OS In Gastric Cancer Patients Research Articles

Meta-Analysis of Efficacy and Safety of Karelizumab Combined with Apatinib in the Treatment of Advanced Gastric Cancer.

Objective To systematically evaluate the clinical efficacy and safety of karelizumab combined with apatinib in the treatment of advanced gastric cancer. Methods The published databases were searched by computer, Chinese: China Biomedical Literature Database (CBM), Wanfang Journal Database, China national knowledge infrastructure (CNKI), and China Science and Technology Journal Database (VIP); English: Embase, Cochrane library, and PubMed. The search time is from the establishment of the database to May 2022, and clinical randomized controlled trials (RCT) with advanced gastric cancer as the research object and karelizumab combined with apatinib as the research variables are collected. According to the bias risk evaluation standard of Cochrane System Evaluator's Manual, the literatures meeting the inclusion standard were evaluated for bias risk, and the meta-analysis was conducted by Review Manager 5.3. Results. A total of 20 articles with 1150 patients were included in this study. All the included 20 articles reported objective remission rate (ORR), and the heterogeneity among 20 studies was low (P > 0.05, I2 = 0%). The ORR of gastric cancer patients in the observation group was significantly higher than that in the blank group [odds ratio (OR) = 1.97, 95% CI [1.53, 2.62], P < 0.01). All the included 20 articles reported disease control rate (DCR), and the heterogeneity among 20 studies was low (P = 0.87, I2 = 0%). The ORR of gastric cancer patients in the observation group was significantly higher than that in the blank group (OR = 3.09, 95% CI [2.29, 4.16], P < 0.01). Three articles in the included literature reported the median OS, and the heterogeneity among the three studies was low (P = 0.70, I2 = 0%). The median OS of gastric cancer patients in the observation group was significantly higher than that in the blank group (MD = 3.97, 95% CI [3.61, 4.39], P < 0.01). There are three reports on median progression-free survival (PFS) in the included literature, and there is high homogeneity among the three studies (P < 0.00001, I2 = 86%). There is no statistical difference between the median PFS of gastric cancer patients in the observation group and the blank group (MD = 1.21, 95% CI [−1.20, 3.70], P = 0.29). The incidence of hypertension in the observation group was significantly higher than that in the blank group [OR = 6.19, 95% CI (1.91, 20.20), P = 0.003]. The incidence of proteinuria in the observation group was significantly higher than that in the blank group [OR = 3.97, 95% CI (1.08, 14.59), P = 0.03]. There was no significant difference in the incidence of other adverse reactions such as hand-foot syndrome, diarrhea, and myelosuppression between the observation group and the blank group. The levels of IFN-γ and TNF-α in the observation group were significantly higher than those in the blank group (P < 0.0001). The levels of IL-10, IL-4, and tumor markers in the observation group were significantly lower than those in the blank group (P < 0.05). Egger's test showed that there was no publication bias in the 20 included studies (P > 0.05). Conclusion Karelizumab combined with apatinib is effective in the treatment of advanced gastric cancer, with low incidence of adverse reactions and high safety. However, a large number of multicenter, large sample size, and high-level RCT are needed for clinical verification.

Identification and Validation of a Pyroptosis-Related Prognostic Model for Gastric Cancer.

Pyroptosis is an inflammatory form of programmed cell death triggered by caspase-1/4/5/11 that plays an important role in the occurrence and development of gastric cancer (GC). We investigated the prognostic value of pyroptosis-related genes in GC. The “LIMMA” R package and univariate Cox analysis were used to find pyroptosis-related genes with differential expression and prognostic value in the TCGA cohort and the identified genes were analyzed for GO enrichment and KEGG pathways. The selected genes were then included in a multivariate Cox proportional hazard regression analysis, and a ten genes prognostic model (BIRC2, CD274, IRGM, ANXA2, GBP5, TXNIP, POP1, GBP1, DHX9, and TLR2) was established. To evaluate the predictive value of the risk score on prognosis, patients were divided into high-risk and low-risk groups according to the median risk score, and survival analysis was carried out. Compared with the low-risk group, the OS of GC patients in the high-risk group was significantly worse. Additionally, these results were verified in the GSE84437 and GSE66229 datasets. Finally, through the combination of prognostic gene characteristics and clinicopathological features, a nomogram was established to predict individual survival probability. The results show that the genetic risk characteristics related to clinical features can be used as independent prognostic indicators for patients with GC. In summary, the pyroptosis-related risk signals proposed in this study can potentially predict the prognosis of patients with GC. In addition, we also found significant infiltration of dendritic cells, macrophages, and neutrophils in tissues of high-risk patients.

Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer

Gastric cancer (GC) has a great fatality rate, meanwhile, there is still a lack of available biomarkers for prognosis. The goal of the research was to discover key and novel potential biomarkers for GC. We screened for the expression of significantly altered genes based on survival rates from two consensus molecular subtypes (CMS) of GC. Subsequently, functional enrichment analysis showed these genes involved in many cancers. And we picked 6 hub genes that could both secreted in the tumor microenvironment and expression enhanced in immune cells. Then, Kaplan Meier survival and expression detected in the tumor pathological stage were utilized to clarify the prognostic of these 6 hub genes. The results indicated that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1, respectively, were significantly associated with poor OS in GC patients. And their expression increased with cancer advanced. Moreover, immune infiltration analysis displayed that those hub genes expression positively with M2 macrophage, CD8+ T Cell, most immune inhibitors, and majority immunostimulators. In summary, our results suggested that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1 were all potential biomarkers for GC prognosis and might also be potential therapeutic targets for GC.

Evaluation of the prognostic value of CBXs in gastric cancer patients

Chromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.

Expression and prognostic significance of thrombospondin gene family in gastric cancer.

Thrombospondins (THBSs) are glycoproteins expressed in the extracellular matrix (ECM) and have critical roles in tumor development and metastasis. However, the diverse expression patterns and prognostic roles of distinct THBS genes in gastric cancer have not been fully elucidated. In the current study, we aimed to investigate the expression patterns of THBSs in gastric cancer (GC) and determine whether they are prognostic markers for this malignancy. mRNA expression status and genetic mutations of THBS family members were performed by using ONCOMINE, UCSC Xena browser, GEPIA, and cBioPortal databases. Prognostic values and function enrichment analysis of the members were assessed via Kaplan-Meier plotter and Metascape. we found that the mRNA expression of THBS1, THBS2, THBS4, and COMP were higher in patients with GC tissues than those in normal gastric mucosa and there was no difference in the mRNA expression of THBS3 between GC and normal tissue. Survival analysis revealed that mRNA levels of THBSs were strongly related to worse OS in GC patients (P<0.05). Overexpression of THBSs indicated poor OS in stage III/IV GC and high expression of THBS1, THBS3, THBS4, and COMP were related to worse OS in stage II GC. Bioinformatics analysis revealed a better understanding the value of THBS family members in GC and suggest that THBSs might serve as potential prognostic biomarkers for GC.

An Immune Cell Signature Is Associated With Disease-Free Survival and Adjuvant Chemosensitivity of Patients With Resectable Gastric Cancer.

Increasing evidence has indicated that current tumor-node-metastasis (TNM) stage alone cannot predict prognosis and adjuvant chemotherapy benefits accurately for stages II and III gastric cancer (GC) patients after surgery. In order to improve the predictive ability of survival and adjuvant chemotherapy benefits of GC patients after surgery, this study aimed to establish an immune signature based on the composition of infiltrating immune cells. Twenty-eight types of immune cell fractions were evaluated based on the expression profiles of GC patients from the Gene Expression Omnibus (GEO) database using single-sample gene set enrichment analysis (ssGSEA). The immunoscore (IS) was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression model. Through the LASSO model, an IS classifier consisting of eight immune cells was constructed. Significant difference was found between high-IS and low-IS groups in the training cohort in disease-free survival (DFS, P < 0.0001) and overall survival (OS, P < 0.0001). Multivariate analysis showed that the IS classifier was an independent prognostic indicator. Moreover, a combination of IS and TNM stage exhibited better prognostic value than TNM stage alone. Further analysis demonstrated that low-IS patients who had more tumor-infiltrating lymphocytes had better response to adjuvant chemotherapy. More importantly, we found that patients with high-IS were more likely to benefit from a Xeloda plus cisplatin regimen after surgery. Finally, we established two nomograms to screen the stage II and III GC patients who benefitted from adjuvant chemotherapy after surgery. The combination of IS classifier and TNM stage could predict DFS and OS of GC patients. The IS model has been proven as a promising tool that can be used to identify the patients with stages II and III GC who may benefit from adjuvant chemotherapy.

