Papers - ITO Takanori

FOLFIRINOX vs. Gemcitabine/Nab-Paclitaxel for Pancreatic Cancer by BRCA2 and TMB Status: A Japanese C-CAT Database Study. Open Access

Mizuno K, Ishikawa T, Ito T, Takano Y, Maeda O, Kawashima H, Ando Y

Cancer science     2026.3

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.70351

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PubMed

Association Between Locomotive Syndrome and N-Terminal Pro B-Type Natriuretic Peptide Concentration in a Health Screening Cohort　― A Retrospective Cross-Sectional Study ― Open Access

Mizuno Chiaki, Hiraiwa Hiroaki, Yokoyama Shinya, Ito Takanori, Sahara Kazuki, Honda Takashi, Tanaka Taku, Kojima Tetsuhito, Kariya Naoyoshi, Ito Ryota, Kazama Shingo, Kondo Toru, Morimoto Ryota, Kawashima Hiroki, Murohara Toyoaki

Circulation Reports   Vol. advpub ( 0 )   2026.3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Locomotive syndrome (LS), an early predictor of physical frailty, is frequently evaluated during health screenings in Japan. However, its relationship with early cardiac dysfunction remains unclear. We investigated the association between LS severity and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration, a myocardial stress biomarker, in a general health screening population.</p><p><b><i>Methods and Results:</i></b> This cross-sectional study analyzed 8,593 individuals who underwent health checkups between 2018 and 2023 in Aichi, Japan. LS was assessed using the Short Test Battery for LS, including physical tests and a 25-item questionnaire, and NT-proBNP was measured from blood samples. Individuals were categorized by LS stage (non-LS and stages 1–3) and NT-proBNP concentration (<55, 55–124, 125–299, ≥300 pg/mL). Logistic regression was used to evaluate the association between LS severity and elevated NT-proBNP (cut-off ≥125 pg/mL). A stepwise increase in NT-proBNP was observed with higher LS stage (P_trend<0.001). Compared with non-LS, LS stages 2 (odds ratio [OR] 2.24; 95% confidence interval [CI] 1.35–3.72) and 3 (OR 3.51; 95% CI 2.02–6.12) were independently associated with elevated NT-proBNP.</p><p><b><i>Conclusions:</i></b> The increase in NT-proBNP with LS severity suggests a link between myocardial stress progression and physical function decline in asymptomatic individuals. LS assessment may help identify early stage cardiovascular dysfunction, although the causal relationship between LS and cardiac dysfunction remains to be clarified.</p>

DOI： 10.1253/circrep.cr-25-0323

Open Access

CiNii Research

Editorial: Comparable Hepatic Fibrosis Risk Demands Equal Vigilance in Lean and Non-Lean Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. Open Access

Yokoyama S, Ito T

Alimentary pharmacology & therapeutics   Vol. 63 ( 6 ) page： 890 - 891   2026.3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Alimentary Pharmacology and Therapeutics  

DOI： 10.1111/apt.70451

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PubMed

Utility of MELD 3.0 and MELD-Na in Predicting Long-term Mortality and Rebleeding after Endoscopic Hemostasis for Acute Variceal Hemorrhaging in Patients with Cirrhosis Open Access

Yokoyama Shinya, Honda Takashi, Ishizu Yoji, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Tsuzuki Tomoyuki, Nakamura Masanao, Kawashima Hiroki

Internal Medicine   Vol. 65 ( 3 ) page： 368 - 378   2026.2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>This retrospective study assessed the longitudinal prognostic accuracy of the Model for End-Stage Liver Disease (MELD), MELD-Na, MELD 3.0, and Child-Pugh scores in predicting mortality and rebleeding risk in patients with liver cirrhosis (LC) following successful endoscopic hemostasis for acute variceal hemorrhaging (AVH). </p><p><b>Methods </b>Time-dependent receiver operating characteristics and survival analyses were performed to predict mortality. The risk of rebleeding was analyzed using a competing risk model. </p><p><b>Patients </b>A total of 168 patients with LC who underwent successful endoscopic treatment, including ligation and sclerotherapy for AVH of the esophagus or stomach, were included. </p><p><b>Results </b>The MELD 3.0, which demonstrated the highest accuracy for predicting mortality, had an average area under the curve of 0.789, remaining above 0.8 for up to 18 months. The survival rate was significantly worse in the high-MELD group (3.0) than in the low-MELD group (3.0), with a hazard ratio (HR) of 3.23 and a shorter median survival time of 113 days versus 1,750 days. Advanced hepatocellular carcinoma and the need for red blood cell transfusion were also independent risk factors for mortality. A high MELD-Na level was the only factor associated with an increased risk of rebleeding (HR, 2.07), and the cumulative rebleeding rate was significantly higher in the high-MELD-Na group than in the low-MELD-Na group. </p><p><b>Conclusion </b>MELD 3.0 and MELD-Na serve as reliable non-invasive tools for predicting the long-term mortality and rebleeding risk after AVH. These scores can aid in clinical decision making, enabling the early identification of high-risk patients for targeted interventions and closer monitoring. </p>

DOI： 10.2169/internalmedicine.5556-25

Open Access

Scopus

PubMed

CiNii Research

Effect of General Anesthesia on Liver and Spleen Stiffness for Predicting High-Risk Varices in Biliary Atresia. Open Access

