Indicator For Gastric Cancer Patients Research Articles

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer.

Disulfidptosis is a novel form of programmed cell death that unveils promising avenues for the exploration of tumor treatment modalities. Gastric cancer (GC) is a malignant tumor characterized by high incidence and mortality rate. However, there has been no systematic study of disulfidptosis-related long noncoding RNAs (DRLs) signature in GC patients. The lncRNA expression profiles containing 412 GC samples were acquired from the Cancer Genome Atlas (TCGA) database. Differential expression analysis was performed alongside Pearson correlation analysis to identify DRLs. Prognostically significant DRLs were further screened using univariate COX regression analysis. Subsequently, LASSO regression and multifactorial COX regression analyses were employed to establish a risk signature composed of DRLs that exhibit independent prognostic significance. The predictive value of this risk signature was further validated in a test cohort. The ESTIMATE, CIBERSORT and ssGSEA methodologies were utilized to investigate the tumor immune microenvironment of GC populations with different DRLs profiles. Finally, the correlation between DRLs and various GC drug responses was explored. We established a prognostic signature comprising 12 disulfidptosis-related lncRNAs (AC110491.1, AL355574.1, RHPN1-AS1, AOAH-IT1, AP001065.3, MEF2C-AS1, AC016394.2, LINC00705, LINC01952, PART1, TNFRSF10A-AS1, LINC01537). The Kaplan-Meier survival analysis revealed that patients in the high-risk group exhibited a poor prognosis. Both univariate and multivariate COX regression models demonstrated that the DRLs signature was an independent prognostic indicator in GC patients. Furthermore, the signature exhibited accurate predictions of survival at 1-, 3- and 5- years with the area under the curve (AUC) values of 0.708, 0.689 and 0.854, respectively. In addition, we also observed significant associations between the DRLs signature and various clinical variables, distinct immune landscape and drug sensitivity profiles in GC patients. The low-risk group patients may be more likely to benefit from immunotherapy and chemotherapy. Our study investigated the role and potential clinical implications of DRLs in GC. The risk model constructed by DRLs demonstrated high accuracy in predicting the survival outcomes of GC and improving the treatment efficacy for GC patients.

Pretreatment platelet-to-lymphocyte ratio (PLR) as a prognosticating indicator for gastric cancer patients receiving immunotherapy

BackgroundPrevious investigations suggest that systemic inflammation markers are able to provide prognostic value in several cancers. This study seeks to characterize the ability of pretreatment platelet-to-lymphocyte ratio (PLR) to prognosticate advanced or metastatic gastric cancer patients (AGC or MGC, respectively) receiving immunotherapy.MethodsAGC and MGC patients exposed to PD-1 inhibitors from January 2016–August 2021 in the Chinese PLA General Hospital were recruited. Correlations between PLR and overall survival (OS), progression-free survival (PFS), and immunotherapy-associated tumor response rates were determined.Results237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42–0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43–0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05).ConclusionsPre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.

Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes

Necroptosis, a type of programmed cell death, has become a potential therapeutic target for solid tumors. Nevertheless, the potential roles of necroptosis-related genes (NRGs) in gastric cancer (GC) remain unknown. The objective of the present study was to create a necroptosis-related prognostic signature that can provide more accurate assessment of prognosis in GC. Using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, we identified differentially expressed NRGs. Univariate analysis and Lasso regression were performed to determine the prognostic signature. Risk scores were calculated and all GC patients were divided into high- and low-risk score group according to the median risk score value. The robustness of this signature was externally validated with data from GSE84437 cohort (n = 431). Survival analysis revealed high-risk score patients had a worse prognosis. Results evidenced that the signature was an independent prognosis factor for survival. Single-sample sequence set enrichment analysis (ssGSEA) exhibited different enrichment of immune cells and immune-related pathways in the two risk groups. Furthermore, a predictive nomogram was generated and showed excellent predictive performance based on discrimination and calibration. In addition, the risk score positively correlated with tumor mutational burden and was associated with sensitivity to multiple anti-cancer drugs. Overall, our work demonstrates a close relationship between necroptosis and the prognosis of GC. The signature we constructed with potential clinical application value, can be used for prognosis prediction and being a potential therapeutic responses indicator in GC patients.