Integrative analysis of epigenomics, transcriptomics, and proteomics to identify key targets and pathways of Weining granule for gastric cancer

Ethnopharmacological relevanceWeining granule (WNG) is a “Qi-Enriching and Kidney-Tonifying, Spleen-Reinforcing and Stasis-Removing” formula for gastric cancer (GC). Past research we noted WNG inhibited cell growth and raised apoptosis in GC. However, the underlying mechanism of WNG for GC have yet to be systematically clarified. Aim of the studyWe sought to characterize the molecular landscape of GC cells in vitro after WNG treated, to identify the molecular targets and pathways that were associated with WNG for inducing the apoptosis of GC cells, and further to clarify underlying molecular mechanism of WNG for GC. Materials and methodsWe performed the techniques of RNA sequencing, tandem mass tags (TMT) based quantitative proteomics, and reduced representation bisulfite sequencing (RRBS) in WNG-treated/or untreated SGC-7901 GC cells to gain a comprehensive molecular portrait of WNG treatment. Then we integrated methylomics, transcriptomics, and proteomics data to carry out the bioinformatics analysis, and constructed the protein-protein interaction (PPI) network to identify molecular targets, and to discover the underlying signaling pathways associated with WNG for GC by network analysis. Besides, we verified the candidate target genes by Kaplan–Meier plotter database. ResultsWe identified 1249 significant differentially expressed genes (DEGs) from RNA expression datasets, 191 significant differentially abunabundant proteins (DAPs) from proteomics datasets, and 8293 significant differentially methylated regions (DMRs) from DNA methylation datasets. GO and KEGG analysis showed DEGs, DAPs, and DMRs enriched in the cancer-related biological processes of calcium signaling pathway, pathways in cancer, metabolic pathways, MAPK signaling pathway, PI3K-Akt signaling pathway, and transcriptional misregulation in cancer. We integrated three profile datasets and performed network analysis to distinguish the hub genes, and finally the genes of SOD2, HMOX1, MMP1, SRXN1, NOTCH1, MAPK14, TXNIP, VEGFA, POLR2F, and HSPA9 were identified. The Kaplan–Meier plotter confirmed that SOD2, MMP1, SRXN1, NOTCH1, MAPK14, TXNIP, VEGFA, and HSPA9 were significantly correlated with OS in GC patients (P < 0.01), while HMOX1 and POLR2F expression were not significantly relevant to survival of GC patients (P > 0.01). ConclusionsSOD2, MMP1, SRXN1, NOTCH1, MAPK14, TXNIP, VEGFA, and HSPA9 were the predictive pharmaceutical targets of WNG for GC. The anticancer function of WNG was significantly associated with the pathways of focal adhesion pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and Wnt signaling pathway.

Abstract 3361: Discovery and preclinical characterizations of a humanized anti-claudin 18.2 antibody SPX-101

Abstract Claudin 18.2 (CLDN 18.2) is a major component of the tight junctions and is highly expressed in several cancers including gastric (80%), esophageal (80%), pancreatic (60%) and lung cancers, but only expressed at very low levels in healthy tissues. The chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. This research aimed to produce humanized anti-claudin18.2 antibodies with enhanced activities and improved pharmaceutical characteristics compared to known CLDN 18.2 antibodies. We used several immunization methods to produce mouse anti-CLDN18.2 antibodies with high affinity and excellent selectivity against CLDN 18.1. Humanization of a selected clone led to a humanized anti-CLDN18.2 antibody (h533o) with significantly improved binding affinity and cellular activity in ADCC and CDC assays compared to zolbetuximab. The binding affinity of h533o was relatively insensitive to elevated temperatures or acidity, suggesting the robustness of target engaging ability in tumor microenvironment. Maturation and selection by the off-rate approach, using phage libraries that systematically modified the CDR regions, identified multiple antibodies with comparable affinity and selectivity. Mutational scan of the Fc region in h533o identified SPX-101 with reduced ADA effect in mice while retaining other favorable properties. SPX-101 suppressed tumor growth in several xenograft mouse models including NUGC4 and HEK293 cells that stably expressed CLDN18.2. In summary, SPX-101 represents a humanized anti-CLDN18.2 antibody with high affinity and specificity, high effector cell-mediated cytotoxicity, low immunogenicity, and in vivo tumor control efficacy in xenograft rodent models. Citation Format: Guidong Zhu, Jichun Ma, Jingdong Ye, Jingdong Qin, Yi Cai. Discovery and preclinical characterizations of a humanized anti-claudin 18.2 antibody SPX-101 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3361.

