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Background: Reducing peritoneal recurrence after radical surgery is an important choice to improve the prognosis of patients with advanced gastric cancer. Intraoperative intraperitoneal chemotherapy has the potential to be a promising treatment strategy. In the present study, we conducted a multi-center, randomized, controlled clinical study to evaluate the efficacy and safety of intraoperative intraperitoneal chemotherapy using sustained-release fluorouracil implants plus radical gastrectomy and adjuvant chemotherapy for cTNM stage III gastric cancer. Methods: The patients were randomized into intraperitoneal chemotherapy group (sustained-release fluorouracil implants administration after standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy) and control group (standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy). A total of 122 patients from three centers were enrolled from September 2015 to February 2017. Results: One hundred and two eligible patients completed the treatment course. The median follow-up time was 41.7 months (36.1–52.9 months). The 3-year progression-free survival rate and overall survival of patients in the intraperitoneal chemotherapy group were 43.9% and 49.1%, respectively, which were significantly better than those of the control group, 31.0% and 38.4%. In the intraperitoneal chemotherapy group, the number of cases with peritoneal recurrence was significantly less than that of the control group, 9 cases (17.3%) vs. 19 cases (44.2%). There were neither significant differences between the groups in the incidence of hematogenous metastasis, lymph node metastasis, nor local metastasis. Conclusion: For cTNM stage III gastric cancer, intraoperative sustained-release fluorouracil implants after radical resection combined with postoperative adjuvant chemotherapy, could significantly reduce the risk of peritoneal recurrence and prolong PFS. Clinical Trial Registration: https://clinicaltrials.gov/ , identifier (NCT02269904). [ABSTRACT FROM AUTHOR]

Background: Emerging evidences suggests that Diosbulbin-B (DB) is effective to improve cisplatin (DDP)-sensitivity in gastric cancer (GC), but its molecular mechanisms were not fully delineated, and this study managed to investigate this issue. Methods: Genes expressions were determined by Real-Time qPCR and Western Blot at transcriptional and translational levels. Cell proliferation and viability were evaluated by cell counting kit-8 (CCK-8) and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. The xenograft tumor-bearing mice models were established, and the tumors were monitored and the immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues. Results: Low-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-mediated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells co-treated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB inhibited spheroid formation and stemness biomarkers (SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo. Conclusions: Collectively, low-dose DB regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC. [ABSTRACT FROM AUTHOR]

Background: Inflammatory indexes are considered to be potential prognostic biomarkers for patients with gastric cancer (GC). However, little evidence has defined the prognostic significance of inflammatory indexes for GC with different Lauren classification. Methods: A total of 852 patients with GC were randomly selected consecutively into intestinal type and diffuse/mixed type groups. Group bias was reduced by propensity score matching. The cutoff values of inflammatory indexes were analyzed by receiver operating characteristic curve. The Kaplan–Meier method and log‐rank test were used to analyze the overall survival (OS). The chi‐square test was used to analyze the association between inflammatory indexes and clinical characteristics. The independent risk factor for prognosis in each group was analyzed by univariate and multivariate analyses based on logistic regression. The nomogram models were constructed by R studio. Results: Intestinal type GC patients (p < 0.05) had a lower percentage of neutrophils in stage I, higher percentage of neutrophils and higher platelet count in stage Ⅲ (p < 0.05). Systemic immune‐inflammation index (SII) (p < 0.001), pTNM stage (p < 0.001), and postoperative chemotherapy (p = 0.002) were independent risk factors for prognosis in the intestinal type group. Platelet–lymphocyte ratio (PLR) (p < 0.001) and pTNM stage (p = 0.001) were independent risk factors for prognosis in the diffuse/mixed type group. The area under the curve of the nomogram model in predicting 5‐year prognosis in the intestinal type group and diffuse/mixed type group were 0.807 and 0.788, respectively. Conclusion: SII combined with postoperative chemotherapy and pTNM stage were used to construct a nomogram model to predict the prognosis of intestinal type GC. PLR combined with pTNM stage can be used to construct a nomogram model for diffuse/mixed type GC patients. [ABSTRACT FROM AUTHOR]

