T-cell exhaustion: A potential target biomarker of the tumour microenvironment affecting oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (EAC) is one of the most common malignant tumours, and the number of patients is increasing year by year. T-cell exhaustion (TEX) is an important risk factor for tumour immunosuppression and invasion, but its underlying mechanism in the pathogenesis of EAC is not clear. METHODS: Unsupervised clustering was performed to screen relevant genes based on Gene Set Variation Analysis scores of the three pathways of the HALLMARK gene set IL2/IFNG/TNFA. Multiple enrichment analyses and data combinations were used to depict the relationship between TEX-related risk models and CIBERSORTx immune infiltrating cells. In addition, to explore the impact of TEX on EAC therapeutic resistance, we assessed the impact of TEX risk models on the therapeutic sensitivity of various novel drugs using single-cell sequencing and searched for their potential therapeutic targets and cellular communication. RESULTS: Four risk clusters of EAC patients were identified by unsupervised clustering and searched for potential TEX-related genes. Based on this, LASSO regression and decision trees were used to construct risk prognostic models containing a total of three TEX-associated genes in EAC. The results showed that TEX risk scores were significantly associated with the survival prognosis of EAC patients in both the Cancer Genome Atlas dataset and the independent validation set of Gene Expression Omnibus. Immune infiltration and cell communication analyses identified mast cell resting as a protective factor in TEX, and pathway enrichment analyses showed that the TEX risk model was highly associated with multiple chemokines as well as inflammation-associated pathways. In addition, higher TEX risk scores were associated with a weak responsiveness to immunotherapy. CONCLUSION: We describe the immune infiltration, prognostic significance and potential possible mechanisms of TEX in the EAC patient population. This is a novel attempt to promote the development of novel therapeutic modalities and immunological target construction for oesophageal adenocarcinoma. It is expected to make a potential contribution to advancing the exploration of immunological mechanisms and the opening of target drugs in EAC.

Association of gallbladder diseases with risk of gastrointestinal polyps.

BACKGROUND: It has not yet been determined whether gastroscopy and colonoscopy screening help patients with gallbladder diseases. We aim to retrospectively investigate the relationship between gallbladder diseases and gastrointestinal polyps in order to provide a theoretical basis for the early screening of gastrointestinal polyps in patients with gallbladder disease. METHODS: This is a retrospective cross-sectional study involving 1662 patients who underwent gastroscopy, colonoscopy, and abdominal ultrasound as part of their health check-up from January 2015 to July 2020. We also compared the patients with and without gallbladder diseases to determine the prevalence of gastrointestinal polyps. RESULTS: Patients with gallbladder polyps had greater odds of having colorectal polyps (adjusted odds ratio (OR)=1.77, 95% confidence interval [Cl]: 1.23 to 2.54, p=0.002) and gastric plus colorectal polyps (adjusted OR=2.94, 95%Cl: 1.62 to 5.32, p<0.001) than those without. Patients with multiple gallbladder polyps had greater odds of having colorectal polyps (adjusted OR=2.33, 95% CI: 1.33 to 4.07, p=0.003) and gastric plus colorectal polyps (adjusted OR=3.95, 95% CI: 1.72 to 9.11, p=0.001), and patients with gallbladder polyps had greater odds of having left-colon polyps (adjusted OR=1.90, 95% CI: 1.25 to 2.88, p=0.003) and colorectal adenoma (adjusted OR=1.78, 95% CI: 1.19 to 2.66, p=0.005). We also noted that women with gallbladder polyps had a higher prevalence of colorectal polyps (OR=2.13, 95% CI: 1.20 to 3.77, p=0.010) and gastric plus colorectal polyps (OR=3.69, 95% CI: 1.58 to 8.62, p=0.003). However, no positive correlation was observed between gallbladder stones and gastrointestinal polyps. CONCLUSIONS: Gallbladder polyps are significant indicators of colorectal and gastric plus colorectal polyps. Hence, gastroscopy and colonoscopy screening should be performed for patients with gallbladder polyps, particularly female patients and those with multiple gallbladder polyps.

Undifferentiated-predominant mixed-type early gastric cancer is more aggressive than pure undifferentiated type: a systematic review and meta-analysis.

