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

Open Access

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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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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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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

Distribution, Characteristics, and Natural History of Diverse Types of Indeterminate Chronic Hepatitis B: A REAL-B Study.

Huang R, Do AT, Toyoda H, Li J, Yasuda S, Tsai PC, Yeh ML, Trinh H, Chau A, Huang DQ, Ogawa E, Ito T, Kozuka R, Atsukawa M, Marciano S, Honda T, Watanabe T, Itokawa N, Preda CM, Tseng CH, Barreira A, Inoue K, Takahashi H, Uojima H, Kawashima K, Hsu YC, Marin RI, Sandra I, Ishigami M, Li J, Zhang J, Do S, Maeda M, Lee DH, Chuang WL, Dai CY, Huang JF, Huang CF, Cheung R, Buti M, Tanaka Y, Yuen MF, Enomoto M, Gadano A, Lim SG, Yu ML, Wu C, Nguyen MH

Alimentary pharmacology & therapeutics   Vol. 62 ( 3 ) page： 349 - 358   2025.8

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

Background and Aims: Chronic hepatitis B (CHB) with indeterminate phase comprises a heterogeneous group of patients. We determined the prevalence of indeterminate CHB overall and characterised novel types and phase transition probabilities of novel types of indeterminate CHB. Methods: CHB patients were enrolled retrospectively from 24 centres (9 countries/regions). Indeterminate phase was defined based on the AASLD 2018 guidance. Results: The cohort included 8375 patients with a mean age of 45.0 ± 13.7 years, 22.5% HBeAg-positive, and median ALT and HBV DNA of 30 U/L and 4.3 ± 2.2 log<inf>10</inf>IU/mL, respectively. Of the total cohort, half (47.2%) were in the indeterminate phase; and of these, the most prevalent group among HBeAg-positive patients was Type 2 (ALT 1–2 × ULN, HBV DNA≥ 20,000 IU/mL; 12.6%), while in HBeAg-negative patients it was Type 6 (ALT<ULN, HBV DNA≥ 2000 IU/mL; 30.1%). Among the 1530 indeterminate patients with long-term follow-up, the 10-year cumulative incidence of phase transition to immune tolerant, immune active and immune inactive phases were 6.5%, 32.1% and 64.3%, respectively. The majority (73.2%) of Type 2 indeterminate patients transitioned to the immune active phase, while only 16.5% of Type 8 (HBeAg-negative, ALT 1–2 × ULN, HBV DNA < 2000 IU/mL) did. Conclusions: Indeterminate CHB can be classified into 10 types, with the most prevalent type being those with HBeAg-negative, HBV DNA ≥ 2000 IU/mL and ALT<ULN (30.1%). The most prevalent HBeAg-positive patients with ALT 1–2 × ULN and HBV DNA ≥ 20,000 IU/mL type was also the most likely to transition to the immune-active phase (73.2% by year-10). The monitoring and management of CHB patients with the indeterminate phase should be individualised according to their types.

DOI： 10.1111/apt.70194

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Author's reply: Letter to the editor: Clinical characteristics of immune checkpoint inhibitor-related pancreatic injury with pancreatitis in patients with advanced malignancies.

Suzuki T, Mizuno K, Ito T

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 57 ( 7 ) page： 1512 - 1513   2025.7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2025.04.033

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PubMed

Steroid initiation dose and duration of steroid reduction for immune checkpoint inhibitor-induced liver injury.

Yamamoto T, Ito T, Suzuki T, Mizuno K, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 7 ) page： 977 - 985   2025.7

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

Aim: Treatment for severe immune checkpoint inhibitor (ICI)-induced liver injury (≥ Grade 3) requires prednisolone (PSL) administration and interruption of the underlying malignancy treatment. If the liver injury improves steadily, a lower initial dose of PSL is beneficial. We aimed to investigate the relationship between the initial dose of PSL and the response to PSL or the duration of PSL dose reduction. Methods: We retrospectively collected clinical data of patients treated with ICIs at Nagoya University Hospital between September 2014 and December 2023. Patients who received PSL for severe ICI-induced liver injury were divided according to the starting dose into group A (0.8 mg/kg/day) and group B (1.0 mg/kg/day). The time to improvement in liver injury and the reduction of the PSL dose to 10 mg/day were compared between the groups. Results: Overall, 1271 patients were treated with ICIs, of whom 80 experienced severe ICI-induced liver injury. Of the patients, 29 did not receive steroids, and five used PSL doses of <0.5 mg/kg/day. There were no significant differences in the baseline characteristics or laboratory data between the groups. The time to dose reduction to 10 mg/day PSL was significantly shorter in group A than in group B. The time to improvement in liver injury did not differ between the two groups. Conclusion: In some patients with severe ICI-induced liver injury, a dose of 0.8 mg/kg/day of PSL is sufficient to achieve a therapeutic effect and shorten the time required to reduce the dose to 10 mg/day.

DOI： 10.1111/hepr.14200

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Pathological significance of intranuclear structures in liver biopsy samples. Open Access

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

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 7 ) page： 1065 - 1074   2025.7

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

Aim: Glycogenated nuclei (GN) are glycogen deposits within the nuclei and are a frequent pathological finding in metabolic dysfunction-associated steatotic liver disease. This study aimed to investigate the relationship between GN and two morphologically distinct types of intranuclear lipid droplets in liver biopsy specimens and to explore their respective pathological significance. Methods: We analyzed 135 liver biopsy specimens. A portion of the liver biopsy specimen was examined using transmission electron microscopy (TEM) to investigate intranuclear lipid droplets in hepatocytes. Nuclear inclusion bodies with clear boundaries and unstained areas on hematoxylin and eosin staining were identified as nuclear glycogen. Results: TEM revealed nucleoplasmic lipid droplets (nLD) in 65% of liver biopsy specimens and invagination of cytoplasmic lipid droplets into the nucleus in 30% of specimens. In contrast, light microscopy detected GN in 82% of specimens. No significant correlations were observed between the frequencies of the two types of intranuclear lipid droplets and nuclear glycogen levels. A significant positive correlation was observed between the frequency of nLD and transaminase levels. Glycogenated nuclei were frequently observed in liver biopsy specimens from patients with MASLD; however, their frequency did not significantly correlate with the degree of hepatic steatosis. Instead, a significant positive correlation was observed between nuclear glycogen and blood HbA1c levels. Conclusions: The two types of intranuclear lipid droplets and nuclear glycogen observed in liver biopsy specimens showed no significant correlation in their formation frequencies, suggesting that they possess distinct pathological significance.

DOI： 10.1111/hepr.14195

Open Access

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PubMed

Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues. 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, 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, 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

Clinical and molecular hepatology   Vol. 31 ( 3 ) page： 1003 - 1017   2025.7

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

Background/Aims: Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment. Methods: We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes. Results: The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001). Conclusions: Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.

DOI： 10.3350/cmh.2024.1070

Open Access

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PubMed

Current management and future perspectives of covert hepatic encephalopathy in Japan: a nationwide survey. Open Access

Miwa T, Tsuruoka M, Ueda H, Abe T, Inada H, Yukawa-Muto Y, Ohara M, Arai T, Tamai Y, Isoda H, Tadokoro T, Hanai T, Ito T, Tamaki N, Sakamaki A, Aoki Y, Tada F, Yoshio S, Takahashi H, Morishita A, Ishikawa T, Inoue J, Suda G, Ogawa C, Atsukawa M, Hiraoka A, Kuroda H, Namisaki T, Honda T, Kawaguchi T, Tanaka Y, Terai S, Ikegami T, Yoshiji H, Iwasa M, Shimizu M

Journal of gastroenterology   Vol. 60 ( 7 ) page： 866 - 876   2025.7

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

Background: Covert hepatic encephalopathy (CHE) leads to devastating outcomes in patients with cirrhosis. This study aims to elucidate the current management and future perspectives of CHE in Japan. Methods: A questionnaire-based cross-sectional study was conducted among physicians involved in managing cirrhosis in Japan. The primary aim was to elucidate the real-world management of CHE, including testing and treatment. Factors influencing the implementation of CHE testing were analyzed using a logistic regression model. Limitations and future perspectives for improving the management of CHE were also evaluated. Results: Of 511 physicians surveyed, 93.9% recognized CHE as a significant problem, and 86.9% agreed that it should be tested. Overall, 62.8% of physicians tested for CHE, whereas 37.2% did not. Multivariable analysis identified institutional factors and certifying board as significant determinants of CHE test implementation. The Stroop (68.2%) and neuropsychiatric tests (57.5%) were the most commonly used methods of identifying CHE. Among those who tested for CHE, 87.7% treated CHE; the most common treatments were lactulose (81.5%), rifaximin (76.3%), and branched-chain amino acids (70.4%). Among non-testers, the primary barrier was the time requirement for testing. Proposals to encourage CHE testing included the development of simple tests and integration of multidisciplinary teams. Conclusions: Most physicians involved in cirrhosis care in Japan recognize CHE as a significant problem that warrants testing. However, testing for CHE remains limited by institutional factors and physician specialties. Time requirements for CHE testing are the primary barrier, and simple tests and multidisciplinary teams are recommended to enhance CHE management.

DOI： 10.1007/s00535-025-02232-0

Open Access

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PubMed

Author's reply: Pancreatic injury in immune checkpoint inhibitor therapy: Clinical management challenges and considerations.

Suzuki T, Mizuno K, Ito T

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 57 ( 7 ) page： 1516   2025.7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2025.04.035

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PubMed

Safety and efficacy of retreatment with immune checkpoint inhibitors after severe immune-related adverse events. Open Access

Mizuno K, Ito T, Sawada T, Kobayashi T, Iwama S, Mori S, Hase T, Fukami Y, Furusawa K, Yura Y, Morimoto R, Sajiki AF, Ushida H, Kato N, Maruyama S, Murohara T, Katsuno M, Ishii M, Akiyama M, Arima H, Kawashima H, Ando Y

The oncologist   Vol. 30 ( 6 )   2025.6

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

Background While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can trigger severe immune-related adverse events (irAEs). The safety and efficacy of ICI retreatment after severe irAEs remain poorly understood. Methods We conducted a retrospective analysis of 1271 patients with malignancies treated with ICIs at a university hospital in Japan between September 2014 and June 2023. We evaluated the incidence and characteristics of severe irAEs, defined as grade ≥3, and the safety and efficacy of ICI retreatment. Results Severe irAEs occurred in 222 patients (17.5%). Patients with single endocrinopathies were excluded, and 46 (28.4%) of the remaining 162 patients underwent ICI retreatment. Upon retreatment, 14 patients (30.4%) experienced recurrent or new grade ≥2 irAEs. One patient who experienced hepatotoxicity (grade 3) at initial ICI treatment developed a recurrence (grade 4). Regarding antitumor response, the objective response rate to retreatment was 28.3% (13/46), with 10.9% achieving complete and 17.4% partial response. The median duration of ICI administration after retreatment was 218 days (95% confidence interval [CI]: 84-399). At 1 year after retreatment, 15.4% (95% CI: 6.8-27.4) of patients discontinued due to irAEs, 44.4% (95% CI: 29.7-58.1) due to disease progression, 6.6% (95% CI: 1.7-16.3) completed planned treatment, and 33.4% (95% CI: 20.3-47.2) continued treatment. Conclusions ICI retreatment after severe irAEs demonstrated a manageable safety profile and promising efficacy, even in patients with grade ≥3 irAEs. ICI retreatment may be a viable option for patients with limited alternatives, particularly those showing favorable antitumor responses at initial treatment.

DOI： 10.1093/oncolo/oyaf120

Open Access

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PubMed

Clinical characteristics of immune checkpoint inhibitor-related pancreatic injury with pancreatitis in patients with advanced malignancies. Open Access

Suzuki T, Mizuno K, Yamamoto T, Ito T, Ishikawa T, Honda T, Akamatsu S, Ishii M, Ando Y, Kawashima H

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 57 ( 6 ) page： 1230 - 1237   2025.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

Background/Purpose: Immune checkpoint inhibitor (ICIs) therapy can cause immune checkpoint inhibitor-related pancreatic injury (ICI-PI). This study aimed to elucidate the clinical characteristics of ICI-PI and explore treatment approaches. Methods: We retrospectively analyzed data from patients with malignancies treated with ICIs at Nagoya University Hospital between September 2014 and June 2023. ICI-PI and pancreatitis were identified and classified using the Common terminology Criteria for Adverse Events (CTCAE) ver.5.0, and the patients with ICI-PI with/without pancreatitis were analyzed. Results: This study included data from 930 patients treated with ICIs. Of these, eight (0.85 %) and 10 (1.08 %) patients were diagnosed with ICI-PI without and with pancreatitis, respectively. Five of the 10 patients received standard pancreatitis treatment, while three received additional glucocorticoid therapy. One patient experienced recurrent pancreatitis and developed a pancreatic pseudocyst, which improved after high-dose glucocorticoid treatment. ICI rechallenge was pursued in five patients. Two patients received ICIs without an interval. Conclusions: ICI-PI with pancreatitis is rare but has become more prevalent with the increasing use of ICIs. Future prospective multicenter studies are needed to confirm these findings and develop standardized diagnostic and treatment protocols.