Yokoyama S, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Shirota C, Tainaka T, Makita S, Nakamura M, Uchida H, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 56 ( 2 ) page： 223 - 232   2026.2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: Liver and spleen stiffness (LS and SS) measurements in predicting high risk varices (HRVs) are reported useful in biliary atresia (BA). In children, inability to temporarily hold their breath may pose challenges in obtaining accurate measurements. This cross-sectional prospective study aimed to evaluate the diagnostic accuracy of LS and SS measurements obtained under general anesthesia during brief pauses in ventilation compared with those obtained in the awake state, in predicting HRVs. Methods: Among patients with BA aged 15 years or younger who underwent esophagogastroduodenoscopy under general anesthesia for evaluation of varices, 43 patients with LS and SS measured both in the awake and anaesthetized states were enrolled. HRVs were defined as large esophagogastric varices or esophagogastric varices of any size with red color signs. Results: The median age was 4 years. Nineteen patients had HRVs. In the HRVs group compared with the non-HRVs group, awake-LS, awake-SS, anesthesia-LS, and anesthesia-SS were significantly higher: 2.23 versus 1.71, 4.40 versus 3.45, 2.56 versus 1.73, and 4.13 versus 3.62 m/s, respectively. The area under the curve for awake-LS, awake-SS, anesthesia-LS, and anesthesia-SS were 0.784, 0.794, 0.814, and 0.698, respectively. Awake-LS and anesthesia-LS showed a strong positive correlation (ρ = 0.894), whereas awake-SS and anesthesia-SS showed a weak correlation (ρ = 0.468). Conclusions: As anesthetics and mechanical ventilation affect abdominal hemodynamics, SS measurements obtained under general anesthesia deviated from those obtained during the awake state. Further research is needed to determine whether mild sedation could help optimize measurement conditions. Trial Registration: This study was registered on the University Hospital Medical Information Network (UMIN000033123).

DOI： 10.1111/hepr.70049

Open Access

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PubMed

Fever following Treatment with Atezolizumab plus Bevacizumab Predicts Liver Injury in Patients with Unresectable Hepatocellular Carcinoma: A Prospective Observational Analysis. Open Access

Ito T, Yamamoto T, Nishida K, Kobayashi Y, Mizuno K, Suzuki T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Ishigami M, Koya T, Nakashima S, Naito T, Yasuda S, Kuzuya T, Toyoda H, Ando Y, Yoshio S, Kawashima H

Liver cancer   Vol. 15 ( 1 ) page： 50 - 62   2026.2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver Cancer  

Introduction: Liver injury is a treatment-related adverse event (liver-TRAE), one of the most common complications of atezolizumab plus bevacizumab (Atez/Bev) therapy, when treating unresectable hepatocellular carcinoma (uHCC). Fever following immune checkpoint inhibitor (ICI) therapy may predict ICI-induced liver injury in various malignancy types. However, the association between fever and liver-TRAEs in patients with uHCC treated with Atez/Bev has not been investigated. We prospectively evaluated the relationship between the onset of liver-TRAEs and preceding fever and sought to identify circulating biomarkers that predict liver injury in patients with Atez/Bev-treated uHCC. Methods: The primary outcome of this prospective, multicenter study was the association between liver-TRAEs (grade ≥2) and the presence of ICI-induced fever before the onset of liver injury. We used a multiplex bead-based immunoassay to evaluate 40 circulating proteins in the serum before and at 1, 3, and 6 weeks after initial Atez/Bev treatment. Results: Among 99 patients receiving Atez/Bev, grade ≥2 liverTRAEs occurred in 10 (10.1%) during the follow-up period (median, 14.7 months). The incidences of liver-TRAEs associated with fever before liver injury were 27.8% (n = 5/ 18) and 6.2% (n = 5/81) in the fever and non-fever groups, respectively. Multivariable analysis showed that the presence of fever was a significant risk factor for liver-TRAEs (odds ratio 7.57; 95% confidence interval, 1.83 33.89; p = 0.006). Furthermore, the prognosis was worse in the liver-TRAE (grade ≥2) group (p = 0.065 for progression-free survival and p = 0.074 for overall survival). Among patients with preceding fever, the liver-TRAE group had significantly lower CXCL-5 levels before treatment, higher IL-6 levels at 1 and 3 weeks, and lower CXCL-5, IFN-γ, and IL-10 levels at 6 weeks (p < 0.05). Conclusion: Fever during Atez/Bev treatment may predict liver-TRAEs, which leads to poor prognosis in patients with uHCC. Altered inflammatory cytokine and chemokine levels may help predict liverTRAEs in patients with fever after Atez/Bev therapy.

DOI： 10.1159/000546967

Open Access

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PubMed

Efficacy and Safety of Atezolizumab Plus Bevacizumab for Patients With Hepatocellular Carcinoma and Child-Pugh Class B. Open Access

Sasaki R, Shimose S, Saeki I, Ito T, Takeuchi Y, Tani J, Tomonari T, Sasaki K, Kakizaki S, Hatanaka T, Miuma S, Shirono T, Iwamoto H, Tanabe N, Yamamoto T, Kanayama Y, Naganuma A, Nishina S, Takayama T, Kobara H, Otsuka M, Kawashima H, Takami T, Kawaguchi T, Miyaaki H, Hepatology InVestigator Experts in Japan (HIVE‐J) Study Group

Liver international : official journal of the International Association for the Study of the Liver   Vol. 46 ( 1 ) page： e70466   2026.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Liver International  

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.

