Background Liver resection (LR) and radiofrequency ablation (RFA) are recommended for patients with up to three hepatocellular carcinomas (HCCs) measuring ≤3 cm and preserved liver function. Nevertheless, treatment allocation is decided according to the preference of the treating doctor. This study aimed to develop a predictive model to guide treatment decisions based on survival outcomes. Methods A total of 18,958 patients with HCC with up to three nodules measuring ≤3 cm were included from the nationwide survey of Japan. Deep survival analysis was performed using the Recurrent Deep Survival Machines (RDSM) model. Model performance was evaluated using 10-fold cross-validation, concordance index (C-index), and overall survival (OS). Survival curves were compared using the log-rank test. Potential confounding factors were identified using 1:1 propensity score matching (PSM). Results Patients who underwent LR showed significantly longer OS than those who underwent RFA (5-year survival rate 81.4% vs. 73.1%; P < 0.005). The trained RDSM model achieved a C-index of 0.68. In the deep learning (DL) model, patients who received the recommended treatment exhibited significantly longer survival than those who did not (5-year survival rate 81.2% vs. 73.9%; P < 0.005; PSM, 81.9% vs. 76.7%; P < 0.005). The DL model recommended LR in 6,966 (84.5%) patients who received RFA, especially those exhibiting typical imaging patterns (early enhancement and washout in the computed tomography (CT) images [85.9% vs. 61.7% and 84.1 vs.74.3%, respectively]). Conclusions DL modeling effectively helped treatment allocation for patients with HCC with up to three nodules measuring ≤3 cm. Our study indicates the potential utilization of DL modeling in the treatment allocation of these patients.

Introduction:Despite recent advances in treatment for unresectable hepatocellular carcinoma (uHCC), median overall survival (OS) in the first-line setting across immune-based combination therapies has plateaued at 16-24 months. Evaluation of potentially more potent therapies is warranted. We report results of the first prospective phase 1b study of lenvatinib (multi-kinase inhibitor) + nivolumab (anti-programmed death receptor1 antibody) for treating advanced uHCC. Methods:This open-label study was conducted in Japan among adults (≥20 years) with histologically/cytologically confirmed HCC. Patients received monotherapy-approved doses of either 8 mg (body weight <60 kg) or 12 mg (body weight ≥60 kg) oral lenvatinib once daily + 240 mg intravenous nivolumab every 2 weeks (days 1 and 15) in 4-week cycles. Part 1 planned to enroll 6 patients to evaluate the tolerability of lenvatinib+nivolumab. Part 2 evaluated safety and preliminary antitumor activity. Primary endpoints were dose-limiting toxicities (DLTs; part 1 only) and safety. Secondary endpoints were objective response rate (ORR) and pharmacokinetics of lenvatinib and nivolumab. Additional exploratory endpoints (including OS and progression-free survival [PFS]; part 2 only) were assessed. Results:No DLT was observed among patients (n = 6) in part 1. Treatment-related adverse events (TRAEs) were observed in all patients (n = 30) in part 1 and 2. The most common TRAEs were palmar-plantar erythrodysesthesia syndrome (60%), dysphonia (53.3%), and decreased appetite (50.0%). Distributions of lenvatinib AUC(0-t) were similar to those observed for lenvatinib in HCC previously and were within the distributions of AUC(0-τ) observed with lenvatinib monotherapy in the REFLECT trial. ORR by mRECIST per investigator review was 66.7% in part 1 and 79.2% in part 2. In part 2, median PFS was 9.07 months by mRECIST per investigator review, and median OS was 26.94 months. Conclusion:Lenvatinib+nivolumab was well tolerated and had encouraging antitumor activity in patients with advanced uHCC in this phase 1b study.

