Journal of Gastroenterology最新文献

Background: Systemic chemotherapy with gemcitabine plus S-1 (GEM + S-1), GEM + CDDP plus S-1 (GEM + CDDP + S-1), or gemcitabine plus cisplatin (GEM + CDDP) is standard treatment for advanced biliary tract cancer (aBTC). We aimed to evaluate the efficacy and safety of combination chemotherapy in older patients with aBTC.

Methods: This multicenter prospective observational study (JON2104-B, UMIN000045156) included patients aged ≥ 70 years with aBTC. Inverse-probability weighting propensity-score analyses (IPW) were used to compare overall survival (OS) as the primary endpoint and progression-free survival (PFS) across treatment groups.

Results: This study included 305 patients between August 2021 and January 2023. Of them, 75, 131, 26, 52, and 10 received GEM + CDDP + S-1, GEM + CDDP, GEM + S-1, gemcitabine, and S-1; their median ages were 74, 75, 77.5, 80, and 80 years, and approximately 24%, 16.8%, 23.1%, 9.6%, and 0% had G-8 scores of > 14, respectively. GEM + CDDP had a safety profile comparable to that of GEM + CDDP + S-1 but was more toxic than gemcitabine. Per IPW, the hazard ratio (HR) for GEM + CDDP + S-1 versus GEM + CDDP was 0.80 for OS (95% confidence interval [CI], 0.55-1.17) and 0.55 for PFS (95% CI 0.38-0.80). The HR for GEM + CDDP versus gemcitabine was 0.74 for OS (95% CI 0.42-1.29) and 0.79 for PFS (95% CI 0.42-1.49).

Conclusions: GEM + CDDP + S-1 was associated with longer PFS without additional toxicity than GEM + CDDP for fit older patients. However, the OS for both were not statistically different. The efficacies of GEM + CDDP and gemcitabine for vulnerable older patients did not also differ significantly. These findings highlight the importance of vulnerability in patients with aBTC.

Background: Dietary fatty acids are involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the mechanism by which dietary fatty acid composition affects MASLD pathogenesis.

Methods: The MASLD mouse model was developed by feeding a high-fat diet (HFD) rich in palmitic acid (PA), trans-fatty acids (TFAs), or oleic acid (OA). For in vitro experiments, Hepa 1-6 cells were exposed to PA, elaidic acid (a representative TFA), and OA. Glycerol-3-phosphate acyltransferase 1 (GPAM) expression in Hepa 1-6 cells was manipulated using a plasmid encoding GPAM and GPAM-specific siRNAs. In addition, GPAM depletion in the liver of HFD-fed mice was achieved using a pH-sensitive multifunctional envelope-type nanodevice as a siRNA carrier. Liver specimens from patients with MASLD were also analyzed.

Results: The TFA group displayed higher serum alanine-aminotransferase and hepatic triglyceride content but lower serum fasting triglyceride and visceral adipose tissue (VAT) compared with that in the PA and OA groups. Hepatic GPAM expression in the TFA group was higher than in the PA group. Consistently, TFA-treated Hepa 1-6 cells showed a greater GPAM increase than that with OA and PA. GPAM-overexpressing Hepa 1-6 cells showed increased triglyceride accumulation, whereas GPAM-deficient cells failed to accumulate triglyceride. Hepatic GPAM knockdown in HFD-fed mice suppressed steatosis and increased VAT. Notably, hepatic GPAM gene expression was higher in patients with severe steatosis than in those with non-severe steatosis.

Conclusions: A TFA-rich HFD increased hepatic GPAM expression, exacerbated steatosis, and decreased VAT. Therefore, GPAM may regulate systemic fat accumulation in the body.

Metastatic liver tumors are more common than primary liver cancers and are the most common liver malignancies. Performing B-mode ultrasonography and contrast-enhanced computed tomography is generally necessary for the diagnosis of liver metastases. However, various modalities, including dynamic contrast-enhanced computed tomography and magnetic resonance imaging using liver-specific contrast agents such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid, fluorodeoxyglucose positron emission tomography, and a combination of positron emission tomography and computed tomography, are also used. Improvements in imaging technology have made the detection of small liver masses possible, and liver metastases are being diagnosed more frequently, both before and after primary tumor treatment. The diagnosis of liver metastasis is related to treatment, and the benefits of liver resection depend on the primary tumor. For colorectal cancer, resection of liver metastases is beneficial. However, resection is not recommended for pancreatic or biliary tract cancers.

Background and aims: Hepatitis B e antigen (HBeAg) seroclearance is crucial in the natural history of chronic hepatitis B (CHB). Little is known about the role of hepatitis B core-related antigen (HBcrAg) levels in predicting spontaneous HBeAg seroclearance.

Methods: This retrospective cohort study included 484 treatment-naïve HBeAg-positive CHB patients with an extended follow-up period at National Taiwan University Hospital. The primary endpoint was spontaneous seroclearance of HBeAg. The association between baseline HBcrAg levels and their kinetic patterns with spontaneous HBeAg seroclearance was assessed.

