BACKGROUND:The metabolic landscape of biliary tract cancer (BTC) remains poorly characterized. This study aimed to identify tumor-specific metabolic alterations in BTC using paired tumor and adjacent normal tissues. METHODS:Metabolomic profiling was performed on paired tumor and adjacent normal tissues from 71 patients with BTC using capillary electrophoresis time-of-flight mass spectrometry. Differential metabolites were identified using paired statistical analysis with false discovery rate correction. Pathway enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes database. RESULTS:Seventeen metabolites were significantly altered between tumor and normal tissues. Pathway analysis identified glycerophospholipid metabolism as the most enriched pathway, driven by water-soluble precursor and intermediate metabolites, including phosphorylcholine, CDP-choline, and ethanolamine phosphate. Hierarchical clustering demonstrated partially distinct metabolic patterns between tumor and normal tissues, with substantial inter-sample variability observed among tumor samples. Metabolites related to amino sugar and nucleotide sugar metabolism were also increased in tumor tissues. Additional pathways, including nicotinate and nicotinamide metabolism and arginine and proline metabolism, were also enriched. Principal component analysis showed partial separation between tumor and normal samples, indicating global metabolic differences between the two groups. These findings indicate metabolic alterations across multiple pathways in BTC. CONCLUSIONS:Paired tissue metabolomics revealed coordinated metabolic alterations in BTC involving choline phospholipid precursor metabolism, amino sugar and nucleotide sugar metabolism, and additional amino acid-related pathways. These results highlight the presence of broad metabolic reprogramming in BTC and underscore the importance of tissue-based metabolomic profiling for characterizing tumor metabolism.

In Japan, endoscopic submucosal dissection (ESD) is the standard treatment for superficial esophageal squamous cell carcinoma (ESCC). Although clinical guidelines outline indications, additional treatment, and stricture prevention, real-world practice patterns remain insufficiently characterized. The present nationwide survey aimed to clarify the current endoscopic management of ESCC in Japan. A web-based, 20-item multiple-choice questionnaire was distributed to endoscopists performing upper gastrointestinal endoscopy at least weekly. Invitations were disseminated through the mailing lists of the Japan Esophageal Society and the individual mailing lists of core study members. The survey assessed diagnostic strategies, endoscopic treatment selection, indications for additional therapy after ESD, and approaches to stricture prevention. Altogether, 303 endoscopists who had performed endoscopic treatment for ESCC within the preceding year were enrolled. Most respondents reported using ESD exclusively. For clinical muscularis mucosa (MM) or shallow submucosa (SM1) lesions, treatment selection depended on circumferential extent, with ESD performed on 95.0

Endoscopic gallbladder stenting is an important definitive treatment option for acute cholecystitis in high-risk patients who are poor surgical candidates. In this study, we aimed to compare the outcomes between a novel 5-Fr spiral-shaped plastic stent (IYO-stent) and conventional 7-Fr double-pigtail stent (C-stent) for permanent transpapillary gallbladder drainage. This retrospective cohort study included 56 patients with acute cholecystitis who underwent permanent endoscopic gallbladder stenting at 2 Japanese centers between 2019 and 2023 (C-stent, n = 27; IYO-stent, n = 29). The primary endpoint was event-free survival (EFS), defined as the time to recurrent cholecystitis, procedure-related complications, stent dysfunction, complications requiring intervention, or death. The secondary endpoints were cholecystitis recurrence-free survival and technical success. The median EFS was 10.6 months (95