The value of spleen density in predicting prognosis of patients with gastric cancer after curative gastrectomy

Objective: To investigate the value of spleen density in predicting the prognosis of patients with gastric cancer after radical gastrectomy. Methods: A total of 415 patients with gastric cancer who underwent radical resection in the Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University from January 2012 to December 2015 were retrospectively analyzed. Of the patients, there were 295 males and 120 femles with a median age of 59 years (range 28-83 years). The patients were divided into diffuse decreased spleen density group (DROSD) (spleen density≤43.0 HU, n=118) and non-diffuse decreased spleen density group (N-DROSD) (spleen density>43.0 HU, n=297) according to the density of spleen detected by computed tomography (CT). The receiver operating characteristic (ROC) curve was used to identify the checkpoint of spleen density in predicting the recurrence of the gastric cancer in those patients. The relationship with clinicopathological factors and prognosis in the two groups were further analyzed. Results: The optimal critical value of spleen density for predicting postoperative recurrence of gastric cancer was 43.0 HU, the area under the curve of ROC was 0.608, and the sensitivity and specificity was 84.9% and 40.4%, respectively. Spleen density was related to albumin, hemoglobin, neutrophil lymphocyte ratio (NLR) and tumor diameter in patients with gastric cancer (all P<0.05). The 5-year disease-free survival rate and 5-year disease-specific survival rate of all the patients was 45.5% and 50.1%, respectively. Univariate survival analysis showed that age, NLR, PLR, tumor location, tumor diameter, Lauren classification, TNM stage, nerve invasion, vascular invasion, DROSD and adjuvant chemotherapy were all related to the 5-year disease-free survival rate (all P<0.05); Age, NLR, tumor location, tumor diameter, Lauren classification, TNM stage, nerve invasion, vascular invasion, DROSD and adjuvant chemotherapy were all related to the 5-year disease-specific survival rate (all P<0.05). Multivariate survival analysis showed that high NLR level (HR=1.501, 95%CI: 1.136-1.984), late TNM stage (HR=2.559, 95%CI: 1.850-3.539), DROSD (HR=2.093, 95%CI: 1.571-2.788) and no adjuvant chemotherapy (HR=1.583, 95%CI: 1.204-2.083) were independent risk factor for the 5-year disease-free survival rate (all P<0.05). Late TNM stage (HR=1.938, 95%CI: 1.395-2.692), DROSD (HR=1.566, 95%CI: 1.180-2.078) and no adjuvant chemotherapy (HR=1.336, 95%CI: 1.016-1.758) were independent risk factors for the 5-year disease-free survival rate (all P<0.05). For stage Ⅰ patients, the 5-year disease-free survival rates of DROSD group and N-DROSD group was 78.6% and 83.7%, respectively; and the 5-year disease-specific survival rates was 85.7% and 89.8%, respectively (both P>0.05). For stage Ⅱ and Ⅲ patients, the 5-year disease-free survival rates of DROSD group and N-DROSD group was 15.4% and 48.8%, respectively, and the 5-year disease-specific survival rates was 17.3% and 54.0%, respectively (all P<0.001). Conclusion: As an imaging evaluation method, spleen density is a new tool, which can be used as a prognostic indicator for gastric cancer patients.

Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer

Immune checkpoint blockade has attracted a lot of attention in the treatment of human malignant tumors. We are trying to establish a prognostic model of gastric cancer (GC) based on the expression profile of immunoregulatory factor-related genes. Based on the TCGA database, we identified 234 differentially expressed immunoregulatory factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) conducted enrichment analysis to clarify the biological functions of differential expression of immunoregulatory factors. STRING database predicted the interaction network between 234 differently expressed immune regulatory factors. The expression of 11 immunoregulatory factors was significantly related to the overall survival of gastric cancer patients. Univariate Cox regression analysis, Kaplan–Meier analysis and multivariate Cox regression analysis found that immunomodulatory factors were involved in the progression of gastric cancer and promising biomarkers for predicting prognosis. Among them, CXCR4 was related to the low survival of GC patients and a key immunomodulatory factor in GC. Based on TCGA data, the high expression of CXCR4 in GC was positively correlated with the advanced stage and grade of gastric cancer and related to poor prognosis. Univariate analysis and multivariate analysis indicated that CXCR4 was an independent prognostic indicator for TCGA gastric cancer patients. In vitro functional studies had shown that CXCR4 promoted the proliferation, migration, and invasion of gastric cancer cells. In summary, this study has determined the prognostic value of 11 immunomodulatory factors in gastric cancer. CXCR4 is an independent prognostic indicator for gastric cancer patients, which may help to improve the individualized prognostic prediction of GC and provide candidates for the diagnosis and treatment of GC.

Duration of Postoperative Fever as a Simple and Useful Prognostic Indicator in Gastric Cancer Patients.

Postoperative inflammation is associated with cancer progression in several cancers. However, the prognostic significance of postoperative fever remains unclear in gastric cancer patients. We enrolled 442 patients with a histopathological diagnosis of gastric adenocarcinoma who underwent curative surgery. The mean duration of postoperative fever ≥ 37°C was 8.7 days (range: 0-186 days) and significantly longer in patients with advanced gastric cancer, venous invasion, and open or total gastrectomy vs. patients with early gastric cancer (P = 0.0072), no venous invasion (P = 0.025), laparoscopic gastrectomy (P = 0.027), and either proximal or distal partial gastrectomy (P = 0.0015). Five-year overall survival rates were 69.5% vs. 83.6% in the prolonged postoperative fever group (≥ 6 days of ≥ 37°C) vs. the nonprolonged group (< 6 days of ≥ 37°C), respectively (P = 0.0008). In patients without Clavien-Dindo classification postoperative infectious complications grade ≥ 2, 5-year overall survival was 69.7% vs. 84.0% in patients with prolonged postoperative fever vs. those without, respectively (P = 0.0067). Five-year disease-specific survival was 85.9% vs. 93.1% in patients with prolonged fever vs. those without, respectively (P = 0.041). Multivariate analysis indicated that postoperative fever was an independent prognostic indicator. Postoperative fever ≥ 37°C duration may be useful in predicting prognosis in gastric cancer patients.

Systemic Immune-Inflammation Index Predicts Overall Survival in Patients with Gastric Cancer: a Propensity Score–Matched Analysis

BackgroundThe systemic immune-inflammation index (SII), integrated by peripheral lymphocyte, neutrophil, and platelet counts, is used as an objective biomarker that reflects the balance between host inflammatory and immune response status in cancer patients. Herein, we examined the prognostic significance of SII in gastric cancer patients. MethodsWe retrospectively reviewed data of 415 patients who underwent curative laparoscopic gastrectomy using propensity score–matched (PSM) analysis. The prognostic value of SII was compared between two groups based on SII values: low SII group (SII < 661.9) and high SII group (SII ≥ 661.9). ResultsIn multivariate analysis, the American Society of Anesthesiologists physical status (ASA-PS) (p < 0.001), tumor differentiation (p = 0.019), pathological stage (p = 0.046), carcinoembryonic antigen (CEA) level (p < 0.001), SII (p = 0.006), and operative procedure (p = 0.009) were independent prognostic factors of overall survival (OS) in the overall PSM cohort. The log-rank test demonstrated that patients with a high SII had significantly worse OS than did those with low SII (p = 0.002). In age-stratified subgroups analysis (< 65/≥ 65 years), multivariate analysis revealed that ASA-PS (p < 0.001), tumor differentiation (p = 0.019), CEA level (p = 0.008), SII (p = 0.013), and operative procedure (p = 0.026) were independent prognostic factors of OS in the elderly group. Similarly, elderly patients with a high SII had significantly worse OS than did those with a low SII (p = 0.009). Meanwhile, SII was not an independent prognostic factor of OS, and no significant association was observed between SII and OS in non-elderly patients. ConclusionsSII was an independent prognostic indicator in gastric cancer patients, especially in the elderly population.