4019 Background: Liver resection (LR) and radiofrequency ablation (RFA) are recommended for patients with early-stage hepatocellular carcinoma (HCC) with three nodules measuring ≤3 cm and preserved liver function. This study aimed to develop a predictive model to guide treatment decisions based on survival outcomes. Methods: This study included 18,958 patients with up to three HCCs measuring ≤3 cm from the nationwide survey of Japan. The Recurrent Deep Survival Machines (RDSM) model was employed for deep survival analysis. We employed 10-fold cross-validation, the concordance index (C-index), and overall survival (OS) to assess model performance. Survival curves were compared using the log-rank test. To identify potential confounding factors, 1:1 propensity score matching (PSM) was performed. Results: Patients undergoing LR demonstrated significantly longer OS than those receiving RFA (5-year survival rate 81.4% vs. 73.1%; P < 0.005). The trained RDSM model achieved a C-index of 0.68. In the deep learning (DL) model, patients undergoing recommended treatment demonstrated significantly longer survival than those who did not (5-year survival rate 81.2% vs. 73.9%; P < 0.005; PSM, 81.9% vs. 76.7%; P < 0.005). The DL modeling recommended LR in 6,966 (84.5%) patients undergoing RFA, especially those showing typical imaging patterns (early enhancement and washout in the computed tomography images [85.9% vs. 61.7% and 84.1 vs.74.3%, respectively]). Conclusions: DL modeling effectively helped treatment allocation for patients with up to three HCCs measuring ≤3 cm. Our study indicates the potential utilization of DL modeling in the treatment allocation of patients with up to three HCCs measuring ≤3 cm.

Introduction Malignant duodenal stenosis is a common complication in patients with pancreatic cancer, significantly impairing quality of life by obstructing oral intake. Duodenal stenting has become a preferred palliative intervention, offering minimally invasive symptom relief and allowing for the continuation of systemic chemotherapy. However, factors influencing stent patency remain underexplored. This study aimed to identify clinical, procedural, and tumor-related factors that affect the patency of uncovered duodenal stents in malignant duodenal stenosis caused by pancreatic cancer. Methods A retrospective cohort study was conducted at Chiba University Hospital, Chiba, Japan, analyzing data from 53 patients who underwent placement of 22 mm uncovered duodenal stents between June 2016 and December 2023. Eligibility criteria included that the primary tumor had not been resected and that no intestinal reconstruction had been performed. Data on patient demographics, tumor characteristics, procedural details, and outcomes were collected. Univariate and multivariate analyses were performed to evaluate factors influencing stent patency using the Kaplan-Meier method and Cox proportional hazards modeling. Results The mean patency duration for uncovered duodenal stents was 474 days, with stent occlusion occurring in 11 (20.8%) patients. Univariate analysis identified prior placement of transpapillary biliary plastic stents as significantly associated with reduced stent patency (p = 0.0057). Multivariate analysis confirmed this as an independent predictor of shorter patency (hazard ratio, 5.75; 95% CI, 1.37-24.22; p = 0.017). Tumor size, chemotherapy administration, and the location of duodenal stenosis were not significantly associated with stent patency. Conclusions Prior placement of transpapillary biliary plastic stents significantly reduces the patency of uncovered duodenal stents in patients with malignant duodenal stenosis caused by pancreatic cancer. This underscores the importance of procedural planning, including consideration of alternative biliary drainage methods, to optimize stent performance and improve patient outcomes.

Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LENtreated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from

ABSTRACTBackgroundPit pattern diagnosis using crystal violet staining for colorectal tumors is useful for qualitative and depth diagnosis. However, due to its reported carcinogenic potential, the use of crystal violet has been restricted. This study was aimed at investigating the efficacy of texture and color enhancement imaging (TXI) magnification in pit pattern diagnosis.MethodsThis study enrolled consecutive patients with consent obtained and with colonic tumors indicated for magnifying endoscopy in which all modalities' images (magnified observation with crystal violet staining (CV), magnified white light observation with indigo carmine (IC‐WLI), and magnified TXI observation with indigo carmine (IC‐TXI)) were evaluable between July 2020 and January 2023. The visibility of the pit pattern using a 5‐point Likert scale and its diagnostic accuracy were compared (IC‐TXI vs. IC‐WLI, reference: CV, by three experts).ResultsA total of 145 colorectal tumors from 145 patients were included. Visibility scores for the pit pattern were significantly higher with IC‐TXI compared to IC‐WLI (all three experts, p < 0.0001). The pit pattern match rate (Type II/III/IV/V) of IC‐TXI compared to CV was also superior to IC‐WLI (72.9% vs. 59.7%; p = 0.02).ConclusionsIC‐TXI provided reasonably good and higher visibility and diagnostic accuracy than IC‐WLI for pit pattern diagnosis of colorectal tumors compared to CV, suggesting it as an alternative to CV.