Background & Aims Combination immunotherapy is the standard first-line treatment for hepatocellular carcinoma. Body composition may affect treatment outcomes; however, the prognostic relevance of skeletal muscle and adipose tissue during immunotherapy remains unclear. We aimed to determine whether integrating skeletal muscle and adipose tissue measurements stratifies survival outcomes in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Methods In this retrospective cohort study, conducted at nine institutions, body composition was assessed using the body mass index, skeletal muscle index at the L3 level, and total fat area at the umbilical level. L3 skeletal muscle index was dichotomized using sex-specific cutoffs, and body mass index and total fat area were dichotomized at the cohort median values. Results Japanese patients (n=445, 74 years median age; 80.4% men) were included. In this cohort, median body mass index, L3 skeletal muscle index (men/women), and total fat area were 23.3, 44.0/37.6 cm2/m2, and 262.8 cm2, respectively. The response rate was 33.0%; the median progression-free and overall survival were 8.4 and 25.1 months, respectively. Low body mass index, L3 skeletal muscle index, and total fat area were associated with poorer overall survival. In the L3 skeletal muscle index × total fat area analysis, the low muscle/low fat group had the poorest overall survival. Per multivariable analysis, this body composition was an independent predictor of poor prognosis. Conclusions Concurrent low skeletal muscle mass and fat area may predict poor prognosis in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Baseline body composition profiling may aid in risk stratification of these patients.

Objective Pemafibrate improves the liver function and lipid profiles in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the data on metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) remain limited. This study evaluated the biochemical changes after pemafibrate treatment in both conditions with dyslipidemia, focusing on alanine aminotransferase (ALT) reduction and the factors associated with the treatment response. Methods This retrospective, single-center cohort study analyzed changes in liver function tests, lipid profiles, and body mass index after 24 weeks of pemafibrate treatment. The factors associated with ALT reduction were assessed using correlation and multivariate regression analyses. Patients were classified as ALT responders or non-responders based on ALT changes at 24 weeks. Patients Ninety-six patients with MASLD and 14 with MetALD were included in the study. Results After 24 weeks, the liver function tests and lipid profiles improved significantly in patients with MASLD, and similar changes were observed in the MetALD subgroup. The median ALT reduction rate was -24.75%. Baseline ALT, AST, and GGT levels correlated with the ALT reduction rate, but none remained significant in the multivariable model using continuous liver enzyme variables. ALT reduction was greater in the MetALD subgroup, although this finding requires further exploration. Conclusion Pemafibrate treatment was associated with an improved liver function and lipid profiles in patients with MASLD complicated by dyslipidemia. The findings in the small MetALD subgroup were exploratory. Baseline ALT, AST, and GGT levels were correlated with ALT reduction, but none were independent predictors in the multivariable model.

OBJECTIVES:Neoadjuvant chemoradiotherapy (NACRT) is increasingly employed for resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet reliable preoperative predictors of pathologic tumor regression are limited. We developed predictive models for pathologic response following NACRT. METHODS:We analyzed prospectively collected Phase II trial data from 169 patients with resectable and borderline resectable PDAC who underwent pancreatic resection after NACRT. Pathologic response was assessed using the College of American Pathologists (CAP) grading system and dichotomized as CAP grades 0-2 versus grade 3. Model A used baseline variables; Model B incorporated post-treatment preoperative and treatment-related variables. Performance was evaluated using the area under the curve (AUC). RESULTS:Among 169 patients, 81 (47.9%) achieved CAP grades 0-2. Model A found no independent baseline predictors (AUC 0.642). In Model B, post-treatment maximum standardized uptake value (SUVmax) emerged as the sole independent predictor of CAP grades 0-2 (OR: 0.81, 95% CI: 0.67-0.96, p = 0.014). Model discrimination was higher with Model B (AUC: 0.745 vs 0.642; p = 0.006 by DeLong test). Risk stratification indicated CAP grade 0-2 rates of 27%, 42%, and 83% (p < 0.001). CONCLUSIONS:Model B improved the prediction of pathologic response after NACRT, with post-treatment SUVmax as the sole independent predictor.