High long non-coding LIFR-AS1 expression correlates with poor survival in gastric carcinoma.

Abundant evidence has demonstrated that long non-coding RNAs (lncRNAs) play key roles in the development of human neoplasms. A novel cancer-related lncRNA, leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1), has been reported to be under-expressed in breast cancer and associated with poor prognosis, but its significance in gastric cancer (GC) remains to be determined. Therefore, we assessed the prognostic and diagnostic value of LIFR-AS1 in GC. Quantitative RT-PCR assay was used to detect the expression levels of LIFR-AS1 in GC tissues and adjacent normal tissues. The correlation between LIFR-AS1 expression and clinicopathological features was analyzed by Pearson's χ2-test. The disease-free survival and overall survival rates of GC patients were calculated by the Kaplan-Meier method. Cox regression analysis was used to assess factors related to survival. In this study, levels of LIFR-AS1 were significantly higher in GC tumor samples relative to adjacent normal tissue samples. A ROC analysis suggested LIFR-AS1 expression could be reliably used to differentiate between normal and GC tumor tissue. In addition, elevated LIFR-AS1 expression was positively correlated with more advanced and aggressive GC features, such as larger tumor size, lymphatic metastasis, and more advanced TNM stage. Survival analyses revealed that elevated LIFR-AS1 expression was correlated with worse overall survival and disease-free survival. Multivariate analysis further confirmed the relevance of LIFR-AS1 as an independent predictor of GC patient outcomes. In summary, these results indicate that the lncRNA LIFR-AS1 is a promising prognostic indicator in GC patients.

Downregulation of miR-484 is associated with poor prognosis and tumor progression of gastric cancer

BackgroundGastric cancer is one of the most common cancers leading to high cancer mortality. MicroRNA-484 (miR-484) has been evaluated as a biomarker for various types of cancers. The subject of this study is to investigate the functional role of miR-484 in gastric cancer.MethodsThe expression of miR-484 in gastric cancer was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Kaplan-Meier survival and Cox regression analyses were employed to explore the prognostic significance of miR-484 in gastric cancer. The functional role of miR-484 in gastric cancer was determined by CCK-8 and Transwell assays.ResultsThe results showed that miR-484 was significantly downregulated in gastric cancer tissues and cell lines. The downregulation of miR-484 was closely related to differentiation, lymph node metastasis, TNM stage, and poor prognosis. Cox regression analyses demonstrated that miR-484 was an independent prognosis indicator for gastric cancer patients. Additionally, the downregulation of miR-484 enhanced cell proliferation, migration, and invasion in gastric cancer cells.ConclusionThese data demonstrated that miR-484 can serve as a potential prognostic biomarker and therapeutic target for gastric cancer and it may be involved in the progression of gastric cancer.

Up-regulation of long noncoding RNA LINC00858 is associated with poor prognosis in gastric cancer.

