Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer.

Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regulates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti-tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.

PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.

RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.

LILRB1+ immune cell infiltration identifies immunosuppressive microenvironment and dismal outcomes of patients with ovarian cancer.

OBJECTIVE: Immune checkpoint inhibitors are commonly used in various types of cancer, but their efficacy in ovarian cancer (OC) is limited. Thus, identifying novel immune-related therapeutic targets is crucial. Leukocyte immunoglobulin-like receptor subfamily B1 (LILRB1), a key receptor of human leukocyte antigen G (HLA-G), is involved in immune tolerance, but its role in tumor immunity remains unclear. METHODS: In this study, immunofluorescence was used to identify the location of LILRB1 in OC. The effect of LILRB1 expression on clinical outcomes in 217 patients with OC was analyzed retrospectively. A total of 585 patients with OC from the TCGA database were included to explore the relationship between LILRB1 and tumor microenvironment characteristics. RESULTS: LILRB1 was found to be expressed in tumor cells (TCs) and immune cells (ICs). High LILRB1+ ICs, but not LILRB1+ TCs, were associated with advanced FIGO stage, shorter survival outcomes, and worse adjuvant chemotherapy responses in OC patients. LILRB1 expression was also associated with high M2 macrophage infiltration, reduced activation of dendritic cells, and dysfunction of CD8+ T cells, suggesting an immunosuppressive phenotype. The combination of LILRB1+ ICs and CD8+ T cell levels could be used to distinguish patients with different clinical survival results. Moreover, LILRB1+ ICs infiltration with CD8+ T cells absence indicated inferior responsiveness to anti-PD-1/PD-L1 therapy. CONCLUSIONS: Tumor-infiltrating LILRB1+ ICs could be applied as an independent clinical prognosticator and a predictive biomarker for therapy responsiveness to OC. Further studies targeting the LILRB1 pathway should be conducted in the future.

Risk Factors and Prognostic Impact of Postoperative Complications in Patients with Advanced Gastric Cancer Receiving Neoadjuvant Chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy is important to improve the prognosis of patients with advanced gastric cancer. However, it may result in postoperative complications (POCs). The aim of this study is to evaluate risk factors and prognostic impact of POCs in patients receiving neoadjuvant chemotherapy. METHODS: We retrospectively collected clinical information of patients who underwent curative gastrectomy after receiving neoadjuvant chemotherapy between 2011 and 2018. Overall survival (OS) was analyzed using the Kaplan-Meier method. Logistic regression and Fisher's exact test were used to evaluate risk factors for complications. RESULTS: A total of 176 patients were included in our study. The 3-year OS rates for the complication group (n = 30) and non-complication group (n = 146) were 36.7% and 52.7%, respectively (p = 0.0294). Age, BMI, multivisceral resection and operation time were independent risk factors for POCs in patients. Patients with multivisceral resection were more likely to suffer from grade III-IV complications (p = 0.026). Inflammation complications might occur in patients with high BMI (p = 0.017). Low preoperative albumin seemed to be a risk factor for leakage complications (p = 0.033). CONCLUSIONS: Our study revealed that patients with POCs had a poor prognosis and we identified the risk factors for complications so that POCs can be avoided in time.

Peritumoral TIGIT+CD20+ B cell infiltration indicates poor prognosis but favorable adjuvant chemotherapeutic response in gastric cancer.