DOI： 10.1111/liv.70466

Open Access

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PubMed

Outcomes of Sequential Immune Checkpoint Inhibitor Retreatment After Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma. Open Access

Ito T, Shimose S, Saeki I, Takeuchi Y, Tani J, Tomonari T, Sasaki R, Sasaki K, Kakizaki S, Hatanaka T, Iwamoto H, Tanabe N, Yamamoto T, Naganuma A, Shirono T, Kanayama Y, Miyaaki H, Nishina S, Takayama T, Kobara H, Otsuka M, Takami T, Kawaguchi T, Kawashima H, Hepatology InVestigator Experts in Japan (HIVE‐J) Study Group

Journal of gastroenterology and hepatology   Vol. 41 ( 1 ) page： 302 - 311   2026.1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology and Hepatology Australia  

Background and Aim: Data on sequential immune checkpoint inhibitor (ICI) retreatment following initial atezolizumab plus bevacizumab (Atez + Bev) are limited. This study aimed to evaluate the efficacy and safety of sequential ICI retreatment in patients with unresectable hepatocellular carcinoma (uHCC). Methods: Of 835 patients with uHCC treated with Atez + Bev, 75 who underwent ICI retreatment after initial Atez + Bev therapy were included in this multicenter retrospective study that assessed the efficacy and safety of ICIs. Results: The participants received one of three sequential retreatments with ICI regimens: durvalumab plus tremelimumab (n = 58), retreatment with Atez + Bev (n = 15), and durvalumab monotherapy (n = 2). The objective response rates (ORRs)/disease control rates (DCRs) for the initial Atez + Bev and sequential ICI retreatment were 34.7%/89.3% and 18.7%/54.7%, respectively. No significant differences in antitumor response were observed among the three ICI retreatment regimens. Patients who achieved a good antitumor response (≥ stable disease) following retreatment showed a significantly longer overall survival. Multivariate analysis identified prior objective response to Atez + Bev as an independent predictor of disease control after retreatment (odds ratio: 3.79, p = 0.016). Immune-related adverse events (irAEs) requiring corticosteroids occurred in 26.7% of the patients during ICI retreatment, with enterocolitis and rash being the most common. The recurrence rate of irAEs was 15.4% in patients with previous steroid-requiring irAEs. Conclusions: Sequential ICI retreatment may be a viable therapeutic option for selected patients with uHCC, particularly those with a favorable response to prior Atez + Bev. Although less effective than first-line therapy, careful patient selection and monitoring ensure efficacy with acceptable safety.

DOI： 10.1111/jgh.70150

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PubMed

Long-Term Effectiveness of Tenofovir Alafenamide Versus Entecavir in Treatment-Naive Chronic Hepatitis B: A Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus.

Li J, Liu JK, Chau A, Linden S, Tsai PC, Nozaki A, Vutien P, Uojima H, Toyoda H, Honda T, Trinh H, Abe H, Ishikawa T, Atsukawa M, Watanabe T, Tsuji K, Huang DQ, Takaguchi K, Itobayashi E, Marciano S, Rui F, Ni W, Takahashi H, Chuang WL, Dai CY, Huang JF, Huang CF, Yeh ML, Zhu Y, Itokawa N, Kozuka R, Inoue K, Senoh T, Maeda M, Ito T, Morimoto M, Cheung R, Gadano A, Enomoto M, Tanaka Y, Lim SG, Wu C, Yu ML, Nguyen MH

The American journal of gastroenterology     2025.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Gastroenterology  

INTRODUCTION: – Although both tenofovir alafenamide (TAF) and entecavir (ETV) are recommended first-line treatments for chronic hepatitis B, comparative data on their effectiveness remain limited. We aim to compare their virologic (VR), biochemical (BR), and complete (CR) response rates.METHODS: – This retrospective study enrolled treatment-naive chronic hepatitis B patients who initiated either TAF or ETV in 2016 or after across 22 international centers and evaluated their treatment response after balancing their characteristics using inverse probability treatment weighting and through Fine-Gray competing-risks analysis of the balanced cohort.RESULTS: – The study included 1, 605 patients (784 TAF and 821 ETV patients with significant background differences) of whom 1, 553 (96.8%) were from Asia. Inverse probability treatment-weighting analysis yielded a total weighted cohort of 1, 660 (822 TAF and 838 ETV patients with balanced characteristics). The 5-year cumulative VRs were high in both groups with a slightly higher rate in TAF patients (98.0% vs 93.9%, P < 0.001), and similar findings were found in a subgroup analysis by median hepatitis B virus (HBV) DNA (5.5 log IU/mL). However, there was no significant difference in the 5-year BR rates overall (93.7 vs 92.8%, P = 0.484) or by alanine aminotransferase (ALT) cutoff of 2× upper limit of normal. TAF patients had a slightly higher 5-year cumulative CR overall (94.9% vs 89.4%, P = 0.001) and in high HBV DNA (96.9% vs 87.9%, P < 0.001) or ALT ≥2× upper limit of normal patients (97.3% vs 90.6%, P < 0.001), but not in those with lower HBV DNA or ALT.DISCUSSION: – BR rates were similar with ETV and TAF, while VR and CR were higher with TAF, although the difference was modest (<5% overall, 7%–9% in high HBV DNA or ALT groups). Antiviral selection between TAF vs ETV should be based mainly on cost, side effect profile, and patient preference.