Thrombocytosis is correlated with poor prognosis in several cancers. Barcelona Clinic liver cancer (BCLC) staging, a major index of prognosis prediction and treatment selection for patients with hepatocellular carcinoma (HCC), has not considered platelet count in its protocol yet. This study evaluated the prognostic impact of platelet count in patients with HCC. Briefly, this retrospective cohort study enrolled 925 patients with BCLC stage B HCC. Baseline characteristics were adjusted using propensity score matching. Log-rank tests were performed to determine whether a threshold platelet count of 150 × 109/L stratified patient prognosis. The primary endpoint was overall death. As a result, patients with platelet counts < 150 × 109/L showed significantly better overall survival compared to patients with platelet counts ≥ 150 × 109/L (hazard ratio = 0.7233). Among 553 patients with ≥ 4 HCC nodules, a platelet count cutoff of 150 × 109/L also differentiated patient prognosis (hazard ratio = 0.6059). After adjusting for the baseline characteristics of patients with ≥ 4 HCC by propensity score matching for age, sex, albumin, total bilirubin, primary or recurrence, and maximum tumor diameter, in the matched-pair cohorts, a platelet count < 150 × 109/L significantly correlated with a better overall survival compared to platelet count ≥ 150 × 109/L (hazard ratio = 0.7096). In conclusions, a lower platelet count correlated with better prognosis in patients with multiple HCC nodules.

Zinc acetate is an established maintenance therapy for Wilson disease as it reduces intestinal copper absorption. However, excessive dietary copper restriction during zinc therapy may contribute to clinically significant copper deficiency. We report a case of copper-deficiency anemia and neutropenia in a woman in her 60s with Wilson disease, hepatic and neurological involvement, and cirrhosis. Three years after transitioning to zinc maintenance therapy, leukopenia and neutropenia reappeared, followed by macrocytosis, and anemia rapidly worsened. At presentation, the neutrophil count was 378/µL, mean corpuscular volume 120.9 fL, and hemoglobin 4.4 g/dL. On detailed dietary history, persistent strict dietary copper restriction was identified, including long-term avoidance of copper-rich foods. After discontinuation of strict copper restriction, red blood cell transfusion, and zinc acetate reduction from 150 to 100 mg/day, hemoglobin stabilized at approximately 10 g/dL, neutropenia improved, and macrocytosis resolved. This case highlights that cytopenia during zinc maintenance therapy for Wilson disease should not be attributed solely to hypersplenism and that dietary practices should be reassessed because persistent strict dietary copper restriction may contribute to iatrogenic copper deficiency.

AIM:Reports on the prevalence of sarcopenia in patients with autoimmune hepatitis (AIH) are limited, and its association with prognosis remains unclear. Therefore, we evaluated sarcopenia-related factors and their prognostic impact associated with AIH and compared these findings with those of patients with primary biliary cholangitis (PBC). METHODS:We retrospectively analyzed 161 patients with AIH or PBC who were followed up at our institution and underwent computed tomography (CT) between January 2004 and February 2025. Data on sex, age, comorbidities, sarcopenia-related factors, treatment, cirrhosis, and clinical outcomes were reviewed. Patients with the PBC-AIH overlap syndrome or concomitant malignancy were excluded. Sarcopenia was assessed using the psoas muscle mass index (PMI) on CT. RESULTS:A total of 67 and 94 patients had AIH and PBC, respectively. The two groups showed no significant differences in the proportion of males, 5-year survival, or the prevalence of cirrhosis at diagnosis and other autoimmune diseases. A low PMI was observed in 32.8% and 17.0% of patients with AIH and PBC, respectively, and was significantly more frequent in patients with AIH (p = 0.02). Among patients with AIH, those with a low PMI had significantly poorer survival than those without it. Factors associated with poor prognosis in patients with AIH included a higher model for the end-stage liver disease (MELD) score, low PMI, and the presence of cirrhosis. CONCLUSION:CT-based assessment of PMI in patients with AIH may provide supplementary prognostic information for risk stratification at diagnosis.