OBJECTIVE: T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a novel immunosuppressive molecule. This study aimed to investigate the expression of TIGIT on B cells and the function of TIGIT+CD20+ B cells in gastric cancer (GC). METHODS: Tumor tissue paraffin-embedded sections and clinicopathological data from 194 patients with GC were collected. Dual immunohistochemistry was performed to detect the expression of TIGIT on B cells. Multiplex immunofluorescence was used to initially explore the relationship between TIGIT+CD20+ B cells and the exhaustion of CD8+ T cells. RESULTS: In GC, TIGIT+CD20+ B cells were observed in intratumor, peritumor, and tertiary lymphoid structures (TLS). Patients with GC having high peritumoral TIGIT+CD20+ B cells infiltration had inferior clinical outcomes and could benefit from adjuvant chemotherapy (ACT). In GC tissues, PD-1+CD8+ T cells were more closer to TIGIT+CD20+ B cells than to TIGIT-CD20+ B cells. CONCLUSIONS: Peritumoral TIGIT+CD20+ B cells infiltration was an independent prognostic predictor for patients with GC and a potential biomarker for ACT selection. TIGIT+CD20+ B cells might affect the exhaustion of CD8+ T cells in GC.

Identification of a Two-Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival in Diffuse-Type Gastric Cancer.

BACKGROUND: It is widely acknowledged that the molecular biological characteristics of diffuse-type gastric cancer are different from intestinal-type gastric cancer. Notwithstanding that significant progress in high-throughput sequencing technology has been made, there is a paucity of effective prognostic biomarkers for diffuse gastric cancer for clinical practice. METHODS: We downloaded four GEO datasets (GSE22377, GSE38749, GSE47007 and GSE62254) to establish and validate a prognostic two-gene signature for diffuse gastric cancer. The TGCA-STAD dataset was used for external validation. The optimal gene signature was established by using Cox regression analysis. Receiver operating characteristic (ROC) methodology was used to find the best prognostic model. Gene set enrichment analysis was used to analyze the possible signaling pathways of the two genes (MEF2C and TRIM15). RESULTS: A total of four differently expressed genes (DEGs) (two upregulated and two downregulated) were identified. After a comprehensive analysis, two DEGs (MEF2C and TRIM15) were utilized to construct a prognostic model. A prognostic prediction model was constructed according to T stage, N stage, M stage and the expression of MEF2C and TRIM15. The area under the time-dependent receiver operator characteristic was used to evaluate the performance of the prognosis model in the GSE62254 dataset. CONCLUSIONS: We demonstrated that MEF2C and TRIM15 might be key genes. We also established a prognostic nomogram based on the two-gene signature that yielded a good performance for predicting overall survival in diffuse-type gastric cancer.

Poor Prognosis and Therapeutic Responses in LILRB1-Expressing M2 Macrophages-Enriched Gastric Cancer Patients.

Immunosuppressive molecules are valuable prognostic biomarkers across different cancer types. Leukocyte immunoglobulin like receptor subfamily B1 (LILRB1) is considered to be an immunosuppressive molecule, which is an important receptor of human leukocyte antigen G. However, the clinical significance of LILRB1 expression in gastric cancer remains unexplored. We analyzed the immunohistochemistry data of 166 gastric cancer patients to determine the clinicopathologic and survival significance of LILRB1. Immunofluorescence was conducted to detect the co-localization of LILRB1 with infiltrating immune cells. Additionally, we also assessed the immune contexture, immune cell functions and tumor microenvironment state related to LILRB1. We found that LILRB1 was mainly present in tumor stroma which was higher in tumor tissues compared with matched adjacent tissues. High-LILRB1 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis showed that LILRB1 had a significant positive correlation with M2 tumor-associated macrophages (TAMs) infiltration. Immunofluorescence confirmed that M2 TAMs were the primary immune cells expressing LILRB1. Dense infiltration of LILRB1+ M2 TAMs yielded an immunosuppressive microenvironment manifested as enriched exhausted CD8+ T cells and increased immunosuppressive cytokines. Moreover, patients with high infiltration of both LILRB1+ cells and M2 TAMs indicated poor prognosis and inferior therapeutic responsiveness to adjuvant chemotherapy. In conclusion, LILRB1+ M2 TAMs were associated with a pro-tumor immune contexture and determine poor prognosis in gastric cancer. Further studies are essential to explore therapeutic targeting LILRB1+ M2 TAMs.

Decision-making of adjuvant therapy in pT1N1M0 gastric cancer: Should radiotherapy be added to chemotherapy? A propensity score-matched analysis.