Background: Surgery combined with postoperative chemotherapy is an effective method for treating patients with gastric cancer (GC) in Asia. The important roles of systemic inflammatory response in chemotherapy have been gradually verified. The purpose of this study was to assess the difference in clinical effectiveness of FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine), and the prognostic value of postoperative platelet–lymphocyte ratio (PLR) in the XELOX group. Methods: Patients who received radical gastrectomy combined with postoperative chemotherapy between 2004 and 2014 were consecutively selected into the FOLFOX and XELOX groups. Group bias was reduced through propensity score matching, which resulted in 278 patients in each group. Cut-off values of systemic immune inflammation (SII) score and PLR were obtained by receiver operating characteristic curve. Kaplan–Meier and Log-rank tests were used to analyze overall survival. The chi-square test was used to analyze the association between clinical characteristics and inflammatory indexes. Univariate and multivariate analyses based on Cox regression analysis showed independent risk factors for prognosis. The nomogram was made by R studio. Results: Patients receiving XELOX postoperative chemotherapy had better survival than those receiving FOLFOX (P < 0.001), especially for stage III GC (P = 0.002). Preoperative SII was an independent risk factor for prognosis in the FOLFOX group, and PLR of the second postoperative chemotherapy regimen in the XELOX group, combined with tumor size and pTNM stage, could construct a nomogram for evaluating recurrence and prognosis. Conclusion: XELOX is better than FOLFOX for treatment of GC in Chinese patients, and a nomogram constructed by PLR, tumor size and pTNM stage can predict recurrence and prognosis. [ABSTRACT FROM AUTHOR]

Purpose. This study is aimed at evaluating the clinicopathological features and prognostic significance of gastric outlet obstruction (GOO) in patients with distal gastric cancer. Methods. A retrospective review of 1564 individuals with distal gastric cancer from 2002 to 2010 was performed. In total, 157 patients had GOO. The clinicopathological features of the patients with GOO were compared with those of the patients without GOO. A Kaplan-Meier survival analysis and Cox proportional hazard model were used to assess the overall survival. Results. The patients with distal gastric cancer with GOO generally presented more aggressive pathologic features, a poorer nutritional status, more duodenal infiltration, and peritoneal dissemination than those with cancer without GOO. In the univariate analysis, curability, GOO, age, prealbumin, albumin, hemoglobin (Hb), the tumor size, the macroscopic type, lymph node metastasis, and the depth of invasion had a statistically significant influence on prognosis. The multivariate analysis showed that curability, GOO, the tumor size, lymph node metastasis, and the depth of invasion were independent prognostic factors. Conclusions. Gastric cancer with GOO exhibits aggressive biological features and has poor outcomes. The multivariate analysis showed that curability, GOO, the tumor size, lymph node metastasis, and the depth of invasion were independent prognostic factors. The gastric outlet status should be considered in the selection of surgical treatment methods for patients with gastric cancer. [ABSTRACT FROM AUTHOR]

The neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are markers of systemic inflammation. However, there is little evidence of the value of inflammation in the early diagnosis of gastric cancer (GC). A total of 2,606 patients diagnosed with GC in the past three years and 3,219 healthy controls over the same period were included in this study. Peripheral blood samples were obtained to analyze the NLR, PLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). The optimal cutoff levels for the NLR and PLR were defined by receiver operating characteristic (ROC) curve analysis (NLR = 2.258, PLR = 147.368). The value of different biomarkers for diagnosing GC was compared by the area under the curve (AUC). The NLR and PLR showed diagnostic sensitivity in GC (AUC = 0.715, AUC = 0.707). Using the Bonferroni correction, the NLR and PLR were superior to CEA and CA19-9 in the diagnosis of GC (P < 0.0001). The systemic inflammatory markers were significantly higher in the early stage of GC than tumor markers. After grouping patients and healthy controls by gender, we found that the diagnostic significance of combined NLR and PLR for GC was greater in male patients than in female patients (P < 0.0001). The diagnostic value of the NLR and PLR in GC is higher than that of the traditional tumor markers CEA and CA19-9. Systemic markers of inflammation are more valuable in male than female patients. [ABSTRACT FROM AUTHOR]

Introduction: The exfoliation of exfoliative cells from gastric serosa into the peritoneum is the main cause of peritoneal metastasis, which is the most common form of postoperative recurrence in gastric cancer. This study investigates the effects of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) on the biological properties of gastric cancer cells.Material and Methods: mRNA expression of VEGF and EGF in gastric cancer tissues from 80 patients suffering from serosa-infiltrated gastric cancer (T3) was examined. The differences of proliferation, movement, adhesion and invasion among 4 gastric cancer cell lines were analysed. The mRNA expression of EGF, EGFR, VEGF and VEGFR in the gastric cancer cell lines was examined before and after adding endostatin (Endostar) or cetuximab (Erbitux) to observe changes of gastric cancer cells.Results: mRNA levels of EGF and VEGF in positive exfoliative cytology cases were significantly higher than negative cases (p < 0.05). The biological properties were reduced sequentially in MGC803, HGC27, BGC823 and SGC7901 (p < 0.05). The mRNA expression of EGF, EGFR, VEGF and VEGFR was the strongest in MGC803, but was attenuated significantly after treatment (p < 0.05).Conclusions: Lower survival was related to positive exfoliative cytology, lymphatic node metastasis, serosa-infiltrated and poorly differentiated gastric cancer. The expression of VEGF and EGF was correlated with the properties of gastric cancer cells. Specific inhibition of VEGF and EGF may impair the biological properties of gastric cancer cells in vitro. [ABSTRACT FROM AUTHOR]