DOI： 10.1016/j.dld.2025.02.027

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PubMed

Gut microbes associated with functional cure of chronic hepatitis B. Open Access

Honda T, Ishigami M, Ishizu Y, Imai N, Ito T, Yamamoto K, Yokoyama S, Muto H, Inukai Y, Kato A, Murayama A, Yoshio S, Ishikawa T, Fujishiro M, Kawashima H, Kato T

Hepatology international   Vol. 19 ( 3 ) page： 519 - 528   2025.6

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Background and aims: Hepatitis B virus (HBV) is prevalent worldwide and is difficult to eradicate. Current treatment strategies for chronic hepatitis B ultimately seek to achieve functional cure (FC); however, the factors contributing to FC remain unclear. We aimed to investigate the gut microbiota profiles of patients with chronic hepatitis B who achieved FC. Methods: Among 105 HBeAg-negative patients with chronic hepatitis B, 70 were enrolled, after excluding patients with cirrhosis or hepatocellular carcinoma and those receiving nucleoside analogs. The gut microbiota of patients who achieved FC was assessed and compared with that of patients with high-titer of HBV DNA (HBV DNA ≥ 3.3 log IU/mL) or low-titer of HBV DNA (HBV DNA < 3.3 log IU/mL). Furthermore, we used cell culture-generated HBV (HBVcc) as a model for HBV infection to evaluate the effects of short-chain fatty acids (SCFAs) produced by the identified bacteria. Results: There was no difference in the alpha or beta diversity of the gut microbiota between the FC group and the other groups. However, compared with the other groups, the FC group presented a greater relative abundance of bacteria that produce SCFAs, especially butyrate. In vitro studies demonstrated that 1.0 mM butyrate reduces HBsAg production in HBVcc-infected cells. Furthermore, butyrate administration was most effective at the post-HBV infection stage. Conclusions: Our findings suggest that butyrate-producing bacteria contribute to FC in HBeAg-negative patients with chronic hepatitis B through butyrate-mediated inhibition of HBV production.

DOI： 10.1007/s12072-025-10776-9

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PubMed

Soluble Siglec-9 Improves Intestinal Barrier Function in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis. Open Access

Muto H, Mizuno F, Honda T, Yokoyama S, Tanaka T, Yamamoto K, Ito T, Imai N, Ishizu Y, Sakai K, Hibi H, Ishigami M, Kawashima H

Metabolites   Vol. 15 ( 6 )   2025.5

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Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM) exerted therapeutic effects in a MASH mouse model. The gut–liver axis is thought to be associated with liver disease progression, and soluble Siglec-9 (sSiglec-9), an immunoinhibitory receptor, is a key protein in SHED-CM that induces anti-inflammatory macrophages and has intestinal epithelial protective effects. Therefore, we evaluated sSiglec-9’s role in intestinal barrier protection in MASH mice. Methods: We evaluated sSiglec-9 effects on intestinal barrier function using in vitro Caco-2 cell monolayers injured by TNF-α and IFN-γ. For the MASH mouse model, male C57BL/6J mice were given a Western diet and high-sugar solution orally; to induce liver injury, CCl4 was intraperitoneally administered for 12 weeks. Mice were treated weekly with 10 ng/g sSiglec-9 or vehicle. Intestinal permeability was assessed by blood 4 kDa FITC-dextran concentration, and intestinal transcriptomes and liver histology were analyzed. Results: sSiglec-9 decreased intestinal permeability and liver inflammation in MASH mice. sSiglec-9 and SHED-CM reduced 4 kDa FITC-dextran permeability in injured Caco-2 cells, and sSiglec-9 significantly reduced intestinal permeability and modulated expression of 34 intestinal genes. The NAFLD Activity Score indicated significantly reduced inflammation following sSiglec-9 treatment. Conclusions: sSiglec-9 may protect intestinal barrier function by mitigating mucosal inflammation. sSiglec-9 treatment may represent a novel therapeutic approach for MASH via gut–liver axis modulation.

DOI： 10.3390/metabo15060366

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PubMed

A clinicopathological study of IgG4-related autoimmune hepatitis and IgG4-hepatopathy. Open Access

Tanaka A, Notohara K, Tobari M, Abe M, Umemura T, Takahashi A, Tsutsui A, Ito T, Tsuneyama K, Masamune A, Harada KI, Ohira H, Kawano M

Journal of gastroenterology   Vol. 60 ( 5 ) page： 632 - 640   2025.5

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

Background and aim: Although IgG4-related autoimmune hepatitis (IgG4-AIH) and IgG4-hepatopathy have been proposed as hepatic phenotypes of IgG4-related disease (IgG4-RD), their definitions and concepts remain insufficiently established. This study aims to conduct a clinicopathological investigation of cases reported as potential IgG4-AIH or IgG4-hepatopathy. Methods: In previous nationwide epidemiological studies conducted in 2015 and 2018, we registered 1096 cases of IgG4-sclerosing cholangitis (IgG4-SC). Among these, 19 cases were identified as potential IgG4-AIH by the attending physicians, and other 20 cases as potential IgG4-hepatopathy with available liver histology were further evaluated using immunohistochemistry to assess the possibility of IgG4-AIH or IgG4-hepatopathy. For this purpose, we provisionally established diagnostic criteria for IgG4-AIH and IgG4-hepatopathy, primarily based on the comprehensive diagnostic criteria for IgG4-RD, which include IgG4 + cell count > 10/HPF and an IgG4 + /IgG ratio > 40%. Results: Of the 19 cases, 2 were diagnosed as IgG4-AIH, with IgG4 + cell counts/HPF of 25.3 and 18.7, and IgG4 + /IgG ratios of 310.2% and 53.4%, respectively. Neither storiform fibrosis nor obliterative phlebitis was observed in the liver of these cases, and both responded excellently to corticosteroid treatment. In addition, from other 20 cases, we diagnosed 8 cases as IgG4-hepatopathy, with IgG4-SC and autoimmune pancreatitis being present in 7 and 2 cases, respectively. Conclusion: This study identified two cases of IgG4-AIH and eight cases of IgG4-hepatopathy. Further studies are necessary to explore the occurrence of IgG4-AIH using these diagnostic criteria in the AIH cohort. The presence of IgG4-hepatopathy may facilitate the diagnosis of IgG4-SC.

DOI： 10.1007/s00535-025-02221-3

Open Access

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PubMed

Antitumor effects and immune-mediated adverse events of durvalumab plus tremelimumab treatment for unresectable hepatocellular carcinoma. Open Access

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

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 4 ) page： 577 - 587   2025.4

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Aim: Durvalumab plus tremelimumab (Dur/Tre) is a first-line systemic treatment option for unresectable hepatocellular carcinoma (uHCC). However, the management of severe immune-mediated adverse events (imAEs) is challenging. Therefore, we investigated the relationship between severe imAEs and antitumor responses in patients with uHCC treated with Dur/Tre. Methods: We included 157 patients with uHCC treated with Dur/Tre in this multicenter, retrospective study and analyzed the relationship between progression-free survival (PFS)/antitumor response and severe imAEs requiring high-dose corticosteroid treatment. Results: Thirty-two patients (20.4%) developed severe imAEs, including enterocolitis/diarrhea (n = 10), liver injury (n = 9), interstitial lung disease (n = 5), rashes (n = 4), cytokine-release syndrome/fever (n = 2), pancreatitis (n = 2), and others (n = 4) (median follow-up period, 6.8 months). Infliximab was administered in six patients with steroid-refractory enterocolitis. Although the objective response rate (ORR) and disease control rate (DCR) were significantly higher with first-line therapy than with later-line therapy (p = 0.026), the frequency of severe imAEs was not significantly different (p = 0.221). The ORR and DCR in patients with and without severe imAEs were 15.6% and 17.6% and 65.6% and 47.2%, respectively, with no significant differences. Five patients with severe imAEs, including rashes and liver injury, showed objective responses (partial response + complete response). Among patients who achieved an objective response, the PFS at 10 months was good (100% and 70.3% with and without high-dose corticosteroids, respectively). Conclusions: Severe imAEs of Dur/Tre treatment requiring high-dose corticosteroid treatment did not affect antitumor efficacy, which differed depending on the type of imAEs. Therefore, appropriately managing imAEs is essential to guide sequential treatment.

DOI： 10.1111/hepr.14151

Open Access

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Limited use of FIB-4 index in patients under 65 years of age with type 2 diabetes mellitus. Open Access

Kim M, Yoon EL, Park H, Ito T, Ishigami M, Jo AJ, Lee CM, Kang BK, Kim HL, Arai T, Atsukawa M, Kawanaka M, Toyoda H, Yu ML, Jun DW, Nguyen MH

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 55 ( 4 ) page： 505 - 514   2025.4

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Aim: Screening for liver fibrosis holds significant importance in patients with type 2 diabetes mellitus (T2DM) due to their elevated risk of advanced hepatic fibrosis. However, it is recognized that the diagnostic performance of the Fibrosis-4 (FIB-4) index is relatively low in T2DM patients. Our study aims to explore the potential and limitations of utilizing FIB-4 as a screening tool in patients with T2DM. Methods: A retrospective biopsy cohort of 1906 patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease from South Korea, Japan, and Taiwan. Diagnostic performance according to T2DM was again compared after propensity score matching on age, sex, and body mass index. Results: Patients with T2DM were significantly older than those without. The area under the receiver operating characteristic curve (AUROC) of FIB-4 for ruling out advanced fibrosis in non-T2DM patients was significantly higher than that of T2DM (0.821 vs. 0.761, p = 0.044). However, the AUROCs of FIB-4 according to the same age groups showed no significant difference between patients with T2DM and without (all p > 0.05). In the middle-aged group, the sensitivity of FIB-4 for ruling out advanced hepatic fibrosis was 77.1% for T2DM and did not differ with that of non-T2DM patients (73.0%) (p = 0.093). After propensity score matching of age, there was no statistically significant difference in the AUROCs of the T2DM and non-T2DM groups (0.860 vs. 0.761, p = 0.142). Conclusion: Although the diagnostic performance of FIB-4 was found to be suboptimal in patients with T2DM, its limited use in individuals under 65 years of age with T2DM still holds value as a screening tool.

DOI： 10.1111/hepr.14152

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Clinical features and pathological findings by liver biopsy in patients with immune-related sclerosing cholangitis induced by immune checkpoint inhibitors.

Yasuda T, Ito T, Ishikawa T, Mizuno K, Yamamoto T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Koshiyama Y, Yasuda S, Toyoda H, Ando Y, Shimoyama Y, Kawashima H

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 57 ( 4 ) page： 877 - 884   2025.4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

Background: Immune-related sclerosing cholangitis (irSC) induced by immune checkpoint inhibitors (ICIs) is relatively rare, and its clinical and pathological features are not well known. Aims: We aimed to compare the clinical course and pathological findings of irSC with those of non-irSC liver injury. Methods: Clinical data were retrospectively collected from 2416 patients with advanced malignancies treated with ICIs between September 2014 and October 2023. The data of patients with severe ICI-induced liver injury who underwent liver biopsy were analyzed and compared between patients with irSC and non-irSC. Results: Ninety-three (3.8 %) patients had severe ICI-induced liver injury, and 38 underwent liver biopsy. Of these, five were diagnosed with irSC. The irSC group had a significantly longer time to onset of ICI-induced liver injury and a lower rate of improvement of liver injury than did the non-irSC group (irSC, 3/5; non-irSC, 32/33). Liver biopsies revealed more moderate-to-severe pathological cholangitis in the irSC group than in the non-irSC group (irSC, n = 5/5; non-irSC, n = 16/33). Other pathological findings were similar between the two groups. Conclusion: Appropriate management of irSC requires an understanding of its characteristics of late onset and steroid resistance, and liver biopsy, in addition to imaging, may be useful for diagnosing irSC.

DOI： 10.1016/j.dld.2025.01.037

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Impact of the fibrosis-4 index in patients with ST-elevated myocardial infarction.

Shibata N, Ito T, Morita Y, Toyoda H, Kanzaki Y, Watanabe N, Yoshioka N, Miyazawa H, Shimojo K, Ohi T, Goto H, Karasawa H, Morishima I

Coronary artery disease   Vol. 36 ( 2 ) page： 99 - 107   2025.3

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Background The fibrosis-4 (FIB4) index, a simple, noninvasive marker used for hepatic diseases, represents adverse outcomes. The aim of the present study was to evaluate whether the FIB4 index can predict adverse outcomes in patients with ST-elevation myocardial infarction (STEMI). Methods We investigated patients with STEMI who underwent primary percutaneous coronary intervention (PCI) and were alive at discharge. The cut-off FIB4 index at discharge was investigated using the survival classification and regression tree (CART) model to predict adverse outcomes. The primary outcome was all-cause mortality. Results Between January 2006 and December 2018, 1354 patients with STEMI (median age, 68 years; men, 76.1%) were investigated. The median value of the FIB4 index was 1.21 (0.84–1.78). The CART model divided the study population into low (FIB4 index <0.945; n = 435), intermediate (0.945 ≤ FIB4 index < 2.185; n = 692), and high (FIB4 index ≥2.185; n = 227) groups based on the significant predictive values for all-cause death. During a median follow-up period of 4.3 years, all-cause death occurred in 208 patients (15.4%). The Kaplan–Meier analysis showed a significant increase in mortality with higher FIB4 index values (log-rank, P < 0.001). The multivariate Cox regression model revealed that the FIB4 index was an independent risk predictor for all-cause death in patients with STEMI [low group as reference vs. intermediate group, hazard ratio: 1.975; 95% confidence interval (CI): 1.166–3.346; P = 0.011 and vs. high group, hazard ratio: 4.633; 95% CI: 2.549–8.418; P < 0.001]. Conclusions The FIB4 index was associated with the risk of all-cause mortality in patients with STEMI who underwent primary PCI.

DOI： 10.1097/MCA.0000000000001431

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Role of noninvasive tests on the prediction of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without cirrhosis: a systematic review and meta-analysis of aggregate and individual patient data.