The present study aimed to investigated the expression pattern of long noncoding RNA LINC00858 (LINC00858) in gastric cancer (GC) patients and its feasibility as a new prognostic biomarker. We examined LINC00858 expression in GC tissues and matched normal tissues from 189 patients using a quantitative reverse transcription-polymerase chain reaction. The correlations of LINC00858 levels in GC patients with clinicopathologic features were analyzed using a chi-squared test. The influence of LINC00858 on the overall survival rate of GC patients was precisely calculated using Kaplan-Meier methods (log rank tests). Multivariate Cox regression assays were carried out for the identification of the independent risk factors for GC. We observed that LINC00858 was distinctly up-regulated in GC tissues compared to adjacent non-tumor specimens (p < 0.01). Higher expression of LINC00858 in GC was found to be associated with TNM stage (p = 0.003) and lymphatic metastasis (p = 0.007). Using Kaplan-Meier assays, we found that patients with high expression levels of LINC00858 had a distinctly poor overall survival and disease-free survival compared to those with low expression levels of LINC00858 (p = 0.0102). Multivariate analyses confirmed that LINC00858 (p < 0.05) was an independent prognosis factor for GC patients. The data obtained in our study indicate that LINC00858 may be used as a novel prognostic indicator in GC patients.

Sodium to globulin ratio as a prognostic factor for patients with advanced gastric cancer

Background: Electrolyte disturbance and systemic inflammation contributes to poor prognosis of cancer patients. Levels of serum sodium and globulin can reflect electrolyte homeostasis and inflammatory state, respectively, therefore have potential as prognostic factors for cancer patients. In this study, we hypothesized that sodium to globulin ratio (SGR) could have superior accuracy in predicting cancer patient survival, than sodium and globulin alone. We therefore sought to investigate its efficacy in prognosis of patients with advanced gastric cancer (GC) receiving first-line chemotherapy.Methods: A total of 265 patients, with advanced GC, were recruited in this retrospective study from January 2014 to January 2019. We first determined SGR cut-off values using the receiver operating characteristic (ROC) analysis, then analyzed the relationship between pretreatment SGR and clinicopathological features and the effect of chemotherapy. Finally, we evaluated progression-free survival (PFS) and overall survival (OS) rates of the entire and subgroup populations using univariate and multivariate logistic regressions.Results: SGR recorded a cut-off value of 5.54, and had a significantly higher area under the curve (AUC) value (0.619, p = 0.001) than fibrinogen (0.575, p = 0.034) and albumin (0.610, p = 0.002) alone. Organ metastasis, and peritoneal invasion ratios, as well as neutrophil and CA72-4 levels varied significantly between the low-SGR (SGR≤ 5.54) and high SGR (SGR> 5.54) groups (all p < 0.05). Specifically, patients in the low-SGR group exhibited significantly lower disease control rates (83.4%) than those in the high-SGR group (97.2%) (p < 0.001). Results from multivariate analysis indicated that high-SGR was an independent risk factor for PFS (Hazard ratio [HR]: 0.539, p < 0.001) and OS (HR: 0.574, p < 0.001). Moreover, patients in the low-SGR group exhibited significantly worse PFS (134 vs. 221 days, p < 0.001) and OS (311 vs. 420 days, p < 0.001) than those in the high-SGR group. Furthermore, subgroup analysis revealed that SGR was still a powerful prognostic indicator in GC patients with good prognosis or normal biochemical indexes, including no peritoneal infiltration, normal neutrophil counts, and normal serum sodium and globulin levels (all p < 0.001).Conclusions: Overall, our findings indicate that SGR is a novel and promising prognostic factor for GC patients. It has superior accuracy, to sodium and globulin alone, hence it is a powerful tool for evaluating effects of treatment, PFS, and OS in patients with advanced GC, who receive first-line chemotherapy.

The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer.

Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC). We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting. THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor. THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.

Prognostic Significance of Pre- and Post-operative Red-Cell Distribution Width in Patients with Gastric Cancer

