Journal of Gastroenterology最新文献

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.

Objectives: This study aimed to clarify the current clinico-epidemiological characteristics of acute pancreatitis (AP) in Japan.

Methods: We conducted a two-stage nationwide survey of patients with AP treated at selected hospitals in 2021, during the COVID-19 pandemic. The first stage estimated the total number of AP patients, while the second collected detailed clinical data.

Results: The estimated number of AP patients requiring hospitalization was 61,080, with an overall incidence rate of 49 per 100,000 persons, decreasing from 78,450 in 2016. Detailed clinical data were obtained for 4,375 patients, including 1,362 (31.1%) classified as severe. The male-to-female ratio was 2.0, with mean ages at onset of 60.1 years for males and 65.4 years for females. The three major causes were alcohol (31.2%), gallstones (22.5%), and idiopathic etiology (22.1%). The AP-associated in-hospital mortality rate was 2.1% in all AP and 5.3% in severe cases, down from 6.1% in the 2016 survey. Antibiotics were administered to 61.2% of mild cases, a significant reduction from 94.5% in 2016. Enteral nutrition was provided to 56.9% of severe cases, up from 31.8% in 2016. Among 124 patients undergoing interventional drainage for walled-off necrosis, 57 were treated using a step-up approach. Notably, no patients underwent upfront surgery as the initial treatment.

Conclusions: During the pandemic, the estimated number of AP cases requiring hospitalization declined for the first time in nearly four decades. Mortality in severe cases improved, and adherence to clinical guidelines on prophylactic antibiotics and enteral nutrition also improved, indicating enhanced management of AP in Japan.

Background: This study examines the influence of H. pylori eradication policies on gastric cancer incidence rates in Japan utilizing nationally representative registry data. It evaluates the impact of the H. pylori eradication policies introduced in 2000 and 2013, along with future eradication scenarios, on age-standardized gastric cancer rates.

Methods: Data from prefectural cancer registries and national health surveys were analyzed using Poisson regression and autoregressive integrated moving average models. Predictors such as H. pylori prevalence, alcohol consumption, salt intake, body mass index, and smoking prevalence were included. The study assessed past policies by comparing incidence rates with and without the policy changes of 2000 and 2013. Future policies were evaluated through five scenarios, incorporating the cumulative impact of eradication efforts from 2000 and 2013, and a projected 75% reduction by 2050. The evaluation also compared eradication targets for age groups 40-69 and 20-39.

Results: Past H. pylori eradication policies were associated with decreased age-standardized gastric cancer incidence rates in Japan, reducing the rate from a projected 39.3 per 100,000 without the 2000 and 2013 policies to 24.9 per 100,000 under current policies. Future policies, integrating the cumulative effects of the 2000 and 2013 eradication efforts and projecting a 75% reduction in H. pylori prevalence, were projected to further reduce gastric cancer incidence.

Conclusion: The H. pylori eradication policies of 2000 and 2013 have significantly reduced gastric cancer incidence rates in Japan. Model projections suggest that expanded eradication efforts could lead to additional reductions, further lowering the future burden of gastric cancer in Japan.

Background: Long-term effects of direct-acting antiviral (DAA) on hepatic reserve and prognosis in hepatitis C virus (HCV)-related decompensated cirrhosis remain unclear.

Methods: Ninety-four patients from a follow-up study of the Japanese phase 3 trial of DAA treatment for decompensated cirrhosis were included.

Results: Twelve, seventy-seven, and ten percent of patients had Child-Pugh class A/B/C, respectively. The sustained virologic response (SVR) rate was 93.6%. The proportion of Child-Pugh A patients was 21% at end of treatment (EOT), and 40%, 42%, 49%, 40% at 24 weeks, 1 year, 3 years, and 5 years after EOT, respectively. A significant breakpoint for Child-Pugh class improvement to A was observed between 24 weeks and 1 year after EOT. The proportions of patients with albumin levels > 3.5 g/dl increased from 11% (baseline) to 39% (5 years after EOT), and significant breakpoint for this improvement was observed between 12 and 24 weeks after EOT. During the 4.8 years from EOT, 19 patients died, and 1 underwent liver transplantation (LT). The five-year LT-free survival rate was 74.7%. Multivariate analysis identified virologic response and Child-Pugh class at 12 weeks after EOT as significant LT-free survival predictors. The four-year LT-free survival rates were 91.5% for SVR patients and 33.3% for virologic failure patients.

Conclusions: In HCV-related decompensated cirrhosis, 5 year LT-free survival rate after DAA was 74.7%, and viral clearance and post-treatment Child-Pugh class were associated with long-term prognosis. Child-Pugh class improved until 24 weeks after EOT, but little change was observed thereafter, which was closely associated with albumin levels.