Siriwong N, Sriphoosanaphan S, Decharatanachart P, Yongpisarn T, Kerr SJ, Treeprasertsuk S, Tiyarattanachai T, Apiparakoon T, Hagström H, Akbari C, Ekstedt M, Yip TC, Wong GL, Ito T, Ishigami M, Toyoda H, Peleg N, Shlomai A, Seko Y, Sumida Y, Kawanaka M, Hino K, Chaiteerakij R

European journal of gastroenterology & hepatology   Vol. 37 ( 3 ) page： 358 - 369   2025.3

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

Background Nonalcoholic fatty liver disease (NAFLD) has been identified as an emerging risk factor for hepatocellular carcinoma (HCC). Identifying non-cirrhotic NAFLD patients at risk for HCC is crucial. We aimed to investigate the utility of noninvasive tests (NITs) as predictors for HCC and to determine optimal and cost-effective NIT cutoffs for HCC surveillance in non-cirrhotic NAFLD patients. Methods Medline, EMBASE, and Scopus databases were searched for studies evaluating the relationship between NITs and HCC in this population. Random-effects models were used to estimate hazard ratios or risk ratios and 95% confidence interval (95% CI). Cutoffs of NITs for identifying high-risk patients for HCC were determined. Results This systematic review comprised 20 studies. A meta-analysis of 379 194 patients was conducted using six studies with individual patient data and five studies with aggregate data. Among NITs studied, fibrosis-4 index (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and NAFLD fibrosis score (NFS) were significantly associated with HCC, with pooled risk ratio (95% CI) of 9.21 (5.79-14.64), pooled hazard ratio of 12.53 (6.57-23.90), and 13.32 (6.48-27.37), respectively. FIB-4, APRI, and NFS of more than 2.06, 0.65, and 0.51 resulted in the highest area under the receiver operating characteristics of 0.83, 0.80, and 0.85, respectively. Surveillance in patients with FIB-4 ≥ 5.91 and NFS ≥ 2.85 would be cost-effective with an annual HCC incidence of ≥15 per 1000 patient-years. Conclusion FIB-4, APRI, and NFS are associated with HCC development in non-cirrhotic NAFLD patients. Different NIT cutoffs may be used to enroll high-risk NAFLD patients for HCC surveillance, according to resource availability in different settings.

DOI： 10.1097/MEG.0000000000002912

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特集 消化管静脈瘤診療Update [胃静脈瘤] 【Note】胃静脈瘤に対するcyanoacrylate注入のコツ

横山 晋也, 石津 洋二, 本多 隆, 今井 則博, 伊藤 隆徳, 山本 健太, 川嶋 啓揮

消化器内視鏡   Vol. 36 ( 12 ) page： 1682 - 1685   2024.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：東京医学社  

DOI： 10.24479/endo.0000001787

CiNii Research

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

Miyamoto H, Kondo Y, Itobayashi E, Uehara M, Hiraoka A, Kudo M, Kakizaki S, Kagawa T, Miuma S, Suzuki T, Sugi K, Suyama K, Beppu T, Toyoda H, Yoshiji H, Uojima H, Miyase S, Inoue K, Tamori A, Ito T, Shimose S, Suda G, Hayashi T, Onishi M, Narahara S, Watanabe T, Iwatsuki M, Fukushima S, Tanaka Y

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 54 ( 12 ) page： 1215 - 1225   2024.12

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

Aim: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. Methods: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. Results: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. Conclusions: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. Clinical trial registration: UMIN Clinical Trials Registry with the number UMIN000043798.

DOI： 10.1111/hepr.14092

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ICIによる肝障害　 Invited Reviewed

伊藤　隆徳、川嶋　啓揮

日消誌121巻12号 『薬物性肝障害』　     2024.12

A Proposal for a Simple Subclassification of Advanced Hepatocellular Carcinoma in Systemic Treatment. Open Access

Imai N, Yamamoto T, Mizuno K, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Kawashima H

Cancers   Vol. 16 ( 22 )   2024.11

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Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment.

DOI： 10.3390/cancers16223797

Open Access

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Modified FIB-4 Index in Type 2 Diabetes Mellitus with Steatosis: A Non-Linear Predictive Model for Advanced Hepatic Fibrosis. Open Access

Kim J, Ito T, Arai T, Atsukawa M, Kawanaka M, Toyoda H, Honda T, Yu ML, Yoon EL, Jun DW, Cha K, Nguyen MH

Diagnostics (Basel, Switzerland)   Vol. 14 ( 22 )   2024.11

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Background: The Fibrosis-4 (FIB-4) index is widely recommended as a first-tier method for screening advanced hepatic fibrosis; however, its diagnostic performance is known to be suboptimal in patients with Type 2 diabetes mellitus (T2DM). We aim to propose a modified FIB-4, using the parameters of the existing FIB-4, tailored specifically for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A total of 1503 patients who underwent liver biopsy were divided into T2DM (n = 517) and non-T2DM (n = 986) groups. The model was developed using multiple regression analysis in the derivation cohort and validated in the validation cohort. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic (AUC) curves. Results: Among the 1503 individuals, those with T2DM were older, more likely to be male, and had a higher prevalence of advanced hepatic fibrosis (≥F3) compared to non-T2DM individuals. Independent risk factors for advanced fibrosis in T2DM included age, AST, AST/ALT ratio, albumin, triglycerides, and platelet count. The optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index) demonstrated superior diagnostic accuracy (AUC 0.771) compared to the FIB-4 (AUC 0.735, p = 0.012). The model showed a higher negative predictive value than the original FIB-4 across all age groups in the diabetic group. Conclusions: The newly optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index), incorporating a non-linear predictive model, improves diagnostic performance (AUC) and the negative predictive value in MASLD with T2DM.

DOI： 10.3390/diagnostics14222500

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肝臓学会医による肝臓学会医のための肝臓爽快特別企画を終えて

由雄 祥代, 鶴岡 未央, 阿部 珠美, 武藤 芳美, 野上 麻子, 伊藤 隆徳, 星川 恭子, 岩本 英希, 村川 美也子, 石川 剛, 阿部 和道, 藤井 英樹, 土谷 薫, 多田 俊史, 黒田 英克, 中川 美奈, 田中 靖人

肝臓   Vol. 65 ( 11 ) page： 541 - 550   2024.11

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人　日本肝臓学会  

<p>第60回日本肝臓学会総会において，田中靖人会長のご支援により若手医師参加型の特別企画を実施する機会を得たのでここに報告する．第1部は講演形式で行い，工藤正俊先生は「知的エンゲル係数」をゼロにし，集中できる時間を作ることの重要性を説いた．海道利実先生は時間管理とプレゼン技術向上の方法を示し，川口巧先生はメディカルスタッフとの連携の重要性を強調した．黒田英克先生は放射線治療の普及を目指し，小玉尚宏先生は研究を楽しむ意義を強調した．伊藤隆徳先生は多施設共同研究のコツを共有し，武藤芳美先生，野上麻子先生，阿部珠美先生，鶴岡未央先生らは肝臓学会の活性化や若手医師の教育についての提案を行った．第2部では，10のラウンドテーブルで第一部演者，ファシリテーター，若手医師が交流し，意見を交換する場を設け，セッションは盛況に終わった．本報告を通じて，今後の日本肝臓学会の更なる発展を期待する．</p>

DOI： 10.2957/kanzo.65.541

CiNii Research

A machine learning algorithm for stratification of risk of cardiovascular disease in metabolic dysfunction-associated steatotic liver disease. Open Access

Shibata N, Morita Y, Ito T, Kanzaki Y, Watanabe N, Yoshioka N, Arao Y, Yasuda S, Koshiyama Y, Toyoda H, Morishima I

European journal of internal medicine   Vol. 129   page： 62 - 70   2024.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Internal Medicine  

Background: Steatotic liver disease (SLD) is associated with adverse cardiac events. Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a condition characterized by the abnormal accumulation of hepatic lipids that is closely linked to five metabolic disorders: overweight or obesity, impaired glucose regulation, hypertension, hypertriglyceridemia, and low high-density lipoprotein-cholesterol. This retrospective study aimed to stratify the risk of cardiac events in patients with MASLD. Methods: Patients diagnosed with MASLD through ultrasonography were evaluated. We implemented a machine learning-based approach using a survival classification and regression tree (CART) model to stratify patients based on age, and the number of risk scores was investigated as a predictor of adverse outcomes in the derivation cohort. The primary outcomes were major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. Results: Among 2,962 patients (median age, 62 years; men, 53.5 %), the distribution of risk factors was as follows: one (10.8 %), two (28.5 %), three (33.0 %), four (19.9 %), and five (7.8 %). Over a median follow-up period of 6.8 years, 170 (5.7 %) patients experienced MACE. In the derivation cohort of 2,073 patients, the CART model identified age ≥60 years old and risk factors ≥4 as significant predictors of MACE. These findings were corroborated in a validation cohort of 889 patients. Patients meeting both criteria exhibited the highest risk of MACE (log-rank test, p < 0.001). Conclusions: Patients aged ≥60 years old with risk factors ≥4 indicates at high risk of MACE in patients with MASLD. This risk stratification system provides a practical tool for identifying high-risk individuals in the MASLD population.

DOI： 10.1016/j.ejim.2024.07.005

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Predicting early rebleeding and mortality after endoscopic hemostasis of esophagogastric varices: Diagnostic performance of aspartate aminotransferase-to-platelet ratio index and model for end-stage liver disease-Na score. Open Access

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

Journal of hepato-biliary-pancreatic sciences   Vol. 31 ( 11 ) page： 830 - 839   2024.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Hepato Biliary Pancreatic Sciences  

Background: Endoscopic variceal ligation and sclerotherapy are recommended for esophagogastric variceal bleeding (EGVB) in cirrhosis but can be complicated by early rebleeding and death. This study aimed to identify noninvasive markers accurately predicting early rebleeding and mortality after endoscopic hemostasis for EGVB. Methods: Among 116 patients with endoscopically confirmed EGVB and endoscopic hemostasis, various noninvasive markers were calculated, and their predictive accuracy was compared by receiver-operating characteristic curve analysis. Endpoints included 5-day rebleeding, 5-day mortality, 6-week rebleeding, and 6-week mortality. Results: The median age was 63 years. Child-Pugh class B and C patients accounted for 40.5% and 34.5%, respectively. Only the aspartate aminotransferase-to-platelet ratio index (APRI) significantly predicted 5-day rebleeding, with an area under the curve (AUC) of 0.777 (95% confidence interval [CI]: 0.537–1). The model for end-stage liver disease-Na (MELD-Na) score showed good predictive accuracy for 5-day mortality (AUC: 0.839, 95% CI: 0.681–0.997), 6-week rebleeding (AUC: 0.797, 95% CI: 0.663–0.932), and 6-week mortality (AUC: 0.888, 95% CI: 0.797–0.979). Conclusions: Patients with cirrhosis with a high APRI and MELD-Na score were at high risk of early rebleeding and death after EGVB. Allocating appropriate monitoring and care for those patients is necessary.

DOI： 10.1002/jhbp.12057

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Outcomes of immune checkpoint inhibitor-induced liver toxicity managed by hepatologists in a multidisciplinary toxicity team.

Ito T, Mizuno K, Yamamoto T, Yasuda T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Hama M, Kataoka T, Shimokata T, Ando Y, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 54 ( 11 ) page： 1060 - 1069   2024.11

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

Aim: To detect immune-related adverse events (irAEs) early and treat them appropriately, our institute established an irAE-focused multidisciplinary toxicity team in cooperation with various departments. This study aimed to evaluate a consultation system involving a team of hepatologists in terms of its utility for the management of severe immune checkpoint inhibitor (ICI)-induced liver toxicity. Methods: To analyze the diagnosis and treatment of severe ICI-induced liver toxicity (Grade 2 requiring corticosteroid therapy and Grade 3 or higher), we examined patients' clinical courses before and after the hepatologist consultation system was established (pre-period, September 2014 to February 2019; post-period, March 2019 to March 2023). Results: The median follow-up period was 392 days. Of the 1247 patients with advanced malignancies treated with ICIs, 66 developed severe ICI-induced liver toxicity (n = 22 and 44 in the pre- and post-periods, respectively). In the pre-period, hepatologist consultations were sought for 15/22 patients, whereas in the post-period, 42/44 patients were referred to and treated by hepatologists. The time from the onset of liver toxicity to the consultation was significantly shorter in the post-period than in the pre-period (mean 1.9 vs. 6.5 days, respectively; p = 0.012). The number of patients with a biopsy-confirmed diagnosis of ICI-induced liver toxicity was significantly higher in the post-period than in the pre-period (n = 22 vs. n = 3, respectively; p = 0.006). Finally, there were no cases of immune-related cholangitis in the pre-period, compared to five cases in the post-period. Conclusion: A hepatologist consultation system in an irAE-focused multidisciplinary toxicity team is useful for managing severe ICI-induced liver toxicity.

DOI： 10.1111/hepr.14043

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Type 2 Diabetes and Hypertension as Risk Factors for Advanced Fibrosis in Biopsy Proven Metabolic Dysfunction-Associated Steatotic Liver Disease.