BACKGROUND & AIMS:Despite the advances in systemic therapy for unresectable hepatocellular carcinoma (HCC), patients with Child-Pugh class B (CP-B) liver function face a significant unmet need. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable HCC and CP-B. METHODS:This retrospective study included 796 patients who received Atez/Bev between October 2020 and July 2024 from 10 institutions in Japan. The median observation period was 14.6 months. The liver function was assessed using the CP classification and modified ALBI (mALBI) grade. The progression-free survival (PFS), overall survival (OS) and median survival time (MST) were evaluated. RESULTS:Patients with CP-B had significantly shorter PFS and OS than those with CP-A (median PFS, 4.6 months vs. 7.0 months; MST, 10.3 months vs. 23.2 months) (PFS, p = 0.009; OS, p < 0.001). Although CP-B was associated with a higher incidence of bleeding-related events, the discontinuation rate due to adverse events did not differ from that of CP-A. As a factor for stratifying CP-B outcomes, significant differences in the PFS, OS and response rate were observed between mALBI grades ≤ 2b and 3 (PFS, p = 0.004; OS, p = 0.024; response rate, p = 0.001). In multivariate analysis, the mALBI grade (hazard ratio [95% CI]: 2.388 [1.186-4.810]; p = 0.014) was extracted as a factor contributing to OS in patients with CP-B. CONCLUSION:Atez/Bev therapy demonstrated efficacy and safety in patients with CP-B, especially when hepatic reserve is maintained within mALBI grade 2b.

Accurate assessment of gastric motility is essential for improving the safety and efficacy of enteral nutrition therapy in elderly patients and individuals with dysphagia undergoing percutaneous endoscopic gastrostomy (PEG). However, a reliable method for long-term, low-invasive, and stable monitoring of gastric motility is yet to be established. We developed a novel measurement system designed to monitor gastric motility by detecting intragastric pressure fluctuations through a pressure sensor affixed to a gastrostomy tube. This system conceptualizes the stomach as a single balloon, enabling real-time, low-invasive recording of pressure variations associated with gastric contractions. For preliminary evaluation, we evaluated the capability of the system to capture responses comparable to electrogastrography (EGG). We performed simultaneous 30-min recordings of EGG and intragastric pressure signals before and after nutrient infusion in a cohort of 20 PEG patients. Furthermore, we analyzed frequency- and time-frequency-domain features using fast Fourier transform, wavelet transform, and coherence analysis. Before infusion, the average dominant frequencies (DFs) of both signals were comparable, indicating no systematic bias between methods. The average coherence was 0.32 f 0.10, suggesting a low-to-moderate correlation. Following infusion, the DF remained consistent across both methods, with a coherence of 0.30 +/- 0.06. These findings suggest that the intragastric pressure signals reflect gastric motility to a degree similar to that of EGG. In conclusion, the proposed system shows the potential as a practical and effective tool for visualizing gastric motility in PEG patients.

Objectives:Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) using lumen-apposing metal stents (LAMS) is a treatment option for acute cholecystitis in high-risk surgical patients. However, data on extremely elderly and frail patients are limited. We report our initial experience with EUS-GBD using electrocautery-enhanced LAMS in this population after reimbursement approval in Japan. Methods:We retrospectively analyzed consecutive patients who underwent EUS-GBD using electrocautery-enhanced LAMS for acute cholecystitis at a single center after reimbursement approval in June 2025. Results:Ten patients (median age, 90 years; median Clinical Frailty Scale score, 7) underwent EUS-GBD. All procedures were performed via a transduodenal approach using a 10-mm LAMS. Technical success was achieved in all patients. Clinical success was achieved in nine of the 10 patients (90%); one patient with Grade III cholecystitis complicated by severe pneumonia and heart failure died on postoperative day 1 before clinical assessment. The median stent deployment time was 3.5 min, and the median total procedure time was 16 min. Cholecystoscopy through the LAMS using a slim endoscope was feasible when required. Conclusion:In this pilot study, EUS-GBD using electrocautery-enhanced LAMS was technically successful in extremely elderly and frail patients. Although short-term outcomes appeared acceptable in most patients, the single POD1 death underscores the importance of careful patient selection. These preliminary findings require validation in larger studies. Trial Registration:N/A.

