Journal of Gastroenterology最新文献

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited treatment options and a poor prognosis. Although immune checkpoint inhibitor (ICI)-based chemotherapy has recently been introduced as a first-line treatment, clinical responses remain highly variable. Currently, no reliable molecular biomarkers are available to predict the therapeutic efficacy of ICC.

Methods: We conducted a retrospective, multicenter cohort study of 25 patients with unresectable ICC treated with gemcitabine, cisplatin, and durvalumab (GCD therapy) between September 2022 and August 2024. Comprehensive genomic profiling was performed in 19 patients (76%) to identify genomic alterations. In selected cases, spatial transcriptomic analysis using the Xenium platform was employed to characterize tumor-immune spatial dynamics.

Results: The median progression-free survival (PFS) was 7.8 months (95% CI: 3.6-10.6), and the median overall survival (OS) was 11.1 months (95% CI: 6.9-18.6). Among genomic alterations, TP53 mutation was the only independent predictor of shorter PFS in multivariate analysis (HR: 4.20; p = 0.036). TP53-mutant tumors were associated with significantly shorter PFS (p = 0.011) and a trend toward worse OS (p = 0.051). Spatial transcriptomic profiling revealed a distinct immunosuppressive microenvironment in TP53-mutated tumors marked by poor CD8⁺ T-cell infiltration, enrichment of CD109⁺ tumor-associated macrophages, and downregulation of antigen-presentation genes TAP1 and TAP2.

Conclusions: This study is the first to identify TP53 mutation as a biomarker of resistance to ICI-based therapy in ICC, and to uncover its immune-evasive phenotype using spatial profiling. These findings provide mechanistic insight into immune evasion and support the development of TP53-guided immunotherapeutic strategies in ICC.

Background: This study aimed to evaluate whether laparoscopic splenectomy and azygoportal disconnection (LSD) can promote decompensated cirrhotic portal hypertension (CPH) patients to achieve recompensation as defined by Baveno VII.

Methods: This retrospective study reviewed clinical records and follow-up data of decompensated CPH patients diagnosed with gastroesophageal variceal bleeding (GEVB) and hypersplenism at our hepatobiliary center from 2013 to 2023. According to treatment strategy, patients were categorized into the LSD arm or the endoscopic therapy (ET) arm. Post-treatment liver function, incidence of decompensation events, recompensation, and overall survival were analyzed across the two arms. Furthermore, the mediating effect of LSD on survival through recompensation was analyzed.

Results: This study enrolled 568 eligible patients, with 300 undergoing LSD and 268 receiving ET. Most patients in both groups showed varying degrees of liver function improvement post-treatment. Overall, 307 patients (54.05%) met the Baveno VII criteria for recompensation. More patients achieved recompensation among those treated with LSD as opposed to ET (73.0% VS. 32.8%, OR = 4.569; 95% CI 3.088-6.760; P < 0.001). Mediation assessment indicated that recompensation accounted for 43.3%, 32.4%, and 16.4% of the effect of LSD on mortality at 3, 5, and 8 years, respectively. Furthermore, younger patients were more likely to achieve recompensation after LSD.

Conclusions: LSD was found to significantly promote recompensation and extend survival in decompensated cirrhosis patients with CPH bleeding and hypersplenism.

Crohn's disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel diseases (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. IBD are multifactorial diseases with a complex etiology, involving an intricate interaction between environmental and genetic factors. Since the discovery of NOD2 gene in 2001, genome-wide association studies have reported more than 200 IBD susceptibility loci. The strongest associations highlighted five main pathways as altered in IBD: bacterial sensing (NOD2), autophagy (ATG16L1, IRGM…), endoplasmic reticulum stress (XBP1, ARG2…), Th-17 immune pathway (IL23-receptor), and the vitamin D receptors (VDR). The pathophysiology of IBD results from an abnormal immune response toward an altered gut microbiota. Although the primum movens remains unknown, an increased intestinal permeability is clearly involved in the genesis of this abnormal crosstalk, leading to whole tissue inflammation. Thus, an excessive intestinal permeability, or "leaky gut", has been described to precede the development of CD. Moreover, in IBD, intestinal permeability is described to be a sensitive prognostic indicator of relapse in patients with quiescent IBD. Thus, the aim of this review is to highlight the molecular and cellular mechanisms by which the main pathways associated with IBD could contribute to alter the intestinal permeability to favour and/or exacerbate chronic inflammation, leading to debilitating diseases.