587 Background: The Phase 2 CHALLENGE trial (jRCTs031210355) evaluated the safety and efficacy of atezo+bev combination therapy in patients with advanced HCC with Child–Pugh class B cirrhosis. Results of the trial’s main analysis demonstrated that atezo+bev was well-tolerated. Here, we present the trial’s final safety and efficacy outcomes. Methods: This multicenter, open-label, single-arm, Phase 2 study enrolled patients with advanced HCC and a Child–Pugh score of 7 or 8 who had not received prior systemic therapy. Patients were administered atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the frequency of severe adverse events (SAEs). Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and frequency of adverse events (AEs). Results: A total of 31 patients were enrolled between December 2021 and April 2023. Child–Pugh score was 7 points in 25 patients (80.6%) and 8 points in 6 patients (19.4%). Fourteen patients (45.2%) were classified as having Barcelona Clinic Liver Cancer stage C. We set 30 eligible patients as the population for analysis. The final analysis performed with a median follow-up duration of 517days showed that the frequency of SAEs was 30.0% (95% confidence interval [CI] 14.7–49.4%). ORRs according to RECIST 1.1 and modified RECIST were 40.0% and 46.7%, respectively. Median PFS, TTP, and OS were 240 days (95% CI: 176–526 days), 240 days (95% CI: 176–526 days), and 470 days (95% CI: 256–576 days), respectively. Frequent Grade ≥3 SAEs were blood bilirubin increased (n=3), proteinuria (n=3), hypoalbuminemia (n=2), and hypertension (n=2). Grade ≥3 severe liver-related AEs occurred in 7 patients (23.3%), including blood bilirubin increased (n=3) and esophageal varices hemorrhage (n=2). Grade ≥3 severe immune-related AEs occurred in 2 patients – these were mucositis oral (n=1) and malaise (n=1). The mean Child–Pugh score (±standard deviation) at the start of treatment was 7.2±0.4, and was 7.0±1.0, 7.2±0.9, and 7.6±1.7 at the third and fifth cycles and at the withdrawal study, respectively. Conclusions: Atezo+bev was well-tolerated with demonstrable anti-tumor effects in patients with unresectable HCC and Child–Pugh class B cirrhosis. Additional studies are warranted to confirm the efficacy results of atezo+bev in this patient group. Clinical trial information: jRCTs031210355.

BACKGROUND:Elobixibat reportedly improves bowel movements in patients with chronic constipation. However, its effect on bowel movements in elderly patients with chronic constipation in clinical settings has not been examined. AIM:To examine bowel movement frequency and stool form before and after elobixibat administration in elderly patients with chronic constipation at our clinic. METHODS:A total of 10 mg elobixibat was administered to 35 (< 65 years old) patients and 45 (≥ 65 years old) patients with chronic constipation. The frequency of bowel movements and stool forms, assessed using the Bristol Stool Form Scale (BSFS), were compared between the two groups 1 week before and after elobixibat administration. RESULTS:In patients aged < 65 years with chronic constipation, the pre-elobixibat frequency of bowel movements and BSFS scores were 2.167 ± 0.732 and 2.286 ± 0.742, respectively. After elobixibat administration, the frequency of bowel movements and BSFS scores improved to 2.389 ± 0.502 and 3.995 ± 0.566, respectively, showing a significant improvement in bowel movement status. In patients aged ≥ 65 years with chronic constipation, the pre-elobixibat frequency of bowel movements and BSFS scores were 2.003 ± 0.733 and 2.217 ± 0.758, respectively. After elobixibat administration, the frequency of bowel movements and BSFS scores improved to 4.402 ± 1.346 and 3.800 ± 0.704, respectively, indicating an improvement in bowel movement status (P < 0.001). No significant differences were observed in the frequency and improvement status of bowel movements or BSFS scores between patients with chronic constipation aged ≥ 65 years and < 65 years. Adverse events due to the administration of elobixibat occurred in 16 cases (20%). No significant differences were found in the incidence of adverse events between patients with chronic constipation aged < 65 years (8 cases, 22.9%) and those aged ≥ 65 years (8 cases, 17.8%). CONCLUSION:Elobixibat is effective in improving bowel movement status in patients with chronic constipation. No significant differences were found in the improvement of bowel movement status or the incidence of adverse events between patients with chronic constipation aged < 65 years and ≥ 65 years, suggesting that the drug may be safely used in elderly patients.

