Increased BTLA and HVEM in gastric cancer are associated with progression and poor prognosis Xiuwen Lan,1,* Sen Li,1,* Hongyu Gao,1 Abiyasi Nanding,2 Lina Quan,3 Chunyan Yang,4 Shaohua Ding,2 Yingwei Xue1 1Department of Gastroenterological Surgery, 2Department of Pathology, 3Department of Hematology, The Affiliated Tumor Hospital, 4Department of Epidemiology and Biostatistic, Public Health School, Harbin Medical University, Harbin, People’s Republic of China *These authors contributed equally to this work Purpose: Deregulation of immune checkpoint molecules by tumor cells is related to immune escape. This study was conducted to investigate the relationship between the appearance of B- and T-lymphocyte attenuator (BTLA) and its ligand herpesvirus entry mediator (HVEM) with the prognosis in gastric cancer patients. Patients and methods: A total of 136 patients with curative gastrectomy were included. The expression of BTLA and HVEM was detected by immunohistochemistry, and its correlation with the clinical significance of gastric cancer was further analyzed. Results: The positivity of BTLA and HVEM was detected in 74.3% (101/136) and 89.0% (121/136) of the gastric cancer specimens, respectively. A high expression of BTLA and HVEM was detected, respectively, in 28.7% (39/136) and 44.9% (61/136) of the specimens. Characteristics analysis showed that the high expression of BTLA was significantly associated with lymph node metastasis (P=0.030). Similarly, the high expression of HVEM was also significantly correlated with lymph node metastasis (P=0.007) and depth of invasion (P=0.011). In addition, there was a positive correlation between the expression of BTLA and HVEM in gastric cancer specimens (r=0.245, P=0.004). Univariate analysis revealed that the high expression of BTLA and HVEM was associated with overall survival of patients along with tumor size, Borrmann type, depth of invasion, lymph node metastasis, and histological grade (P<0.05). Multivariate analysis established that the high expression of HVEM (P=0.010), depth of invasion (P=0.001), lymph node metastasis (P<0.001), and histological grade (P=0.027) were independent prognostic factors associated with overall survival in patients with gastric cancer. Conclusion: The increased BTLA and HVEM levels correlate with the development and poor prognosis of gastric cancer. HVEM is an important prognostic indicator, and BTLA/HVEM pathway is considered to be a promising candidate for immunotherapy of gastric cancer. Keywords: gastric cancer, B- and T-lymphocyte attenuator, herpesvirus entry mediator, prognostic

Derived neutrophil to lymphocyte ratio and monocyte to lymphocyte ratio may be better biomarkers for predicting overall survival of patients with advanced gastric cancer Shubin Song, Chunfeng Li, Sen Li, Hongyu Gao, Xiuwen Lan, Yingwei Xue Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China Background and objectives: Preoperative systemic inflammatory response and nutritional status play important roles in the tumorigenesis, progression, and prognosis of gastric cancer (GC). This research is designed to investigate the prognostic value of the biomarkers including the neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI) in predicting overall survival in patients with GC. Methods: A total of 1,990 consecutive GC patients who underwent gastrectomy from 2007 to 2011 were enrolled and divided into high level and low level based on the optimal cut-off points for NLR, dNLR, MLR, PLR, and PNI, respectively. The clinicopathological characteristics of the two levels were comparatively analyzed. Overall survival analysis was executed using these biomarkers and clinicopathological characteristics. Results: The number of metastatic lymph nodes, distant metastasis, American Joint Committee on Cancer TNM stage, radicality, tumor size, metastatic lymph nodes ratio, ascites, and Hb were all significantly associated with NLR, dNLR, MLR, PLR, and PNI. All of these five biomarkers were closely associated with overall survival in univariate analyses, but only dNLR and MLR were significant in multivariate model. dNLR and MLR can be bonded to predict survival, but whether separate or together, dNLR and MLR were mainly significant in advanced stages. Conclusion: Although preoperative NLR, dNLR, MLR, PLR, and PNI in peripheral blood proved significant prediction of prognoses of postoperative GC patients, dNLR and MLR may be better biomarkers for predicting overall survival, especially in advanced GC patients. Keywords: gastric cancer, prognosis, survival, biomarker, systemic inflammatory response