Background: Early gastric cancer (EGC) with metastatic lymph nodes (mLNs) has a relatively higher recurrence rate and poorer prognosis than EGC without mLNs. However, the postoperative treatment directions of pT1N1M0 vary from different guidelines. This study attempted to confirm the value of postoperative treatments in pT1N1M0 GC patients. Methods: Overall, 379 patients with pT1N1M0 GC following gastrectomy from 2000 to 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score-matched (PSM) analysis was used to reduce bias. Overall survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. Results: Before matching, the results of survival analyses indicated that adjuvant chemotherapy (ACT) and chemoradiotherapy (ACRT) could significantly prolong the survival time of the cohort (P < 0.05). After PSM analysis, 136 patients remained and ACRT maintained significance in the survival analysis (P = 0.018). Furthermore, patients with well or moderately differentiated GC (HR = 0.226, P =0.018) or intestinal type GC (HR = 0.380, P = 0.040) achieved a significantly superior prognosis with ACRT, compared to patients receiving ACT. Conclusion: The survival benefit of ACRT and ACT for pT1N1M0 GC patients following gastrectomy was confirmed in the SEER cohort. RT added to ACT might be recommended according to Lauren's classification and tumor grade in clinical decision making.

Increased Expression of LIPC Is Associated with Aggressive Phenotype of Borrmann Type 4 Gastric Cancer.

PURPOSE: To investigate lipase C hepatic type (LIPC) expression in Borrmann type 4 gastric cancer and its correlation with clinical outcome. The biological roles of LIPC in Borrmann type 4 gastric cancer progression were also investigated. METHODS: We determined LIPC expression in 324 primary gastric cancer tissues and 178 matched adjacent non-tumor tissues by immunohistochemistry. We explored the role of LIPC in Borrmann type 4 gastric cancer cell (OCUM-1) migration, invasion, proliferation, cell cycle, and expression of epithelial-mesenchymal transition-related genes by knocking down LIPC expression. RESULTS: LIPC expression was upregulated in Borrmann type 4 gastric cancer tissues compared with other types of gastric cancer and adjacent non-tumor tissues. High LIPC expression correlated with lymph node metastasis, advanced TNM stage, and poor overall survival in Borrmann type 4 gastric cancer patients. Multivariate analysis demonstrated that high LIPC expression was an independent prognostic factor in patients with Borrmann type 4 gastric cancer. By reducing LIPC expression, OCUM-1 cell invasion and migration were suppressed and Snail and MMP2 expression was downregulated, while E-cadherin expression was upregulated. CONCLUSIONS: High LIPC expression correlates with poor clinical outcome and plays an important role in regulating cell migration and invasion in Borrmann type 4 gastric cancer.

Thirty-year trends in clinicopathologic characteristics and prognosis after gastrectomy for gastric cancer: A single institution in Northern China.

Background: We integrated changes in the trends in clinicopathologic characteristics and postoperative prognosis in patients with gastric cancer Northern China over a 30-year period. Methods: A retrospective analysis of patients undergoing gastric cancer resection and complete follow-up information from January 1981 to December 2010 in the first affiliated Hospital of China Medical University was carried out. We divided the patients into three consecutive periods. Results: A total of 3,520 patients were included in this study. The proportion of lower tumors increased (from 58.8 to 66.9%), while that of upper tumors decreased (from 21.3 to 13.4%). The proportion of tumors > 5cm decreased (from 58.6 to 41.1 %), but the increasing trend of poorly differentiated gastric cancer was obvious (from 60.1 to 75.7%). The percentage of early gastric cancer increased from 10.0 to 15.5 during the study periods, and that of TNM stage Ⅳ cancer decreased from 38.6 to 28.1. In surgery treatment, the rate of radical resection increased to 92.1% in recent period, and the average number of retrieved lymph nodes increased. The 5-year survival rate gradually increased from 36.5% to 48.5% (p<0.001). The Multivariate analysis showed that age, tumor size, T stage, N stage, number of retrieved lymph nodes and resection type were independent prognostic factors for gastric cancer. Conclusion: The patterns of clinicopathologic features for gastric cancer changed during the 30-year period in North China. Overall survival (OS) could be increased by early detection of tumors and standard surgical treatment.