BackgroundHigh red cell distribution width (RDW) is reportedly provoked by chronic inflammation and poor nutritional status; high pre-operative RDW is related to poor prognosis in some cancers. However, the prognostic significance of post-operative RDW in gastric cancer (GC) patients is unclear. MethodsWe enrolled 221 patients who had undergone curative surgery for histopathologically diagnosed gastric adenocarcinoma. ResultsOptimal cutoff values were determined by ROC analysis to be 14.85 (pre-operative) and 14.05 (post-operative). We accordingly divided patients into the high (pre-RDWHigh; ≥ 14.85) and low (pre-RDWLow; < 14.85) pre-operative RDW groups, and the high (post-RDWHigh; ≥ 14.05) and low (post-RDWLow; < 14.05) post-operative RDW subgroups. Five-year overall survival (OS) rates differed significantly in pre-RDWHigh group (52.4%) and pre-RDWLow group (78.0%; P < 0.0001). Five-year OS rates also differed significantly in post-RDWHigh (52.7%) and post-RDWLow subgroups (88.3%; P < 0.0001). Multivariate analysis showed post-operative RDW, but not pre-operative RDW, to be an independent prognostic indicator for OS. ConclusionsPost-operative RDW may be a useful prognostic indicator in GC patients.

Increased regulatory B cells are involved in immune evasion in patients with gastric cancer

Accumulating evidence has indicated that immune regulatory cells are involved in the establishment of tumoral immune evasion. However, the role of regulatory B cells (Bregs) in this remains unclear. Here, we identified a role for Bregs in immune evasion in gastric cancer (GC) patients. The frequency of peripheral Bregs was significantly higher in GC patients than in healthy controls (P = 0.0023). Moreover, the frequency of CD19+CD24hiCD27+ B cells in GC tissue was significantly higher than in peripheral blood and healthy gastric tissue. Carboxyfluorescein succinimidyl ester labeling revealed that CD19+CD24hiCD27+ B cells could suppress the proliferation of autologous CD4+ T cells. Moreover, CD19+CD24hiCD27+ B cells inhibited the production of interferon-gamma by CD4+ T cells. Double staining immunohistochemistry of interleukin-10 and CD19 revealed 5-year overall survival rates of 65.4% and 13.3% in BregLow and BregHigh groups, respectively (P < 0.0001). Multivariate analysis indicated that the frequency of Bregs was an independent prognostic indicator in GC patients. Taken together, our results show the existence of Bregs in GC tissue, and indicate that they are significantly correlated with the prognosis of GC patients.

The prognostic value of lymph node ratio for local advanced gastric cancer patients with adjuvant chemoradiotherapy after D2 gastrectomy.

This study aimed to find the prognostic factors of local advanced gastric cancer patients with adjuvant concurrent chemoradiotherapy after radical D2 gastrectomy, and explore the prognostic value of lymph node ratio (LNR).We retrospectively analyzed 164 gastric cancer patients enrolled in West China Hospital from 2006 to 2013, who underwent D2 radical gastrectomy and adjuvant chemoradiotherapy. With univariate analysis and the Cox regression model, we evaluated the association of LNR and other clinical pathological characteristics with overall survival (OS) and relapse-free survival (RFS) of patients.Of 164 gastric cancer patients, the median age at diagnosis was 60 (IQR 51–66), with 121 males (73.78%) and 43 females (26.22%). The median follow-up time was 41.5 months. One-year and 3-year OS rate of the whole cohort was 97.6% and 88.4%, with 1-year RFS rate of 90.2% and 3-year RFS rate of 76.8%, respectively. In the univariate analysis, we found that age >60years (P = .025), TNM stage III (P = .014), LNR >0.25 (P = .006) and radiation dose <45Gy (P = .048) predicted worse OS. Further multivariate analysis indicated that age >60y (HR 2.375, 95% CI 1.100–5.128; P = .028), TNM stage III (HR 7.692, 95% CI 1.009–58.824; P = .049) and LNR >0.25 (HR 2.439, 95% CI 1.075–5.525; P = .033) were independent prognostic factors for unfavorable OS. The COX analysis showed that related prognostic factors of worse RFS were TNM stage III (HR 3.802, 95% CI 1.506–9.615; P = .049) and LNR >0.25 (HR 2.326, 95% CI 1.332–4.065; P = .003).LNR can be used as an important prognostic indicator for gastric cancer patients with D2 resection and adjuvant chemoradiotherapy, and LNR more than 0.25 indicates poor prognosis.