Background: Immune-mediated adverse events (imAEs) are a significant concern in patients with unresectable hepatocellular carcinoma (uHCC) undergoing combination immunotherapy with durvalumab and tremelimumab (Dur/Tre). This study aimed to investigate the potential association of risk factors, particularly nutrition and immune markers, associated with the development of imAEs.

Methods: Between November 2022 and December 2024, 312 patients with uHCC treated with Dur/Tre were enrolled and retrospectively analyzed. Clinical characteristics, inflammatory markers, and nutritional indices (Geriatric Nutritional Risk Index [GNRI], body mass index, Prognostic Nutritional Index-Onodera, C-reactive protein-to-albumin ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio) were evaluated to identify predictors for imAE development.

Results: The imAEs occurred in 122 patients (39.1%), most commonly affecting dermatological, gastrointestinal, and endocrine systems. On multivariate analysis, only normal GNRI (≥ 98) was independently associated with a higher incidence of imAE (odds ratio: 1.99, 95% confidence interval: 1.05-3.79, P = 0.036). Patients with GNRI ≥ 98 also showed better overall survival (OS) than those with GNRI < 98 (not reached vs. 12.5 months, P < 0.001). Among patients who developed imAEs, no significant differences were observed in the imAE types or high-dose steroid use between the GNRI ≥ 98 group (n = 66) and the GNRI < 98 group (n = 56) (40.9% vs. 58.9%, P = 0.069).

Conclusions: Normal GNRI status (≥ 98) was associated with an increased risk of imAE development and improved OS in patients with uHCC receiving Dur/Tre therapy. GNRI may be a useful clinical factor for identifying patients at higher risk of developing imAEs.

Background: In Japan's deceased-donor liver transplantation (DDLT), a new allocation policy based on the Model for End-Stage Liver Disease (MELD) score, including the exceptional MELD system (Ex-MELD), which periodically assigns additional points to the basal MELD score, was implemented in May 2019. We assessed the current state of this system for adult candidates with chronic end-stage liver disease.

Methods: Adult candidates (≥ 18 years) registered in the Japan Organ Transplant Network for DDLT as Status 2 cases (including chronic end-stage liver disease patients) between May 2019 and April 2023 were evaluated. We divided them into the MELD, Ex-MELD (major) [start 16 points, 2 points by 180 days], and Ex-MELD [hepatocellular carcinoma (HCC)] groups. Transplant probability and waitlist mortality rates were compared using competing risk analyses. The annual proportion of DDLT and the transition of median MELD at transplantation were also investigated.

Results: There were 757 candidates in MELD,126 in Ex-MELD (major), and 99 in Ex-MELD (HCC) groups. The transplant probability rates were not significantly different (3-year transplant probability rate; MELD: 24.0% vs. Ex-MELD (major): 21.0% vs. Ex-MELD (HCC): 24.1%). The rate in the Ex-MELD (major) increased dramatically as the waiting period lengthened. The waitlist mortality rates in the Ex-MELD (major) group were significantly lower (3-year waitlist mortality rate; MELD: 50.5% vs. Ex-MELD (major): 25.0% vs. Ex-MELD (HCC): 57.0%). Although the proportion of Ex-MELD (major) increased yearly in the transplanted cases, the median MELD at transplantation did not change significantly.