Patient Selection for Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Patients with high-risk stage II colon cancer (CC) are recommended to undergo adjuvant chemotherapy (ACT). However, whether such patients can benefit from ACT remains unclear. This meta-analysis aimed to investigate the clinicopathologic parameters that are important for selecting patients for ACT in high-risk stage II CC. METHODS: We systematically retrieved articles from PubMed, the Cochrane Library, and Embase that were published up to September 13, 2018. We analyzed overall survival (OS) and disease-free survival (DFS) based on hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A total of 23 cohort studies and 1 randomized controlled trial were included in our study. Overall analyses showed that ACT improved OS (HR=0.64, 95% CI=0.51-0.80, P<0.001) and DFS (HR=0.46, 95% CI=0.28-0.76, P=0.002) in patients with high-risk stage II CC. Subgroup analyses showed that ACT improved OS in patients with localized intestinal perforation and obstruction and pT4 lesions and improved OS and DFS in patients with <12 sampled lymph nodes. However, ACT had no significant effect on OS in patients with lymphovascular invasion, perineural invasion, or poorly differentiated histology. CONCLUSIONS: Our study suggests that not all high-risk factors (lymphovascular invasion, perineural invasion, poorly differentiated histology) show a benefit from ACT. Randomized controlled trials selectively targeting high-risk patients will need to be conducted in the future.

The Prognosis Value of Lymphatic Vessel Invasion in pN0 Gastric Cancer Patients with Insufficient Examined Lymph Nodes.

OBJECTIVES: To investigate the prognosis value of lymphatic vessel invasion (LVI) in pN0 gastric cancer patients with insufficient examined lymph nodes (ELNs). METHODS: Clinicopathologic and prognostic data of pN0 gastric cancer patients with insufficient ELNs who underwent radical surgery in our institution were retrospectively studied. RESULTS: Firstly, we confirmed that less than 16 but not less than 30 ELNs were insufficient ELNs in the present study. Of the 350 pN0 patients with < 16 ELNs, 64 patients (18.29%) had LVI. The overall survival (OS) of patients with LVI was significantly poorer than those without LVI. Multivariate analysis suggested that LVI was one of the independent factors predicting prognosis of pN0 patients with < 16 ELNs. Further analyses suggested that there were similar prognoses between pN0 patients with < 16 ELNs who had LVI and pN1 patients, and between pN0 patients with < 16 ELNs who had no LVI and pN0 patients with ≥ 16 ELNs, respectively. Therefore, we proposed a novel pN classification, in which LVI-positive pN0 gastric cancer with < 16 ELNs was classified as pN1 disease. Two-step multivariate analysis demonstrated that the novel pN classification was more suitable for prognostic assessment than the original one. CONCLUSIONS: LVI is a powerful and independent prognostic factor for pN0 gastric cancer patients with < 16 ELNs, and node-negative gastric cancer with < 16 ELNs which had LVI should be considered as node-positive disease. LVI is an effective indicator identifying patients stage migration happens to in pN0 patients with < 16 ELNs.

The optimal strategy of multimodality therapies for resectable gastric cancer: evidence from a network meta-analysis.

