Endoscopic ultrasound-based application system for predicting endoscopic resection-related outcomes and diagnosing subepithelial lesions: Multicenter prospective study.

OBJECTIVES: Subepithelial lesions (SELs) are associated with various endoscopic resection (ER) outcomes and diagnostic challenges. We aimed to establish a tool for predicting ER-related outcomes and diagnosing SELs and to investigate the predictive value of endoscopic ultrasound (EUS). METHODS: Phase 1 (system development) was performed in a retrospective cohort (n = 837) who underwent EUS before ER for SELs at eight hospitals. Prediction models for five key outcomes were developed using logistic regression. Models with satisfactory internal validation performance were included in a mobile application system, SEL endoscopic resection predictor (SELERP). In Phase 2, the models were externally validated in a prospective cohort of 200 patients. RESULTS: An SELERP was developed using EUS characteristics, which included 10 models for five key outcomes: post-ER ulcer management, short procedure time, long hospital stay, high medication costs, and diagnosis of SELs. In Phase 1, 10 models were derived and validated (C-statistics, 0.67-0.99; calibration-in-the-large, -0.14-0.10; calibration slopes, 0.92-1.08). In Phase 2, the derived risk prediction models showed convincing discrimination (C-statistics, 0.64-0.73) and calibration (calibration-in-the-large, -0.02-0.05; calibration slopes, 1.01-1.09) in the prospective cohort. The sensitivities and specificities of the five diagnostic models were 68.3-95.7% and 64.1-83.3%, respectively. CONCLUSION: We developed and prospectively validated an application system for the prediction of ER outcomes and diagnosis of SELs, which could aid clinical decision-making and facilitate patient-physician consultation. EUS features significantly contributed to the prediction. TRIAL REGISTRATION: Chinese Clinical Trial Registry, http://www.chictr.org.cn (ChiCTR2000040118).

Susceptibility-guided sequential strategy versus empirical therapy for Helicobacter pylori infection: study protocol for a randomised controlled trial.

BACKGROUND: New treatment strategies are required against infections caused by Helicobacter pylori, which grows increasingly resistant to antibiotics. Polymerase chain reaction-based methods for antibiotic susceptibility testing are available for detecting H. pylori-specific mutations that confer resistance to clarithromycin and levofloxacin. Several meta-analyses have compared eradication rates for susceptibility-guided versus empirical therapy for H. pylori treatment; however, all have significant limitations and high heterogeneity, and the results are contradictory. The main objective of this trial is to assess whether a sequential strategy based on molecular susceptibility testing-guided therapy for H. pylori has a better eradication rate than empirical therapy. METHODS: This trial is designed as a prospective, randomised, open-label, active-controlled and single-centre study. Men and women who are H. pylori-positive, naïve to treatment, and aged 18-65 years will be recruited. A total of 500 participants will be randomised to receive either empirical therapy or a susceptibility-guided sequential strategy. Bismuth quadruple therapy will be the empirical first-line therapy, and in case of failure, high-dose dual (proton-pump inhibitor + amoxicillin) treatment will be the rescue therapy. For the susceptibility-guided sequential strategy, regimen selection will be based on H. pylori susceptibility to clarithromycin (first-line) and levofloxacin (rescue). A first-line treatment of clarithromycin triple therapy will be selected for clarithromycin-sensitive strains. For clarithromycin resistance, a high-dose dual therapy will be selected. During the rescue treatment, a levofloxacin quadruple regimen will be selected for levofloxacin-sensitive strains, and a furazolidone quadruple regimen will be selected for others. The primary outcome is the first-line eradication rate in both groups, and the overall (including first and rescue therapies) H. pylori eradication rate in both groups is one of the secondary outcomes. The eradication rates of H. pylori will be analysed by intention-to-treat analysis, modified intention-to-treat analysis, and per-protocol analysis. DISCUSSION: This randomised controlled trial will provide objective and valid evidence about the value of polymerase chain reaction-based molecular methods for antibiotic susceptibility testing in guiding H. pylori eradication. TRIAL REGISTRATION: Clinicaltrials.gov NCT05549115. Released on 18 September 2022. First posted on 22 September 2022. Enrolment of the first participant on 20 September 2022. The study is retrospectively registered.

Development and Validation of an Automatic Image-Recognition Endoscopic Report Generation System: A Multicenter Study.

INTRODUCTION: Conventional gastrointestinal (GI) endoscopy reports written by physicians are time consuming and might have obvious heterogeneity or omissions, impairing the efficiency and multicenter consultation potential. We aimed to develop and validate an image recognition-based structured report generation system (ISRGS) through a multicenter database and to assess its diagnostic performance. METHODS: First, we developed and evaluated an ISRGS combining real-time video capture, site identification, lesion detection, subcharacteristics analysis, and structured report generation. White light and chromoendoscopy images from patients with GI lesions were eligible for study inclusion. A total of 46,987 images from 9 tertiary hospitals were used to train, validate, and multicenter test (6:2:2). Moreover, 5,699 images were prospectively enrolled from Qilu Hospital of Shandong University to further assess the system in a prospective test set. The primary outcome was the diagnosis performance of GI lesions in multicenter and prospective tests. RESULTS: The overall accuracy in identifying early esophageal cancer, early gastric cancer, early colorectal cancer, esophageal varices, reflux esophagitis, Barrett's esophagus, chronic atrophic gastritis, gastric ulcer, colorectal polyp, and ulcerative colitis was 0.8841 (95% confidence interval, 0.8775-0.8904) and 0.8965 (0.8883-0.9041) in multicenter and prospective tests, respectively. The accuracy of cecum and upper GI site identification were 0.9978 (0.9969-0.9984) and 0.8513 (0.8399-0.8620), respectively. The accuracy of staining discrimination was 0.9489 (0.9396-0.9568). The relative error of size measurement was 4.04% (range 0.75%-7.39%). DISCUSSION: ISRGS is a reliable computer-aided endoscopic report generation system that might assist endoscopists working at various hospital levels to generate standardized and accurate endoscopy reports (http://links.lww.com/CTG/A485).