Postoperative ratio of the maximum C-reactive protein level to the minimum peripheral lymphocyte count as a prognostic indicator for gastric cancer patients

Inflammation, together with immune and nutritional status, are associated with the progression of various cancer types. We evaluated the prognostic significance of the postoperative ratio (post-CLR) of the maximum C-reactive protein value (post-CRPMax) to the minimum peripheral lymphocyte count (post-LCMin) in patients with gastric cancer (GC). The subjects of this retrospective study were 227 patients who underwent curative surgery for histopathologically diagnosed gastric adenocarcinoma. The 5-year overall survival (OS) rates differed significantly between the post-CLRHigh (≥ 152.6) group and the post-CLRLow (< 152.6) group for all patients (45.0% vs. 68.4%, respectively; P < 0.001). The 5-year disease-specific survival (DSS) rates were also significantly related to post-CLR for all patients, (80.6% vs. 64.3% for the post-CLRLow and the post-CLRHigh groups, respectively; P = 0.002). Among patients without infectious complications, the CLR affected both the 5-year OS rate (48.4% vs. 69.2% for the post-CLRHigh and the post-CLRLow groups, respectively; P = 0.006) and the 5-year DSS rate (80.2% vs. 67.0% for the post-CLRLow and the post-CLRHigh groups, respectively; P = 0.027). Multivariate analysis revealed that post-CLR was an independent prognostic indicator for both the OS and DSS of all patients. Our finding show that the post-CLR can help predict the prognosis of GC patients.

High Expression of Peroxiredoxin 1 Is Associated with Epithelial-Mesenchymal Transition Marker and Poor Prognosis in Gastric Cancer.

BackgroundRecent studies show that peroxiredoxin 1 (Prdx1) contributes to the progression and poor prognosis of carcinoma through multiple mechanisms. However, there is little information on its expression and prognostic value in gastric cancer. This study investigated the expression of Prdx1 in gastric cancer, along with evaluating its clinical-pathological and prognostic importance.Material/MethodsA total of 189 pairs of gastric cancer and paracarcinomatous tissues were assessed for Prdx1 expression and its association with clinical characteristics. The molecular mechanism was further investigated through in vitro experimentation.ResultsThe mRNA and protein levels of Prdx1 in the GC tissues were higher than in the peri-tumor tissues. We also found that high Prdx1 expression was positively correlated with the lymph node invasion and poor prognosis. It also served as an autonomous prognostic factor for patients with gastric cancer. Moreover, Prdx1 regulates the invasion and metastasis of GC cell lines through inhibiting E-Ca expression.ConclusionsPrdx1 can promote epithelial-mesenchymal transition and gastric cancer progression. Therefore, it might be a therapeutic target and prognostic indicator for gastric cancer patients.

Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation.

Aims: Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-κB) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IκB-α in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-κB in GC cells. Results: DATS attenuated NF-κB signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IκB-α to suppress NF-κB activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-κB inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumors. Innovation and Conclusion: We conclude that DATS exerts its anti-GC activity and enhances chemosensitivity of GC to DOC by epigenetic upregulation of MT2A to attenuate NF-κB signaling. Our findings delineate a mechanistic basis of MT2A/NF-κB signaling for DATS- and DOC-mediated anti-GC effects, suggesting that MT2A may be a chemosensitivity indicator in GC patients receiving DOC-based treatment and a promising target for more effective treatment of GC by combination of DATS and DOC. Antioxid. Redox Signal. 24, 839–854.