Abstract 534: Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format

Abstract This research aimed to produce anti-claudin18.2 (CLDN 18.2)/anti-PD-L1 bispecific antibodies to enhance the therapeutic index and expand the responsive population of the parent anti-CLDN 18.2 and anti-PD-L1 antibodies through the mechanisms of tumor-specific distribution and synergistic tumor killing. CLDN 18.2 is highly expressed in several tumors but is minimally expressed in normal tissues and a chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. However, the response rate was moderate (~10%), leaving room for further improvement. Anti-PD-L1 antibodies showed remarkable efficacy in lung cancer and melanoma but in various settings of gastric cancer they showed weaker benefits, which warrant optimization. We designed anti-claudin18.2/anti-PD-L1 bispecific antibodies in the SMARTOPTM format, where a single-chain diabody containing optimized CLDN 18.2 and PD-L1 binding variable domains is connected to the Fc domain by linkers that can be optimized by phage display libraries. The bispecific antibodies were selected by affinity at low pH values and slow off-rate to improve the therapeutic window by enhancing tumor retention and preserving or improving binding affinity in the low pH tumor microenvironment. Immunogenicity was optimized by mutating the surface residues and disulfide bonds were inserted to improve stability. A representative bispecific antibody SPX-301 showed comparable binding affinity to the CLDN 18.2 and PD-L1 antigens to the parent antibodies (SPX-101 and durvalumab, respectively). SPX-301 represents a novel anti-claudin18.2/anti-PD-L1 bispecific antibody in the SMARTOPTM format. The format demonstrated excellence retention of antigen binding affinity, high expression levels, minimal aggregation, and straightforward purification. The preclinical characterizations of SPX-301 will also be presented. Citation Format: Guidong Zhu, Jingdong Ye, Jichun Ma, Jingdong Qin, Yi Cai. Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 534.

High Level of Legumain Was Correlated With Worse Prognosis and Peritoneal Metastasis in Gastric Cancer Patients.

Background: Accumulating evidence has demonstrated that legumain (LGMN) is abnormally expressed in several malignancies and functions as an oncogene. However, the association between LGMN and gastric cancer (GC) has not yet been fully elucidated. In this study, we performed a comprehensive analysis of the role of LGMN in clinicopathologic characteristics and survival of GC patients.Methods: The study had two patient cohorts, The Cancer Genome Atlas (TCGA) cohort and the Zhongshan Hospital cohort, both of which were used to analyze the role of LGMN in GC samples. The relationship between LGMN and clinicopathologic characteristics was determined by the Chi-square test and logistic regression analysis. The Kaplan–Meier method and Cox proportional hazards regression analysis were conducted to investigate the prognostic role of LGMN in GC patients. Moreover, a nomogram was constructed based on the factors that were independently associated with peritoneal metastasis. Finally, the gene set enrichment analysis (GSEA) was conducted to explore the underlying pathways through which LGMN was involved in GC progression.Results: The mRNA and protein levels of LGMN were significantly upregulated in GC tissues, especially for diffuse-type GC. High level of LGMN was independently associated with poor prognosis in both TCGA and Zhongshan cohorts. Further analysis showed that increased protein level of LGMN was related to peritoneal metastasis in GC patients. In a nomogram model, the LGMN expression could help predict the possibility of peritoneal metastasis in GC patients. LGMN was a strong determinant for prediction of peritoneal metastasis. GC patients with high LGMN expression tended to have worse survival together with more frequent diffuse-type tumors and increased risk of peritoneal metastasis. The GSEA results showed that focal adhesion, ecm receptor interaction, cell adhesion molecules cams, TGF-β signaling pathway, JAK-STAT signaling pathway, gap junction, etc. were differentially enriched in the phenotype with high LGMN expression.Conclusion: LGMN was an independent prognostic factor for OS in GC patients. Increased expression of LGMN was significantly associated with peritoneal metastasis. The nomogram based on LGMN might guide the clinical decisions for patients with GC.

