Journal of Gastroenterology最新文献

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: 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.

Background: Intracellular calcium (Ca²⁺) signaling regulates key cancer processes. Research findings suggest that the SEC61 complex, involved in protein translocation, contributes to calcium leakage from the endoplasmic reticulum. However, the mechanism by which SEC61 Translocon Subunit Gamma (SEC61G), a component of this complex, influences colorectal cancer (CRC) progression remains unclear.

Methods: Bioinformatics analysis was performed using The Cancer Genome Atlas data sets to identify candidate genes on chromosome 7p, examine their association with DNA copy number amplification. In addition, SEC61G expression in CRC cells and tissues was validated using reverse-transcription quantitative polymerase chain reaction and immunohistochemistry. Moreover, in vitro and in vivo experiments were performed to investigate the effects of SEC61G overexpression and knockdown on CRC cell proliferation. Furthermore, publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) data were used to validate the role of SEC61G in CRC.

Results: SEC61G was significantly upregulated in CRC tissues and was correlated with poor prognosis in patients with CRC. SEC61G overexpression enhanced cell proliferation and activated the EGFR pathway, promoting cell cycle progression from the G1 to S phase. In addition, SEC61G overexpression increased cytosolic Ca²⁺ levels, which activated EGFR signaling via calmodulin. Moreover, analyses of scRNA-seq and ST-seq data confirmed that SEC61G expression was higher in tumor epithelial cells and that it was co-expressed with EGFR pathway-related genes.

Conclusions: SEC61G promotes CRC progression by regulating cytosolic Ca²⁺ concentration, EGFR activation, and cell cycle progression, highlighting its potential as a prognostic biomarker and therapeutic target in CRC.

Background: Direct-acting-antivirals (DAAs) achieve high sustained-virologic response (SVR) rates, even in patients with hepatitis C virus (HCV)-related decompensated liver cirrhosis (LC). However, predictors of post-treatment liver function improvement and survival remain unclear. This study evaluated pretreatment angiopoietin-2 (Ang2) levels as a predictor of prognosis and liver functional reserve after DAA treatment.

Methods: This multicenter retrospective study included 123 patients with HCV-related decompensated LC treated with sofosbuvir/velpatasvir. Serum Ang2 levels were quantified, and liver function was assessed using the Child-Pugh grading at baseline and 12 weeks after the end of treatment (SVR12). Factors associated with prognosis and post-SVR liver functional reserve (Child-Pugh grade C) were investigated.

Results: Multivariate Cox regression analysis revealed that, in addition to age and creatinine levels at SVR12, baseline Ang2 levels (hazard ratio [HR] = 1.151 per 1000 pg/mL, P = 0.033) and Child-Pugh grade C at SVR12 (HR = 11.765, P < 0.001), but not baseline Child-Pugh grade C, were significantly associated with the overall survival. Multivariate analysis revealed that baseline Ang2 levels and baseline Child-Pugh grade C were significantly and independently associated with Child-Pugh grade C at SVR12. The combination of elevated baseline Ang2 levels (≥ 8684 pg/mL; 1 point) and baseline Child-Pugh grade C (1 point) effectively stratified patients with a high likelihood of having Child-Pugh Grade C at SVR12. The incidence rates were as follows: 0 points, 2.1% (2/96); 1 point, 37.5% (9/24); and 2 points, 100% (2/2) (P < 0.001).

Conclusions: Pretreatment Ang2 levels predict survival and liver functional reserve after SVR in HCV-related decompensated LC.