLFOX was the main regimen in FP (62%), followed by 5FU cisplatin (38%). Carboplatin paclitaxel was the main regimen in the TP group. There was no statistically significant difference between the FP and TP arms in terms of PFS, RR, and median OS. The estimated median PFS was 6.39 (95% CI, 5.54-11.15) for the FP group vs 6.92 months (95% CI, 6.13-9.02) for the TP group, (p = 0.90). Objective response rate was (48% for FP group Vs 56% for TP group, p = 0.70). There was more significant grade 4-5 toxicity in FP vs TP based regimen (79 % vs 55 % respectively, p = 0.004). Conclusions: The efficacy of fluoropyrimidine platinum doublet chemotherapy appears to be as comparable to taxane based platinum doublet in the frontline treatment of mGEC. However, the fluorpyrimidine based regimen appears to have more toxicity. Consideration of treatment adverse effects ought to be a key factor in determining the choice of either regimen in mGEAC.
Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer (EC).
Authors: Saba Nabil F. , Force Seth D , Staley Charles A. , Fernandez Felix G , Willingham Field F. , Allan Pickens , Cardona Kenneth , Chen Zhengjia , Cardin Dana Backlund , Lambright Eric , Nesbitt Jon , Higgins Kristin Ann , Harvey R Donald , Owonikoko Taofeek Kunle , Ramalingam Suresh S. , Shin Dong Moon , Beitler Jonathan Jay , El-Rayes Bassel F. , Landry Jerome C , Chakravarthy Anuradha Bapsi
Published: September 2018

e15607

Background: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation and platinum agents in EC. We conducted a multi-institutional phase IB trial to determine the recommended phase II dose (RP2D) of concurrent everolimus with carboplatin and radiation in non-metastatic EC pts. Methods: Patients with untreated, localized EC and ECOG performance status 0-1 were eligible. Following two cycles of induction Capecitabine/Oxaliplatin (XELOX), pts without evidence of disease progression, received concurrent chemoradiation (total dose: 50.4Gy in 28 fractions), weekly carboplatin (AUC = 2), and escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. There were two screen failures (thrombocytopenia, metastases) and 4 pts were removed due to poor tolerance of XELOX (2 pts) or disease progression (2 pts). A total of 13 pts with stage II/III (6/7) EC completed concurrent therapy. Median age 58 (44-71yrs), 85% males; all had adenocarcinoma deemed resectable. One pt at dose level 1 (2.5 mg/QOD), was replaced due to ongoing anxiety. One of 6 pts had a DLT (bowel ischemia). At dose level 2 (2.5mg/QD), 2 out of 6 patients had a DLT (fever with neutropenia and nausea). The RP2D of everolimus was 2.5 mg QOD. Clinically relevant ≥ grade 3 toxicities included lymphopenia (25%), dehydration (12%), fatigue, leukopenia, hyponatremia, abdominal pain, vomiting (each 6%). R0 resection was achieved in 100%; a pathologic response rate (RR) of 40% and a pathologic complete response (pCR) rate of 23% were observed. The 2-year PFS and OS were 50% and 49.6% respectively. Conclusions: The RP2D of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD. Despite the 100% R0 resection rate, the pCR and OS rates were within the expected historical controls. (The study was funded by Novartis Pharmaceuticals) Clinical trial information: NCT01490749.
Oncological outcomes in a cohort of patients with biliary tract carcinoma in a Mexican reference center.
Authors: Meneses Medina Mónica Isabel , Huitzil Melendez Fidel David
Published: September 2018