Annexin A2 (ANXA2) has been well known to associate with the progress of malignant tumor. However, the biological behavior of ANXA2 in gastric cancer (GC) remains unclear. We made a hypothesis in transcriptome level from TCGA datasets. Then, we used immunohistochemical staining to quantify the expression level of ANXA2 protein in GC tissues compared with adjacent tissues. Quantitative real-time PCR and western blot were used for analyzing ANXA2 expression in human GC (SGC-7901, MKN-45, BGC-823, and AGS) cell lines. We investigated the effect of a lentivirus-mediated knock-down of ANXA2 on the proliferation, invasion and migration of gastric cancer AGS cells. Cell proliferation was examined by MTT and colony formation tests. Cell apoptosis and cycle were measured by flow cytometry. Migration and invasion were detected by transwell assay. We found that high expression of ANXA2 can increase the mobility of cancer cells from TCGA datasets. ANXA2 was upregulated in GC tissues compared with adjacent tissues. AGS cell line displayed significantly higher expression of ANXA2 among the four GC cell lines. In addition, ANXA2 silencing led to a weakened ability of proliferation, invasion, and migration in GC cells; targeting of ANXA2 may be a potential therapeutic strategy for GC patients. [ABSTRACT FROM AUTHOR]

Purpose: Systemic Inflammation Response Index (SIRI), based on peripheral neutrophil, monocyte, and lymphocyte counts, was recently developed and used as a marker to predict the survival of patients with malignant tumours. Cancer stem cells (CSCs) can contribute to gastric cancer progression and recurrence. It is not clear whether SIRI is associated with CSCs during gastric cancer development. Methods: The SIRI was developed in a training cohort of 455 gastric cancer patients undergoing curative resection between 2007 and 2009, and validated in a validation cohort of 327 patients from 2010 to 2011. CD44 + CSCs were measured on tumour sections by immunohistochemical analysis. Results: An optimal cut-off point for the SIRI of 0.82 divided the gastric cancer patients into a low SIRI group (SIRI < 0.82) and a high SIRI group (SIRI ≥ 0.82) in the training cohort. Compared with patients who had a SIRI < 0.82, patients who had a SIRI ≥ 0.82 had a shorter disease-free survival (DFS) (HR 2.529; 95% CI 1.922-3.326; p < 0.001) and shorter disease-special survival (DSS) (HR 2.692; 95% CI 2.022-3.585; p < 0.001) in the training cohort, comparable DFS and DSS findings were observed in the validation cohort, even for patients in pathological TNM stage of I subgroup. A SIRI ≥ 0.82 was significantly associated with older age, larger tumour, higher pathological TNM stage, lymphovascular invasion, and perineural invasion. Additionally, patients in the low SIRI group were prone to DFS and DSS benefits from postoperative adjuvant chemotherapy. Univariate and multivariate analyses revealed that SIRI was an independent predictor for DFS and DSS. Furthermore, gastric cancer patients with CD44 + CSCs scores had higher SIRI level (mean 1.198 vs. 0.835; p < 0.001). In patients with CD44 + CSCs, those with SIRI ≥ 0.82 had higher recurrence rates and shorter survival time than patients with SIRI < 0. 82. Conclusions: SIRI was a useful prognostic indicator of poor outcomes in patients with gastric cancer and is a promising tool for gastric cancer treatment strategy decisions. The dismal outcomes in patients with high SIRI might be related to CSCs. [ABSTRACT FROM AUTHOR]