Results: Of 484 patients with a mean follow-up period of 7.80 years, 331 (68.4%) achieved spontaneous HBeAg seroclearance, corresponding to an annual rate of 8.76%. Lower baseline HBcrAg levels correlated with an increased likelihood of HBeAg seroclearance (log-rank P < .001). When HBcrAg kinetics were assessed based on baseline and year 3 levels, patients with HBcrAg levels persistently < 10⁵ KU/mL (HR: 2.66; 95% CI: 1.75-4.04) and those declining to < 10⁵ KU/mL (HR: 2.31; 95% CI: 1.50-3.55) had an increased likelihood of HBeAg seroclearance when compared to those with persistently high HBcrAg levels. This association remained statistically significant in multivariate analysis after adjusting for baseline viral factors. In addition, HBcrAg kinetics were consistently associated with HBeAg seroclearance in immune-tolerant patients.

Conclusions: HBcrAg < 10⁵ KU/mL, or a decline to this threshold, identified HBeAg-positive CHB patients with higher likelihood of spontaneous HBeAg seroclearance. Persistently high HBcrAg may indicate earlier CHB phases and inform management strategies.

Background: Carotegrast methyl is approved for treating patients with moderately active ulcerative colitis with inadequate response to 5-aminosalicylic acid agents. However, real-world evidence to guide optimal use is limited. This retrospective study aimed to characterise suitable patient profiles, identify biomarkers predictive of carotegrast methyl efficacy, and determine the appropriate timing for treatment evaluation.

Methods: We analysed data from 186 patients enrolled in a phase 3 trial of carotegrast methyl (96 carotegrast methyl, 90 placebo). We assessed biomarkers (leucine-rich α-2 glycoprotein, C-reactive protein, faecal calprotectin, and anti-integrin αvβ6 antibody titres) alongside clinical outcomes and assessed symptom diaries and maintenance therapies.

Results: Low disease activity at baseline (partial Mayo score ≤ 5) was associated with higher remission rates (56.1 vs. 33.3%). Anti-integrin αvβ6 antibody titres of < 44.6 U/mL at baseline predicted higher clinical remission rates (49.1 vs. 26.8%). Symptom improvement was detectable from week 2. Faecal calprotectin correlated with the endoscopic subscore at the end of treatment (ρ = 0.566); a faecal calprotectin level of < 387.5 µg/g predicted Mayo endoscopic subscore 0/1. Most patients maintained remission with oral 5-aminosalicylic acid alone; the 1-year maintenance rate was 56.5%.

Conclusions: Carotegrast methyl appears most effective in patients with moderately active ulcerative colitis with low disease activity, with week 2 and beyond as an appropriate time point for assessing efficacy. Anti-integrin αvβ6 antibody titre shows promise in predicting response to carotegrast methyl. Faecal calprotectin may serve as a non-invasive surrogate for evaluating endoscopic healing.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), which is the cancer type with the most dismal prognosis. Since IPMNs are detectable by imaging, they offer a rare window of opportunity for early intervention for PDAC development. Despite their clinical visibility, the molecular pathogenesis of IPMNs remained incompletely understood, and no effective non-surgical therapeutic strategies have been established to date. In the past few decades, however, substantial progress has been made in elucidating their molecular pathology. Next-generation sequencing technologies demonstrated the comprehensive genetic mutation profile of IPMNs in the early 2010s. Elucidation of these mutation profiles enabled the establishment of genetically engineered mouse models, successfully recapitulating the natural development of human IPMNs and their progression to invasive cancer. Rapid evolution of "omics" technologies in recent years has facilitated the application of mass spectrometry, single-cell sequencing and spatial transcriptomics to IPMNs, significantly advancing our understanding of their pathophysiology. These techniques elucidated the changes in transcriptome, proteome, metabolome, microbiome, and tumor microenvironment associated with IPMN development and progression. This review summarizes current insights into the molecular and cellular landscapes of IPMN tumorigenesis, with particular emphasis on the mechanisms driving malignant progression.

Background: Tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations are the mainstay of treatment for gastrointestinal stromal tumors (GISTs). Comprehensive genomic profiling (CGP) has recently been incorporated into routine practice for various solid tumors, facilitating personalized treatment strategies. We elucidated the current status and clinical significance of CGP in patients with advanced GISTs.

Methods: In this multicenter retrospective cohort study, we analyzed 36 patients with unresectable or recurrent GISTs who underwent CGP testing between November 2019 and February 2025. Specimen details, genomic alterations, expert panel assessments, and treatment implementations were collected. Turnaround time and overall survival (OS) were evaluated.

Results: Among the patients, 75% underwent CGP during or post-third-line treatment. Actionable and druggable alterations were identified in 97.2% and 52.8%, respectively. Expert panel-recommended treatment was proposed for 12 patients (33.3%); however, only one received CGP-guided therapy. The median turnaround time and OS from CGP were 63 days (range, 41-100) and 19.9 months (range, 0.8-68.0), respectively. Most patients were microsatellite-stable with low tumor mutational burden. Among non-KIT genes, CDKN2A and CDKN2B alterations were the most frequently identified. Furthermore, patients harboring these alterations showed poorer OS post-recurrence (CDKN2A: HR 3.09, 95% CI 1.17-8.18, p = 0.017; CDKN2B: HR 2.55, 95% CI 0.86-8.18, p = 0.081).

Conclusions: CGP revealed actionable alterations in most patients with advanced GISTs; however, its impact on treatment decisions remains limited under current practice. Early CGP implementation may facilitate access to matched therapies or clinical trials, enabling prognostic stratification in patients with advanced GISTs.

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.

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: 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.