B3GALT4 remodels the tumor microenvironment through GD2-mediated lipid raft formation and the c-met/AKT/mTOR/IRF-1 axis in neuroblastoma.

BACKGROUND: Beta-1,3-galactosyltransferase-4 (B3GALT4) plays a critical regulatory role in tumor biology. However, the role of B3GALT4 in modulating the tumor microenvironment (TME) of neuroblastoma (NB) remains unknown. METHODS: Public datasets and clinical NB samples were collected to evaluate the expression and clinical significance of GD2 and B3GALT4 in NB patients. CCK-8, colony formation, and transwell assays and experiments in tumor-bearing mouse models were conducted to investigate the function of B3GALT4. Flow cytometry, ELISA, immunohistochemistry, immunofluorescence, western blotting, and chemotaxis assays were conducted to ascertain the immunomodulatory mechanism of B3GALT4. The combined therapeutic effect of the lipid raft inhibitor MßCD and anti-GD2 mAb was validated in a murine model of NB. RESULTS: GD2 was overexpressed in NB tissues and high expression of GD2 was associated with poor prognosis in NB patients. B3GALT4 was downregulated in NB tissues, and low expression of B3GALT4 indicated poor prognosis in NB patients. Silencing B3GALT4 significantly enhanced tumor progression both in vitro and in vivo. Meanwhile, the overexpression of B3GALT4 increased the recruitment of CD8+ T lymphocytes via the chemokines CXCL9 and CXCL10. Additionally, B3GALT4 regulated NB-cell GD2 expression and lipid raft formation. Mechanistically, B3GALT4 regulated the expression of CXCL9 and CXCL10 via the c-Met signaling in the lipid rafts and the downstream AKT/mTOR/IRF-1 pathway. The lipid raft inhibitor, MßCD, attenuated B3GALT4 deficiency-induced tumor progression and immune evasion. Last, MßCD combined with anti-GD2 mAb treatment significantly enhanced the antitumor effect and the infiltration of CD8+ T cells. CONCLUSIONS: Upregulation of B3GALT4 promotes the secretion of CXCL9 and CXCL10 to recruit CD8+ T lymphocytes via the GD2-mediated lipid rafts and the c-Met/AKT/mTOR/IRF-1 pathway. Moreover, lipid raft inhibitors may enhance the efficacy of anti-GD2 immunotherapy for NB.

Development of a risk-scoring system to evaluate the serosal invasion for macroscopic serosal invasion positive gastric cancer patients.

BACKGROUND: The status of serosal invasion is often discordance between pathological and intraoperative evaluation. Our study sought to develop a risk-scoring system (RSS) to predict the probability of pT4a for macroscopic serosal invasion (MSI) positive patients and reevaluate the serosal invasion status. PATIENTS AND METHODS: A total of 1301 pT3/pT4a gastric cancer patients with curative surgery were reviewed. We constructed the RSS to predict the probability of pT4a and assigned MSI-positive patients into different risk groups based on the risk scores. The prognostic significance of these risk groups was also evaluated. RESULTS: Univariate and multivariate analyses identified that tumor location, Lauren type, Borrmann type, tumor size, lymphovascular invasion and pN stage were risk factors related to pT4a. Survival analyses showed that pT3 MSI-positive patients in high-risk group had similar survival with pT4a patients. We incorporated these two groups into one stage and proposed a novel revised-T stage. Two-step multivariate analyses indicated that the revised-T stage showed better prediction ability for prognosis and peritoneal recurrence assessment than original pT stage and MSI status. CONCLUSIONS: In our present study, we developed a RSS to predict the probability of pT4a for MSI-positive patients. Based on our RSS, we proposed a treatment algorithm to reevaluate the tumor invasion for MSI-positive patients in clinical practice. Future studies should include other preoperative predictors to improve the clinical utility of our model.

Alcohol drinking and gastric cancer risk: a meta-analysis of observational studies.

BACKGROUND: Many studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta-analysis of observational studies to explore the association. MATERIALS AND METHODS: We searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose-response analysis to quantify the association. Cochran Q test and I2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed. RESULTS: 75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15-1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01-1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98-1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03-1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06-1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84-1.16, P = 0.857) for wine drinking. CONCLUSIONS: Our meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research.

The clinicopathological and prognostic significances of CDC73 expression in cancers: a bioinformatics analysis.

CDC73 interacts with human PAF1 complex, histone methyltransferase complex and RNA polymerase II for transcription elongation and 3' end processing. Its down-regulated expression was immunohistochemically detected in gastric, colorectal, ovarian and head and neck cancers, and positively correlated with aggressive behaviors and unfavorable prognosis of malignancies. We performed a bioinformatics analysis by using Oncomine, TCGA and KM plotter databases. It was found that CDC73 mRNA was overexpressed in gastric, lung, breast and ovarian cancers, even stratified by histological subtypes (p<0.05). CDC73 mRNA expression was stronger in gastric intestinal- than diffuse-type carcinomas (p<0.05), and positively correlated with distant metastasis and TNM staging of lung cancer (p<0.05). CDC73 mRNA expression was positively related to both overall and progression-free survival rates of the patients with gastric cancer, even stratified by gender, lymph node involvement, or treatment (p<0.05), while versa for breast cancer (p<0.05). The prognostic significance of CDC73 mRNA was dependent on the datasets and pathological grouping in lung and ovarian cancers. These findings indicated the CDC73 mRNA overexpression was positively linked to carcinogenesis. It is cautious to employ CDC73 mRNA to evaluate the clinicopathological behaviors and prognosis of cancers.