Inukai Y, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Shimizu T, Hattori M, Takeyama T, Ando Y, Nishikawa T, Morita K, Toyoda H, Ishigami M, Kawashima H

Journal of digestive diseases   Vol. 25 ( 11-12 ) page： 685 - 693   2024.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Digestive Diseases  

Objectives: To identify the diagnostic criteria for metabolic dysfunction–associated steatotic liver disease (MASLD) related to liver fibrosis and to characterize patients with cryptogenic steatotic liver disease (SLD) (non-MASLD) among those previously diagnosed with nonalcoholic fatty liver disease (NAFLD). Methods: This multicenter retrospective study included 511 patients diagnosed with NAFLD via liver biopsy, and the prevalence of MASLD was assessed based on the diagnostic criteria. Patients were divided into those who met the MASLD criteria and those who did not, and the characteristics of advanced fibrosis and associated cardiometabolic factors were evaluated. Results: Of the 475 patients with NAFLD, 458 (96.4%) met the criteria for MASLD, showing a high overlap between classical NAFLD and MASLD populations. Severe fibrosis was observed, regardless of the number of cardiometabolic factors. Hypertension and diabetes mellitus significantly contributed to advanced fibrosis (≥ F3), with odds ratio of 1.92 and 2.00 (95% confidence interval of 1.17–3.16 and 1.22–3.28, respectively; both p < 0.01) on multivariate analysis. The other seventeen (3.6%) patients did not meet the diagnostic criteria for MASLD. Among them, seven had significant fibrosis and a high fibrosis-4 index. Conclusions: Diabetes mellitus and hypertension are key metabolic factors associated with advanced fibrosis. Some cases, classified as cryptogenic SLD, also exhibit significant fibrosis. Consequently, identifying high-risk patients, including those undergoing noninvasive tests for fibrosis, is crucial.

DOI： 10.1111/1751-2980.13325

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A 70-year-old Woman with Asymptomatic Ferroportin Disease Open Access

Ishikawa Tetsuya, Tatsumi Yasuaki, Kato Koichi, Hayashi Yumi, Imai Norihiro, Ito Takanori, Ishizu Yoji, Ishigami Masatoshi, Nihei Wataru, Kato Ayako, Hayashi Hisao

Internal Medicine   Vol. 63 ( 17 ) page： 2421 - 2425   2024.9

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

<p>A 59-year-old Japanese woman presented with hyperferritinemia. We decided against iron removal treatment because there were no symptoms or signs of iron-induced organ damage. A follow-up study revealed a gradual increase in transferrin saturation. The patient underwent a second examination at 66 years old. A liver biopsy showed substantial iron deposits in hepatocytes and Kupffer cells but no inflammation or fibrosis. Serum hepcidin-25 levels were highly parallel with hyperferritinemia. A genetic analysis revealed a <i>G80S</i> mutation in <i>SLC40A1</i>. These features are compatible with those of ferroportin disease. The patient remained asymptomatic at 70 years old, suggesting that the iron-loading condition may have been benign. </p>

DOI： 10.2169/internalmedicine.2392-23

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Predictability of noninvasive liver fibrosis score for cardiac events in patients with nonalcoholic fatty liver disease.

Shibata N, Ito T, Toyoda H, Tanaka A, Morita Y, Kanzaki Y, Watanabe N, Yoshioka N, Yasuda S, Morishima I

Nutrition, metabolism, and cardiovascular diseases : NMCD   Vol. 34 ( 9 ) page： 2115 - 2123   2024.9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nutrition Metabolism and Cardiovascular Diseases  

Background and aims: Patients with nonalcoholic fatty liver disease (NAFLD) have a higher risk of cardiac events. However, although the severity of liver fibrosis is related to worsening prognosis in patients with NAFLD, it is unclear whether the noninvasive liver fibrosis score has a predictive value for cardiac events. Methods and results: We evaluated 4071 patients with NAFLD diagnosed using ultrasonography. Liver fibrosis was assessed and divided into three groups based on the Fibrosis-4 (FIB4) index and NAFLD fibrosis score (NFS). The primary outcome of this study was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. The median age of the evaluated patients was 61 (52–69) years, and 2201 (54.1%) were male. During the median follow-up period of 6.6 years, 179 (4.4%) patients experienced MACE. Kaplan–Meier survival analysis demonstrated that MACE increased progressively with the FIB4 index (log-rank, p < 0.001) and NFS (log-rank, p < 0.001). Multivariable analysis showed that the higher the FIB4 index, the higher the risk for MACE (low group as reference vs. intermediate group, hazard ratio [HR]: 1.860 [95% confidence interval (CI), 1.326–2.610; p < 0.001]; vs. high group, HR:3.325 [95% CI, 2.017–5.479; p < 0.001]), as well as NFS (low NFS group as reference vs. intermediate group, HR: 1.938 [95% CI, 1.391–2.699; p < 0.001]; vs. high group, HR: 3.492 [95% CI, 1.997–6.105; p < 0.001]). Conclusions: The FIB4 index and NFS are associated with the probability of MACE in patients with NAFLD. Clinical trials: The study design was approved by the ethics review board of Ogaki Municipal Hospital (approval number: 20221124–12, registration date: November 28th, 2022). https://www.ogaki-mh.jp/chiken/kenkyu.html.

DOI： 10.1016/j.numecd.2024.03.025

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Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma. Open Access

Yamamoto T, Ito T, Mizuno K, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H

Anticancer research   Vol. 44 ( 9 ) page： 4101 - 4111   2024.9

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Background/Aim: The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. Patients and Methods: In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m²) and low- (<25 kg/m²) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. Results: Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). Conclusion: Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

DOI： 10.21873/anticanres.17239

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Reply - Letter to the editor.

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

Clinical nutrition (Edinburgh, Scotland)   Vol. 43 ( 8 ) page： 1855 - 1856   2024.8

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

DOI： 10.1016/j.clnu.2024.06.031

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Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real‑world practice. Open Access

Shimose S, Saeki I, Tomonari T, Ito T, Tani J, Takeuchi Y, Yoshioka N, Naito T, Takeuchi M, Kakizaki S, Hatanaka T, Sasaki K, Yasunaka T, Sakata M, Iwamoto H, Itano S, Shirono T, Tanabe N, Yamamoto T, Naganuma A, Nishina S, Otsuka M, Kawashima H, Takayama T, Takami T, Kawaguchi T

Oncology letters   Vol. 28 ( 2 ) page： 397   2024.8

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

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first‑line therapy for patients with unre‑ sectable hepatocellular carcinoma (u‑HCC), its outcomes in real‑world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u‑HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression‑free survival (PFS), therapeutic response and adverse events (AEs) were assessed.

DOI： 10.3892/ol.2024.14530

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Diagnostic guide for immune checkpoint inhibitor-induced liver injury. Open Access

Ito T, Takeuchi Y, Mizuno K, Imai M, Yoshimaru Y, Abe K, Abe M, Matsuura T, Yokode M, Shiokawa M, Kodama Y, Komuta M, Harada K, Tanaka A

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 54 ( 8 ) page： 719 - 726   2024.8

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

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

DOI： 10.1111/hepr.14078

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Clinical Outcomes of Use of the Porous Glass Membrane Pumping Emulsification Device During Transarterial Chemoembolization for Hepatocellular Carcinoma. Open Access

Mizuno F, Imai N, Mizuno K, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Kawashima H

Anticancer research   Vol. 44 ( 7 ) page： 3185 - 3191   2024.7

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

Background/Aim: The porous glass membrane pumping emulsification device enhances local therapeutic effects of transarterial chemoembolization for hepatocellular carcinoma (HCC); however, limited clinical outcomes have been reported. This study aimed to investigate the efficacy and safety of transarterial chemoembolization using the glass membrane pumping emulsification device for HCC. Patients and Methods: Between 2019 and 2023, 58 patients (median age=73 years) with unresectable HCC underwent 73 transarterial chemoembolizations using the glass membrane pumping emulsification device at the Nagoya University Hospital. Treatment effects were assessed using contrast-enhanced computed tomography 1-3 months after therapy and every 2-3 months thereafter. Results: The median size of treated tumors was 25.5 mm (45 solitary nodules). The median dosage of ethiodized oil mixed with the epirubicin solution was 3 ml. Complete and partial response were observed in 73% and 11% of patients, respectively. Local control rates at 6 and 12 months were 82.8% and 59.8%, respectively. The median time to recurrence after treatment was 581 days. No major treatment-related complications occurred. The number of tumors and therapeutic effects of the initial transarterial chemoembolization were significantly associated with better local control. Conclusion: The glass membrane pumping emulsification device facilitated the accumulation of more concentrated ethiodized oil within the tumor and effective local control.

DOI： 10.21873/anticanres.17133

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Sex and ethnic disparities in hepatitis B evaluation and treatment across the world. International coauthorship Open Access

Kudaravalli S, Huang DQ, Yeh ML, Trinh L, Tsai PC, Hsu YC, Kam LY, Nguyen VH, Ogawa E, Lee DH, Ito T, Watanabe T, Enomoto M, Preda CM, Ko MKL, Wan-Hin Hui R, Atsukawa M, Suzuki T, Marciano S, Barreira A, Do S, Uojima H, Takahashi H, Quek SXZ, Toe Wai Khine HH, Ishigami M, Itokawa N, Go MS, Kozuka R, Marin RI, Sandra I, Li J, Zhang JQ, Wong C, Yoshimaru Y, Vo DKH, Tseng CH, Lee CJ, Inoue K, Maeda M, Hoang JK, Chau A, Chuang WL, Dai CY, Huang JF, Huang CF, Buti M, Tanaka Y, Gadano AC, Yuen MF, Cheung R, Lim SG, Trinh HN, Toyoda H, Yu ML, Nguyen MH

Journal of hepatology   Vol. 81 ( 1 ) page： 33 - 41   2024.7

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

Background & Aims: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. Methods: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. Results: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). Conclusions: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. Impact and implications: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

DOI： 10.1016/j.jhep.2024.02.033

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Severe hepatic steatosis promotes increased liver stiffness in the early stages of metabolic dysfunction-associated steatotic liver disease.

Kumada T, Toyoda H, Ogawa S, Gotoh T, Suzuki Y, Sugimoto K, Yoshida Y, Kuroda H, Kamada Y, Sumida Y, Ito T, Akita T, Tanaka J

Liver international : official journal of the International Association for the Study of the Liver   Vol. 44 ( 7 ) page： 1700 - 1714   2024.7

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

Background & Aims: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction–associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. Methods: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. Results: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483–4.547) and albumin–bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284–6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584–4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >−5% and <5% in patients with LSM stage 1 or 2–4 (≥2.5 kPa). Conclusions: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

DOI： 10.1111/liv.15920

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Guide for the Diagnosis 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, Kodama Yuzo, Komuta Mina, Harada Kenichi, Tanaka Atsushi

Kanzo   Vol. 65 ( 6 ) page： 268 - 276   2024.6

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

<p>With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (as an immune-related adverse event [ICI-induced liver injury]) has become a major problem in clinical settings. Comprehensive evaluations comprising the clinical course, blood tests, imaging, and pathological examination by liver biopsy are essential for diagnosing ICI-induced liver injury. Similar to other drug-induced liver injuries, the liver injury type based on R-value is useful for determining treatment strategies. Acute hepatitis is a typical pathological finding in ICI-induced liver injury. It is characterized by diffuse lobular injury with CD8-positive lymphocytic infiltration. Most patients with ICI-induced cholangitis are classified as non-hepatocellular-injury type. They respond poorly to corticosteroid treatment. Gastroenterologists and physicians in other departments should collaborate to achieve early diagnosis and appropriate treatment of ICI-induced liver injury.</p>

DOI： 10.2957/kanzo.65.268

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RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

Tanaka A, Tsuji K, Komiyama Y, Tsuruya K, Kakisaka K, Tsutsui A, Ichimoto K, Ueno M, Okazaki Y, Kamimura H, Takai A, Yamashiki N, Ito T, Watanabe M, Abe M, Harada KI, Kagawa T

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 54 ( 6 ) page： 503 - 512   2024.6

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

Aim: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. Methods: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. Results: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. Conclusion: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

DOI： 10.1111/hepr.14046

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Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center. Open Access

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

Clinical nutrition (Edinburgh, Scotland)   Vol. 43 ( 6 ) page： 1425 - 1432   2024.6

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

Background & aims: Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. Methods: Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below −1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. Results: A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34–0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00–1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97–1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. Conclusion: The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

DOI： 10.1016/j.clnu.2024.04.034

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Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey Open Access

Miyamoto T., Izawa K., Masui S., Yamazaki A., Yamasaki Y., Matsubayashi T., Shiraki M., Ohnishi H., Yasumura J., Kawabe T., Miyamae T., Matsubara T., Arakawa N., Ishige T., Takizawa T., Shimbo A., Shimizu M., Kimura N., Maeda Y., Maruyama Y., Shigemura T., Furuta J., Sato S., Tanaka H., Izumikawa M., Yamamura M., Hasegawa T., Kaneko H., Nakagishi Y., Nakano N., Iida Y., Nakamura T., Wakiguchi H., Hoshina T., Kawai T., Murakami K., Akizuki S., Morinobu A., Ohmura K., Eguchi K., Sonoda M., Ishimura M., Furuno K., Kashiwado M., Mori M., Kawahata K., Hayama K., Shimoyama K., Sasaki N., Ito T., Umebayashi H., Omori T., Nakamichi S., Dohmoto T., Hasegawa Y., Kawashima H., Watanabe S., Taguchi Y., Nakaseko H., Iwata N., Kohno H., Ando T., Ito Y., Kataoka Y., Saeki T., Kaneko U., Murase A., Hattori S., Nozawa T., Nishimura K., Nakano R., Watanabe M., Yashiro M., Nakamura T., Komai T., Kato K., Honda Y., Hiejima E., Yonezawa A., Bessho K., Okada S., Ohara O., Takita J., Yasumi T., Nishikomori R.