DOI： 10.14309/ajg.0000000000003881

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PubMed

Hepatitis B Virus RNA Predicts Hepatocellular Carcinoma Despite Viral Suppression. Open Access

Kumada T, Toyoda H, Yasuda S, Koshiyama Y, Ito T, Akita T, Tanaka J

Alimentary pharmacology & therapeutics     2025.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Alimentary Pharmacology and Therapeutics  

Background: Despite achieving undetectable hepatitis B virus (HBV) DNA levels with nucleos(t)ide analogue (NA) therapy, patients with chronic hepatitis B (CHB) remain at risk of hepatocellular carcinoma (HCC). Novel covalently closed circular DNA activity biomarkers may improve risk stratification. Aims: To comprehensively assess the association between serum HBV RNA and hepatitis B core-related antigen (HBcrAg) levels, measured upon achieving undetectable HBV DNA levels, and subsequent HCC development in NA-treated patients with CHB. Methods: We retrospectively analysed 311 patients with CHB who achieved undetectable HBV DNA levels during NA therapy between 2000 and 2024. Serum HBV RNA (≥ 10 copies/mL) and HBcrAg (≥ 2.1 log U/mL) were measured in stored samples collected when HBV DNA first became undetectable. Cox regression analysis was performed to identify the factors associated with HCC development. Results: During a median follow-up of 11.0 years, 31 (10.0%) patients developed HCC. At viral suppression, 132 (42.4%) patients had HBV RNA ≥ 10 copies/mL. HCC incidence was significantly higher in patients with quantifiable HBV RNA than in those with unquantifiable HBV RNA (15-year incidence, 17.8% vs. 8.8%, p = 0.026). Quantifiable HBV RNA independently predicted HCC (adjusted hazard ratio [aHR], 3.313; 95% confidence interval [CI]: 1.154–9.507; p = 0.026). HBcrAg showed no association (aHR, 0.821; 95% CI: 0.253–2.669; p = 0.743). Patients with quantifiable HBV RNA and albumin-bilirubin score ≥ −2.60 had the highest risk (5-year incidence: 15.8%). Conclusions: HBV RNA levels at viral suppression predict HCC development in NA-treated patients with CHB, outperforming HBcrAg. Incorporating HBV RNA assessment can improve risk-stratified HCC surveillance strategies.

DOI： 10.1111/apt.70483

Open Access

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PubMed

A case of pregnancy with liver cirrhosis managed by cesarean section at 26 gestational weeks

Suzuki Takaya, Imai Norihiro, Sahara Kazuki, Mizuno Fumitaka, Matsuda Yoshitaka, Yamamoto Takafumi, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishikawa Tetsuya, Kawashima Hiroki

Kanzo   Vol. 66 ( 12 ) page： 518 - 525   2025.12

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japan Society of Hepatology  

<p>A woman in her 40s, gravidity 2, parity 1, with a longstanding history of chronic liver disease since childhood, suspected to be autoimmune hepatitis, was diagnosed with cirrhosis during a previous pregnancy. She had previously delivered via cesarean section at 30 weeks of gestation. In her current pregnancy, she developed edema at 20 weeks. By 25 weeks, she experienced significant weight gain and worsening liver function. Due to the high risk of maternal liver failure, she underwent three sessions of plasma exchange, followed by a cesarean delivery at 26 weeks and 6 days. Postpartum, her liver function improved, and her weight decreased. Pregnancies complicated by cirrhosis require careful monitoring, particularly for esophageal and gastric varices and fluid overload. A prepregnancy MELD score of ≥10 is associated with a high risk of severe maternal and fetal complications.</p>

DOI： 10.2957/kanzo.66.518

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CiNii Research

Association of Metabolic-Associated Steatotic Liver Disease With Clinical Outcomes of Durvalumab and Tremelimumab in Advanced Hepatocellular Carcinoma Patients: A Multicenter Study.

Hatanaka T, Shimose S, Ito T, Tani J, Tomonari T, Saeki I, Takeuchi Y, Sasaki K, Honma Y, Sasaki R, Yoshioka N, Naito T, Takeuchi M, Yasunaka T, Sakata M, Iwamoto H, Itano S, Kanayama Y, Shirono T, Tanabe N, Yamamoto T, Naganuma A, Nishina S, Otsuka M, Kobara H, Takami T, Takayama T, Kawaguchi T, Kawashima H, Harada M, Miyaaki H, Kakizaki S, Hepatology InVestigator Experts in Japan (HIVE‐J) Study Group

