Journal of Gastroenterology最新文献

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.

Primary sclerosing cholangitis (PSC) is an idiopathic chronic cholestatic disease with a poor prognosis. As there were no specific biomarkers for diagnosing PSC, we developed diagnostic criteria in 2016 based on cholangiography and elevated biliary enzymes. Novel findings and knowledge have subsequently accumulated, and we now propose the 2024 diagnostic criteria, to overcome several limitations of the 2016 diagnostic criteria. The Intractable Hepato-Biliary Diseases Study Group in Japan of the Committee of Research on Measures for Intractable Diseases established a working group consisting of experts in PSC comprising gastroenterologists, endoscopists, hepatologists, liver-transplant surgeons, pediatric hepatologists, pathologists, and radiologists. This working group proposed the 2024 diagnostic criteria after several discussions and public hearings. There are additional diagnostic targets; small duct PSC, pediatric PSC, and PSC recurrence following liver transplantation differ from the 2016 diagnostic criteria, which were for diagnosing large duct PSC in adults. The 2024 diagnostic criteria facilitate the use of magnetic resonance cholangiography in addition to endoscopic retrograde cholangiography in imaging, and incorporate gamma-glutamyl transferase for evaluating cholestasis to diagnose pediatric patients. Furthermore, PSC recurrence following liver transplantation can be diagnosed based on a liver biopsy and characteristic biliary findings. We hope that the 2024 diagnostic criteria will help not only hepatologists treating adults but also general physicians, pediatric hepatologists, and liver-transplant surgeons who manage patients with various forms of PSC.

The underlying causes of irritable bowel syndrome (IBS) and functional dyspepsia (FD) have remained largely elusive, but emerging data suggest immune activation and loss of small intestinal homeostasis may explain a major subgroup. FD and IBS symptoms often overlap and may occur early in the post-prandial period, suggesting the origin of symptoms may be much higher in gastrointestinal tract than colon. There is strong evidence low-grade duodenal inflammation, comprising eosinophils and/or mast cells associated with increased permeability, is present at least in a major subset with FD and IBS. This hypothesis is further supported by evidence of circulating increased small intestinal homing T cells and altered duodenal microbiota. We hypothesize a major etiologic pathway whereby interaction of food with intestinal bacteria switches on small intestinal immune activation in FD and IBS leading to presentation of antigens to the mucosa. While the low FODMAP diet provides symptom relief in both IBS and FD, this diet notably also reduces common food protein antigens (e.g., wheat, milk, soy) and urinary histamine levels. The obvious but often overlooked fact that food ingestion usually requires the act of eating adds nuance to determining whether food components or eating itself induces symptoms and that both need to be considered in DGBI in clinical practice. The exciting observations about subtle inflammation in DGBIs offer hope for new diagnostic biomarkers, and if considered in the context of altered dietary patterns and validated against symptom responses, will pave the way for novel DGBI treatment options.

Background: The management and characteristics of ulcerative colitis (UC) have evolved over time. We aimed to clarify how changing clinical profiles and treatment options affect patient outcomes.

Methods: This retrospective multicenter study of 13 hospitals divided diagnostic era into six periods: Era 1 (before June 30, 1998) and five subsequent 5-year intervals, with Era 6 (July 1, 2018-June 30, 2023) representing the most recent period. We compared therapeutic trends and outcomes across diagnostic eras, including the risk of first systemic steroid, advanced therapy (ADT) use, colectomy, UC-associated neoplasia (UCAN), and extracolonic malignancies.

Results: We included 1,867 UC patients. The proportion of elderly onset cases was significantly higher in Eras 5-6 (13%) compared to Eras 1-4 (0%-8.1%). Aminosalicylate intolerance was significantly more frequent in Era 6 (10%) and was significantly associated with earlier systemic steroid and ADT use, though not with colectomy or UCAN. While prescribing patterns of conventional therapies remained unchanged, the preferred first-line ADT shifted from infliximab to vedolizumab in recent diagnostic years. The cumulative risk of colectomy and UCAN did not significantly differ between eras. However, the cumulative risk of extracolonic malignancy was significantly higher in recent diagnostic years and significantly associated with older age at diagnosis.

Conclusions: In the recent diagnostic era, the increase in elderly onset UC has been accompanied by a higher malignancy risk, favoring vedolizumab as first-line ADT, especially in elderly patients. Increased aminosalicylate intolerance has led to earlier initiation of systemic steroids and ADTs, which may contribute to improved outcomes.

Background: Sarcopenia is an important prognostic factor for cancer patients. Here, we prospectively examined the effects of sarcopenia on progression-free survival (PFS) and overall survival (OS) of patients with pancreatic ductal adenocarcinoma (PDAC) treated with first-line gemcitabine and nab-paclitaxel (GnP).

Methods: This single-center prospective study enrolled patients with unresectable PDAC treated with first-line GnP between May 2020 and January 2024. The skeletal muscle index (SMI) was used as an index of sarcopenia. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 diagnostic algorithm. PFS and OS of patients with/without sarcopenia were compared. The univariate and multivariate analyses were performed to identify variables significantly associated with prognosis. Changes in skeletal muscle mass (SMM) were also compared with patient prognosis.

Results: Of the 66 patients who received first-line GnP, 21 had sarcopenia. The median PFS of those with or without sarcopenia was 3.7 and 6.9 months, respectively (p = 0.045); the median OS was 8.4 and 15.1 months, respectively (p = 0.006). Multivariate analysis identified sarcopenia as an independent prognostic factor for PFS and OS (p = 0.009, p = 0.005, respectively). The rates of major grade 3 or 4 adverse events were significantly higher in the sarcopenia group (p = 0.008). In the sarcopenia group, an early increase in SMM was an independent good prognostic factor (p = 0.041).