Platelet and blood coagulation abnormalities frequently occur in cancer patients. Fibrinogen is an important hemostatic factor that regulates the hemostatic pathway. Hyperfibrinogenemia is increasing recognized as an important risk factor influencing cancer development and outcome. However, few reports have investigated the prognostic potential of fibrinogen for predicting the survival of gastric cancer (GC) patients. The primary aim of this study was to evaluate the usefulness of preoperative serum fibrinogen as a biomarker for predicating tumor progression and survival of patients with GC. This retrospective study was conducted in GC patients who underwent gastrectomy from 2005 to 2007. Patient demographics, clinicopathological characteristics, preoperative plasma fibrinogen levels and median survival time (MST) were analyzed. Univariate and multivariate proportional hazard analysis of risk factors were used. This study included 1196 patients (885 males and 311 females) with GC, more than half of whom had advanced GCs. Radical lymph node dissection was performed in 71.6 % of these patients. MST was 41.9 ± 32.4 months. Patient survival was significantly affected by family GC history (p <0.05), lymph node dissection mode (p <0.001), tumor size (≥5 cm; p <0.001), tumor location (p < 0.001), poor tumor differentiation (p <0.001), tumor histologic classification (p <0.001), extent of tumor invasion (p <0.001), number of metastatic lymph nodes (p <0.001), advanced stage of disease (p 150 min; p 200 ml; p <0.001), postoperative transfusion, preoperative serum fibrinogen levels, CEA levels and CA 19-9 levels (p <0.001). Multivariate analysis indicated that the independent prognostic factors significantly associated with poor survival included non-radical lymph node dissection, palliative lymph node dissection, multi-organ involvement, advanced TNM stages, poor tumor differentiation, higher preoperative serum fibrinogen levelsand higher CA19-9 levels. Serum fibrinogen levels are positively correlated with advanced tumor stages and poor survival in GC patients undergoing gastrectomy. Preoperative plasma fibrinogen levels are an independent risk factor for survival in these patients. Serum fibrinogen is a useful biomarker for patients with clinically advanced GC.

Background and objectives: The dismal prognosis of gastric cancer patients is a global problem. We aim to evaluate the clinicopathologic features and prognostic factors of proximal and distal gastric cancer. Materials and methods: Gastric cancer cases diagnosed and treated at the same surgical unit between 2007 and 2010 were reviewed. Follow-up data from all patients were collected for at least 5 years until 2015. A total of 964 patients were studied (distal gastric cancer [DG], n=777 and proximal gastric cancer [PG], n=187). Results: DG patients had a relatively higher percentage of females, more thorough therapy (R0 [D0/D1/D2]), fewer combined organ resections, younger age, smaller tumors (<5 cm), shorter surgery durations, less blood loss during surgery, and a relatively lower percentage of nodal metastases and a TNM stage of 4 (p<0.05). A significantly higher 5-year survival rate was observed in DG patients compared to PG patients (DG: 51%, PG: 28%; p<0.001). A multivariate analysis demonstrated that tumor size, blood loss during surgery, surgery approach of lymph node dissection, treatment with palliative surgery, histopathologic type, TNM stage, and tumor location were independent predictors of poor outcome. Conclusion: The different characteristics and prognosis of DG and PG cases have implications for the development of guiding strategies for a surgical program and assessment of prognosis of gastric cancer patients based on tumor location.

The prognostic significance of tumor size in gastric cancer is not well defined. The objective of this study was to identify the prognostic value of tumor size in patients with gastric cancer. We retrospectively reviewed a total of 1800 patients with gastric cancer admitted to our hospital between 1997 and 2007. These patients were divided into two groups according to tumor size: small size group (SSG, tumor ≤5 cm) and large size group (LSG, tumor >5 cm). We compared clinico-pathologic features of the two groups and investigated the prognostic factors by performing univariate, multivariate, and stage- stratified analyses according to tumor size. LSG had more aggressive clinico-pathologic features than SSG. Tumor size was an independent prognostic indicator in patients with gastric cancer. In a stratified-pT, pN, and pTNM analysis, survival of patients with LSG was significantly worse than that of patients with SSG and advanced stage. Tumor size was not a significant predictor of survival in patients with early stage tumors. Large tumor size was associated with shorter survival in patients with stages N0, N1, N2, and N3, and stages I, II, III, and IV. Tumor size is a simple and practical prognostic factor in patients with gastric cancer. Tumor size could supplement clinical staging in the future.

Background: To explore the role of preoperative prealbumin levels in predicting the prognosis of patients with gastric cancer. Methods: A total of 989 gastric cancer patients in the Affiliated Tumour Hospital of Harbin Medical University who underwent gastrectomy were included in this retrospective study. The preoperative prealbumin level, clinicopathological data, and follow-up data were recorded. According to the maximum chi-square survival correlation value, the survival of patients with low preoperative prealbumin (<140 mg/L) and high preoperative prealbumin (≥140 mg/L) were compared using the log-rank test and the Cox proportional hazard regression model. Results: Based on the best cut-off value of 140 mg/L, we divided the patients into the lower prealbumin group (<140 mg/L) and the higher prealbumin group (≥140 mg/L). Compared with the higher prealbumin group, the lower prealbumin group were older and had larger tumor volumes, lower hemoglobin (Hb) levels, and more upper gastric cancer tumors. The univariate analysis showed that prealbumin and other clinicopathological factors, including age, hemoglobin, tumor size, macroscopic type, cell differentiation, liver metastasis, operation type, N stage, and T stage, were significant prognostic factors. The multivariable analysis showed that age, prealbumin, macroscopic type, location, T stage, and N stage were independent prognostic factors. Conclusions: The preoperative prealbumin level was an independent prognostic factor for patients with gastric cancer. The preoperative prealbumin level can be used to predict the prognosis of patients with gastric cancer and guide clinical practice.