e15618

Background: In Mexico there is scarce information about oncological outcomes of biliary tract carcinomas (BTC). Methods: we retrospectively reviewed medical records from 150 patients with histologically confirmed BTC (excluding gallbladder cancer) treated in our institution from January 2005 to December 2015.Clinical and pathological information was recorded. Survival was estimated by Kaplan Meir method and compared by Log rank test. Results: we found 63.3% women and 36.7% men, with a median age of 62 years (23 - 88). Tumor localization was intrahepatic in 34.7%, hilar in 43.3% and distal in 22%. Clinical stage was advanced in 71%, regional in 13% and local in 16%. Diagnostic delay was 3.7 months (0.37 - 32.9). For patients with localized disease (which included local and regional disease, n=43), a potentially curative surgery was attempted in 64% (n=27), achieving a R0 resection in 59% (n=16) of cases. There was a 3.9 months (0.83-29.63) treatment initiation delay. There were 7 surgical deaths. For advanced disease (n=107), treatment initiation delay was 4.2 months (0.5 - 34.5), 59% (n=63) of patients did not received oncological active treatment, and 26% (n=28) of patients received a systemic palliative chemotherapy, more frequently gemcitabine (n=20). At progression just eleven patients received a second chemotherapy line. In localized disease resected patients by univariate analysis high levels of CA 19.9 (p=0.04) and CEA (0.03) were associated with decreased survival. For patients with advanced disease prognostic factors included poorly differentiated histology (p=0.04), high bilirrubin level (p=0.04), low albumin level (p=0.001), abscense of chemotherapy (p=0.000) and high CEA levels (p=0.03). Conclusions: Survival is poor in this Mexican cohort of patients with BTC possibly related to diagnostic and therapeutic delay and advanced disease at presentation. [Table: see text]
Safety and efficacy of chemosaturation in patients with primary and secondary liver tumours: A single-centre experience after 54 treatments.
Authors: Kirstein Martha , Marquardt Steffen , Jedicke Nils , Marhenke Silke , Koppert Wolgang , Manns Michael , Wacker Frank , Vogel Arndt
Published: September 2018

e15625

Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT Delivery System; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumours while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyse the safety and efficacy of the second generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Results: A total of 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors (ocular melanoma [OM] n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1) and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumours had durable disease stabilisation (40%). Median OS, PFS and hPFS were 261, 117 and 135 days, respectively. Tumour volume negatively correlated with OS. Complications and toxicites included thrombopenia, cardiovascular events, ulcerous bleeding and edema. Conclusions: Second generation CS-PHP seems to be effective and tolerable. Patient selection based on tumour volume end entity is of importance. Particularly patients with OM and hepatobiliary tumours represent promising candidates for CS-PHP.
The effect of treatment delay on survival in patients with hepatocellular cancer.
Authors: Akce Mehmet , Sansgiry Shubhada , Temple Sarah Louise , Davila Jessica , Sada Yvonne
Published: September 2018

e15645

Background: Hepatocellular cancer (HCC) is the fastest increasing cause of cancer related death in the U.S. Only one-third of patients are candidates for curative treatment, and treatment delays occur in 30% of patients. Data on the effect of treatment delays on HCC survival outcomes are limited to small single center studies. The aim of this study was to identify predictors of treatment delays and the impact of treatment delay on survival. Methods: We conducted a retrospective study using a national cohort of patients from the Department of Veterans Affairs who were diagnosed with HCC from October 1, 2004 to September 30, 2011. Demographics, clinical factors, treatment and death were ascertained from the medical records. Treatment delay was defined as greater than 60 days between HCC diagnosis and first treatment. Treatment was categorized as curative (surgery or ablation), liver-directed therapy, or chemotherapy. Cox Proportional Hazard models were used to examine the effect of treatment delay on survival stratified by stage (BCLC 0 and A, B, or C). Results: Among 742 patients with HCC, 223 (30%) had a treatment delay. The majority of patients were Barcelona Stage C (43%), and 131 patients (17.7%) had metastatic disease. On univariate analysis, patients with treatment delay were more likely to have tumor board discussion, single tumors, and PTSD (p < 0.05). Treatment delay was not associated with increased risk of death for patients with BCLC stage 0 and A (HR 0.74 [0.48-1.14]) or BCLC stage B (HR 0.83 [0.61-1.14]). For BCLC stage C, treatment delay was associated with a 50% decrease in risk of death (HR 0.50 [0.37-0.67]), adjusting for demographics, clinical factors, stage, and treatment. Patients with BCLC stage C HCC and treatment delay were more likely to have curative intent therapy (32.9% vs 16.3%) or liver directed therapy (43.4% vs 36.3%, p = 0.0006) than those with no delay. Conclusions: Treatment delays occurred in 30% of patients. Treatment delay was not associated with increased risk of death for earlier stage HCC, but treatment delay was associated with decreased risk of death for patients with BCLC stage C. This finding may be due to delays from coordination of curative and liver directed therapy that may result in improved survival.
Evidence-based treatment algorithm for BCLC C advanced hepatocellular carcinoma: A comprehensive review and meta-analysis.
Authors: Prajapati Hasmukh J. , "Kevin" Kim Hyun S.
Published: September 2018