Glutathione Peroxidase 8 as a Prognostic Biomarker of Gastric Cancer: An Analysis of The Cancer Genome Atlas (TCGA) Data.

BackgroundGlutathione peroxidase 8 (GPX8) has previously been shown to play a role in Keshan disease. In the present study, we explored the prognostic relevance of GPX8 expression in patients with gastric cancer (GC) based upon The Cancer Genome Atlas (TCGA) data.Material/MethodsWe assessed the relationship between the expression of GPX8 and clinicopathological findings in GC patients via logistic regression analyses, Kruskal-Wallis tests, and Wilcoxon signed-rank tests. We further assessed the prognostic relevance of specific variables using Kaplan-Meier and Cox regression analyses. We lastly conducted gene set enrichment analyses (GSEA).ResultsWe detected a significant association between elevated GPX8 levels and more advanced GC tumor stage (OR=5.92 for I vs. IV), as well as more advanced T (OR=22.91 for T1 vs. T4) and N classification (OR=1.82 for N0 vs. N3). We found worse prognosis in patients expressing high levels of GPX8 relative to those with lower expression of this gene (P=0.021). In a univariate analysis, we found high GPX8 expression was strongly correlated with worse OS (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.01–1.08; P=0.018), and multivariate analysis confirmed that GPX8 expression independently predicts GC patient OS (HR: 1.04; CI: 1.00–1.08, P=0.041). GSEA revealed that elevated GPX8 expression was associated with enrichment of pathways consistent with MAPK signaling, JAK/STAT signaling, TGF-β signaling, melanoma, and basal cell carcinoma.ConclusionsThe expression of GPX8 may have prognostic relevance, being positively associated with worse OS in GC patients.

Prognostic value of modified Glasgow Prognostic Score (mGPS) and neutrophil-lymphocyte ration (NLR) after curative resection for gastric cancer.

295 Background: Several biomarkers based on serum chemistry have been reported to be associated with the prognosis of several types of cancers. This retrospective study aimed to investigate the prognostic value of preoperative mGPS and NLR after curative resection for gastric cancer. Methods: A total of 295 patients who underwent curative gastrectomy for primary gastric cancer at our institution from January 2013 to December 2017 were enrolled in this study. The mGPS was calculated by CRP and Alb using standard thresholds ( &gt; 0.5 mg/dL for CRP and &lt; 3.5 g/dL for Alb). The NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. The survival curves of patients stratified by each parameter were plotted by the Kaplan-Meier method and compared by log-rank test. Multivariate Cox proportional hazards regression models were used to select parameters independently correlated with prognosis. Results: The median follow-up time was 36.7 months, and 29 patients died during follow-up. The estimated 5-year survival rate was 83.1%. Results from the univariate analyses showed mGPS2 (CRP &gt; 0.5 mg/dL and Alb &lt; 3.5 g/dL) was associated with poor survival while NLR and NLRc was not (P &lt; 0.001, P = 0.506, and P = 0.423, respectively). In the multivariate analyses, the mGPS2 was identified as an independent predictive factor for OS in gastric cancer patients after curative resection (HR: 2.624; 95% CI: 1.058-6.505; P = 0.037). Conclusions: Preoperative mGPS2 was associated with worse survival after curative resection of gastric cancer patients. Based on our study, those with mPGS2 may be warranted to receive additional therapy or nutritional support to acquire better survival.