Background: Controversy continues regarding the optimal strategy of multimodality therapies for resectable gastric cancer. The aim of this network meta-analysis was to determine the efficacy of surgery combined with neoadjuvant or adjuvant chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) by integrating the direct and indirect method. Methods: A systematic search for randomized controlled trials (RCTs) was performed through Medline, Embase, CENTRAL, and PMC databases. Overall survival (OS) was the primary outcome of interest. A Bayesian network meta-analysis was conducted and treatments were ranked based on their effectiveness for improving survival. Results: Fifty-six RCTs involving 12,435 patients were included. Overall analysis showed that neoadjuvant CRT resulted in a statistically significantly better OS compared with adjuvant CT, adjuvant RT, adjuvant CRT, neoadjuvant CT, neoadjuvant RT, and surgery alone. Moreover, subgroup analysis of D2 lymphadenectomy revealed that neoadjuvant CRT was not significant superior to neoadjuvant CT (HR = 0.67, 95% CrI 0.41-1.08), adjuvant CRT (HR = 0.67, 95% CrI 0.37-1.21), and adjuvant CT (HR = 0.60, 95% CrI 0.35-1.04). With a tendency to survival benefit, neoadjuvant CRT had an 89% probability of being the best selection. Conclusions: Our study showed no significant survival advantage for neoadjuvant CRT, though the highest probability of being the best treatment was observed. Further clinical trials are essential to determine the value of neoadjuvant CRT, especially in D2 lymphadenectomy subgroup.

Comparative efficacy of targeted maintenance therapy for newly diagnosed epithelial ovarian cancer: a network meta-analysis.

Background: The number of published randomized clinical trials (RCTs) using targeted maintenance therapy for newly diagnosed epithelial ovarian cancer is increasing. Our objective was to evaluate the comparative effectiveness of each maintenance therapy using a network meta-analysis. Materials and methods: A systematic search for RCTs was conducted using Medline, Embase, and CENTRAL databases followed by a Bayesian network meta-analysis. The primary outcome was progression-free survival (PFS) and the secondary outcome was overall survival (OS). Pooled hazard ratios (HRs) with 95% credible intervals (95% CrIs) were used to estimate outcomes. Results: A total of 11 RCTs involving 6631 patients were included. Network meta-analysis showed that pure maintenance therapy with pazopanib resulted in a significantly better PFS compared with placebo (HR, 0.77; 95% CrI, 0.65-0.92). Bevacizumab-throughout treatment was also associated with a better PFS (HR, 0.76, 95% CrI, 0.69-0.84). However, anti-CA-125 monoclonal antibodies (abagovomab and oregovomab) showed no significant survival benefit. Moreover, combined analysis showed that targeted-throughout was not significantly superior to pure targeted maintenance therapy for PFS and OS. Stratified analysis showed paralleled results with no significant difference between pazopanib pure maintenance and bevacizumab-throughout treatments. Conclusion: Our study showed a survival advantage conferred by pazopanib and bevacizumab as maintenance therapy in newly diagnosed epithelial ovarian cancer. Further clinical trials are essential to both determine the effect of bevacizumab in the maintenance stage and identify the specific subgroup(s) that benefit.

Effects of metastasectomy and other factors on survival of patients with ovarian metastases from gastric cancer: a systematic review and meta-analysis.