INTRODUCTION:Reliable closure of mucosal/full-thickness defects after endoscopic treatment is crucial to prevent complications. Although various techniques have been clinically introduced, a direct comparison of these techniques has not been conducted. Thus, the present ex vivo study aimed to evaluate the closure strength of these methods. METHODS:Using a porcine stomach, 4 × 2.5-cm mucosal and full-thickness defects were prepared. Each closure was performed for three specimens. For the mucosal defects, the following methods were performed in the mucosal (Group M) and muscular-mediated mucosal (Group MM) closures: simple clipping (Clip-M), loop-assisted closure (Loop-M), line-assisted closure (Line-M), and endoscopic hand suturing (EHS-M); Clip-MM, Line-MM, and EHS-MM. For the full-thickness defects, a single-layered closure (Group F) was performed by loop-assisted closure (Loop-F), line-assisted clip closure (Line-F), and EHS (EHS-F). The maximum tension (N) was measured using a mechanical traction device by mechanically pulling both ends of the specimen. RESULTS:In the closure of mucosal defects, among the techniques in Group M, EHS-M (11.32 ± 2.1 N) demonstrated the highest strength as compared to the other three methods. For Group MM, EHS-MM (13.1 ± 5.3 N) showed the highest strength, significantly outperforming Clip-MM (p = 0.03). Among the full-thickness defect closure methods, EHS-F (9.5 ± 0.73 N) had the significantly highest strength among the three methods. CONCLUSIONS:Our ex vivo data showed that EHS has superior closure strength in both mucosal and full-thickness defects. Surgery-oriented endoscopic closure appears a reliable method for artificially created intraluminal defects.

Complete resection remains the only potentially curative treatment for localized intrahepatic cholangiocarcinoma (iCCA), yet postoperative recurrence is common, particularly in patients with high-risk disease. Neoadjuvant systemic therapy may permit earlier control of occult micrometastatic disease, optimize the delivery of systemic treatment, and provide an in vivo assessment of tumor biology prior to major hepatectomy. These potential benefits must be balanced against treatment-related toxicity, surgical delay, and the risk of disease progression precluding resection. Early evidence was primarily derived from retrospective studies, which yielded inconsistent survival outcomes and exhibited substantial vulnerability to confounding and treatment-selection bias. The single-arm NEO-GAP trial subsequently demonstrated the feasibility of administering neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel followed by surgical resection. More recently, the randomized phase II–III ZSAB-neoGOLP trial showed that neoadjuvant gemcitabine–oxaliplatin, lenvatinib, and toripalimab followed by surgery prolonged median event-free survival compared with upfront surgery (median: 18.0 vs. 8.7 months) without substantially compromising surgical feasibility. However, the interim overall survival analysis was inconclusive, and the generalizability of these findings beyond selected, medically fit patients treated at Chinese centers remains uncertain. This narrative review critically appraises the evolving evidence, discusses patient selection and perioperative treatment, and identifies priorities for future research. Current evidence supports the selective consideration of neoadjuvant therapy in medically fit patients with technically resectable but oncologically high-risk iCCA, rather than its routine use in all resectable cases.

OBJECTIVES:Progression of hepatocellular carcinoma (HCC) and cardiovascular thrombosis (CVT) has a bidirectional causal relationship. CVT complications will increase in patients with HCC due to etiology shift from viral hepatitis to metabolic dysfunction-related steatohepatitis. AIM:This study aimed to evaluate the clinical impact of CVT, focusing on patients with HCC treated after transarterial chemoembolization. METHODS:A retrospective cohort study enrolled 402 patients including 79 patients with CVT in a single university hospital. Cox proportional hazard model analysis was performed to identify independent prognostic factors. After adjusting for baseline characteristics by propensity score matching, the survival impact of the CVT complication was evaluated using the Kaplan-Meier curve. RESULTS:A multivariate analysis determined that CVT complication was an independent risk factor for overall deaths in patients with HCC (HR = 1.751, IQR 1.203-2.548, p < 0.05). Propensity score matching generated a pair of 54-patient cohorts. The median survival time of patients with CVT (1106 days) shortened to half compared to those without CVT (2707 days, HR = 2.298, IQR: 1.399-4.169, p = 0.0020). While recurrence-free survival was not significantly different (p > 0.05), post-recurrence survival was shorter in patients with CVT (2150 days vs. 1008 days, HR = 1.945, IQR: 1.150-3.740, p = 0.0188). CONCLUSIONS:Assuming that the expected life expectancy is only half that of uncomplicated cases of CVT, CVT might be a major prognostic factor in patients with HCC, following tumor burden and functional hepatic reserve.