Yoshiyuki Ueno

Background/Objectives: Sustained drug-free status is an emerging milestone after atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. We examined baseline host biomarkers associated with achievement of 6-month sustained drug-free status and evaluated a composite stratification score. Methods: This multicentre retrospective study included patients treated with atezolizumab plus bevacizumab. The endpoint required systemic therapy discontinuation after complete response or no viable disease, followed by at least 6 months without viable or recurrent hepatocellular carcinoma and sustained normalization of initially elevated tumour markers. The PAN-DF score (preserved hepatic reserve, altered immune-inflammatory status, and nutritional-immune reserve for achieving drug-free status) combined modified albumin–bilirubin grade, neutrophil-to-lymphocyte ratio, and prognostic nutritional index. Results: Among 655 patients, 25 achieved the endpoint; median post-discontinuation follow-up was 533 days. In the complete-case cohort (n = 473; 17 events), achievement rates were 0.0%, 2.9%, 3.7%, and 13.6% for scores 0–3. Each one-point increase was associated with higher odds of achievement (odds ratio 2.90, 95% confidence interval 1.51–5.55; p = 0.001), and the area under the curve was 0.719. The examined baseline tumour-related factors were not significantly associated with the primary endpoint, and the examined host-related factors were not associated with objective response. Conclusions: Selected baseline host biomarkers were associated with achievement of 6-month sustained drug-free status. PAN-DF stratified the observed probability of this outcome and may help identify patient groups with a relatively higher likelihood of a sustained drug-free state, supporting early multidisciplinary planning.

Background and Aim: The optimal treatment strategy for patients with intermediate‐stage hepatocellular carcinoma beyond the up‐to‐seven criteria (Barcelona Clinic Liver Cancer B2) remains uncertain. Although transarterial chemoembolization has long been the standard of care, its efficacy is limited in this subgroup, and systemic therapies have recently been introduced. We aimed to explore treatment modalities associated with survival beyond that predicted by a previously validated prognostic model. Methods: We retrospectively analyzed 113 patients diagnosed with BCLC‐B2 stage hepatocellular carcinoma between 2017 and 2024. Predicted survival was calculated using a previously established prognostic model, and treatment benefits were evaluated by comparing observed survival with predicted outcomes. Logistic and linear regression analyses were performed to identify factors associated with survival gain. Results: The median observed survival was 26.0 months, compared with a model‐predicted survival of 24.7 months. Treatment with atezolizumab plus bevacizumab was significantly associated with survival exceeding model predictions (odds ratio: 3.77, p = 0.0065). Linear regression analysis confirmed that atezolizumab plus bevacizumab was independently associated with a greater survival benefit (β = 0.192, p = 0.0084). Subgroup analysis demonstrated that this association was particularly pronounced in patients with high tumor burden (tumor number plus size ≥ 11), whereas no significant associations were observed for lenvatinib, STRIDE, or cabozantinib. Conclusions: Atezolizumab plus bevacizumab was associated with survival beyond that predicted by a prognostic model in patients with BCLC‐B2 stage hepatocellular carcinoma, particularly those with high tumor burden. These findings should be considered exploratory and associative rather than evidence of a causal treatment effect.

Background and Aims: Primary biliary cholangitis (PBC) frequently impairs health‐related quality of life (HRQOL); however, longitudinal changes in symptoms and their relationship with prognosis remain unclear. We aimed to elucidate the current status of symptoms and HRQOL in Japanese patients with PBC, evaluate 10‐year changes in PBC‐40 scores, and examine associations with long‐term outcomes. Methods: This multicenter observational study comprised three analyses: (i) a 2025 cross‐sectional study assessing associations between clinical parameters, PBC‐40 (symptom indicators), and EQ‐5D‐5 L (HRQOL indicators); (ii) a longitudinal PBC‐40 study comparing scores from 2015 to 2025; and (iii) a longitudinal outcome study evaluating 2015 PBC‐40 scores and clinical parameters in relation to survival through 2025. Results: In 2025%, 20%–50% of all patients ( n = 239) had moderate/severe PBC‐40 scores in each domain. EQ‐5D‐5L scores were significantly lower in women < 59 years versus general population, with multivariable analysis identifying itch, fatigue, and social domains as independent contributors to impaired HRQOL. Across a 10‐year follow‐up, overall significant deterioration was observed in symptoms ( p = 0.0015), itch ( p = 0.0039), and cognitive ( p = 0.0011) domains, while interindividual variability was greatest in itch and emotional and smallest in symptoms. In longitudinal outcome study ( n = 410), no PBC‐40 domain predicted death or liver transplantation. Conclusions: HRQOL in patients with PBC was significantly impaired in younger female. Over 10 years, overall and interindividual changes in domain scores greatly varied, suggesting that symptom burdens are driven by heterogeneous underlying mechanisms. HRQOL impairment represents distinct dimensions of disease impact in PBC, independently of long‐term outcomes.