Arthritis and Rheumatology   Vol. 76 ( 6 ) page： 949 - 962   2024.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Arthritis and Rheumatology  

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor-α agents was effective for IBD– and CAPS-associated symptoms not resolved by canakinumab monotherapy. Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. (Figure presented.).

DOI： 10.1002/art.42808

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Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma. Open Access

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

Cancers   Vol. 16 ( 9 )   2024.4

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The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

DOI： 10.3390/cancers16091675

Open Access

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PubMed

A new criterion including the aspartate aminotransferase-to-platelet ratio index and liver and spleen stiffness to rule out varices needing treatment in children with biliary atresia: Modification of the Baveno VII criteria. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Muto H, Shirota C, Tainaka T, Sumida W, Makita S, Takada S, Nakagawa Y, Maeda T, Nakamura M, Ishigami M, Uchida H, Kawashima H

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 54 ( 4 ) page： 347 - 357   2024.4

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Aims: Biliary atresia (BA) is a congestive biliary disease that develops in the neonatal period or early infancy. It may present with portal hypertension and varices needing treatment (VNT) even after successful Kasai portoenterostomy. This study aimed to stratify the risk of VNT in children and adolescents with BA. Methods: In this prospective cross-sectional study, we measured liver stiffness (LS) and spleen stiffness (SS) by two-dimensional shear wave elastography and checked for VNT endoscopically in 53 patients with BA who attended for follow-up between July 2018 and September 2022. Varices needing treatment were defined as large esophageal varices, esophageal varices of any size with red color signs, and/or gastric varices along the cardia. Results: Twenty-five patients (aged 0–18 years) had VNT. Eighteen patients met the Baveno VI criteria (LS <20 kPa; platelet count >150 000/L) and were deemed to be at low risk of VNT (spared endoscopies) while three had missed VNT (16.7%). Applying the Baveno VII criteria, which combines the SS cut-off value of 40 kPa with the Baveno VI criteria, resulted in five missed VNTs among 22 spared endoscopies (22.7%). A modification of the Baveno VII criteria using the aspartate aminotransferase-to-platelet ratio index (APRI) instead of the platelet count with cut-off values of 25 kPa, 30 kPa, and 1.04 for LS, SS, and APRI, respectively, missed only one VNT (5.0%) among 20 spared endoscopies. Conclusions: A novel diagnostic criterion that combines LS, SS, and APRI reduced the risk of missing VNT to 5% in children and adolescents with BA.

DOI： 10.1111/hepr.13976

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Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis. International coauthorship Open Access

Le MH, Le DM, Baez TC, Dang H, Nguyen VH, Lee K, Stave CD, Ito T, Wu Y, Yeo YH, Ji F, Cheung R, Nguyen MH

Clinical and molecular hepatology   Vol. 30 ( 2 ) page： 235 - 246   2024.4

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Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events. Methods: We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events. Results: 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m². Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis (P<0.05). Conclusions: People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex.

DOI： 10.3350/cmh.2023.0485

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Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma. Reviewed

Sasaki K, Kawamura Y, Ogawa C, Yabushita K, Watanabe S, Hayashi H, Kochi T, Tomonari T, Ninomiya M, Takai K, Imajo K, Ito T, Kita R, Mawatari S, Nishina S, Toyoda H

Cureus   Vol. 16 ( 4 ) page： e57800   2024.4

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DOI： 10.7759/cureus.57800

PubMed

Identification of the Microbiome Associated with Prognosis in Patients with Chronic Liver Disease. Open Access

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

Microorganisms   Vol. 12 ( 3 )   2024.3

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We investigated the prognostic role of the gut microbiome and clinical factors in chronic liver disease (hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]). Utilizing data from 227 patients whose stool samples were collected over the prior 3 years and a Cox proportional hazards model, we integrated clinical attributes and microbiome composition based on 16S ribosomal RNA sequencing. HCC was the primary cause of mortality, with the Barcelona Clinic Liver Cancer staging system-derived B/C significantly increasing the mortality risk (hazard ratio [HR] = 8.060; 95% confidence interval [CI]: 3.6509–17.793; p < 0.001). Cholesterol levels < 140 mg/dL were associated with higher mortality rates (HR = 4.411; 95% CI: 2.0151–9.6555; p < 0.001). Incertae sedis from Ruminococcaceae showed a protective effect, reducing mortality risk (HR = 0.289; 95% CI: 0.1282 to 0.6538; p = 0.002), whereas increased Veillonella presence was associated with a higher risk (HR = 2.733; 95% CI: 1.1922–6.2664; p = 0.017). The potential of specific bacterial taxa as independent prognostic factors suggests that integrating microbiome data could improve the prognosis and treatment of chronic liver disease. These microbiome-derived markers have prognostic significance independently and in conjunction with clinical factors, suggesting their utility in improving a patient’s prognosis.

DOI： 10.3390/microorganisms12030610

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PubMed

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study. International coauthorship

Chau A, Yeh ML, Tsai PC, Huang DQ, Kim SE, Trinh H, Yoon EL, Oh H, Jeong JY, Ahn SB, An J, Tseng CH, Hsu YC, Jeong SW, Cho YK, Shim JJ, Kim HS, Ito T, Marciano S, Kawashima K, Suzuki T, Watanabe T, Nozaki A, Ishikawa T, Inoue K, Eguchi Y, Uojima H, Abe H, Takahashi H, Chuma M, Ishigami M, Hoang JK, Maeda M, Huang CF, Gadano A, Dai CY, Huang JF, Tanaka Y, Chuang WL, Lim SG, Cheung R, Yu ML, Jun DW, Nguyen MH

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   Vol. 22 ( 3 ) page： 572 - 580.e5   2024.3

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

Background & Aims: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. Methods: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. Results: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17–1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03–1.31; P = .016), but VR and HCC risks were similar. Conclusions: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

DOI： 10.1016/j.cgh.2023.09.002

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PubMed

A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial. Open Access

Kudo M, Ueshima K, Saeki I, Ishikawa T, Inaba Y, Morimoto N, Aikata H, Tanabe N, Wada Y, Kondo Y, Tsuda M, Nakao K, Ito T, Hosaka T, Kawamura Y, Kuzuya T, Nojiri S, Ogawa C, Koga H, Hino K, Ikeda M, Moriguchi M, Hisai T, Yoshimura K, Furuse J, Arai Y

Liver cancer   Vol. 13 ( 1 ) page： 99 - 112   2024.2

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Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14.21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child- Pugh A liver function, 0.2 prior TACE sessions, tumor size .10 cm, number of tumors .10, and ECOG performance status 0.1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. Themedian age was 72 years, 77.4% of patientsweremen, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1.31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months. NR). LENTACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

DOI： 10.1159/000531377

Open Access

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PubMed

Successful Treatment with Steroids in a Patient with Vanishing Bile Duct Syndrome and Acute Tubular Necrosis Open Access

Mizuno Fumitaka, Imai Norihiro, Yasuda Kazushi, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki

Internal Medicine   Vol. 63 ( 1 ) page： 57 - 61   2024.1

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

<p>Vanishing bile duct syndrome (VBDS) is a rare but potentially serious cholestatic liver disease caused by various etiologies, including drugs. We herein report a complicated case of VBDS with acute tubular necrosis (ATN) that improved significantly with steroid treatment. An Asian man in his 30s was admitted with the acute onset of severe jaundice and a decline in the renal function. Although initial treatment with ursodeoxycholic acid did not reduce jaundice or renal dysfunction, steroid treatment remarkably improved the VBDS and ATN to within the respective normal ranges. Steroid treatment can be considered in cases of VBDS that appear to have an immune-mediated cause. </p>

DOI： 10.2169/internalmedicine.1826-23

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CiNii Research

Alpha-fetoprotein and des-gamma-carboxy prothrombin can predict the objective response of patients with hepatocellular carcinoma receiving durvalumab plus tremelimumab therapy. Open Access

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

PloS one   Vol. 19 ( 9 ) page： e0311084   2024

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Durvalumab plus tremelimumab (Durva/Treme) combined immunotherapy is the first-line therapy recommended for unresectable hepatocellular carcinoma (HCC). Since sequential therapy is more effective in improving prognosis, tumor markers have been used as predictive biomarkers for response to systemic therapy. This study aimed to investigate the predictive ability of objective response (OR) by tumor markers for Durva/Treme therapy against HCC. In this multicenter study, 110 patients with HCC who received Durva/Treme therapy were retrospectively enrolled. The OR rate was 15.5%. To aid early decision-making regarding OR, we evaluated the predictors contributing to OR in two steps: before (first step) and 4 weeks after (second step) treatment induction. Changes in tumor markers (alpha-fetoprotein [AFP] and des-gamma-carboxy prothrombin [DCP]) from baseline to 4 weeks after treatment (ΔAFP/ΔDCP) were included as the input factors. In the first step, multivariable analysis identified only the baseline AFP level (odds ratio 3.497, p = 0.029) as a predictor of OR. Patients with AFP ≥ 400 ng/mL had a significantly higher OR rate than those with < 400 ng/mL (28.2 vs. 8.5%, p = 0.011), and there was no significant difference in progression-free survival (PFS) between the two groups. When AFP/DCP response was defined as a ≥10% reduction from baseline, multivariable analysis showed that AFP response (odds ratio 6.023, p = 0.042) and DCP response (odds ratio 11.657, p = 0.006) were both independent predictors of OR in the second step. The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy.

DOI： 10.1371/journal.pone.0311084

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Immunoglobulin-like transcript 2 as an impaired anti-tumor cytotoxicity marker of natural killer cells in patients with hepatocellular carcinoma. Open Access

Sakata T, Yoshio S, Yamazoe T, Mori T, Kakazu E, Aoki Y, Aoyanagi N, Okamoto T, Ito T, Toyoda H, Kawaguchi T, Ono Y, Takahashi Y, Taketomi A, Kanto T

Frontiers in immunology   Vol. 15   page： 1389411   2024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Introduction: Natural killer (NK) cells play a pivotal role in immune surveillance in the liver. We aimed to identify potential targets for NK cell-mediated immune intervention by revealing the functional molecules on NK cells in HCC patients. Methods: To evaluate the impact of aging on NK cell phenotypes, we examined NK cells from healthy volunteers (HVs) of various ages. Because ILT2 expression on CD56^dim NK cells increased with increasing age, we enrolled age-matched HCC patients and HVs. We determined the NK cell phenotypes in blood mononuclear cells (PBMCs) and intrahepatic lymphocytes (IHLs) from cancerous and non-cancerous tissues. We evaluated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells in vitro. Results: ILT2-positive CD56^dim NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56^dim NK cells were increased in cancerous IHLs compared with non-cancerous IHLs and PBMCs. We examined the impact of macrophage migration inhibitory factor (MIF) on ILT2 expression in co-cultures of HCC cells and NK cells. The enhanced expression of ILT2 on CD56^dim NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4. ILT2-positive CD56^dim NK cells exhibited lower capacities for cytotoxicity and ADCC than ILT2-negative cells, which were partially restored by ILT2 blockade. Conclusions: In HCC patients, ILT2 is a signature molecule for cancerous CD56^dim NK cells with impaired cytolytic capacity. The MIF-CXCR4 interaction is associated with ILT2 induction on CD56^dim NK cells and ILT2 serves as a target for functional NK cell restoration.

DOI： 10.3389/fimmu.2024.1389411

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ICI-induced liver injury Reviewed

ITO Takanori, KAWASHIMA Hiroki

Nippon Shokakibyo Gakkai Zasshi   Vol. 121 ( 12 ) page： 948 - 956   2024

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

DOI： 10.11405/nisshoshi.121.948

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特集 NASH/NAFLDアップデート:患者数急増時代の実践ガイド 新しい話題と今後の展望 非肥満,lean NASH/NAFLDとは

伊藤 隆徳, 石上 雅敏, 川嶋 啓揮

診断と治療   Vol. 111 ( 12 ) page： 1649 - 1654   2023.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：診断と治療社  

DOI： 10.34433/dt.0000000523

CiNii Research

Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis. Open Access

Sugiyama Y, Yamamoto K, Honda T, Kato A, Muto H, Yokoyama S, Ito T, Imai N, Ishizu Y, Nakamura M, Asano T, Enomoto A, Zaitsu K, Ishigami M, Fujishiro M, Kawashima H

Hepatology international   Vol. 17 ( 6 ) page： 1378 - 1392   2023.12

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

Background: Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing the serum and hepatic bile acid levels. This study aimed to investigate the impact of these factors on liver tumor. Methods: C57BL/6J mice received a one-time intraperitoneal injection of 25-mg/kg diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan). Results: Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibat treatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion: Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

DOI： 10.1007/s12072-023-10581-2

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Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

Huang DQ, Tran A, Yeh ML, Yasuda S, Tsai PC, Huang CF, Dai CY, Ogawa E, Ishigami M, Ito T, Kozuka R, Enomoto M, Suzuki T, Yoshimaru Y, Preda CM, Marin RI, Sandra I, Tran S, Quek SXZ, Khine HHTW, Itokawa N, Atsukawa M, Uojima H, Watanabe T, Takahashi H, Inoue K, Maeda M, Hoang JK, Trinh L, Barnett S, Cheung R, Lim SG, Trinh HN, Chuang WL, Tanaka Y, Toyoda H, Yu ML, Nguyen MH

Hepatology (Baltimore, Md.)   Vol. 78 ( 5 ) page： 1558 - 1568   2023.11

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Background and Aims: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. Approach and Results: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log<inf>10</inf> IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively (p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase<upper limit of normal. In multivariable Cox proportional hazards analysis adjusted for age, sex, HBeAg, HBV DNA, alanine transaminase, diabetes, and platelets, antiviral therapy remained an independent predictor of reduced HCC risk (adjusted HR = 0.3, 95% CI: 0.1-0.6, p = 0.001). Conclusions: Antiviral therapy reduces HCC risk by 70% among patients with indeterminate-phase CHB. These data have important implications for the potential expansion of CHB treatment criteria.