Conclusions: We clearly showed the current status of adult Status 2 candidates.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. Immunotherapy, though effective in various tumors, has limited efficacy in PDAC due to immune tolerance. Thus, identifying new targets to enhance immunotherapy response is crucial.

Methods: This study used bioinformatics analysis and public database data to identify STYK1 as a potential PDAC biomarker. We analyzed STYK1 expression in PDAC tissues, its link to patient prognosis and immune cell infiltration. In vitro experiments assessed the impact of STYK1 knockdown on PDAC cell proliferation, migration, and invasion. Immunohistochemical analysis was performed on 79 PDAC tissue samples to evaluate CD8⁺ T cell infiltration. In vivo studies examined the effects of STYK1 knockdown on tumor growth, T cell infiltration and activation, especially with anti-PD-L1 antibodies. We also investigated the molecular mechanisms of STYK1's regulation of T cell infiltration, focusing on its association with CCL20 and its role beyond the PD-1/PD-L1 pathway.

Results: Elevated STYK1 expression in PDAC tissue is associated with poor prognosis and reduced CD8⁺ T cell infiltration. STYK1 knockdown inhibits PDAC cell proliferation, migration, and invasion in vitro. In vivo, it decreases tumor growth and, when combined with anti-PD-L1 antibody treatment, significantly enhances T cell infiltration and activation without affecting PD-L1 expression. STYK1 regulates T cell infiltration via CCL20, independently of the PD-1/PD-L1 signaling pathway.

Conclusions: STYK1 is a potential predictive biomarker for immunotherapy response in PDAC, as its regulation of T cell infiltration via CCL20, independent of the PD-1/PD-L1 pathway, may provide a strategy to potentially augment immunotherapy efficacy, pending mechanistic confirmation.

Background & aim: The course of ulcerative colitis (UC) involves successive periods of remission and exacerbation but is difficult to predict. Gut dysbiosis in UC has already been intensively investigated. However, are periods of exacerbation and remission associated with specific disturbances in the composition of the intestinal microbiota and its metabolome? Our goal was to answer this question and to identify bacteria and metabolites necessary to maintain the remission.

Methods: We enrolled 65 individuals, including 20 UC patients in remission, 15 in exacerbation, and 30 healthy controls. Metagenomic profiling of the gut microbial composition was performed based on 16S rRNA V1-V9 sequencing. Stool and serum metabolic profiles were studied by chromatography combined with mass spectrometry.

Results: We revealed significant differences in the gut bacterial and metabolic composition between patients in active UC and those in remission, as well as in healthy controls. As associated with UC remission we have identified following bacteria: Akkermansia, Agathobacter, Anaerostipes, Enterorhabdus, Coprostanoligenes, Colinsella, Ruminococcus, Subdoligranulum, Lachnoclostridium, Coriobacteriales, Erysipelotrichaceae, and Family XII, and compounds - 1-hexadecanol, phytanic acid, squalene, adipic acid, cis-gondoic acid, nicotinic acid, tocopherol gamma, ergosterol and lithocholic acid. Whereas, in the serum lithocholic acid, indole and xanthine were found as potential candidates for biomarkers of UC remission.

Conclusion: We have demonstrated that specific bacteria, metabolites, and their correlations could be crucial in the remission of UC among Polish patients. Our results provide valuable insights and a significant source for developing new hypotheses on host-microbiome interactions in diagnosis and course of UC.

