Journal of Gastroenterology最新文献

Objectives: Sedation is increasingly essential for gastrointestinal endoscopy. Remimazolam, an ultra-short-acting benzodiazepine, has a shorter pharmacokinetic half-life than midazolam. The aim of this study was to determine whether remimazolam provides superior procedural sedation in Japanese patients.

Methods: The cohort of this prospective, multicenter, randomized, single-blind controlled trial comprised adults (18-80 years) scheduled for sedated upper gastrointestinal endoscopy. Participants were randomized to remimazolam and midazolam groups. The primary outcome was the proportion of ambulatory patients 5 min after endoscopy. Secondary outcomes were successful pre-procedure sedation (Modified Observer's Assessment of Alertness/Sedation ≤ 4), dose of sedative to achieve sedation, time to ambulation, and adverse events.

Results: From October 2024 to January 2025, 40 patients were enrolled. After excluding two outliers 38 were analyzed (remimazolam, n = 20; midazolam, n = 18). Ambulation at 5 min occurred in 85.0% (17/20) of the remimazolam versus 0.0% (0/18) of the midazolam group (p < 0.0001). Mean time from procedure end to walking was 4.25 min (range 0.0-10.0) for remimazolam and 35.56 min (10.0-60.0) for midazolam (p < 0.0001). Pre-procedure sedation was successful (MOAA/S ≤ 4) in 100% of both groups. Mean doses to achieve sedation were 4.30 mg (3.0-7.0) for remimazolam and 3.11 mg (2.0-5.0) for midazolam (p = 0.003). Hypoxemia occurred in 5.0% of the remimazolam and 33.3% of the midazolam group (p = 0.038).

Conclusions: In upper gastrointestinal endoscopy, remimazolam achieved markedly faster recovery and a lower incidence of hypoxemia than midazolam. Rates of achieving target sedation were equivalent. These findings indicate remimazolam is an effective and potentially safer sedative option for Japanese patients undergoing endoscopy.

Trial registration: This research was registered with the Japan Registry of Clinical Trials (trial number jRCTs071240062) on September 26, 2024.

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: The transient receptor potential cation channel subfamily V member 6 (TRPV6) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of TRPV6-related pancreatitis and the impact of pancreas-specific deletion of Trpv6 on pancreatitis in mice.

Methods: Clinical information of the patients carrying functionally impaired TRPV6 variants, defined by Ca²⁺ imaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan-Meier analysis. As controls, Japanese patients with alcohol-unrelated pancreatitis carrying pathogenic variants in PRSS1 or SPINK1, as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific Trpv6 conditional knockout mouse was established by crossing the Trpv6 floxed mouse and the Pdx-1-Cre mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein.

Results: Ninety-four patients with functionally impaired TRPV6 variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16 years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30 years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50 years, respectively. Pancreas-specific Trpv6 knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells.

Conclusions: Functionally impaired TRPV6 variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.

Background: The long-term local control and effect of photodynamic therapy (PDT) using talaporfin sodium and a diode laser (talaporfin PDT) on overall survival (OS) for local failure after chemoradiotherapy (CRT) for esophageal cancer are unknown. Here, we present a 5-year survival analysis for talaporfin PDT.

Methods: This was a prospective follow-up analysis of an open-label, multicenter, phase 2 study of local failure after CRT or radiotherapy in patients who received talaporfin PDT. The primary endpoint was the overall OS. The secondary endpoints were progression-free survival (PFS), local progression-free survival (L-PFS) with local progression or recurrence and death as events, and local time to progression (L-TTP) with only local progression or recurrence as events.

Results: Between November 2012 and December 2013, 26 patients with oesophageal squamous cell carcinoma underwent talaporfin PDT. The baseline T stages were cT1 in 14 patients, cT2 in 6 patients, and cT3 in 6 patients. Pre-PDT T stages were cT1b for 19 and cT2 for 7 patients, and no lymph nodes or distant metastases were detected. At a median 6.8-year follow-up, the median OS and 5-year OS rates were 4.2 years (95% confidence interval [CI]: 1.6-7.3) and 40.6% (95% CI: 21.7-58.7), respectively. The median PFS and L-PFS were 1.1 and 2.1 years, respectively. The 5-year local progression-free rate was 84.9%. No treatment-related deaths occurred.

Conclusion: Talaporfin PDT for patients with oesophageal cancer with local failure after CRT can achieve long-term local complete response and long-term survival as a minimally invasive salvage treatment.

Trial registration number: UMIN000009184.

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.

Background: We sought to evaluate the predictive value of protease-3 (PR3)-anti-neutrophil cytoplasmic antibodies (ANCAs) and myeloperoxidase (MPO)-ANCA for primary nonresponse (PNR) to biologic agents in patients with ulcerative colitis (UC).

Methods: A multicenter, prospective cohort study was conducted. Patients with UC who initiated biologic agents (anti-TNF, anti-integrin, or anti-IL12/23 agents) as their first-line therapy were enrolled. PNR was defined as failure to achieve a partial Mayo Score improvement of at least 2 points by weeks 14-16 or necessitating treatment modification. Logistic regression identified PNR predictors.

Results: Among 95 biologic-naïve UC patients, 38 received anti-TNF, 39 received anti-integrin, and 18 received anti-IL12/23 agents. PR3-ANCA positivity was observed in 47.4% of anti-TNF recipients. The PNR rate among PR3-ANCA-positive patients receiving anti-TNF therapy was 66.7%, significantly higher than in PR3-ANCA-negative patients (25.0%, P = 0.02). Multivariate logistic regression confirmed PR3-ANCA as an independent risk factor for PNR to anti-TNF therapy (OR 5.61; 95% CI 1.37-26.82; P = 0.02). By contrast, PR3-ANCA did not predict PNR to anti-integrin therapy, but the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammatory index (SII) were identified as significant predictors. Only one of 95 patients tested positive for MPO-ANCA, precluding statistical analysis for its association with PNR.

Conclusion: In patients with UC, PR3-ANCA is a significant predictor of PNR to anti-TNF therapy, but not to anti-integrin therapy. PLR and SII may predict PNR to anti-integrin therapy. PR3-ANCA could aid biologic selection, optimizing personalized UC treatment and healthcare resource utilization.

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.