DOI： 10.1097/HEP.0000000000000459

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Clinical course and prognosis of patients with hepatocellular carcinoma and haemophilia. Open Access

Matsuda N, Imai N, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Kawashima H

European journal of gastroenterology & hepatology   Vol. 35 ( 10 ) page： 1211 - 1215   2023.10

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

Introduction Although patients with haemophilia are known to develop hepatocellular carcinoma (HCC) at a lower age than patients without, there are few reports on the clinical course and prognosis of HCC. Aim We aimed to investigate the clinical course and prognosis of patients with HCC and haemophilia. Methods Twenty-two patients with haemophilia, who were initially diagnosed with HCC between 2003 and 2021, were included. Their clinical courses and prognoses were retrospectively analysed. The results were compared with those of the 24th Nationwide Follow-up Survey of Primary Liver Cancer. Results All 22 patients were male; of these, 20 patients had haemophilia A, and 2 had haemophilia B. The mean age of diagnosis was 63 years (range 45-78 years) which is lower than the mean of 72 years reported in the Nationwide Survey. The mean diameter of the largest tumour was 30 mm (range 11-70 mm), and 18 tumours (82%) were solitary at the initial diagnosis. Standard treatments for HCC were performed in all patients. Sixty-one transarterial chemoembolisation, 28 RFA, 10 hepatectomies, and 2 radiation treatments were performed, and molecular-targeted agents were administered to 5 patients during their clinical courses. No deaths were associated with complications of HCC treatments. The median survival time after initial treatment was 6.4 years (range 0.9-18.7 years) which did not differ much from the median survival time of 5.8 years in the Nationwide Survey. Conclusion Standard treatment for HCC could improve the prognosis of patients with HCC and haemophilia.

DOI： 10.1097/MEG.0000000000002628

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Identification of clinical phenotypes associated with poor prognosis in patients with nonalcoholic fatty liver disease via unsupervised machine learning.

Ito T, Morooka H, Takahashi H, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Ishigami M, Kamada Y, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)

Journal of gastroenterology and hepatology   Vol. 38 ( 10 ) page： 1832 - 1839   2023.10

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

Background and Aims: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. Methods: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. Results: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3–4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m² and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m²). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. Conclusions: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

DOI： 10.1111/jgh.16326

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Diagnostic Performance of the Fibrosis-4 Index and Nonalcoholic Fatty Liver Disease Fibrosis Score in Lean Adults With Nonalcoholic Fatty Liver Disease. International coauthorship International journal Open Access

Park H, Yoon EL, Ito T, Jo AJ, Kim M, Lee J, Kim HL, Arai T, Atsukawa M, Kawanaka M, Toyoda H, Ishigami M, Yu ML, Jun DW, Nguyen MH

JAMA network open   Vol. 6 ( 8 ) page： e2329568   2023.8

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IMPORTANCE: The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited. OBJECTIVE: To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023. MAIN OUTCOMES AND MEASURES: The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated. RESULTS: A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age-and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P =.28) and NFS (lean, 0.790 vs nonlean, 0.755; P =.54) between the 2 groups were comparable in the age-and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend <.001), while those of the FIB-4 did not (P for trend =.05 and P =.20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P =.09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P =.03). CONCLUSIONS AND RELEVANCE: In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.

DOI： 10.1001/jamanetworkopen.2023.29568

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Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. International coauthorship

Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, Lee K, Stave CD, Henry L, Barnett SD, Cheung R, Nguyen MH

Journal of hepatology   Vol. 79 ( 2 ) page： 287 - 295   2023.8

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

Background & Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. Methods: We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD. Results: A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005). Conclusions: NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

DOI： 10.1016/j.jhep.2023.03.040

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特集 浮腫と脱水-Q＆Aで学ぶジェネラリストのための体液量異常診療 浮腫をきたす疾患の診断とそのマネジメント 肝硬変による浮腫のメカニズムとマネジメント

伊藤 隆徳, 石上 雅敏, 川嶋 啓揮

medicina   Vol. 60 ( 8 ) page： 1248 - 1252   2023.7

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：株式会社医学書院  

DOI： 10.11477/mf.1402229037

CiNii Research

特集 肝疾患-診療のチェックポイント2023 第Ⅰ部　診断のチェックポイント　第5章　肝疾患鑑別診断のチェックポイント　1.薬物性肝障害が疑われるとき

伊藤 隆徳, 山本 崇文, 水野 和幸, 石上 雅敏, 川嶋 啓揮

臨床消化器内科   Vol. 38 ( 7 ) page： 799 - 806   2023.6

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本メディカルセンター  

DOI： 10.19020/cg.0000002668

CiNii Research

Significance of pretreatment alpha-fetoprotein in patients with compensated severe fibrosis after hepatitis C viral eradication.

Ishigami M, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Kawashima H

Journal of hepato-biliary-pancreatic sciences   Vol. 30 ( 6 ) page： 834 - 842   2023.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Hepato Biliary Pancreatic Sciences  

Background: We aimed to investigate the factors associated with improvement of liver functional reserve after sustained virological response using interferon-free, direct-acting antiviral combination treatment in patients with compensated, severe fibrosis. Methods: Between September 2014 and April 2020, 492 patients received direct-acting antiviral combination treatment in our hospital. Among them, 173 patients who had severe fibrosis based on a fibrosis-4 index ≥3.25, showed sustained virological response after treatment. We investigated the dynamic change in albumin-bilirubin score and the baseline factors associated with its improvement, 48 weeks after treatment. Results: The baseline significant factors associated with albumin-bilirubin ≦ −0.5 were lower albumin (HR: 15.625, 95% CI: 4.273–58.824, P <.001), higher hepatitis C virus RNA (HR: 4.995, 95% CI: 1.882–13.260, P =.001), and higher alpha-fetoprotein (HR: 1.033, 95% CI: 1.011–1.055, P =.003). Patients with alpha-fetoprotein ≧10 ng/mL showed significant improvement of albumin-bilirubin score from baseline to 48 weeks after treatment compared to those with alpha-fetoprotein <10 ng/mL (P <.001). Conclusions: Baseline serum alpha-fetoprotein might be a predictive factor for improvement of liver function after sustained virological response in patients with severe fibrosis.

DOI： 10.1002/jhbp.1309

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Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis. Open Access

Yamamoto T, Mizuno K, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Ishikawa T, Kanamori A, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Ishii M, Sone M, Ando Y, Akiyama M, Ishigami M, Kawashima H

Investigational new drugs   Vol. 41 ( 3 ) page： 512 - 521   2023.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Investigational New Drugs  

Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

DOI： 10.1007/s10637-023-01366-3

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Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

Yamauchi R, Ito T, Yoshio S, Yamamoto T, Mizuno K, Ishigami M, Kawashima H, Yasuda S, Shimose S, Iwamoto H, Yamazoe T, Mori T, Kakazu E, Kawaguchi T, Toyoda H, Kanto T

Journal of gastroenterology   Vol. 58 ( 6 ) page： 565 - 574   2023.6

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

Background: Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients. Methods: This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs). Results: The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8–9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100–calcium-binding protein A8/S100–calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α‐fetoprotein levels as independent predictors of PD. In the sub-analysis of Child–Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN. Conclusion: High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.

DOI： 10.1007/s00535-023-01985-w

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Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma. Open Access

Mizuno K, Imai N, Yamamoto T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Kuzuya T, Ishigami M, Kawashima H

Cancers   Vol. 15 ( 10 )   2023.5

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

Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

DOI： 10.3390/cancers15102853

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Distinct features of two lipid droplets types in cell nuclei from patients with liver diseases. Open Access

Imai N, Ohsaki Y, Cheng J, Zhang J, Mizuno F, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishigami M, Wake H, Kawashima H

Scientific reports   Vol. 13 ( 1 ) page： 6851   2023.4

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Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

DOI： 10.1038/s41598-023-33977-4

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Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger Than 60 Diabetic NAFLD patients. International coauthorship Open Access

Ito T, Nguyen VH, Tanaka T, Park H, Yeh ML, Kawanaka M, Arai T, Atsukawa M, Yoon EL, Tsai PC, Toyoda H, Huang JF, Henry L, Jun DW, Yu ML, Ishigami M, Nguyen MH, Cheung RC

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   Vol. 21 ( 4 ) page： 1013 - 1022.e6   2023.4

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

Background & Aims: Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized. Methods: We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM. Results: By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m²), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63–0.66). Conclusions: FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients.

DOI： 10.1016/j.cgh.2022.05.015

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Proteomic Analysis Reveals Changes in Tight Junctions in the Small Intestinal Epithelium of Mice Fed a High-Fat Diet. Open Access

Muto H, Honda T, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Maeda K, Ishikawa T, Adachi S, Sato C, Tsuji NM, Ishigami M, Fujishiro M, Kawashima H

Nutrients   Vol. 15 ( 6 )   2023.3

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

The impact of a high-fat diet (HFD) on intestinal permeability has been well established. When bacteria and their metabolites from the intestinal tract flow into the portal vein, inflammation in the liver is triggered. However, the exact mechanism behind the development of a leaky gut caused by an HFD is unclear. In this study, we investigated the mechanism underlying the leaky gut related to an HFD. C57BL/6J mice were fed an HFD or control diet for 24 weeks, and their small intestine epithelial cells (IECs) were analyzed using deep quantitative proteomics. A significant increase in fat accumulation in the liver and a trend toward increased intestinal permeability were observed in the HFD group compared to the control group. Proteomics analysis of the upper small intestine epithelial cells identified 3684 proteins, of which 1032 were differentially expressed proteins (DEPs). Functional analysis of DEPs showed significant enrichment of proteins related to endocytosis, protein transport, and tight junctions (TJ). Expression of Cldn7 was inversely correlated with intestinal barrier function and strongly correlated with that of Epcam. This study will make important foundational contributions by providing a comprehensive depiction of protein expression in IECs affected by HFD, including an indication that the Epcam/Cldn7 complex plays a role in leaky gut.

DOI： 10.3390/nu15061473

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Prevalence, characteristics, and mortality outcomes of obese and nonobese MAFLD in the United States. International coauthorship

Dao AD, Nguyen VH, Ito T, Cheung R, Nguyen MH

Hepatology international   Vol. 17 ( 1 ) page： 225 - 236   2023.2

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

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) establishes new criteria for diagnosis of fatty liver disease independent of alcohol intake. We aimed to describe the prevalence and compare characteristics and mortality outcomes of persons with nonobese and obese MAFLD. Methods: Using data from 13,640 participants from the third National Health and Nutrition Examination Survey (NHANES III) 1988–1994, we identified participants with fatty liver on ultrasound who had MAFLD and analyzed them by the presence of obesity. Results: Overall prevalence of MAFLD was 19%; amongst those, 54% were obese and 46% were nonobese. Nonobese MAFLD was more common in participants older than 65 than in younger participants (56.8% vs. 43.2%, p < 0.0001). Nonobese MAFLD was more common in males (63.2% vs. 48.3%, p < 0.0001). Obese MAFLD was more common in females (51.7% vs. 48.3%, p < 0.0001). After adjusting for several demographic factors and alcohol use, older age [adjusted odds ratio (aOR) 1.02, 95% CI 1.00–1.02, p = 0.003] and being male (aOR: 1.65, 95% CI 1.25–2.17, p = 0.001) were independent risk factors for nonobese MAFLD. Nonobese MAFLD participants had a higher 20-year cumulative incidence for all-cause mortality compared to obese MAFLD participants (33.2% vs. 28.8%, p = 0.0137). However, nonobese MAFLD was not independently associated with mortality after adjusting for relevant confounders, while FIB-4 > 1.3 and cardiovascular disease were the strongest risk factors associated with increased mortality [adjusted hazard ratio (aHR) > 2.7 for both, p < 0.0001 for both]. Conclusions: Nonobese MAFLD constitutes about half of the MAFLD in the United States, especially among males and the elderly. Notably, nonobese MAFLD carries higher mortality than obese MAFLD. Screening and diagnosis of MAFLD should be considered in nonobese populations.

DOI： 10.1007/s12072-022-10436-2

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Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients International coauthorship Open Access

Liu J.K., Vutien P., Huang D.Q., Ishigami M., Landis C.S., Nguyen M.H., Daniel P.C.Y.N., Ito T., Dang H., Maeda M., Leong J.

Clinical Gastroenterology and Hepatology   Vol. 21 ( 2 ) page： 538 - 540.e4   2023.2

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

DOI： 10.1016/j.cgh.2022.01.035

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Endoscopic injection sclerotherapy with polidocanol for cardiac varices in children and adolescents. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Hinoki A, Sumida W, Shirota C, Tainaka T, Makita S, Yokota K, Uchida H, Ishigami M

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie   Vol. 30 ( 2 ) page： 109 - 112   2023.2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Archives De Pediatrie  

Background: Like esophageal varices, cardiac varices are often treated with endoscopic variceal ligation (EVL). However, we previously reported that EVL for cardiac varices may be associated with a high risk of rebleeding from the ulcer if the O-ring spontaneously drops off early. The efficacy and safety of para-variceal endoscopic injection sclerotherapy (EIS) with polidocanol for the treatment of cardiac varices in children and adolescents were evaluated. Methods: Eleven patients under 18 years of age with portal hypertension who underwent para-variceal EIS with polidocanol for cardiac varices with red signs, which were considered to be at high risk of bleeding, were retrospectively reviewed. Results: One session of para-variceal polidocanol-EIS was performed for each of the 11 patients. One patient experienced temporary hypoxia due to aspiration of saliva when the tracheal intubation tube was removed after the procedure but recovered by endotracheal suctioning; there were no other adverse events. In six of the eight cases in which efficacy could be evaluated, eradication of cardiac varices was achieved. Conclusion: Para-variceal polidocanol-EIS may be considered instead of EVL for small cardiac varices with red signs in pediatric patients with cardiac varices.