• High-dose DB specifically decreased CircRNA CDR1as levels in gastric cancer cells instead of hepatocytes. • Low-dose DB has little effects on cell viability of both gastric cancer cells and hepatocytes. • Downregulation of CircRNA CDR1as specifically triggered low-dose DB induced gastric cancer cell death. • MiR-7-5p/REGγ axis was the downstream target of CircRNA CDR1as. Diosbulbin-B (DB) was the main compound of Dioscorea bulbifera L , which was widely used for cancer treatment in Asia. However, the hepatotoxicity induced by high-dose DB seriously limited its possibility using for gastric cancer (GC) treatment in clinic. In this study, we found that DB inhibited GC cells and hepatocytes cell viability in a dose- and time-dependent manner. Specifically, high-dose DB (50μM) significantly inhibited cell proliferation and promoted cell apoptosis, while low dose DB (12.5μM) had little effects on cell viability. Besides, high-dose DB (50μM) significantly decreased CircRNA CDR1as levels in gastric cancer cells instead of hepatocytes. Notably, knock-down of CircRNA CDR1as triggered low-dose DB (12.5μM) induced GC cell death, but had little effects on hepatocytes proliferation and apoptosis. Further results showed that CircRNA CDR1as increased REGγ expressions in GC cells by sponging miR-7-5p, and high-dose DB (50μM) increased miR-7-5p levels and inhibited REGγ expressions in GC cells instead of hepatocytes. In addition, either downregulated miR-7-5p or overexpressed REGγ reversed the promoting effects of downregulated CircRNA CDR1as on low-dose DB-induced GC cell death. Taken together, we concluded that knock-down of CircRNA CDR1as specifically promoted the cytotoxic effects of low-dose DB on GC cells instead of hepatocytes by regulating miR-7-5p/REGγ axis. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the clinical effects and survival prognosis of radical gastrectomy assisted by external vision in gastric cancer. Methods. A total of 60 hospitalized gastric cancer patients from June 2016 to December 2018 were selected and divided into the observation group and control group according to different surgical procedures. The control group was treated with traditional open radical gastrectomy, while the observation group was treated with radical gastrectomy assisted by an external vision microscope. Relevant surgical indicators, visual analogue scale (VAS), postoperative complications, and life quality assessment were analyzed and compared between the two groups. Results. The incision length and intraoperative blood loss in the observation group were smaller than those in the control group, and the difference was statistically significant (P < 0.05); compared with the control group, the observation group had significantly shorter hospital stay, earlier postoperative first exhaust time, and lower gastric fluid volume at the 3rd day after surgery (P < 0.05). The pain scores of the observation group at 1, 4, and 12 weeks after surgery were lower than those of the control group (P < 0.05), and the difference was significant. The quality of life scores at the 1st week and 12th week after surgery showed that the dysphagia symptom scores of the observation group and the control group were significantly reduced but the two groups had significant differences in fatigue, physical function, pain score, postoperative pain, and overall quality of life. The observation group was significantly better than the control group (P < 0.05). Follow-up studies showed no significant difference between mortality and cancer recurrence (P > 0.05); the patients recovered well at postoperation, and the diet of the observation group was better than that of the control group (P < 0.05); gastric reflux and knife pain were less than those of the control group (P < 0.05). Conclusion. Radical gastrectomy assisted by external vision for gastric cancer yields clinical benefits for gastric cancer patients, which not only dramatically shortened the length of hospital stay but also effectively ameliorated the quality of life of patients, all indicating that external vision-assisted surgery was significantly better than traditional gastrectomy in improving the postoperative quality of life of gastric cancer patients in the absence of increasing the risk of adverse events. [ABSTRACT FROM AUTHOR]

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Purpose: Epithelial to mesenchymal transition (EMT) can contribute to gastric cancer (GC) progression and recurrence following therapy. Tumor-associated neutrophils (TANs) are associated with poor outcomes in a variety of cancers. However, it is not clear whether TANs interact with the EMT process during GC development. Methods: Immunohistochemistry was performed to examine the distribution and levels of CD66 + neutrophils in samples from 327 patients with GC. CD66b + TANs were isolated either directly from GC cell suspensions or were conditioned from healthy donor peripheral blood polymorphonuclear neutrophils (PMNs) stimulated with tumor tissue culture supernatants (TTCS) and placed into co-culture with MKN45 or MKN74 cells, after which migration, invasion and EMT were measured. Interleukin-17a (IL-17a) was blocked with a polyclonal antibody, and the STAT3 pathway was blocked with the specific inhibitor AG490. Results: Neutrophils were widely distributed in gastric tissues of patients with GC and were enriched predominantly at the invasion margin. Neutrophil levels at the invasion margin were an independent predictor of poor disease-free survival (DFS) and disease-specific survival (DSS). IL-17a + neutrophils constituted a large portion of IL-17a-producing cells in GC, and IL-17a was produced at the highest levels in co-culture compared with that in TANs not undergoing co-culture. TANs enhanced the migration, invasion and EMT of GC cells through the secretion of IL-17a, which activated the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in GC cells, while deprivation of IL-17a using a neutralizing antibody or inhibition of the JAK2/STAT3 pathway with AG490 markedly reversed these TAN-induced phenotypes in GC cells induced by TANs. Conclusions: Neutrophils correlate with tumor stage and predict poor prognosis in GC. TANs produce IL-17a, which promotes EMT of GC cells through JAK2/STAT3 signalling. Blockade of IL-17a signalling with a neutralizing antibody inhibits TAN-stimulated activity in GC cells. Therefore, IL-17a-targeted therapy might be used to treat patients with GC. [ABSTRACT FROM AUTHOR]