BACKGROUND: Studies have shown that differentiated-predominant mixed-type early gastric cancer (EGC) is more aggressive than pure differentiated-type EGC. However, the biological behaviour of undifferentiated-predominant mixed-type (MU) EGC and pure undifferentiated-type (PU) EGC are controversial. This study was conducted to compare the biological behaviour of MU EGC and PU EGC. METHODS: A systematic review and meta-analysis of observational studies was conducted using literature published through PubMed and Embase from inception to 9 November 2021. Inclusion criteria were: (1) a direct or indirect comparison of MU and PU; (2) patients with EGC; (3) a specified outcome of lymph node metastasis (LNM), lymphovascular invasion, submucosal invasion and/or ulcer findings; and (4) the primary lesion was obtained. The literature search, data extraction and quality assessment were performed by two independent reviewers. The meta-analysis was conducted with a random-effect model using the Mantel-Haenszel method. RESULTS: Twelve publications with 5644 patients were included. Patients with MU EGC had significantly higher risk of LNM (OR 2.28; 95% CI 1.72 to 3.03) and submucosal invasion (OR 2.19; 95% CI 1.90 to 2.52) compared with patients with PU EGC. No difference was found between patients with MU and PU EGC with respect to lymphovascular invasion risk (OR 1.81; 95% CI 0.84 to 3.87). After stratifying the data according to depth of tumour invasion, a significantly higher risk for LNM was associated with intramucosal MU EGC (OR 2.56; 95% CI 1.66 to 3.95) and submucosal MU EGC (OR 2.63; 95% CI 2.06 to 3.06). Submucosal MU EGC also had a significantly higher risk of lymphovascular invasion (OR 2.40; 95% CI 1.79 to 3.21) compared with submucosal PU EGC. DISCUSSION: Patients with MU EGC had an increased risk of submucosal invasion and LNM compared with patients with PU EGC . MU patients with submucosal EGC also had an increased lymphovascular invasion risk compared with PU patients. Therefore, attention should be focused on the clinical management of patients with MU EGC.

Identification of a novel m6A-related lncRNA pair signature for predicting the prognosis of gastric cancer patients.

BACKGROUND: Accumulating studies have demonstrated that lncRNAs play vital roles in the prognosis of gastric cancer (GC); however, the prognostic value of N6-methyladenosine-related lncRNAs has not been fully reported in GC. This study aimed to construct and validate an m6A-related lncRNA pair signature (m6A-LPS) for predicting the prognosis of GC patients. METHODS: GC cohort primary data were downloaded from The Cancer Genome Atlas. We analysed the coexpression of m6A regulators and lncRNAs to identify m6A-related lncRNAs. Based on cyclical single pairing along with a 0-or-1 matrix and least absolute shrinkage and selection operator-penalized regression analyses, we constructed a novel prognostic signature of m6A-related lncRNA pairs with no dependence upon specific lncRNA expression levels. All patients were divided into high-risk and low-risk group based on the median risk score. The predictive reliability was evaluated in the testing dataset and whole dataset with receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis was used to identify potential pathways. RESULTS: Fourteen m6A-related lncRNA pairs consisting of 25 unique lncRNAs were used to construct the m6A-LPS. Kaplan-Meier analysis showed that the high-risk group had poor prognosis. The area under the curve for 5-year overall survival was 0.906, 0.827, and 0.882 in the training dataset, testing dataset, and whole dataset, respectively, meaning that the m6A-LPS was highly accurate in predicting GC patient prognosis. The m6A-LPS served as an independent prognostic factor for GC patients after adjusting for other clinical factors (p < 0.05). The m6A-LPS had more accuracy and a higher ROC value than other prognostic models for GC. Functional analysis revealed that high-risk group samples mainly showed enrichment of extracellular matrix receptor interactions and focal adhesion. Moreover, N-cadherin and vimentin, known biomarkers of epithelial-mesenchymal transition, were highly expressed in high-risk group samples. The immune infiltration analysis showed that resting dendritic cells, monocytes, and resting memory CD4 T cells were significantly positively related to the risk score. Thus, m6A-LPS reflected the infiltration of several types of immune cells. CONCLUSIONS: The signature established by pairing m6A-related lncRNAs regardless of expression levels showed high and independent clinical prediction value in GC patients.