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 12 ) page： 1642 - 1651   2025.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: This study aimed to evaluate the association between the efficacy of durvalumab plus tremelimumab (Dur/Tre) and metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with hepatocellular carcinoma (HCC). Methods: A total of 239 patients with HCC who received Dur/Tre between March 2023 and October 2024 at multiple institutions in Japan were retrospectively analyzed. Patients were categorized into three groups based on underlying liver disease: viral-related HCC (n = 126), MASLD-related HCC (n = 30), and nonviral, non-MASLD HCC (n = 83). Results: The overall response rates (ORR) were 17.5%, 16.7%, and 19.3% in viral-related HCC, MASLD-related HCC, and nonviral, non-MASLD HCC, respectively. The disease control rates (DCR) were 44.4%, 46.7%, and 51.8%, respectively. No significant differences in ORR (p = 0.6) or DCR (p = 0.9) were observed among the three groups. The median PFS was 3.7 months (95% CI, 2.8–4.9) in patients with viral-related HCC, 3.6 months (95% CI, 2.3–4.8) in patients with MASLD-related HCC, and 4.4 months (95% CI, 2.6–5.8) in patients with nonviral, non-MASLD HCC. The median OS was 14.4 months (95% CI, 9.8–NA) in patients with viral-related HCC and 11.0 months (95% CI, 6.4–NA) in patients with MASLD-related HCC, whereas it was not reached in patients with nonviral, non-MASLD HCC. No statistically significant differences in PFS (p = 1.0) and OS (p = 0.3) were found among the groups. Conclusions: Dur/Tre showed comparable efficacy in MASLD-related HCC and other etiologies, warranting confirmation in larger cohorts.

DOI： 10.1111/hepr.70023

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PubMed

Morphological alterations of peridroplet mitochondria in human liver biopsy. Open Access

Kawecka H, Imai N, Ohsaki Y, Cheng J, Liu D, Zhang J, Mizuno F, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishikawa T, Woźniak M, Wake H, Kawashima H

Scientific reports   Vol. 15 ( 1 ) page： 38650   2025.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Mitochondrial dysfunction and the accumulation of lipid droplets (LD) contribute to the pathogenesis of liver diseases. Mitochondria bound to LD, termed peridroplet mitochondria (PDM), form a subpopulation with distinct functions compared to cytoplasmic mitochondria (CM). In this first in vivo human liver study, we aimed to investigate the morphological differences between PDM and CM and to assess their associations with clinical parameters. Our analysis of mitochondrial ultrastructure using transmission electron microscopy images of human liver biopsies showed that CM were significantly smaller, more spherical, and solid, whereas PDM were larger and more elongated. Overall, PDM exhibited more uniform morphology, while CM displayed disease-specific morphological alterations. CM were associated with serum liver enzyme levels and high-density lipoprotein cholesterol, suggesting sensitivity to liver stress and a potential role in liver cholesterol transport. In contrast, PDM were associated with serum triglyceride levels, indicating a role in lipid metabolism. Total PDM and LD counts showed a positive correlation, reinforcing their close functional relationship. These findings show that PDM and CM represent distinct mitochondrial subpopulations with unique morphologies and differing associations with hepatic pathophysiological pathways, which highlights the significance of LD interactions in contributing to mitochondrial heterogeneity.

DOI： 10.1038/s41598-025-22496-z

Open Access

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PubMed

Differential HCC risk among HBV indeterminate types at baseline and by phase transition.

Huang R, Trinh HN, Yasuda S, Chau A, Maeda M, Do AT, Huang DQ, Ito T, Honda T, Ishigami M, Kozuka R, Preda CM, Tseng CH, Marciano S, Tsai PC, Lee DH, Wong CC, Do S, Kawashima K, Zhang J, Marin RI, Sandra I, Li J, Ogawa E, Cheung R, Li J, Yu ML, Gadano A, Hsu YC, Buti M, Enomoto M, Lim SG, Wu C, Toyoda H, Nguyen MH

Gut   Vol. 74 ( 11 ) page： 1873 - 1882   2025.10

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gut  

Background Patients with chronic hepatitis B (CHB) with indeterminate phase make up a diverse cohort with likely different outcomes. Objective We compared the hepatocellular carcinoma (HCC) risk in indeterminate CHB with different baseline types and by phase transition. Design This was a retrospective cohort study of 1986 (94.2% Asian) patients with indeterminate CHB from nine countries/regions. Patients were classified according to baseline hepatitis B e- antigen (HBeAg), alanine aminotransferase (ALT) and HBV DNA. The cumulative HCC incidence was compared. Results Based on the 2018 American Association for the Study of Liver Disease guidance, most indeterminate patients were HBeAg negative (84.9%). The 20- year HCC incidence was highest in type 1 (HBeAg positive, ALT<1×upper limit of normal (ULN), HBV DNA ALT < 1×upper limit of normal (ULN), HBV DNA 20 000–106 IU/mL, 36.2%) and lowest in type 8 (HBeAg negative, ALT 1–2×ULN, HBV DNA<2000 IU/mL, 1.9%). The 20- year HCC incidence of those who remained indeterminate was 4.7%. Cumulative HCC incidence rates were high in patients with indeterminate CHB who transitioned to immune tolerant (15 years: 16.5%) or immune active (20 years: 13.7%) phase but low for those who transitioned to immune inactive phase (20 years: 2.5%). In multivariable analysis, compared with type 8, higher HCC risk was seen with HBeAg- positive type 1 (adjusted HR (aHR)=40.1, p<0.001), type 2 (ALT 1–2×ULN, HBV DNA≥20 000 IU/mL, aHR=25.1, p<0.001), HBeAg- negative type 9 (ALT > 2×ULN, HBV DNA<2000 IU/mL, aHR=4.6, p=0.032) and type 10 (ALT<1×ULN, HBV DNA<2000 IU/mL but with moderate to severe inflammation/fibrosis, aHR=7.3, p=0.033). Similar directions in HCC risks were found in analyses based on the 2017 European Association for the Study of the Liver guideline.