e15649

Background: Barcelona clinic liver cancer (BCLC) C advanced hepatocellular carcinoma (aHCC) has a poor prognosis. Different treatment methods have shown a survival benefit. The purpose of the study is to suggest the treatment algorithm based on a comprehensive review of the literature on aHCC treated with different methods. Methods: Studies were identified by searching Google Scholar using the following keywords: ‘‘advanced hepatocellular carcinoma’’ or ‘‘advanced HCC’’ or “BCLC C” in a time period from 2008 to 2017. Search identified more than 700 articles. Then, articles were searched manually for BCLC C HCC. Articles were excluded if they dealt with only liver metastases or portal vein thrombosis, or if they did not report median survival. A total of 3 randomized control studies (RCT) and 21 non-RCT studies met the inclusion criteria and were reviewed. Results:Overall median survivals (OS) according to different methods is shown in table 1. OSs of aHCC treated with TACE, Yittrium 90 transarterial radioembolization (Y90 TARE) and sorafenib were not significantly different (p>0.5). The pooled results of NRCT demonstrated that Child Pugh class A or without portal vein thrombosis (PVT) or ECOG PS 0 treated with TACE had best median survivals of 15 months(m), 17 m and 20 m respectively. Conclusions: No treatment method appears clearly better than any other. However, aHCC patients with Child Pugh class A or ECOG PS 0 or without PVT treated with TACE showed highest survival. Sorafenib/TACE or sorafenib/Y90 TARE combinations show promise as an effective and a tolerable treatment strategy for advanced HCC. Radiation therapy alone showed poor survival benefit. [Table: see text]
Comparison of prognostic models for hepatocellular carcinoma (HCC) in patients treated with the sorafenib: Results from a Canadian multi-center HCC database.
Authors: Samawi Haider , Sim Hao-Wen , Chan Kelvin K. , Alghamdi Mohammed Abdullah , Lee-Ying Richard M. , Knox Jennifer J. , Gill Parneet , Romagnino Adriana , Batuyong Eugene , Ko Yoo-Joung , Cheung Winson Y. , Tam Vincent C. ,   On Behalf of the CHORD Consortium
Published: September 2018

e15653

Background: Several staging systems and models (TNM, BCLC, Okuda, CLIP and ALBI) have been developed to estimate the prognosis of patients with HCC. Most of these were developed prior to the prevalent use of sorafenib. The purpose of this study was to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib. Methods: Patients who received sorafenib for the treatment of HCC between January 1, 2008 and June 30, 2015 in the provinces of British Columbia and Alberta, as well as Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre in Toronto, Ontario were included. Survival outcomes for each model were assessed with Kaplan-Meier (KM) curves and compared with the log-rank test. Time dependent area under the curve (t-AUC) was used to test the discriminatory power of each model (higher t-AUC = more discriminatory power). Akaike information criterion (AIC), a measure of goodness-of fit of models while penalizing overly complex models, was used to compare the models (lower AIC = better model). Results: A total of 681 patients were included in this analysis. Median age was 64 years (range 8-91). Majority were males (80%), had a Child-Pugh score A (86%), ECOG performance status 0 (30%) and 1 (60%). 37% of patients were of East Asian ethnicity. Most common etiology for liver disease was hepatitis B (33%) and C (29%). At start of sorafenib, most patients were BCLC stage C (92%) and TNM stage IV (61%). The median overall survival for the entire cohort was 9.2 months (95% CI 8-10.4). See table below for t-AUC and AIC results. Conclusions: According to ourlarge multi-center study, CLIP appears to be the most informative in predicting survival in HCC patients treated with sorafenib. Prospective studies are needed to determine its role in patient selection for clinical trials and in guiding treatment decisions. The TNM and BCLC staging systems were the least useful in predicting survival in this population. [Table: see text]