Ferroptosis is a form of nonapoptotic cell death that is driven by iron-dependent lipid peroxidation and is relevant to a wide range of biological processes, such as development, aging, immunity, and cancer. Ferroptosis has also been linked to numerous hepatic metabolic pathways, including the metabolism of iron, fatty acids, and amino acids, such as cysteine. During the last decade, studies on the biology of and molecules regulating ferroptosis have shed light on the role of ferroptosis in liver disease and its implications. The susceptibility of liver cells to ferroptosis determines the extent of liver injury and affects the progression of nonneoplastic diseases, whereas liver cancer cells display intrinsic or acquired resistance to ferroptosis, which promotes cancer progression. These findings indicate that ferroptosis represents a promising target for the prevention and treatment of many forms of liver disease. In this review, we provide an update on the mechanisms regulating ferroptosis, focusing on the peroxidation of phospholipids, the antioxidant pathways that limit lipid peroxidation, and the regulation of the labile iron pool, all of which are closely connected. We also summarize the roles and importance of ferroptosis in the pathogenesis of liver disease, and the therapeutic potential of targeting ferroptosis in liver diseases.

Background: Various subtypes of tumor-infiltrating lymphocytes (TILs) are associated with prognosis in various cancer types. In esophageal squamous cell carcinoma (ESCC), TILs have been associated with prognosis in advanced stages of the disease. However, their significance in superficial esophageal squamous cell carcinoma (SESCC) remains unknown. In this study, we investigated the role of TILs in SESCC.

Methods: First, we included 212 SESCC lesions with a diameter of 10-20 mm (65 pT1a-EP, 74 pT1a-LPM,40 pT1a-MM, and 33 pT1b-SM lesions) that were resected at our hospital from November 2007 to December 2019. We then examined changes in TILs related to tumor invasion. We evaluated the phenotype and number of TILs using triple immunofluorescence staining for CD4, CD8, and FoxP3. In addition, we selected 97 consecutive pT1b-SM lesions treated during the same period. These specimens were used to examine the association between TILs and lymph node metastasis (LNM) in pT1b-SM cases.

Results: The number of CD4 + , CD8 + , and FoxP3 + TILs infiltrating the tumor increased significantly with increasing invasion depth. In pT1b-SM lesions, CD4 + , CD8 + , and FoxP3 + TIL counts were significantly higher in the invasive front (IF) than in the tumor center (CT). Moreover, in patients undergoing surgical resection or endoscopic submucosal dissection (regardless of additional chemoradiotherapy), the number and ratio of FoxP3 + TILs in IF were significantly higher in patients with LNM than in those without, suggesting their potential utility as predictive biomarkers.

Conclusions: The number and ratio of FoxP3 + TILs in the IF may be an indicator of LNM risk in SESCC.

Background: Reprogramming glucose metabolism is a hallmark of human cancer during its occurrence and development. However, the comprehensive glycometabolism signature and underlying mechanism in CRC prognosis and immune response remind to be elucidated.

Methods: A prognostic model derived from 297 glycometabolism-related genes (GRGs) was developed using LASSO-Cox and nomogram algorithms. Immune dysfunction between high-risk (Risk^H) and low-risk (Risk^L) groups was compared using CIBERSORT, TIMER, and TIDE analyses. The expression and function of key genes, including secreted frizzled-related protein 2 (SFRP2), were validated using PCR, western blotting, immunohistochemistry, transwell assays, and metastatic model in mice. Luciferase reporter and chromatin immunoprecipitation were used to determine the transcription regulation of ENO2 by TCF4.

Results: More than half of the GRGs (152 out of 297) showed differential expression, mainly those associated with glycolysis and biosynthesis. The GRG-risk score outperformed other clinical indicators (AUC = 0.810) and served as an independent risk predictor (P < 0.001, HR = 3.180). The Risk^H group showed increased infiltration of immune cells and higher immune checkpoint expression. Mechanistically, SFRP2, a key gene in Risk^H, promoted CRC glycolysis and metastasis via enolase 2 (ENO2) activation through the TCF4/β-catenin axis. Inhibiting ENO2 reversed SFRP2-induced metastasis. Coexpression of SFRP2 and ENO2 correlated with poorer survival and higher recurrence.

Conclusion: The Risk^H group is characterized by glycolysis overactivation and immune exclusion. SFRP2 and ENO2 have emerged as promising treatment targets for high-risk CRC patients.