Background: Carbon-ion radiotherapy (CIRT) is an effective local treatment for hepatocellular carcinoma (HCC); however, evidence on systemic immunotherapy after CIRT and the role of CIRT following immunotherapy remains limited. This study aimed to assess clinical outcomes and sequencing of CIRT and systemic immunotherapy in real-world practice. Methods: We retrospectively analyzed 41 patients with HCC who received CIRT and systemic immunotherapy (atezolizumab plus bevacizumab or durvalumab plus tremelimumab). Patients were categorized into three groups: (i) systemic immunotherapy for recurrent HCC after CIRT (n = 20), (ii) curative-intent CIRT after systemic immunotherapy (n = 10), and (iii) CIRT for residual or insufficiently responding lesions (≤3 lesions) after systemic immunotherapy (n = 11). Results: In group (i), 14 of 20 patients achieved complete or partial responses. These responders had low tumor burden (within the up-to-7 criteria) and preserved liver function (modified albumin–bilirubin grade 1/2a) at treatment initiation and demonstrated significantly longer progression-free and overall survival than those with stable or progressive disease. In group (ii), 4 of 10 patients achieved a clinical complete response and became drug-free; notably, all had solitary intrahepatic tumors at immunotherapy initiation. In group (iii), the rate of transition to clinical complete response was low, and disease control remained limited. Conclusions: Systemic immunotherapy demonstrated high effectiveness in recurrent HCC following CIRT, particularly in patients with low tumor burden and preserved liver function. Moreover, curative-intent CIRT after immunotherapy may benefit patients with solitary intrahepatic tumors but appears limited in those with insufficient response to immunotherapy, including residual oligolesions.

Background: /Aims : Direct-acting antiviral agents (DAA) effectively cure chronic hepatitis C (CHC) whereas curative therapy for chronic hepatitis B (CHB) is rare. We aimed to compare HCC incidence between suppressed CHB versus cured CHC patients with cirrhosis. Methods: We analyzed 5773 cirrhosis patients from 43 centers in 9 countries: 1877 with treated and suppressed CHB and 3896 with DAA-cured CHC using inverse probability treatment weight (IPTW) and competing risk analysis via Fine and Gray method. Results: After IPTW (on age, sex, ethnicity, study location, albumin, total bilirubin, creatinine, platelet, tobacco use, alcohol use, diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, steatotic liver disease, obesity, and follow-up years), two study groups became similar in relevant characteristics. The 5-year cumulative HCC incidence was significantly higher in suppressed CHB compared to cured CHC (18.1% vs. 7.4%, P P P P P =0.954). On multivariable analysis, CHB suppression P P =0.04) were associated with higher HCC risk. Conclusion: HCC risk remains high in both treated and suppressed CHB cirrhosis and cured CHC cirrhosis. However, with prolonged CHB suppression, risk of HCC can be reduced, highlighting benefits of early treatment and viral suppression in patients with CHB.

Helicobacter pylori ( H. pylori ) infects the gastric epithelium of approximately half of the global population, and is a well-known risk factor for developing gastric cancer. Despite the clinical significance of H. pylori infection, many genetic factors that contribute to susceptibility remain unidentified. While it is well-established that H. pylori infection can result in gastritis and peptic ulcers, which may progress to gastric cancer, its causal link to other diseases remains unclear. We performed the genome-wide association study (GWAS) for anti- H. pylori IgG antibody titers, which were validated as a surrogate marker for H. pylori infection by the correlation with clinical traits, followed by gene-based and pathway analyses, involving up to 140,863 individuals. This included 56,967 in the discovery phase, and 68,211 in the replication phase from Japanese cohorts, and an additional 15,685 from European populations in a cross-ancestry meta-analysis. We reveal significant associations between H. pylori infection and polymorphisms in the Human Leukocyte Antigen (HLA) class II region within the Major Histocompatibility Complex (MHC), as well as genes related to innate immunity, including CCDC80 , NFKBIZ , TIFA , PSCA , and TRAF3 . Mendelian randomization (MR) analysis revealed that genetic liability to H. pylori infection has both positive and negative causal relationships with a variety of diseases, including autoimmune-related diseases such as Type 1 diabetes, Hashimoto’s disease, atopic dermatitis, as well as traits like body height and weight. These genetic findings strongly support the notion that genetic liability to H. pylori infection influences not only gastrointestinal diseases, but also a broader spectrum of health issues, thereby providing valuable insights for public health strategies and personalized medicine approaches.