Background: Peutz-Jeghers syndrome (PJS), a rare genetic disorder characterized by hamartomatous gastrointestinal polyps, poses increased risks of various cancers. Despite the importance of early intervention, the optimal timing for jejunal-ileal polypectomy remains unclear owing to the limited number of comparative studies.

Methods: Herein, we conducted a nationwide survey in Japan and analyzed data from 184 patients with PJS identified through a two-stage sampling process. The initial screening of 2912 medical institutions yielded 1748 facilities, of which 1077 responded to the survey. Time-dependent Cox proportional hazards models and logistic regression analyses were used to examine the association between the timing of jejunal-ileal polypectomy and the risk of surgery for intussusception.

Results: Among 184 patients (47.0% women; mean age, 33.5 years), intussusception was the most common complication (67.7%). In the Cox proportional hazards analysis excluding surgeries within 1 year of diagnosis, early jejunal-ileal polypectomy was associated with a reduced risk of surgery for intussusception (adjusted hazard ratio, 0.17; 95% confidence interval [CI] 0.04-0.74, p = 0.018). Logistic regression analysis showed higher odds of surgery in the late treatment group compared with the early treatment group (adjusted odds ratio, 4.26; 95% CI 1.38-13.16, p = 0.012).

Conclusions: Early jejunal-ileal polypectomy may reduce the risk of intussusception in patients with PJS. However, the need for frequent endoscopic procedures must be balanced considering patient burden. These findings support the importance of early intervention and highlight the need for optimized surveillance strategies that consider clinical effectiveness and patients' quality of life.

Background: Pancreaticobiliary maljunction (PBM) contributes to epithelial hyperplasia and, ultimately, the development of gallbladder cancer (GBC). Despite its clinical significance, the molecular and cellular mechanisms driving carcinogenesis in GBC with PBM remain poorly elucidated. This study investigated the oncogenic mechanisms, biomarkers, and performance associated with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeted therapies in GBC with PBM.

Methods: Overall, 127 surgically treated patients were stratified as follows: Group A, normal gallbladder; Group B, PBM; Group C, GBC without PBM; and Group D, GBC with PBM. We performed whole-exome sequencing (WES) for Group D and human epidermal growth factor receptor 2 immunohistochemistry (HercepTest) for the entire cohort. Fluorescence in situ hybridization (FISH) was used to clarify human epidermal growth factor receptor 2 (HER2) expression in cases with equivocal HercepTest results.

Results: ERBB2 amplification was detected in 50% of Group D patients. The proportion of HER2 protein expression scores ≥ 2 + was highest in Group D compared with that in the other groups (50.0% vs. 0% in Groups A and B and 15.6% in Group C) (P = 0.006, chi-squared test). Finally, 37.5% and 13.3% of cases in Groups D and C, respectively, showed HER2 overexpression (P = 0.037, chi-squared test).

Conclusions: This is the first evaluation of HER2/ERBB2 expression in GBC with PBM based on WES, HercepTest, and FISH. The significant increase in ERBB2 expression, driven by the synergistic interplay between GBC and PBM, underscores a critical molecular interaction that may inform the development of targeted therapeutic strategies.

Aim: We investigated the usefulness of serum CXCL10 levels for predicting prognosis in hepatitis C virus (HCV)-infected patients with compensated and decompensated cirrhosis (cLC and dLC) after direct-acting antiviral (DAA) therapy.

Methods: This nationwide multicenter study enrolled 212 HCV-associated LC patients, consisting of 113 cLC and 99 dLC patients, receiving DAA therapy, who had preserved serum samples. Serum CXCL10 levels were measured at pretreatment (pre-CXCL10) and posttreatment (12 or 24 weeks after the end of treatment: EOT12W or EOT24W) (post-CXCL10). We evaluated the relationship between these levels and liver transplantation (LT)-free overall survival (OS) and clinical outcomes.

Results: During the observational period (median: 37 months), 27 patients developed dLC events and 20 died. The post-CXCL10 levels were significantly higher in dLC than in cLC (P = 0.006) and among patients who died than those who survived (P < 0.001). The cutoff value of serum post-CXCL10 level for discriminating the occurrence of death (345 pg/mL) could predict LT-free OS in groups of all, cLC, and dLC patients (P < 0.001, P = 0.007, and P < 0.001, respectively). Multivariate analysis on factors associated with LT-free OS demonstrated that age (HR 1.076; P = 0.013), Child-Pugh score at EOT12W (HR 1.575; P = 0.009), and serum post-CXCL10 level (HR 1.003; P = 0.001) were independent factors.