Objective Abstaining from alcohol improves the outcome of alcohol-related cirrhosis. This study evaluated the effect of alcohol abstinence on the outcomes of patients with alcohol-related cirrhosis recruited from a Methods This single-center retrospective study recruited 116 patients with alcohol-related cirrhosis who were admitted to our department between April 2014 and October 2022. Taking the day of discharge as day 0, the patients were divided into two groups based on their subsequent behavior (abstinence/non-abstinence from alcohol). The study analysis included 98 patients after excluding 13 who died during hospitalization and 5 for whom follow-up at our hospital ended after discharge. We evaluated differences in the patient survival between the abstaining and drinking groups. Results The abstaining and drinking groups comprised 57 and 41 patients, respectively. We excluded from the analysis 10 and 6 patients with viable hepatocellular carcinoma in the abstaining and drinking groups, respectively. The findings revealed that the survival rate plateaued in the abstaining group from the third year onward, whereas the survival rate in the drinking group gradually decreased with time. Conclusion Our findings suggest that at least two years of alcohol abstinence is required to sustain the survival of patients with alcohol-related cirrhosis. The data collected by our hospital retrospectively demonstrated the importance of abstinence on a timescale of years of sustained abstinence.

Background and Aim:Acute-on-chronic liver failure (ACLF) carries high short-term mortality, but real-world evidence under the Japanese ACLF criteria remains limited. We assessed incidence, clinical profile, outcomes, and prognostic factors at a tertiary center in urban Japan. Methods:We retrospectively reviewed 363 consecutive hospitalizations of patients with cirrhosis (2014-2022) at a tertiary care center in Japan. ACLF per Japanese criteria was categorized as confirmed (meeting both PT INR/PT activity and bilirubin thresholds) or extended (meeting either biochemical criterion alone). We pre-specified a parsimonious Cox model with age (per 10 years) and MELD-Na (per 5 points); the primary outcome was time to all-cause death within 90 days (administrative censoring at day 90). Results:ACLF occurred in 40/363 (11.0%) patients (confirmed n = 10, extended n = 30). Frequent precipitants were infection, gastrointestinal bleeding, and alcohol use, often in combination. The 90-day mortality by Kaplan-Meier was 30.5%. Age (per 10 years) was associated with higher 90-day mortality (HR, 2.29; 95% CI 1.31-4.00; p < 0.01), as was Model for End-Stage Liver Disease including sodium (MELD-Na) (per 5 points) (HR, 1.74; 95% CI 1.16-2.63; p < 0.01). Conclusions:In this Japanese single center cohort, ACLF (per national criteria) was not rare and carried substantial short-term mortality. Age and MELD-Na were dominant prognostic factors, underscoring early trigger control (notably infection, gastrointestinal bleeding, and alcohol cessation) and timely risk stratification in routine care.

BACKGROUND AND AIMS:This study aimed to evaluate the efficacy and safety of transpapillary simultaneous side-by-side (SBS) stenting using uncovered self-expandable metal stents (UCSEMSs) at the initial endoscopic retrograde cholangiopancreatography (ERCP) for unresectable malignant hilar biliary obstruction (UMHBO). METHODS:A total of 67 patients with UMHBO who underwent simultaneous SBS stenting at our institution were retrospectively divided into two groups: the SBS stenting at the initial ERCP group (n=13) and the SBS stenting at the subsequent ERCP group (n=54). Clinical outcomes were compared between the groups. RESULTS:There were no significant differences between the SBS stenting at the initial ERCP group and the SBS stenting at the subsequent ERCP group in procedural time (median: 50 vs. 40 minutes, p=0.31), functional success rate (69.2% vs. 83.3%, p=0.25), adverse event rate (30.8% vs. 14.8%, p=0.18), recurrent biliary obstruction (RBO) rate (23.1% vs. 38.9%, p=0.29), technical success rate of re-intervention (100% vs. 90.5%, p=0.58), cumulative time to RBO (not reached vs. 252 days, p=0.80), or median overall survival (73 vs. 212 days, p=0.12). CONCLUSIONS:Simultaneous SBS stenting using UCSEMSs at the initial ERCP is a safe and effective strategy for managing UMHBO, with outcomes comparable to those of SBS stenting performed at the subsequent ERCP.