Abstract 2310: Epigenetic silencing of a potential tumor suppressor NR4A3 by aberrant JAK/STAT signaling predicts prognosis in gastric cancer

Abstract Gastric cancer is the second leading cause of cancer worldwide. Epigenetic silencing of tumor-suppressors has emerged as an important underlying mechanism in the gastric carcinogenesis. Previous studies showed that infection of H. pylori activates JAK/STAT3 signaling pathway in gastric cancer. However, the role of this aberrant signaling remains unclear. We hypothesized that activation of JAK/STAT signaling leads to epigenetic silencing of STAT3 target genes in gastric cancer. To test this hypothesis, a constitutively activated mouse STAT3 mutant (STAT3c) was transfected into MKN28 gastric cancer cells in which the JAK/STAT signaling pathway is inactive. STAT3c stable transfectant (S16) showing hyperphosphorylation of STAT3 demonstrated increased cell proliferation as compared to vector control (C9). Integrative expression microarray coupled with bioinformatic analysis identified putative STAT3 targets, NR4A3 that are down-regulated in S16 cells. In association with up-regulation of DNMT1, NR4A3 exhibited increased promoter methylation in S16 but not C9 cells as demonstrated by bisulphite sequencing and demethylation treatment. Interestingly, NR4A3 was also found to be epigenetically silenced in AGS cells where JAK/STAT signaling is constitutively activated. ChIP-PCR experiment revealed that STAT3 bound to the putative STAT3 binding site in NR4A3 promoter of AGS cells. Depletion of STAT3 by lenti-viral knockdown restored NR4A3 expression in this cell. Interestingly, luciferase reporter assay using the NR4A3 promoter containing putative STAT3 binding site exhibited a further 1.6 fold increment after deleting the STAT3 binding region (P &amp;lt; 0.005). Ectopic expression of NR4A3 in AGS cells reduced cancer cell growth in colony formation assay (P &amp;lt; 0.001). In clinical specimens, quantitative MSP demonstrated a significant correlation between the degree of NR4A3 methylation and STAT3 nuclear translocation in 72 gastric tumor samples (P &amp;lt; 0.05). Importantly, methylation of NR4A3 was significantly associated with patients with shorter survival (P &amp;lt; 0.05). In conclusion, our result demonstrated that aberrant JAK/STAT3 signaling confers epigenetic silencing of a potential tumor suppressor, NR4A3 in gastric cancer. Methylation of NR4A3 may be able to serve as a prognostic indicator in gastric cancer patients. Citation Format: Michael W. Y. Chan, Li-Han Zeng, Liang-Yu Chang, Claudia Dittner, Jian-Liang Chou, Yao-Ting Huang, Alfred S.L. Cheng, Jiayuh Lin, Kun-Tu Yeh. Epigenetic silencing of a potential tumor suppressor NR4A3 by aberrant JAK/STAT signaling predicts prognosis in gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2310. doi:10.1158/1538-7445.AM2014-2310

High expression of integrin-linked kinase predicts aggressiveness and poor prognosis in patients with gastric cancer

Integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase, has been reported to be highly expressed in many human malignancies, including gastric cancer. However, the prognostic significance of ILK expression in gastric cancer remains to be elucidated. In the present study, ILK expression in 95 gastric tumor tissues and 30 adjacent non-cancerous gastric mucosa was evaluated by immunohistochemistry and correlated with clinicopathological characteristics and patients’ outcome. The results showed that high ILK expression was observed in 47.4% (45/95) of gastric cancer tissues, but only in 20.0% (6/30) of adjacent gastric mucosa. Clinicopathological analysis indicated that high ILK expression was significantly associated with poor tumor differentiation (P=0.024), advanced TNM stage (P=0.006), tumor invasion (P=0.001), and lymph node metastasis (P=0.014). Kaplan–Meier survival curves demonstrated that patients with high ILK expression had substantially shorter overall survival that those with low ILK expression (P=0.043, log-rank test). Furthermore, Cox multivariate regression analysis identified ILK expression as an independent prognostic factor for overall survival of gastric cancer patients (hazard ratio, 1.95; 95% confidence interval, 1.02–3.13; P=0.026). In conclusion, our data suggest that ILK may contribute to the malignant progression of gastric cancer and serve as a novel prognostic indicator for gastric cancer patients.