DOI： 10.1016/j.arcped.2022.11.016

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Clustering using unsupervised machine learning to stratify the risk of immune-related liver injury.

Yamamoto T, Morooka H, Ito T, Ishigami M, Mizuno K, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Yokota K, Hase T, Maeda O, Hashimoto N, Ando Y, Akiyama M, Kawashima H

Journal of gastroenterology and hepatology   Vol. 38 ( 2 ) page： 251 - 258   2023.2

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

Background and Aim: Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis. Methods: We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters. Results: This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70–108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77–4.50, P < 0.001; HR: 2.87, 95% CI: 1.47–5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-to-lymphocyte ratio, and liver metastases between both clusters. Conclusions: The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

DOI： 10.1111/jgh.16038

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The presence of high-risk varices after sclerotherapy in biliary atresia. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Shirota C, Tainaka T, Sumida W, Makita S, Takimoto A, Nakagawa Y, Takada S, Ishigami M, Uchida H, Kawashima H

Pediatrics international : official journal of the Japan Pediatric Society   Vol. 65 ( 1 ) page： e15454   2023.1

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Background: Esophagogastric varices (EGVs) may develop as a result of portal hypertension in children with biliary atresia (BA). Although endoscopic injection sclerotherapy (EIS) with ethanolamine oleate (EO) is reported useful for children, risk factors associated with the presence of high-risk EGVs after treatment remain unknown. Methods: The subjects were BA patients under 15 years of age who underwent EO-EIS. We retrospectively reviewed a total of 28 treatment sessions of EGVs with red signs and those larger than F2, which were considered to be at high risk of bleeding. Survival analysis was performed for the presence of high-risk EGVs at the time of follow-up endoscopy as the occurrence of an event. Results: Univariate analysis showed a significantly increased risk of the presence of high-risk EGVs post-EO-EIS in patients with increased liver stiffness (LS) and Mac-2 binding protein glycan isomer (M2BPGi), with hazard ratios of 1.48 and 1.15, respectively. The median presence-free period was significantly shorter in the LS ≥ 2.8 m/s patients than in those with LS <2.8 m/s (189 vs. 266 days). Similarly, the median presence-free period was significantly shorter in patients with M2BPGi ≥ 4.0 than in those with M2BPGi < 4.0 (182 vs. 203 days). The results of multivariate analysis revealed that the risk of the presence of high-risk EGVs was significantly higher only in the high-LS group, with a hazard ratio of 2.76. Conclusions: Increased LS is associated with risk of the presence of high-risk EGVs following EO-EIS in children with BA.

DOI： 10.1111/ped.15454

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Bulevirtide and tenofovir combination therapy for hepatitis D virus infection: longer treatment and more diverse trial populations are needed. International coauthorship

Ito T, Nguyen MH

The Lancet. Infectious diseases   Vol. 23 ( 1 ) page： 14 - 16   2023.1

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DOI： 10.1016/S1473-3099(22)00412-1

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Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet.

Zhao M, Ma L, Honda T, Kato A, Ohshiro T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Tsuji NM, Ishigami M, Fujishiro M

Digestive diseases and sciences   Vol. 68 ( 1 ) page： 155 - 163   2023.1

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Background: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. Aims: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. Methods: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. Results: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. Conclusions: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH. Graphical Abstract: [Figure not available: see fulltext.].

DOI： 10.1007/s10620-022-07489-6

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Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes. International coauthorship Open Access

Ito T, Nguyen MH

Journal of hepatocellular carcinoma   Vol. 10   page： 413 - 428   2023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Hepatocellular Carcinoma  

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

DOI： 10.2147/JHC.S347959

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Differences in the Intestinal Microbiome Associated with Diarrhea during Lenvatinib Treatment for Hepatocellular Carcinoma. Open Access

Inukai Y, Yamamoto K, Honda T, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Ishigami M

Digestive diseases (Basel, Switzerland)   Vol. 41 ( 1 ) page： 138 - 147   2023

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Introduction: Lenvatinib has been widely used for the treatment of advanced hepatocellular carcinoma (HCC). Some adverse events, including diarrhea, have been reported for lenvatinib. Diarrhea may be associated with the changes in the intestinal microbiome; however, the underlying mechanism has not been elucidated. Aim: In this study, we aimed to investigate the relationship between the intestinal microbiome and diarrhea caused by lenvatinib via analysis of fecal samples collected before treatment. Methods: A total of 21 patients with advanced HCC who were treated with lenvatinib were enrolled. Fecal samples were collected from patients. The patients were divided into diarrhea (n = 8) and nondiarrhea groups (n = 12). We compared the characteristics of patients, incidence of adverse events, composition of the intestinal microbiome, and enrichment of functional pathways between both groups using QIIME2 and PICRUSt2. Results: The median age of the two groups was 73 years. The nondiarrhea group comprised a relatively higher number of male patients than the diarrhea group; however, there were no significant differences in patient characteristics between both groups. The proportion of the microbiome was similar, and alpha and beta diversities were not significantly different between both groups. The relative abundance of order Bacteroidales, including Parabacteroides and Prevotella, was higher in the diarrhea group than in the nondiarrhea group. PICRUSt2 analysis showed some metabolic pathways, including butanoate (butyrate) metabolism, were enriched in the nondiarrhea group when compared with those in the diarrhea group. Conclusion: Differences in the intestinal microbiomes and their functions may influence the incidence of diarrhea during lenvatinib treatment.

DOI： 10.1159/000524298

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寄生虫感染による孤立性壊死性結節の一例

服部 真代, 伊藤 隆徳, 山本 健太, 水野 史崇, 佐藤 浩司, 松原 宏紀, 石津 洋二, 石川 卓哉, 古澤 健司, 服部 昌志, 川嶋 啓揮

超音波検査技術抄録集   Vol. 48 ( 0 ) page： S207 - S207   2023

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DOI： 10.11272/jssabst.48.0_s207

CiNii Research

Relationship between low-back pain and flexibility in children: A cross-sectional study. Open Access

Ito T, Sugiura H, Ito Y, Narahara S, Natsume K, Takahashi D, Noritake K, Yamazaki K, Sakai Y, Ochi N

PloS one   Vol. 18 ( 11 ) page： e0293408   2023

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Low-back pain is common among school-aged children. Decreased trunk flexibility in childhood influences low-back pain in adulthood. Previous studies examining the association between low-back pain and trunk flexibility in children are insufficient. Examining this association among elementary school children may help to better understand trunk flexibility in children with low-back pain and to modify the management of inflexibility. Therefore, this study aimed to identify the prevalence of low-back pain and its relationship with physical function among elementary school students. School-aged children aged 6–12 years were recruited in Japan between May 2018 and March 2023. Fingertip-to-floor distance, back muscle strength, pelvic tilt angle during gait, and the visual analog scale for low-back pain were measured. In addition, factors independently related to low-back pain were determined through logistic regression analysis. Low-back pain was reported in 9.6% of the 394 participants (boys, 191; girls, 203). All children with low-back pain presented with back pain when they moved; however, the pain was non-specific. Logistic regression analysis showed that the fingertip-to-floor distance was an independent risk factor for low-back pain (odds ratio, 0.921; p = 0.007). The odds ratios calculated in the logistic regression analysis confirmed that low-back pain frequency increased as the fingertip-to-floor distance decreased. The risk of low-back pain was associated with inflexibility, regardless of sex and muscle strength. These findings suggest that children with low-back pain must increase their trunk and lower extremity flexibility.

DOI： 10.1371/journal.pone.0293408

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Pipeline Esophagogastric Varices Secondary to Extrahepatic Portal Vein Obstruction Treated Endoscopically with the Assistance of Transileocolic Obliteration Open Access

Yokoyama Shinya, Ishizu Yoji, Honda Takashi, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Komada Tomohiro, Hayashi Masamichi, Ishigami Masatoshi

Internal Medicine   Vol. 61 ( 23 ) page： 3503 - 3511   2022.12

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<p>Endoscopic injection sclerotherapy (EIS) for esophagogastric varices (EGV) was attempted for a 29-year-old man with extrahepatic portal vein obstruction. However, pipeline varices characterized by a large blood flow volume were present, and the sclerosant did not accumulate sufficiently in them. Transileocolic obliteration (TIO) using coils was performed, but some EGVs and palisading veins remained. Thus, EIS was performed once again immediately after TIO. Since a reduction in the intravariceal blood flow was achieved by preceding TIO, effective injection of sclerosant into the vessels was possible. For pipeline varices difficult to treat endoscopically, combination therapy with TIO may be effective. </p>

DOI： 10.2169/internalmedicine.9404-22

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Factors associated with the progression of myosteatosis in patients with cirrhosis. Open Access

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Fujishiro M

Nutrition (Burbank, Los Angeles County, Calif.)   Vol. 103-104   page： 111777   2022.11

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Objectives: The presence of myosteatosis is one factor associated with poor prognosis for patients with cirrhosis; however, the factors contributing to worsening myosteatosis are, to our knowledge, unknown. The aim of this study was to clarify the changes in myosteatosis, and the factors involved in these changes. Methods: The present study enrolled 178 patients with cirrhosis who underwent computed tomography twice to measure changes in skeletal muscle attenuation (SMA) at the L3 level. Factors associated with SMA and those associated with changes in SMA were examined. Results: Using linear multiple regression analysis, age (β = –0.22), skeletal muscle index (SMI; skeletal muscle area divided by height squared; β = 0.25), and visceral and subcutaneous fat indices (VFI and SFI; the visceral and subcutaneous fat areas at the umbilical level divided by height squared; β = –0.08, β = –0.06, respectively) were identified as associated with SMA. The 100-d change in SMA was –0.21 ± 1.29 Hounsfield units (HU). Changes in SMI and SMA were positively associated (R = 0.183, P = 0.014), whereas those in VFI and SMA were negatively associated (R = –0.172, P = 0.022). No association was noted between the 100-d changes in SFI and SMA. In patients whose SMI increased and VFI decreased, the 100-d change in SMA was 0.24 ± 1.82 HU, which was marginally different from that in patients whose SMI decreased and VFI increased (–0.44 ± 1.32 HU, P = 0.077). Conclusions: In patients with cirrhosis, myosteatosis progressed, and decreases in SMI and increases in VFI were correlated with its progression.

DOI： 10.1016/j.nut.2022.111777

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An improved method to assess skeletal muscle mass in patients with liver cirrhosis based on computed tomography images. Open Access

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 11 ) page： 937 - 946   2022.11

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

Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat-infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low-fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low-fat SMI was significantly correlated with handgrip strength (males, R = 0.393, p = 0.002; females, R = 0.423, p < 0.001) and LFI (males, R = −0.535, p = 0.035; females, R = −0.368, p = 0.039), whereas conventional SMI was not. When using low-fat SMI, patients with low skeletal muscle mass had significantly low handgrip strength, LFI, SPPB, and physical and social-related QOL score than those without. By contrast, no significant differences were found for any items when using conventional SMI. Conclusions: Low-fat SMI is a good index of skeletal muscle mass that appropriately reflects skeletal muscle function.

DOI： 10.1111/hepr.13820

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Combined ultrasound and magnetic resonance elastography predict hepatocellular carcinoma after hepatitis C virus eradication.

Kumada T, Toyoda H, Yasuda S, Ogawa S, Gotoh T, Tada T, Ito T, Sumida Y, Tanaka J

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 11 ) page： 957 - 967   2022.11

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Aim: Elastography is an established, noninvasive method for measuring liver stiffness using to 2-D shear-wave elastography (2D-SWE) or magnetic resonance elastography (MRE). The aim of this study was to determine the usefulness of combined measurement using 2D-SWE and MRE to stratify the risk of developing hepatocellular carcinoma (HCC) in patients who achieved hepatitis C virus eradication. Methods: Five hundred and twenty-five patients who underwent 2D-SWE and MRE before antiviral therapy and who achieved eradication were enrolled. The optimal 2D-SWE and MRE cutoff values were determined using time-dependent receiver operating characteristic (ROC) curves for predicting HCC development. Inverse probability of treatment weighting (IPTW) and a Cox proportional hazards model were used to adjust the cumulative incidence rate of HCC development for potential imbalances. Results: Time-dependent ROC analysis showed that the optimal cut-off values of 2D-SWE and MRE for predicting HCC development were 11.7 and 4.5 kPa, respectively. The IPTW-adjusted cumulative incidence rate of HCC development in patients with both an 2D-SWE value ≥ 11.7 kPa and an MRE value ≥ 4.5 kPa had a higher hazard ratio (28.080; 95% confidence interval, 5.527–132.600; p < 0.001) than those with either an 2D-SWE value < 11.7 kPa or an MRE value < 4.5 kPa. Conclusions: The combined measurement of 2D-SWE and MRE was very effective for identifying patients at high risk of HCC development. US-based elastography should be performed first, and if the 2D-SWE value is high, MRE should then be carried out to confirm the degree of liver stiffness.