Ovarian metastasis from gastric cancer (Krukenberg tumor [KT]) has no consensus treatment and the role of surgical treatment is still controversial. Identifying prognostic factors for KT could help guide the management of this tumor. We used a meta-analysis to evaluate the prognostic value of metastasectomy and other factors in patients with KT to develop a treatment plan. We searched literature in PubMed, Cochrane library and EMBASE. We analyzed hazard ratios (HR) and 95% confidence intervals (CI) with respect to overall survival (OS). The meta-analysis included 12 cohort studies with 1,031 patients associated with longer OS following metastasectomy (HR = 0.41; 95% CI = 0.32-0.53; P < 0.001), R0 resection (HR = 0.37; 95% CI = 0.26-0.53; P < 0.001), metachronous ovarian metastasis (HR = 0.74; 95% CI = 0.58-0.93; P = 0.012), size of KT (<5 cm) (HR = 0.74; 95% CI = 0.58-0.95; P = 0.019), ECOG PS (Eastern Cooperative Oncology Group performance status) 0 to 1 (HR = 0.48; 95% CI = 0.29-0.80; P = 0.004), tumor confined to ovary (HR = 0.40; 95% CI = 0.16-0.99; P = 0.047), and tumor confined to pelvic cavity (HR = 0.36; 95% CI = 0.14-0.92; P = 0.033). Shorter OS was associated with peritoneal carcinomatosis (HR = 2.00; 95% CI = 1.25-3.21; P = 0.004), ascites (HR = 1.66; 95% CI = 1.19-2.31; P = 0.003) and positive CEA (HR = 1.41; 95% CI = 1.10-1.82; P = 0.007). Gastrectomy led to a slight improvement in OS, but without statistical significance (HR = 0.69; 95% CI = 0.47-1.02; P = 0.061). No significant difference in OS was observed in patients with signet-ring cells (HR = 1.17; 95% CI = 0.91-1.51; P = 0.226), bilateral ovarian metastasis (HR = 0.87; 95% CI = 0.70-1.08; P = 0.212), age ≥ 50 years (HR = 0.93; 95% CI = 0.71-1.22; P = 0.619), positive CA19-9 (HR = 1.01; 95% CI = 0.75-1.35; P = 0.960), and positive CA-125 (HR = 0.98; 95% CI = 0.73-1.33; P = 0.915). Various factors affect OS in patients with KT.

Smoking status and subsequent gastric cancer risk in men compared with women: a meta-analysis of prospective observational studies.

BACKGROUND: Smoking is one of the well-established risk factors for gastric cancer incidence, yet whether men are more or equally susceptible to gastric cancer due to smoking compared with women is a matter of controversy. The aim of this study was to investigate and compare the effect of sex on gastric cancer risk associated with smoking. METHODS: We conducted a systemic literature search in MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify studies published from inception to December 2018. We included prospective observational studies which reported effect estimates with 95% confidence intervals (CIs) for associations of current or former smokers with the incidence of gastric cancer by sex. We calculated the ratio of relative risk (RRR) with corresponding 95% CI based on sex-specific effect estimates for current or former smokers versus non-smokers on the risk of gastric cancer. RESULTS: We included 10 prospective studies with 3,381,345 participants in our analysis. Overall, the summary RRR (male to female) for gastric cancer risk in current smokers was significantly increased compared with non-smokers (RRR: 1.30; 95% CI: 1.05-1.63; P = 0.019). Furthermore, there was no significant sex difference for the association between former smokers and gastric cancer risk (RRR: 1.20; 95% CI: 0.92-1.55; P = 0.178). However, the result of sensitivity analysis indicated the pooled result was not stable, which was altered by excluding a nested case-control study (RRR: 1.31; 95% CI: 1.10-1.57; P = 0.002). CONCLUSION: This systematic review showed a potential sex difference association between current smokers and the risk of gastric cancer. The sex differential in smokers can give important clues for the etiology of gastric cancers and should be examined in further studies.

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. METHODS: Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. RESULTS: 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. CONCLUSIONS: This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases.

SPHK1-induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination.

Gastric cancer peritoneal dissemination (GCPD) has been recognized as the most common form of metastasis in advanced gastric cancer (GC), and the survival is pessimistic. The injury of mesothelial cells plays an important role in GCPD. However, its molecular mechanism is not entirely clear. Here, we focused on the sphingosine kinase 1 (SPHK1) in human peritoneal mesothelial cells (HPMCs) which regulates HPMCs autophagy in GCPD progression. Initially, we analyzed SPHK1 expression immunohistochemically in 120 GC peritoneal tissues, and found high SPHK1 expression to be significantly associated with LC3B expression and peritoneal recurrence, leading to poor prognosis. Using a coculture system, we observed that GC cells promoted HPMCs autophagy and this process was inhibited by blocking TGF-ß1 secreted from GC cells. Autophagic HPMCs induced adhesion and invasion of GC cells. We also confirmed that knockdown of SPHK1 expression in HPMCs inhibited TGF-ß1-induced autophagy. In addition, SPHK1-driven autophagy of HPMCs accelerated GC cells occurrence of GCPD in vitro and in vivo. Moreover, we explored the relationship between autophagy and fibrosis in HPMCs, observing that overexpression of SPHK1 induced HPMCs fibrosis, while the inhibition of autophagy weakened HPMCs fibrosis. Taken together, our results provided new insights for understanding the mechanisms of GCPD and established SPHK1 as a novel target for GCPD.