Neutrophil-Lymphocyte Ratio is a Predictor of Venous Thromboembolism in Gastric Cancer Patients

The neutrophil-lymphocyte ratio (NLR) reflects inflammatory status. An elevated NLR has been reported to be a prognostic indicator in some malignant tumors. The aim of this study was to determine whether NLR at the time of venous thromboembolism (VTE) diagnosis is a prognostic factor for the response to anticoagulation and survival in gastric cancer patients treated with anticoagulation for VTE. We retrospectively enrolled 73 gastric cancer patients newly diagnosed with VTE, from among 597 patients pathologically confirmed for gastric cancer between January 2008 and December 2013. Univariate and multivariate analyses were performed to identify clinicopathological predictors in respect to the response to anticoagulation and overall survival. Compared with the low NLR group, patients with high NLR presented more frequently with advanced tumor stage (p = 0.046) and deeper tumor depth (p = 0.033). Patients with poor histology differentiation (p = 0.045), high NLR (p = 0.001), and low albumin (p = 0.016) were statistically correlated with the poor response to anticoagulation. Multivariate analysis revealed that a high level of NLR (hazard ratio, 1.56, 95% CI: 1.32 - 1.87, p = 0.032) and advance cancer stage (hazard ratio, 2.11, 95% CI: 1.29 - 3.44, p = 0.043) were independent poor prognostic factors for OS in gastric cancer patients with VTE. The results demonstrated that the NLR at the time of VTE diagnosis could be a useful biomarker for predicting the response to anticoagulation and survival in gastric cancer patients with VTE.

Association between promoter methylation and protein expression of tumor suppressor genes with clinical characteristics in gastric carcinoma and its effect on the biological function of gastric cancer.

e15509 Background: Studies showed that the gene promoter methylation may be the third important mechanisms of gene expression regulation. Abnormal methylation of tumor suppressor gene can be detected in the early stage of tumor, by screening the methylation profile of gastric cancer (GC), it can provide theoretical and experimental evidence for early diagnosis, treatment and prognosis. Methods: Detecte p16, hMLH1 and CDH1 promoter methylation, the p16, hMLH1 and E-cadher expression in GC tissues and its correlation with clinicopathological features and prognosis. Detect methylation of hMLH1 promoter and mRNA expression in GC cell line and normal gastric mucosa cell line. Clone formation assay and Transwell test. Results: The methylation of hMLH1 and CDH1 in GC and adjacent tissues were statistically significant . The methylation of hMLH1 was related to alcohol , CA199 level and Borrman. The methylation of CDH1 was related to the CEA level. The methylation of hMLH1 promoter is related to OS in GC patients. The methylation of p16 and CDH1 was not related to the OS ofGC patients. The GC patients with 0 or 1 gene methylation had a better prognosis than those with 3 or 2 gene methylation. The p16, hMLH1 and E-cadherin protein expression in GC and adjacent tissues were statistically significant. The p16 protein expression was related to tumor size. The hMLH1 protein expression was related to the CA199 level and tumor size. The E-cadherin expression in GC patients with drinking history was lower than ones without drinking history. The p16, hMLH1 and E-cadherin protein expression was not related to the OS of GC patients. There was a negative correlation between hMLH1 gene methylation and its protein expression in GC. The number of clones in the control group and the experimental group were 180 ± 3 and 169 ± 6. The number of cells in the control group and the experimental group were 135 ± 4.08 and 125 ± 4.18. Conclusions: The methylation of multiple genes is associated with the prognosis, which can provide theoretical basis for accurate treatment and prognosis for GC patients.

Lectin-like oxidized low-density lipoprotein receptor-1 facilitates metastasis of gastric cancer through driving epithelial-mesenchymal transition and PI3K/Akt/GSK3\u03b2 activation

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern recognition receptor that plays a critical role in vascular diseases and host immune response. Recently, our research discovered that LOX-1 could facilitate the uptake of dying cells and cross-presentation of cellular antigen via binding with heat shock proteins, which have a close relationship with gastric neoplasia. Therefore, we speculated that LOX-1 may serve as an oncogene in gastric cancer (GC) development and progression. In this study, through immunohistochemistry staining assay and cancer-related databases, we found that LOX-1 expression was up-regulated in GC tissues and correlated with a poor prognosis in GC patients. The expression of LOX-1 was an independent prognostic factor for OS in GC patients, and the incorporation of LOX-1 with TNM stage is more accurate for predicting prognosis. Additionally, in vitro study by transwell assay and western blot analysis confirmed that LOX-1 could promote the migration and invasion of GC cells by driving epithelial-mesenchymal transition and PI3K/Akt/GSK3β activation. Taken together, we first explored the expression profiles, clinical significance and biological function of LOX-1 in GC, and these data suggest that LOX-1 may represent a promising prognostic biomarker for GC and offer a novel molecular target for GC therapies.