DOI： 10.1136/gutjnl-2025-335033

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Impact of alcohol consumption and muscle mass on bone mineral density in metabolic dysfunction and alcohol-associated liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). Open Access

Yokoyama S, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Kojima T, Kariya N, Nakamura M, Kawashima H

Clinical nutrition ESPEN   Vol. 69   page： 145 - 153   2025.10

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Nutrition Espen  

Background and aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are newly defined conditions within steatotic liver disease (SLD). We have previously reported that lean physique, hypertriglyceridemia and weak grip strength are risk factors for decreased bone mineral density (BMD) in patients with MASLD. While BMD is influenced by both alcohol consumption and metabolic dysfunction, the specific relationship between SLD and decreased BMD remains unclear. This study aimed to elucidate the impact of alcohol consumption in patients with MetALD and MASLD, and to identify risk factors for decreased BMD in patients with MetALD in a health examination setting. Methods: This retrospective cross-sectional study analyzed individuals who underwent health examinations from April 2018 to March 2023. BMD was determined at the calcaneus using an AOS-10SA bone densitometer. Decreased BMD was defined as T-scores below −1.0 standard deviation or ongoing treatment for osteoporosis. Results: We evaluated 1,945 patients with MetALD and MASLD. The median age was 53 years (interquartile range: 47–61 years), and men comprised 83.9 % of the cohort. In multivariate analysis of patients with MetALD and MASLD, the following were identified as independent risk factors for decreased BMD: lean physique (odds ratio [OR]: 0.52, 95 % confidence interval [CI]: 0.39–0.70), hypertriglyceridemia (OR: 1.27, 95 % CI: 1.02–1.57), male sex (OR: 1.63, 95 % CI: 1.06–2.50), older age (OR: 1.02, 95 % CI: 1.00–1.03), low creatinine levels (OR: 0.40, 95 % CI: 0.17–0.97), and low grip strength (OR: 0.97, 95 % CI: 0.95–0.99). Notably, moderate alcohol consumption was associated with a lower risk of decreased BMD (OR: 0.71, 95 % CI: 0.55–0.92) compared to no/light alcohol consumption. A total of 535 individuals were diagnosed with MetALD. In these patients, weak grip strength was the only independent risk factor for decreased BMD (OR: 0.96, 95 % CI: 0.93–1.00). BMD values showed a weak but significant positive correlation with grip strength measurements (ρ = 0.149, P < 0.001). Conclusions: Our study revealed that moderate alcohol consumption was associated with preserved BMD in patients with MetALD and MASLD, while patients with weak grip strength appear to be at higher risk for decreased BMD in MetALD. Low grip strength likely indicates reduced systemic skeletal muscle mass, suggesting a potential relationship with decreased BMD. Our findings suggested that patients with weak grip strength should be prioritized for BMD assessment in MetALD, enabling early intervention for bone health management. The study highlights the complex relationship between moderate alcohol consumption, muscle strength, and bone health in patients with MetALD and MASLD.

DOI： 10.1016/j.clnesp.2025.07.002

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PubMed

Impact of Concurrent Steatotic Liver Disease and Chronic Hepatitis B on Treatment Response to Nucleos(t)ide Analogs. Open Access

Chau A, Li J, Jun DW, Hsu YC, Toyoda H, Yeh ML, Watanabe T, Honda T, Trinh H, Nozaki A, Uojima H, Ishikawa T, Huang DQ, Vutien P, Marciano S, Abe H, Atsukawa M, Enomoto M, Takahashi H, Tsuji K, Takaguchi K, Itobayashi E, Huang R, Tsai PC, Dai CY, Huang JF, Huang CF, Yoon E, Kim SE, Ahn SB, Kim GA, Jung JH, Jeong SW, Oh H, Hsiao T, Maeda M, Tseng CH, Yasuda S, Ishigami M, Chuma M, Ito T, Kawashima K, Liu JK, Itokawa N, Kozuka R, Inoue K, Senoh T, Chuang WL, Gadano A, Tanaka Y, Lim SG, Wu C, Cheung R, Yu ML, Nguyen MH