Background & Aims: Direct‐acting antiviral agents (DAA)‐mediated HCV cure correlates with better outcomes, but there are insufficient data on detailed mortality‐related risk factors after cure. This study sought to clarify mortality and associated risk factors post‐HCV cure. Methods: The study included HCV patients with sustained virological response following DAA (DAA‐SVR) from 39 REAL‐C centres in North America, Europe and Asia‐Pacific. The primary outcome was all‐cause mortality in DAA‐SVR patients. Mortality rate per 1000 patient‐years (PY) was calculated as the number of deaths divided by total PY multiplied by 1000. Results: A total of 10 034 DAA‐SVR patients (stratified by cirrhosis status: 5611 non‐cirrhosis, 4153 compensated, 270 decompensated) were included. With a median follow‐up of 4.76 PY, 4.9% (491) died. The all‐cause mortality rates were 6.2, 13.1, 60.0 and 10.4 per 1000 PY for patients without cirrhosis, compensated and decompensated cirrhosis, and overall patients, respectively. The 5‐year cumulative survival was 95.1% (94.5%–95.6%) overall, with the lowest rate of 73.9% (67.0%–79.5%) in decompensated cirrhosis. Non‐liver‐related death was the main cause in non‐cirrhosis (non‐liver‐related vs. liver: 5.2 vs. 0.8 per 1000 PY)/compensated cirrhosis (8.2 vs. 4.8 per 1000 PY), while liver‐related death was dominant in decompensated cirrhosis (24.7 vs. 33.8 per 1000 PY). Risk factors for higher mortality included age > 65 (3.2‐fold), male (1.5‐fold), cirrhosis (decompensated 7.6‐fold) and baseline DM (1.5‐fold). Conclusion: This study showed significant age, sex, fibrosis stage and DM differences in mortality and causes among DAA‐SVR patients. It provided granular subgroup data for precision medicine to support individualised care, future modelling studies and public health planning.

Anorexia nervosa (AN) leads to severe dietary restriction, low body weight, and in many patients, hepatocellular steatosis. Clinically, hepatic fat in AN is usually macrovesicular, whereas microvesicular steatosis is more often associated with severe starvation and mitochondrial dysfunction. The precise mechanisms underlying starvation‐associated microvesicular steatosis in AN, however, remain unclear. We therefore developed a murine model that combines food restriction with excessive activity to mimic the metabolic stress of AN and compared it with simple starvation, high‐fat diet (HFD), and normal diet controls. Five‐week‐old female C57BL/6 mice were assigned to food restriction (FR, n = 18), AN ( n = 13), HFD ( n = 11), or control (Ctr, n = 11) groups. FR and AN mice underwent time‐restricted feeding until achieving approximately 25% body weight loss; AN mice were additionally housed with activity wheels. Body weight was monitored throughout. On Day 17, serum and liver samples were collected for biochemistry, histology (H&E, Oil Red O, adipophilin immunostaining and electron microscopy) and exploratory RNA‐seq analysis of metabolic pathways, including β‐oxidation and lipid transport. Two FR mice died during the experiment, whereas no deaths occurred in the AN, HFD or Ctr groups. Both FR and AN groups showed marked weight loss compared with Ctr ( p < 0.05). Histology revealed focal small‐droplet steatosis in a subset of AN mice and large‐droplet steatosis in HFD mice, whereas FR mice showed minimal steatosis. Oil Red O staining confirmed small‐droplet fat in 23.1% of AN mice and also demonstrated lipid accumulation in HFD mice. Adipophilin‐positive areas were significantly increased in FR, AN and HFD groups versus Ctr ( p < 0.05), although no significant difference was detected between AN and FR. Biochemically, FR and AN mice exhibited lower TG and Glu and higher AST compared with Ctr ( p < 0.05). RNA‐seq showed clustering of AN and FR, distinct from HFD and Ctr, and suggested alterations in pathways related to fatty‐acid oxidation and lipid handling. We established a starvation‐ and exercise‐associated AN model that reproduces early, modest microvesicular steatosis and metabolic liver injury. Given the short observation period and limited extent of steatosis, RNA‐seq findings should be regarded as preliminary and hypothesis‐generating. Prolonged protocols and direct assessment of β‐oxidation and lipid transport will be required to build a more robust disease model.