CXCR5+CD8+ T cells could induce the death of tumor cells in HBV-related hepatocellular carcinoma.

The follicular CXCR5+CD8+ T cells have recently emerged as a critical cell type in mediating peripheral tolerance as well as antiviral immune responses during chronic infections. In this study, we investigated the function of CXCR5+CD8+ T cells in HBV-related hepatocellular carcinoma patients. Compared to CXCR5-CD8+ T cells, CXCR5+CD8+ T cells presented elevated PD-1 expression but reduced Tim-3 and CTLA-4 expression. Upon anti-CD3/CD28 stimulation, CXCR5+CD8+ T cells demonstrated higher proliferation potency than CXCR5-CD8+ T cells, especially after PD-1 blockade. CXCR5+CD8+ T cells also demonstrated significantly higher granzyme B synthesis and release, as well as higher level of degranulation. Tumor cells were more readily eliminated by CXCR5+CD8+ T cells than by CXCR5-CD8+ T cells. Interestingly, we found that B cells were more resistant to CXCR5+CD8+ T cell-mediated killing than tumor cells, possibly through IL-10-mediated protection. In addition, the CXCR5+CD8+ T cell-mediated cytotoxic effects on tumor cells could be significantly enhanced by PD-L1 blockade. Together, we presented that in patients with in HBV-related hepatocellular carcinoma, CXCR5+CD8+ T cells could mediate tumor cell death more potently than the CXCR5-CD8+ T cells in vitro while the autologous B cells were protected.

CD25-expressing Th17 cells mediate CD8+ T cell suppression in CTLA-4 dependent mechanisms in pancreatic ductal adenocarcinoma.

The tumor-associated immune response is governed by the signalling events of various regulatory molecules, one of which is the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In conventional T cells, CTLA-4 could outcompete CD28 in binding to CD80/86 but does not produce a co-stimulatory signal, resulting in T cell anergy. CTLA-4 in regulatory T cells (Tregs) could also function in a cell-extrinsic fashion by removing CD80/CD86 from the antigen-presenting cells (APCs), thus preventing further priming of other T cells. In this study, we examined the role of CTLA-4 in CD4+ T cell subsets from pancreatic cancer patients. In circulating CD4+ T cells, the expression of CTLA-4 was low at baseline but was significantly upregulated following T cell stimulation. Interestingly, the CTLA-4-expressing CD4+ T cells at baseline were overwhelmingly FOXP3-expressing. With the increase of T cell stimulation, the proportion of ROR gamma t-expressing CD4+ T cells was progressively increased. By CD25 vs. CCR6 staining, the CD25+CCR6+ and the CD25+CCR6- CD4+ T cells both presented high levels of CTLA-4 expression, but only the CD25+CCR6+ and the CD25-CCR6+ expressed significant amounts of IL-17. When incubated with autologous CD8+ T cells, the CD25+CCR6+ Th17 cells presented significantly higher suppressive function than the CD25-CCR6+ Th17 cells in a CTLA-4-dependent manner. Finally, the CTLA-4-expressing Th17 cells were present at higher levels in the tumor-infiltrating lymphocytes than in circulating blood. Overall, these data suggest that CTLA-4 expressing Th17 cells may present regulatory activities in pancreatic cancer patients.

Cytotoxic T-lymphocyte antigen-4 +49G/A polymorphism and susceptibility to pancreatic cancer.

Although pancreatic cancer has been extensively studied, few risk factors have been identified. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays important roles in downregulating T-cell activation, thereby attenuating antitumor responses and increasing cancer susceptibility. The CTLA-4 gene +49G/A polymorphism (rs231775) has been reported to be associated with various cancers. The current study evaluated the association of the CTLA-4 gene +49G/A polymorphism with pancreatic cancer in the Chinese population. Six hundred and two pancreatic cancer patients and 651 healthy controls were investigated for CTLA-4 +49G/A polymorphism by polymerase chain reaction-restriction fragment length polymorphism analysis. Data showed that prevalence of CTLA-4 gene +49 AA genotype and +49 A allele was significantly higher in pancreatic patients compared to controls (odds ratio [OR]=2.20, 95% confidence interval [CI]: 1.23-2.95, p=0.007; OR=1.32, 95% CI: 1.03-1.69, p=0.029; and OR=1.47, 95% CI: 1.03-2.09, p=0.033). These results indicate that the CTLA-4 +49G/A polymorphism is associated with increased risk of pancreatic cancer.