Journal of viral hepatitis   Vol. 32 ( 10 ) page： e70081   2025.10

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Viral Hepatitis  

Data is limited regarding response to nucleos(t)ide analogs (NA) among patients with concurrent steatotic liver disease (SLD) and chronic hepatitis B (CHB). We investigated the outcomes of NA therapy between SLD-CHB and non-SLD CHB patients in a multinational CHB cohort. Adult CHB patients treated with ETV, TDF, or TAF from 28 sites (United States, Taiwan, Japan, Korea, China, Singapore, Argentina) were retrospectively analysed. SLD was diagnosed by imaging. Propensity score matching (PSM) was used to balance the SLD-CHB and non-SLD CHB groups, and competing risks analysis was used to compare incidence and sub-distribution hazard ratios (SHRs) of VR, BR, and CR. The study included 4600 patients (26.7% with SLD). SLD-CHB patients (vs. non-SLD CHB) were younger (49.4 vs. 50.9 years, p < 0.001), more likely male (68.0% vs. 61.6%), from the West (24.9% vs. 19.3%), and with higher BMI (25.3 vs. 23.5) but less likely to have advanced fibrosis (22.6% vs. 35.9%), all p < 0.001. Following PSM, baseline characteristics became balanced between the two groups. The 5-year cumulative rates for the SLD-CHB versus non-SLD CHB groups were as follows: VR (87.9% vs. 89.8%, p = 0.16), BR (86.8% vs. 89.2%, p = 0.096), and CR (77.5% vs. 81.0%, p = 0.085). After multivariable analysis, SLD-CHB patients had a significantly lower likelihood of achieving BR (SHR = 0.77, CI: 0.68–0.88, p < 0.001) and CR (SHR = 0.84, CI: 0.72–0.97, p = 0.019), but not VR. Among CHB patients treated with NA therapy, SLD was associated with a 23% lower likelihood of biochemical response and a 16% lower likelihood of complete response but did not impact virologic response.

DOI： 10.1111/jvh.70081

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PubMed

A Guide for the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Induced Liver Injury

Ito Takanori, Takeuchi Yasuto, Mizuno Kazuyuki, Imai Michitaka, Yoshimaru Yoko, Abe Kazumichi, Abe Masanori, Matsuura Takanori, Yokode Masataka, Shiokawa Masahiro, Ogasawara Sadahisa, Kodama Yuzo, Komuta Mina, Harada Kenichi, Sakamoto Naoya, Tanaka Atsushi

Kanzo   Vol. 66 ( 9 ) page： 375 - 387   2025.9

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japan Society of Hepatology  

<p>The diagnosis of liver injury caused by immune checkpoint inhibitors (ICIs) as an immune-related adverse event (irAE) requires comprehensive clinical examination, blood and imaging tests, and pathological investigation of liver biopsy when necessary. Furthermore, the extent of liver injury is classified based on the R-value, which helps exclude ICI-induced cholangitis and determine appropriate treatment strategies. The typical pathological finding in ICI-induced liver injury is acute hepatitis, characterized by diffuse lobular injury with CD8⁺ lymphocytic infiltration, with the first-line treatment being corticosteroids. In nonhepatocellular injury types, ursodeoxycholic acid is used as an adjunct, whereas mycophenolate mofetil is considered an additional immunosuppressive agent in steroid-refractory cases. Re-administration of ICI after improvement in liver injury may increase the risk of re-injury or irAE in other organs; therefore, treatment decisions should be made following thorough discussions between a multidisciplinary team, including the primary physician, gastroenterologists, and other specialists.</p>

DOI： 10.2957/kanzo.66.375

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CiNii Research

Impact of metabolic dysfunction on treatment responses to nucleos(t)ide analogues in chronic hepatitis B: a retrospective multi-center REAL-B cohort study. Open Access

Huang R, Jun DW, Toyoda H, Hsu YC, Trinh H, Nozaki A, Ishikawa T, Watanabe T, Uojima H, Huang DQ, Honda T, Tanaka Y, Vutien P, Marciano S, Abe H, Enomoto M, Atsukawa M, Takahashi H, Tsuji K, Itobayashi E, Takaguchi K, Tsai PC, Dai CY, Huang JF, Huang CF, Yeh ML, Yoon E, Kim SE, Ahn SB, Kim GA, Jung JH, Jeong SW, Oh H, Tseng CH, Ishigami M, Chau A, Hsiao T, Maeda M, Yasuda S, Chuma M, Ito T, Kawashima K, Liu JK, Gadano A, Kozuka R, Itokawa N, Inoue K, Senoh T, Li J, Chuang WL, Cheung R, Wu C, Yu ML, Nguyen MH

EClinicalMedicine   Vol. 87   page： 103407   2025.9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Eclinicalmedicine  

Background: Metabolic dysfunction is associated with liver disease but it is unclear if it would impact responses to antiviral treatment in chronic hepatitis B (CHB) patients. Methods: Using data from an international consortium of 4507 treatment-naïve CHB patients who initiated nucleos(t)ide analogues (NAs) between January 2004 and August 2024 from 32 centers and propensity-score matching (PSM) to balance the background of patients with and without metabolic disease (diabetes, obesity, dyslipidemia, or hypertension), we compared their biochemical (BR), virologic (VR), and complete (CR) response. Findings: More than half (54.8%) had at least one metabolic disease. Patients with metabolic disease (vs. no) were older and more likely male. In the PSM cohort of 893 pairs of patients, patients with metabolic disease had significantly lower 5-year cumulative BR (91.3% vs. 95.8%, P < 0.001) and CR rates (81.8% vs. 87.4%, P = 0.008), but similar VR (93.5% vs. 94.1%, P = 0.65) and HBeAg seroconversion rates (27.0% vs. 29.7%, P = 0.92). On multivariable Cox regression, metabolic disease was associated with lower BR (adjusted hazard ratio [aHR] 0.73, P < 0.001) and CR (aHR 0.79, P = 0.001), especially in those with ≥3 metabolic diseases (aHR 0.55 for BR; aHR 0.53 for CR, both P < 0.001). Interpretation: The presence and number of metabolic diseases were significantly and incrementally associated with lower BR. Metabolic disease should be taken into consideration in the management of CHB patients receiving NAs treatment. Funding: None.