CD147 expression was positively linked to aggressiveness and worse prognosis of gastric cancer: a meta and bioinformatics analysis.

CD147 (also named as Basigin or EMMPRIN) might promote cancer invasion and metastasis by inducing MMP and VEGF synthesis in tumor microenvironment. We performed a systematic meta and bioinformatics analysis through multiple online databases up to March 14, 2017. Up-regulated CD147 expression was found in gastric cancer, compared with normal mucosa (p < 0.05). The male patients with gastric cancer showed higher CD147 expression than the female ones (p < 0.0001). CD147 expression was positively correlated with tumor size, depth of invasion, lymph node metastasis, TNM staging and unfavorable prognosis of gastric cancer (p < 0.05). At mRNA level, CD147 expression was higher in intestinal-type and mixed-type gastric carcinomas than normal tissues (p < 0.05). CD147 mRNA expression was negatively associated with histological grading and dedifferentiation of gastric cancer (p < 0.05). A higher CD147 mRNA expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by clinicopathological features (p < 0.05). These findings indicated that CD147 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

The roles of maspin expression in gastric cancer: a meta- and bioinformatics analysis.

Maspin is a mammary serine protease inhibitor that is encoded by human SERPINB5 gene, and inhibits invasion and metastasis of cancer cells as a tumor suppressor. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to Feb 10, 2017. We found down-regulated maspin expression in gastric cancer, compared with normal mucosa and dysplasia (p < 0.05). Maspin expression was negatively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer (p < 0.05). Nuclear maspin expression was higher in intestinal- than diffuse-type carcinoma (p < 0.05). An inverse association between maspin expression and unfavorable overall survival was found in patients with gastric cancer (p < 0.005). According to bioinformatics databases, SERPINB5 mRNA expression was higher in gastric cancer than normal tissues (p < 0.05), and negatively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer (p < 0.05). According to KM plotter, we found that a higher SERPINB5 expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters (p < 0.05). These findings indicated that maspin expression might be employed as a potential marker to indicate gastric carcinogenesis, subsequent progression, and even prognosis.

The meta and bioinformatics analysis of GRP78 expression in gastric cancer.

GRP78 is a molecular chaperone located in endoplasmic reticulum, and induces folding and assembly of newly-synthesized proteins, proteasome degradation of aberrant proteins, and translocation of secretory proteins, autophagy, and epithelial-mesenchymal transition. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. It was found that up-regulated GRP78 expression in gastric cancer, compared with normal mucosa at both protein and mRNA levels (p < 0.05). GRP78 expression was positively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer (p < 0.05), while its mRNA expression was negatively correlated with depth of invasion, histological grading and dedifferentiation (p < 0.05). A positive association between GRP78 expression and unfavorable overall survival was found in patients with gastric cancer (p < 0.005). A higher GRP78 mRNA expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters, or as an independent factor (p < 0.05). These findings indicated that GRP78 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

A Nomogram for Predicting Overall Survival of Gastric Cancer Patients with Insufficient Lymph Nodes Examined.

Insufficient number of examined lymph nodes (eLNs) was considered to increase significantly the risk of stage migration in gastric cancer patients. The aim of our study is to establish a nomogram predicting the overall survival (OS) for patients with an insufficient number of eLNs. A total of 872 gastric cancer patients with extended lymphadenectomies were assigned randomly (2:1) to the development cohort and the validation cohort. The nomogram was established based on the Cox regression model using the development cohort. The concordance index (C-index) was used to evaluate the discriminative ability. We also compared our model with two other staging systems. Using multivariate analysis, age, sex, tumor location, depth of invasion, macroscopic type, lymphovascular invasion, the number of eLNs, and metastatic lymph nodes were selected and incorporated into the nomogram. The C-index of the nomogram was 0.742 and 0.743 in development and validation cohorts, respectively, which were significantly superior to the C-indices (range 0.705-0.712, all P < 0.001) of American Joint Committee on Cancer (AJCC) seventh edition and lymph node ratio staging systems in both cohorts. We established a nomogram which could predict accurately OS for gastric cancer patients with insufficient number of eLNs.

Rare upper gastrointestinal hemorrhage of cetuximab: A case report.

RATIONALE: cetuximab, an epidermal growth factor receptor inhibitor, is a targeted therapeutic regimen of colorectal cancers. Several common adverse effects have been found, such as cutaneous or gastrointestinal toxicity. However, according to the articles had been published, upper gastrointestinal bleeding (UGIB) is considered to be rare and its mechanism remains unclear. PATIENT CONCERNS: In this report, we presented a 42-year-old male patient with advanced recto-sigmoid cancer. After palliative operation, the patient suffered from complete upper gastrointestinal (GI) obstruction, which was induced by extensive abdominal metastasis of the tumor. Considering his poor condition, we chose the targeted drug, cetuximab, as his further treatment. But after the application of cetuximab, the UGIB immediately happened twice in this patient. DIAGNOSIS: UGIB, as a rare complication of cetuximab, occured to the patient. INTERVENTIONS: We stopped the bleeding with thrombin, hemocoagulase and somatostatin and suspended the subsequent treatment plan of cetuximab. At the same time, anti-shock treatment was given immediately. OUTCOMES: He was died of respiratory and circulatory failure caused by UGIB and advanced tumor eventually. LESSONS: UGIB should be considered as a rare but severe complication of cetuximab. When cetuximab is applied for patients with advanced colon tumors, more cautions should be required if the patients are accompanied by upper gastrointestinal obstruction. In addition, for those patients who suffered from UGIB recently, cetuximab should be prohibited if the Rockall score ranged > 5 points.