Diagnostic and Prognostic Value of Serum MicroRNA-206 in Patients with Gastric Cancer

Aims: Recent studies have demonstrated that microRNAs (miRNAs) can serve as useful biomarkers for human cancers. The aim of this study was to evaluate the expression level of serum miRNA-206 in patients with gastric cancer (GC) and investigate its diagnostic and prognostic value. Methods: Quantitative real-time PCR was performed to evaluate serum miRNA-206 levels in 150 GC patients and 150 healthy volunteers. The association between miRNA-206 expression and clinicopathological factors as well as patient's survival was analyzed. Receiver operator curve (ROC) analysis was carried out to assess the potential value of serum miRNA-206 for GC diagnosis. Results: Serum miRNA-206 was down-regulated in GC patients compared with healthy controls (P < 0.001). Decreased serum miRNA-206 expression was significantly associated with deep local invasion, positive lymph node metastasis, and advanced clinical stage. Serum miRNA-206 expression was found to be significantly up-regulated in paired post-operative samples and reduced in patients with GC recurrence. ROC curve analysis showed that serum miRNA-206 was a useful marker for GC diagnosis, and could discriminate between recurred and non-recurred patients. Multivariate Cox regression analysis confirmed low serum miRNA-206 expression as an independent unfavorable prognostic factor for both DFS and OS of GC patients. Conclusions: These results suggest that serum miRNA-206 might not only serve as a novel diagnostic biomarker for GC, but also predict cancer recurrence and patient's prognosis.

Prognostic Role of the Circulating Tumor Cells Detected by Cytological Methods in Gastric Cancer: A Meta-Analysis.

Objective. We performed a meta-analysis of available studies to assess the prognostic value of circulating tumor cells detected by cytological methods for patients with gastric cancer. Methods. Two authors systematically searched the studies independently with key words in PubMed, MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane Library (from inception to April 2016). The estimated hazard ratio, risk ratio, odds ratio, and their 95% confidence intervals were set as effect measures. All analyses were performed by STATA 12.0. Results. Sixteen studies were included in this meta-analysis. CTCs-high status was significantly associated with poor overall survival (HR = 2.23, 95% CI: 1.86–2.66) and progression-free survival (HR = 2.02, 95% CI: 1.36–2.99). CTCs-high status was also associated with depth of infiltration (OR = 2.07, 95% CI: 1.16–3.70), regional lymph nodes metastasis (OR = 1.85, 95% CI: 1.26–2.71), and distant metastasis (OR = 2.83, 95% CI: 1.77–4.52). For unresectable gastric cancer patients, CTCs-high status was significantly associated with poor overall survival, progression-free survival, and disease control rate before and during chemotherapy group. Conclusions. Our meta-analysis has evidenced the significant prognostic value of CTCs detected for both PFS and OS in gastric cancer patients. For patients treated with chemotherapy alone, we proved that CTCs detected by cytological method showed a significant prognostic value and poor response to chemotherapy.

Tumor volume as a prognostic factor was superior to the seventh edition of the pT classification in resectable gastric cancer