Should All Stage N3b Patients with Advanced Gastric Cancer Be Considered Equivalent? A 30-Year Single Center Study.

PURPOSE: To investigate the survival of stage N3b patients with advanced gastric cancer (AGC) after radical surgery and to evaluate the TNM staging of subgroups of stage N3b patients. METHODS: We reviewed the data of 222 stage N3b patients with AGC who underwent D2/D3 radical surgery. Depending on the number of metastatic lymph nodes (MLNs), we divided N3b patients into several groups and compared the survival differences among them. We found that survival of patients with 16-20 MLNs was better than that of patients with ≥ 21 MLNs. Therefore, we divided the N3b patients into two subgroups and defined patients with 16-21 MLNs as N3b1 and patients with ≥ 21 MLNs as N3b2. Then, we compared survival differences between the two groups and their subgroups. Patients who underwent palliative surgery served as the reference group. In addition, we selected stage IIIB, IIIC, and IV patients from the same database to properly re-classify the N3b subgroups in the TNM staging system. RESULTS: Survival differed significantly between the new N3b1and N3b2 groups and between the new N3b1 group and the palliative group. However, the survival of the new N3b2 group was similar to that of the palliative group. Comparisons of survival according to T staging revealed similarities between the following groups: (1) stages T2-3N3b1 and IIIB, (2) stages T4N3b1 and IIIC, and (3) stages T2-4N3b2 and IV. CONCLUSIONS: All stage N3b patients with AGC should not be considered equivalent. A significant difference in survival was observed between stage N3b1 and N3b2 patients after radical surgery, while the survival of stage N3b2 patients was similar to that of patients who undergo palliative surgery. We recommend re-classifying stage T2-3N3b1 as TNM stage IIIB, stage T4N3b1 as stage IIIC, and T2-4N3b2 as stage IV.

Palliative gastrectomy plus chemotherapy versus chemotherapy alone for incurable advanced gastric cancer: a meta-analysis.

BACKGROUND: Whether palliative gastrectomy combined with chemotherapy can improve the survival of patients with advanced gastric cancer remains controversial. We performed a meta-analysis to clarify whether palliative gastrectomy plus chemotherapy can benefit patients with incurable advanced gastric cancer and to explore the best candidates in this patient population. METHODS: We searched the literature systematically using electronic databases including PubMed, EMBASE, and the Cochrane Library. And HRs and their 95% CIs were used to express the results for overall survival (OS) and progression-free survival (PFS). RESULTS: One randomized controlled trial with 175 patients and 12 cohort studies with 2,193 patients were analyzed. The pooled HR for OS (HR=0.43, 95% CI=0.29-0.65, P<0.001), subgroup analysis of stage M1 (HR=0.53, 95% CI=0.40-0.72, P<0.001), peritoneal dissemination (HR=0.46, 95% CI=0.28-0.73, P=0.001), and liver metastasis (HR=0.46, 95% CI=0.33-0.65, P<0.001) all indicated the superiority of palliative gastrectomy plus chemotherapy. However, the pooled HR for PFS (HR=0.61, 95% CI=0.33-1.13, P=0.110) got separate outcome. CONCLUSION: The results of this meta-analysis indicated that palliative gastrectomy plus chemotherapy can improve OS for incurable advanced gastric cancer. In addition, analyses based on liver metastasis and peritoneal dissemination demonstrated the advantages of palliative gastrectomy plus chemotherapy. However, the PFS of incurable advanced gastric cancer with palliative gastrectomy plus chemotherapy was no better than that under chemotherapy alone.