DOI： 10.1016/j.eclinm.2025.103407

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PubMed

A novel approach to evaluate the therapeutic efficacy of durvalumab and tremelimumab combination therapy in hepatocellular carcinoma.

Tomonari T, Shimose S, Saeki I, Tani J, Honma Y, Ito T, Takeuchi M, Naito T, Takeuchi Y, Sasaki R, Sasaki K, Hatanaka T, Kakizaki S, Kanayama Y, Naganuma A, Tanabe N, Tanaka H, Kawano Y, Sato Y, Nishina S, Miyaaki H, Otsuka M, Kawashima H, Harada M, Kobara H, Takami T, Kawaguchi T, Takayama T, Hepatology InVestigator Experts in Japan (HIVE‐J) Study Group

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 8 ) page： 1184 - 1192   2025.8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology Research  

Aim: This study aimed to evaluate the efficacy of durvalumab + tremelimumab (Dur + Tre) in real-world clinical practice, characterize “stable disease (SD),” and identify SD responders (SD-R) who benefit from Dur + Tre treatment. Methods: This multicenter observational study included 212 patients with unresectable hepatocellular carcinoma (u-HCC) treated with Dur + Tre between March 2023 and November 2024. The patients were categorized into 95 first-line and 117 later-line cases, respectively. Sequential cutoff points for depth of response (DOR) and progression-free survival (PFS) were tested to identify subgroups with survival outcomes comparable to those of responders. Results: Disease control rate (DCR) and PFS were significantly better in the first-line setting for both response evaluation criteria in solid tumors (RECIST) and modified RECIST (mRECIST) criteria. Patients who achieved PFS of ≥84 days or RECIST DOR of ≤–10% were classified as SD-R, as they had long-term survival outcomes similar to those with PR or CR. Furthermore, the CR + PR + SD-R group had significantly better survival outcomes than the other groups (p < 0.01), and multivariate analysis confirmed that SD-R was an independent prognostic factor with the strongest impact on survival outcomes (hazard ratio = 0.11). Conclusions: In real-world clinical practice, Dur + Tre is highly effective as a first-line treatment for u-HCC. Additionally, patients with SD who met the SD-R criteria (PFS ≥84 days or RECIST DOR ≤−10%) showed survival outcomes comparable to those of patients with PR or CR. These findings may help identify patients who are most likely to benefit from treatment and improve their prognoses.

DOI： 10.1111/hepr.14212

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PubMed

The benefit of conversion therapy for patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab using newly established oncological resectability criteria in Japan. Open Access

Shimose S, Saeki I, Ito T, Takeuchi Y, Tani J, Tomonari T, Sasaki R, Sasaki K, Kakizaki S, Hatanaka T, Iwamoto H, Tanabe N, Yamamoto T, Naganuma A, Shirono T, Kanayama Y, Nishina S, Takayama T, Kobara H, Otsuka M, Kawashima H, Takami T, Kawaguchi T, representing the Hepatology InVestigator Experts in Japan (HIVE-J) Study Group

Hepatology international   Vol. 19 ( 4 ) page： 846 - 855   2025.8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hepatology International  

Background: This study aimed to investigate the changes in oncological resection status in patients with unresectable hepatocellular carcinoma (u-HCC) receiving atezolizumab plus bevacizumab (Atez/Bev) and the impact of conversion therapy following Atez/Bev treatment. Methods: This cohort included 631 patients with u-HCC treated with Atez/Bev. Tumors were assessed using oncological resectability criteria and categorized as borderline resectable 1 (BR1, n=166) or borderline resectable 2 (BR2, n=465). Results: Overall, 129 (20.4%) patients were downstaged based on oncological resectability criteria. Among them, 28 (16.8%) patients were downstaged from BR1 to resectable (R), and 49 (10.5%) and 52 (11.1%) patients were downstaged from BR2 to R and from BR2 to BR1, respectively. The percentage of patients who underwent conversion therapy was 5.4%. For patients categorized as BR1 and BR2 before Atez/Bev treatment, the rates of conversion therapy were 8.4% (14/166) and 4.3% (20/465), respectively. Overall survival (OS) was significantly higher in the conversion therapy group than in the partial response group (not reached vs. 36.4 months, p=0.001), with no significant differences compared to the complete response group. The median recurrence-free survival was 15.7 months after conversion therapy. Although there were differences in patient background data at the time of conversion therapy, surgery had a significantly higher RFS than radiofrequency ablation (not reached vs. 10.0 months, p=0.008). Conclusions: When feasible, conversion therapy should be considered to improve the prognosis of u-HCC patients treated with Atez/Bev. Moreover, oncological resectability criteria may provide a useful tool for investigators regarding conversion therapy.

DOI： 10.1007/s12072-025-10781-y

Open Access

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PubMed