PurposeTo demonstrate that the seventh edition of the tumor-node-metastasis (TNM) classification for gastric cancer (GC) should be updated with the tumor volume (pTV) for the improvement of its prognostic prediction accuracy. MethodsA total of 497 stage TNM I–III GC patients who underwent curative gastrectomy between January 2003 and December 2007 in our center were enrolled in this study. pTV equals to (tumor diameter/2)2 × pT stage. ResultsIn the step 1 multivariate analysis, depth of invasion (pT) was confirmed to be an independent prognostic factors. However, when pTV was included in the step 2 multivariate analysis, pTV classification became significant, while pT classification disappeared. pT classification was substituted by pTV. For patients in each of the pT, significant differences in survival could always be observed among patients in different pTV classification. For patients in each pTV classification, prognosis was highly homologous between those in different pT classifications. TNM classification and the tumor volume-node-metastasis (TvNM) classification were directly compared for convenience. We found the TvNM classification (HR = 1.687, P < 0.001) was the most appropriately prognostic classification for predicting the OS of gastric cancer patients after curative surgery. ConclusionspTV maybe an independent prognostic factor in overall survival in GC, and pTV staging system maybe more reliable than the Union International Center Cancer and American Joint Committee (UICC/AJCC) on cancer pT system for prognostic assessment. pTV should be recommended as an important clinicopathologic variable for enhancement the accuracy of the prognostic prediction of GC patients in clinic.

The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta-analysis

The prognostic role of matrix metalloproteinase 2 (MMP-2) in gastric cancer remains controversial. We systematically reviewed the evidence for assessment of MMP-2 expression in gastric cancer to elucidate this issue. Pubmed, Embase and Web of Science were searched to identify eligible studies to evaluate the association of MMP-2 expression and overall survival and clinicopathological features of gastric cancer. MMP-2 overexpression was significantly correlated with poor OS of gastric cancer patients (HR 1.92, 95 % CI 1.48-2.48). Subgroup analysis indicated that MMP-2 overexpression had an unfavorable impact on OS in Asian countries (HR 2.23, 95 % CI 1.57-3.17) and European countries (HR 1.43, 95 % CI 1.13-1.80). Furthermore, MMP-2 overexpression was significantly associated with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95 % CI 1.64-2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95 % CI 1.63-4.12), lymph node metastasis (positive vs negative: OR 2.21, 95 % CI 1.69-2.88), and distant metastasis (positive vs negative: OR 4.44, 95 % CI 1.24-15.94). This meta-analysis indicated that MMP-2 overexpression might be a predictive factor for poor prognosis for gastric cancer.

P-0024 The Efficacy and Tolerability of Modified DCF in Patients with Advanced or Recurrent Gastric Cancer: A Retrospective Analysis

ABSTRACT Introduction Although docetaxel, cisplatin and 5FU (DCF) significantly has improved TTP, and OS in gastric cancer patients, the use of DCF has restricted because of severe toxicities. In real world, the dose of DCF has frequently modified according to clinician’s experiences and intuition. In this report, we introduce new modified DCF (mDCF) regimen and report efficacy and tolerability of mDCF in advanced or recurrent gastric cancer. Methods Total 24 patients with advanced or recurrent gastric cancer treated with mDCF at Seoul Paik Hospital between Mar 2007 and June 2010 were reviewed. Treatment protocol was 60mg/m2 of docetaxel, 50mg/m2 of cisplatin on D1, and 950mg/m2/day of 5FU continuous infusion on D1-3 until disease progression or intolerance to chemotherapy. All clinical data were collected retrospectively. Results Of 24, 22 patients were assessable for response. The ORR was 37.3 % (9/24), including 1 CR, and TCR 70.8 % (17/24). Median PFS and OS were 6.13 months (95% CI, 2.5-9.7) and 8.2 months (95% CI, 3.1-13.3). Grade 3 or 4 hematologic toxicities were neutropenia in 10 patients (41.7%), anemia in 3 patients (12.5%) and thrombocytopenia 4 patients (16.7%). The treatment related death occurred in 2 patients (8.3%) due to sepsis. The median cycle of chemotherapy was 6 (range: 1-15). Half of 24 patients (50%) received chemotherapy more than 8 cycles, and 2 patients (8.3%) received 15 cycles with tolerable toxicities. In this extended chemotherapy group, median PFS and OS were 10.9 months (95% CI, 4.4-17.3) and 14.1 months (95%CI, 6.7-21.5). Conclusion The presented mDCF showed favorable ORR, TCR, and acceptable toxicity profiles in patients with advanced gastric cancer. Chemotherapy with mDCF was safely used more than 8 cycles in patients who responded to mDCF. This extended mDCF could be an alternative choice after 4 or 6 cycles mDCF.