PURPOSE:This study aimed to identify the significant factors associated with liver transplant-free survival time in Japanese patients with large-duct primary sclerosing cholangitis (PSC) by evaluating the association between various parameters and clinical scores at PSC diagnosis. METHODS:This single-center retrospective study investigated factors influencing liver transplant-free survival in Japanese large-duct PSC patients. Univariate analysis using log-rank tests identified significant clinical parameters and scoring systems, which were further analyzed with multivariate Cox proportional hazards models to determine independent predictors of liver transplant-free survival. RESULTS:A total of 77 patients with large-duct PSC were included. The univariate analysis identified that age (p < .001), serum albumin level (p = .024), Child-Pugh score (p = .0012), albumin-bilirubin score (p = .0083), Amsterdam-Oxford PSC score (p < .001), and revised Mayo risk score (p < .001) were significant predictors of liver transplant-free survival time. However, the multivariate analysis revealed that only the Amsterdam-Oxford PSC score remained as an independent factor significantly associated with liver transplant-free survival time (hazard ratio: 12.90, 95% confidence interval: 2.78-59.81, p = .0011). CONCLUSIONS:This study underscored the importance of utilizing the Amsterdam-Oxford PSC score in clinical practice to assess disease prognosis and guide patient management in Japanese patients with large-duct PSC.

The performance of endoscopic evaluation of ulcerative colitis (UC) using conventional scoring, including Mayo endoscopic subscore (MES) and ulcerative colitis endoscopic index of severity (UCEIS), is not satisfactory. Recently, the usefulness of novel image-enhanced endoscopy (IEE) such as texture and color enhancement imaging (TXI) and red dichromatic imaging (RDI) has been reported in the endoscopic evaluation of UC. We evaluated the performance of IEEs in UC, particularly focusing on the correlation with MES and UCEIS, and prediction of relapse. This is a prospective, observational study. UC patients in clinical remission who underwent colonoscopy with evaluation of IEEs and follow-up for > 3 months were analyzed. TXI and RDI were evaluated using the previously reported scoring system (TXI 0–2 and RDI 1–4). The IEE scores were compared with the conventional scoring, fecal calprotectin levels, and histological findings using Geboes score, and patient’s clinical relapse rate stratified by each IEE score was examined. Both TXI and RDI scores were well-correlated with MES and UCEIS (both p < 0.001), fecal calprotectin levels (p = 0.015 and p = 0.006), and histology evaluated with Geboes score. In the Geboes subscore, the subscore 2B (neutrophil infiltration in lamina propria) was the most correlated with each endoscopic scoring. RDI 3–4 was significantly correlated with subsequent relapse (hazard ratio 3.56, 95

Cancer cachexia, which is characterized by weight loss and muscle weakness, is common in patients with pancreatic cancer. Anamorelin, a ghrelin receptor agonist, has shown potential for the management of cachexia in various cancers. We herein report a 64-year-old man with unresectable pancreatic cancer who experienced significant weight gain with anamorelin, allowing for continued chemotherapy and an improved quality of life. Despite disease progression, his response suggests the potential utility of anamorelin as a supportive therapy. Cachexia's complex metabolic changes make treatment difficult; however, anamorelin's appetite and weight gain effects highlight its possible role in managing cachexia in pancreatic cancer. Therefore, further research is required in this regard.

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. 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. 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

AIM:This study aimed to evaluate the safety and efficacy of durvalumab plus tremelimumab in patients with advanced hepatocellular carcinoma who have previously received atezolizumab plus bevacizumab (Atez/Bev). Additionally, it seeks to assess the feasibility of administering immunotherapy after the occurrence of immune-mediated adverse events (imAEs) in real-world clinical practice. METHODS:This retrospective study analyzed data from patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab at four Japanese institutions. Clinical outcomes, adverse events, tumor dynamics, and serum cytokine and chemokine levels were evaluated, with a focus on efficacy following prior Atez/Bev treatment. RESULTS:Durvalumab plus tremelimumab was administered to 68 patients. The objective response rate was 10.3%, and the disease control rate was 58.8%. Median progression-free survival was 3.1 months (95% confidence interval 2.0-4.9). imAEs occurred in 50.0% of patients, with colitis being the most common (22.1%). Durvalumab was safely readministered to 14 patients after imAE resolution, although five experienced recurrence. Among 33 patients (48.5%) previously treated with Atez/Bev, improved responses were noted, including two partial responses. Tumor growth dynamics decreased in 60.0% of patients receiving sequential therapy. Common adverse events included elevated liver enzymes (aspartate aminotransferase 50.0%, alanine aminotransferase 48.5%), pruritus (45.6%), and rash (44.1%). CONCLUSIONS:Durvalumab plus tremelimumab therapy is feasible with proper imAE management and patient selection. Sequential treatment following Atez/Bev offers clinical benefit in advanced hepatocellular carcinoma, although some may experience rapid progression. Further biomarker research is needed to optimize immunotherapy strategies.