Conclusions: Sarcopenia is an independent indicator of poor prognosis in patients with PDAC treated with first-line GnP. Increasing SMM in patients with sarcopenia may prolong PFS.

Background: Anorectal malignant melanoma (ARMM) is a refractory malignancy that not only responds poorly to radiotherapy but also to immunotherapy. Tumor microenvironment (TME) components play an essential role in tumor progression and therapeutic response. However, TME characteristics of ARMM are not well understood.

Methods: We conducted a single-cell RNA sequencing on tumor and blood tissue from three ARMM patients, and combined with cutaneous melanoma datasets from the Gene Expression Omnibus database for a comprehensive joint analysis.

Results: Our findings revealed that cancer cells have four major patterns of chromosomal mutations. ARMM cancer cells exhibited marked intratumoral heterogeneity, and elevated angiogenesis, hypoxia, stemness, and epithelial-mesenchymal transition characteristics. We also identified the cancer stem cell subpopulation c5_Mel_CD55_VEPH1 in ARMM. Notably, we observed that CD8 + T cells in ARMM were poorly infiltrated and predominantly in a terminal exhausted state. Moreover, we identified a unique population of PLAU + fibroblast cells (iCAF_PLAU) in ARMM that likely have differentiated from myofibroblasts under hypoxic conditions. The iCAF_PLAU population enhances the stemness and aggressiveness of cancer cells through the ligand-receptor pairs WNT5A_FZD3_LRP6 and NRG1_ERBB3. In addition, iCAF_PLAU secretes CCL2, which binds to CCR1 on SPP1 + macrophages (TAM_SPP1) cells, leading to the activation of NFKBIA in TAM_SPP1 and subsequent upregulation of IL6, which may be linked to the exhaustion process of CD8 + T cells. Immunofluorescence staining confirmed the co-localization of iCAF_PLAU with TAM_SPP1 and TAM_SPP1 with CD8 + T cells.

Conclusion:  Our data suggest a potential role of iCAF_PLAU in mediating cell-cell interactions within the TME of ARMM, highlighting potential therapeutic targets for this aggressive malignancy.

Background: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are distinct gastrointestinal disorders with overlapping symptoms and pathophysiological background. The long-term risk of IBD is unclear in IBS patients.

Methods: Overall, 447,631 participants free of IBD at baseline (2006-2010) and 76,992 individuals who completed Digestive Health Questionnaire (2017-2018) from UK Biobank were enrolled in longitudinal cohort and cross-sectional analysis, respectively. The primary outcome was incident IBD in the cohort design, and Cox proportional hazards model was conducted to estimate the associated hazard ratio (HR). Prevalent IBD was defined as primary outcome in the cross-sectional design, and logistic regression was performed to estimate the associated odds ratio (OR).

Results: In the cohort design, 2,916 incident IBD cases were identified during a median 14.2 years' follow-up, with 2,097 ulcerative colitis (UC) and 1,015 Crohn's disease (CD), respectively. IBS patients had a 68%, 60%, and 104% increased risk of IBD (HR = 1.68, 95% CI:1.47-1.92), UC (HR = 1.60, 1.36-1.89), and CD (HR = 2.04, 1.66-2.51) versus non-IBS participants. Moreover, a greater risk of incident IBD persisted in IBS patients even after 10 years' duration (HR = 1.55, 1.27-1.89). In cross-sectional analysis, IBS patients exhibited significantly elevated odds of IBD (OR = 2.40, 2.14-2.70), UC (OR = 2.18, 1.92-2.48), and CD (OR = 3.15, 2.68-3.70). A greater odds of IBD was observed among all IBS subtypes, with IBS-D showing the highest odds (OR = 3.72, 3.24-4.28).

Conclusions: The risk of incident IBD, either UC or CD, is significantly higher in IBS patients compared with the general population, especially in IBS-D patients.

Background: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, which is often driven by chromosomal amplifications at 1q. Vacuolar sorting protein 45 (VPS45), a gene located on chromosome 1q, is involved in the endocytic recycling pathway; however, its role in HCC remains unclear. In this study, we aimed to investigate the functional significance of VPS45 in the progression of HCC.

Methods: VPS45 expression was analyzed using public databases, clinical HCC samples, and cell lines. Functional assays, including VPS45 knockout and rescue experiments, were conducted to assess the effect on tumor progression in vitro and in vivo. The molecular mechanisms underlying VPS45 function, particularly its role in β1 integrin recycling and FAK-AKT signaling activation, were also explored.

Results: VPS45 expression was significantly elevated in HCC owing to DNA copy number amplification and correlated with poor prognosis. Moreover, VPS45 knockout suppressed cell proliferation, migration, and invasion, while promoting apoptosis. VPS45 interacted with syntaxin16 and rabenosyn-5 to facilitate the recycling of β1 integrin to the cell membrane, thereby activating FAK-AKT signaling, which promotes oncogenic phenotypes. In xenograft models, VPS45 knockout significantly suppressed tumor growth, further supporting its role in HCC progression.

Conclusions: VPS45 is a key oncogene in HCC that promotes tumor progression by enhancing β1 integrin recycling and activating FAK-AKT signaling. Given its strong association with poor prognosis and tumor malignancy, VPS45 may serve as a promising prognostic biomarker and a potential therapeutic target for HCC.