Conclusions: The serum post-CXCL10 level was independently related to survival in HCV-associated LC patients.

Background: The incidence of gastric cancer among younger patients is increasing globally, with growing attention being paid to the role of homologous recombination deficiency (HRD). However, the effect of HRD on treatment outcomes and prognosis in this population remains unclear.

Methods: We analyzed clinical and genomic data from the Center for Cancer Genomics and Advanced Therapeutics database. Younger patients (≤ 39 years, n = 140) were compared with older patients (≥ 65 years, n = 1118) diagnosed with gastric cancer. This study focused on mutations in homologous recombination repair (HRR) genes and their association with tumor mutation burden (TMB), microsatellite instability (MSI), and treatment outcomes.

Results: In older patients, HRD was associated with higher TMB and microsatellite instability-high (MSI-H) status, whereas no such correlations were observed in younger patients. Notably, MSI-H status was not observed in the younger group. Younger patients with HRD had a significantly shorter time to treatment failure (TTF) and overall survival (OS) than those without HRD. Conversely, in older patients, there was no significant difference in TTF or OS based on HRD status.

Conclusion: HRR gene mutations influence genomic profiling, TMB, and MSI differently depending on the age of gastric cancer onset, suggesting potential effects on treatment efficacy and prognosis.

Background: Increasing evidence reveals that immune cells significantly contribute to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant has been linked to hepatic inflammation and fibrosis; however, its role in immune cell infiltration and activation within the liver remains unclear.

Methods: Seventy patients with MASLD were prospectively enrolled. Genomic DNA was extracted from buccal swabs or liver biopsy samples, followed by single nucleotide polymorphism genotyping to determine the rs738409 SNP genotype at codon 148 of PNPLA3. Immunohistochemistry was conducted using CD3 and CD68 antibodies to quantify T cell and macrophage infiltration, respectively. Total RNA extracted from biopsy specimens was used for quantitative reverse transcription polymerase chain reaction to assess the expression of specific markers associated with immune cell activation.

Results: Among the 70 patients with MASLD, 34 had the GG genotype, whereas 21 and 15 had the GC and CC genotypes, respectively. The GG genotype group showed a higher proportion of advanced fibrosis (F3 or F4) than the GC + CC group (P = 0.051). GG genotype carriers exhibited significantly higher CD3⁺ and CD68⁺ cell counts in the periportal region than the GC/CC carriers (P < 0.05). The transcriptomic analysis revealed elevated expression of markers associated with chronic antigen stimulation and immune cell activation (CD8A, GZMB, CCL2, and TIMP1) in GG carriers compared with those of GC and CC (P < 0.05). Furthermore, correlations among various markers, including inflammatory, steatosis-associated, and fibrosis-associated markers, exhibited consistent positive correlations.

Conclusions: Our findings revealed that the PNPLA3 I148M variant and increased immune cell infiltration and activation were significantly correlated within the MASLD liver. Further studies are needed to elucidate the mechanistic links between this genetic variant and liver inflammation.

Background: Simple, accurate methods are required for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). Although the fatty liver index (FLI) is a simple and useful biomarker for steatotic liver disease (SLD), its optimal cutoff values for diagnosing MASLD and MASLD with increased alcohol intake (MetALD) remain unclear.

Methods: This cross-sectional study included 2512 adults undergoing health checkups with abdominal ultrasonography (AUS) and vibration-controlled transient elastography (including control attenuation parameter [CAP]). We used CAP 268 dB/m as the cutoff for SLD diagnosis. We analyzed the diagnostic performance of FLI for MASLD and MetALD. Optimal cutoff values were determined using area under receiver operating characteristics curve (AUROC) and Youden index.

Results: Among 2512 individuals studied, 956 had SLD, including 648 with MASLD, 231 with MetALD, and 67 with alcohol-associated liver disease. The distribution of FLI values (< 30, 30-60, > 60) was 46%, 31%, and 23% in males and 83%, 12%, and 5%, in females. For MASLD, the AUROC and optimal FLI cutoff values were 0.786 and 26.7. When analyzing by sex, these values were 0.729 and 26.9 for males and 0.886 and 19.2 for females. For MetALD, the corresponding values were 0.835 and 34.5. When analyzing by sex, these values were 0.764 and 44.4 for males and 0.95and 30.8 for females. Diagnostic agreement rate between AUS and CAP was 78.3% in all, and 74.9% in males and 84.1% in females.

Conclusion: The optimal FLI cutoff for MetALD was higher than for MASLD, with noticeable sex differences observed.