DOI： 10.1111/hepr.13814

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Decreased appetite is associated with the presence of sarcopenia in patients with cirrhosis. Open Access

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Kawashima H

Nutrition (Burbank, Los Angeles County, Calif.)   Vol. 103-104   page： 111807   2022.11

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Objectives: To our knowledge, the relationship between appetite and sarcopenia in patients with cirrhosis is unknown. The aims of this study were to examine the factors associated with decreased appetite and to clarify the relationship between appetite and sarcopenia. Methods: This study included 61 patients with cirrhosis. The patients were asked to describe their appetite using a numerical rating scale (NRS) from 0 (none at all) to 10 (most), with ≤5 defined as decreased appetite. The clinical characteristics, gastrointestinal symptoms as assessed using the Gastrointestinal Symptom Rating Scale, handgrip strength, and skeletal muscle area at the third vertebra were collected retrospectively. Sarcopenia was diagnosed according to the criteria of the Japan Society of Hepatology. The differences in these factors between patients with and without decreased appetite, and the factors associated with the presence of sarcopenia were examined. Results: Alcoholic liver disease was the most common etiology. The median Model for End-Stage Liver Disease score was 8 (interquartile range = 7 - 10) and hepatocellular carcinoma was present in 35 patients. Overall, 36% of the patients with cirrhosis had decreased appetite. Patients with decreased appetite had a higher frequency of abdominal pain and acid reflux–related symptoms and significantly lower handgrip strength than patients without, among both men (P = 0.034) and women (P = 0.017). The multivariate analysis identified a decrease in appetite as a significant factor associated with the presence of sarcopenia (NRS one increase, odds ratio, 0.701; 95% confidence interval, 0.502–0.977; P = 0.036). Conclusion: Decreased appetite was associated with the presence of sarcopenia.

DOI： 10.1016/j.nut.2022.111807

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Additional survival follow-up of TACTICS-L: Transcatheter arterial chemoembolization therapy (TACE) in combination strategy with lenvatinib in (LEN) patients with unresectable hepatocellular carcinoma in Japan Open Access

Inaba Y., Ueshima K., Ishikawa T., Saeki I., Morimoto N., Aikata H., Tanabe N., Wada Y., Kondo Y., Tsuda M., Nakao K., Ikeda M., Moriguchi M., Ito T., Hosaka T., Koga H., Hino K., Kawamura Y., Yoshimura K., Kudo M.

ANNALS OF ONCOLOGY   Vol. 33   page： S1472 - S1472   2022.11

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DOI： 10.1016/j.annonc.2022.10.131

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Effect of illness uncertainty on alanine transaminase levels and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease. Open Access

Ozawa N, Sato K, Sugimura A, Maki S, Tanaka T, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishigami M, Fujishiro M, Ishikawa T, Ando S

Nagoya journal of medical science   Vol. 84 ( 4 ) page： 857 - 864   2022.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nagoya Journal of Medical Science  

Patients with nonalcoholic fatty liver disease (NAFLD) have illness uncertainty. The purpose of this longitudinal study was to investigate the effect of the degree of illness uncertainty in patients with NAFLD on liver function values. We conducted a questionnaire survey and collected blood samples from outpatients with NAFLD. The items in the questionnaire were measured for illness uncertainty using the Japanese version of the Mishel Uncertainty in Illness Scale-Community (MUIS-C). Blood samples were collected at baseline and after 1 year. We divided the patients into two groups: one with high illness uncertainty and the other with low illness uncertainty. We then compared changes in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels over time from baseline using multiple regression analysis. This study analyzed 148 patients with NAFLD; 75 were male and 73 were female, with a mean age of 58.4 ± 12.3 years. The group with higher illness uncertainty had significantly higher ALT and AST levels at 1 year (b =.185 and.183, respectively) than the group with lower illness uncertainty. High illness uncertainty in patients with NAFLD can lead to higher ALT and AST levels. Healthcare providers must focus on reducing illness uncertainty in patients with NAFLD.

DOI： 10.18999/nagjms.84.4.857

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HIGHER HEPATOCELLULAR CARCINOMA (HCC) INCIDENCE IN CHRONIC HEPATITIS C (CHC) PATIENTS AFTER HEPATITIS C VIRUS (HCV) CURE COMPARED TO TREATED CHRONIC HEPATITIS B (CHB): RESULTS FROM A MULTINATIONAL REAL-WORLD COHORT OF PATIENTS WITH CIRRHOSIS

Park Jiyoon, Tran Sally, Ogawa Eiichi, Huang Chung-Feng, Toyoda Hidenori, Chen Chien Hung, Yeh Ming-Lun, Tseng Cheng-Hao, Hsu Yao-Chun, Kawashima Keigo, Preda Carmen, Istratescu Doina, Yasuda Satoshi, Nozaki Akito, Chuma Makoto, Oh Hyunwoo, Shim Jae-Jun, Jeong Soung Won, An Jihyun, Ahn Sang Bong, Kim Sung Eun, Yoon Eileen, Lee Han Ah, Kim Hyoung Su, Cho Yong Kyun, Uojima Haruki, Trinh Huy, Atsukawa Masanori, Itokawa Norio, Okubo Tomomi, Abe Hiroshi, Lee Dong Hyun, Jun Mi Jung, Landis Charles, Liu Joanne, Enomoto Masaru, Watanabe Tsunamasa, Ji Fanpu, Wang Wenjun, Yu Li, Xie Qing, Fukunishi Shinya, Asai Akira, Yokohama Keisuke, Ishikawa Toru, Liu Li, Li Junyi, Takahashi Hirokazu, Inoue Kaori, Eguchi Yuichiro, Ishigami Masatoshi, Ito Takanori, Huang Daniel, Wong Grace L., Wong Vincent, Lu Chengzhen, Zang Wenqian, Li Jia, Ueno Yoshiyuki, Haga Hiroaki, Marciano Sebastian, Jing Liang, Ye Qing, Lam Carla, Ho Dang Kh, Do Son T., Huang Rui, Takaguchi Koichi, Senoh Tomonori, Chien Nicholas, Maeda Mayumi, Kudaravalli Sahith, Henry Linda, Chuang Wan-Long, Dai Chia-Yen, Huang Jee-Fu, Gadano Adrian C., Yuen Man-Fung, Lim Seng Gee, Cheung Ramsey, Tanaka Yasuhito, Jun Dae Won, Yu Ming-Lung, Nguyen Mindie H.

HEPATOLOGY   Vol. 76   page： S377 - S379   2022.10

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Liver Stiffness Measurements by 2D Shear-Wave Elastography: Effect of Steatosis on Fibrosis Evaluation.

Kumada T, Toyoda H, Yasuda S, Ogawa S, Gotoh T, Ito T, Tada T, Tanaka J

AJR. American journal of roentgenology   Vol. 219 ( 4 ) page： 604 - 612   2022.10

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

BACKGROUND. Hepatic steatosis has been found not to affect liver stiffness measurements (LSM) from MR elastography (MRE). However, the effect of steatosis on LSM from 2D shear-wave elastography (SWE) remains controversial. OBJECTIVE. The purpose of this study was to evaluate the effect of hepatic steatosis on the diagnostic performance of LSM from 2D SWE (LSM<inf>2D SWE</inf>) for evaluation of liver fibrosis with LSM from MRE (LSM<inf>MRE</inf>) as the reference standard. METHODS. This retrospective study included 888 patients (442 women, 446 men; median age, 67 years) with chronic liver disease who underwent LSM by both 2D SWE and MRE within a 3-month window. Steatosis was also assessed on ultrasound examinations by ultrasound-guided attenuation parameter (UGAP) and on MRI examinations by proton density fat fraction (PDFF). Fibrosis stages and steatosis grades were classified according to previously established thresholds. The effect of steatosis on LSM<inf>2D SWE</inf> was evaluated by Kruskal-Wallis tests with post hoc tests and ROC analysis. RESULTS. LSM<inf>2D SWE</inf> were significantly higher in patients with severe steatosis than those without steatosis by MRI PDFF among patients with F0 fibrosis (5.5 kPa [IQR, 4.7–6.0 kPa] vs 4.7 kPa [IQR, 4.2–5.5 kPa], p = .009) and F1 fibrosis (6.3 kPa [IQR, 6.0–7.2 kPa] vs 5.9 kPa [IQR, 5.0–6.6 kPa], p = .009). LSM<inf>2D SWE</inf> were significantly higher in patients with severe steatosis than those without steatosis by UGAP among patients with F1 fibrosis (6.6 kPa [IQR, 5.9–7.3 kPa] vs 5.9 kPa [IQR, 5.1–6.5 kPa], p = .008). Otherwise, LSM<inf>2D SWE</inf> did not vary significantly across steatosis grades at a given fibrosis stage (all p > .05). Sensitivity and specificity for ≥ F1 fibrosis were 63.8% and 91.5% in patients without versus 60.4% and 80.9% in patients with severe steatosis by MRI PDFF and were 62.4% and 91.5% in patients without versus 72.1% and 78.3% in patients with severe steatosis by UGAP. CONCLUSION. Severe hepatic steatosis may result in overestimation of LSM<inf>2D SWE</inf> in patients without or with mild steatosis, reducing the specificity of liver fibrosis detection. CLINICAL IMPACT. Assessment of UGAP at 2D SWE may help identify patients in whom LSM<inf>2D SWE</inf> should be assessed with caution. In patients with no or mild steatosis by 2D SWE and severe steatosis by UGAP, MRE helps provide a more reliable measure of liver fibrosis.

DOI： 10.2214/AJR.22.27656

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USEFULNESS OF MUTATIONS INDUCED IN THE CORE REGION BY INTERFERON-BASED THERAPY

Honda Takashi Honda, Ishigami Masatoshi, Kato Asuka, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Ishizu Yoji, Yasuda Satoshi, Toyoda Hidenori, Kumada Takashi, Ishikawa Tetsuya, Kawashima Hiroki

HEPATOLOGY   Vol. 76   page： S262 - S263   2022.10

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GLOBAL INCIDENCE OF NON-ALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Le Michael, Le David M., Baez Thomas, Wu Yuankai, Lee Eunice Y., Ito Takanori, Nguyen Mindie H.

HEPATOLOGY   Vol. 76   page： S850 - S850   2022.10

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ANOREXIA IS ASSOCIATED WITH THE PRESENCE OF SARCOPENIA IN PATIENTS WITH CIRRHOSIS

Ishizu Yoji, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Honda Takashi Honda, Ishigami Masatoshi, Kawashima Hiroki

HEPATOLOGY   Vol. 76   page： S1181 - S1181   2022.10

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ANTIVIRAL THERAPY REDUCES HEPATOCELLULAR CARCINOMA RISK AMONG HBV PATIENTS IN THE INDETERMINATE PHASE

Huang Daniel, Tran Andrew Khoa, Yeh Ming-Lun, Tsai Pei-Chien, Chuang Wan-Long, Huang Chung-Feng, Dai Chia-Yen, Toyoda Hidenori, Yasuda Satoshi, Trinh Huy, Ogawa Eiichi, Ishigami Masatoshi, Ito Takanori, Kozuka Ritsuzo, Enomoto Masaru, Tanaka Yasuhito, Suzuki Takanori, Yoshimaru Yoko, Preda Carmen, Marin Raluca, Sandra Irina, Quek Sabrina, Khine Htet Htet Toe Wai, Itokawa Norio, Atsukawa Masanori, Uojima Haruki, Watanabe Tsunamasa, Takahashi Hirokazu, Inoue Kaori, Maeda Mayumi, Hoang Joseph, Trinh Lindsey, Cheung Ramsey, Lim Seng Gee, Yu Ming-Lung, Nguyen Mindie H.

HEPATOLOGY   Vol. 76   page： S34 - S35   2022.10

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CIRRHOSIS INCIDENCE AND LONG-TERM MORTALITY RATE AMONG LEAN, OVERWEIGHT, AND OBESE PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN THE UNITED STATES

Nguyen Vy H., Ha Audrey, Park Jung Eun, Rouillard Nicholas, Le Richard H. X., Fong Ashley, Maeda Mayumi, Ito Takanori, Nguyen Mindie H.

HEPATOLOGY   Vol. 76   page： S742 - S743   2022.10

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CLINICAL COURSE AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEMOPHILIA

Imai Norihiro, Ishigami Masatoshi, Matsuda Noritaka, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi Honda, Kawashima Hiroki

HEPATOLOGY   Vol. 76   page： S1330 - S1330   2022.10

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Factors linked to hepatocellular carcinoma development beyond 10 years after viral eradication in patients with hepatitis C virus.

Kumada T, Toyoda H, Yasuda S, Ito T, Tsuji K, Fujioka S, Hiraoka A, Kariyama K, Nouso K, Ishikawa T, Tamai T, Tada T, Tanaka J

Journal of viral hepatitis   Vol. 29 ( 10 ) page： 919 - 929   2022.10

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The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p = 0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508–5.693, p = 0.0015), fibrosis-4 (FIB-4) score > 3.25 (aHR 4.364; 95%CI 2.206–8.633, p < 0.0001) and alpha-fetoprotein ≥5.0 ng/ml (aHR 2.381; 95%CI 1.325–4.280, p = 0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366–16.190, p = 0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240–6.935, p = 0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400–12.350, p = 0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words).

DOI： 10.1111/jvh.13728

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Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade. Open Access

Kobayashi T, Iwama S, Yamagami A, Yasuda Y, Okuji T, Ito M, Zhou X, Ando M, Onoue T, Miyata T, Sugiyama M, Hagiwara D, Suga H, Banno R, Hase T, Morise M, Ito T, Kikumori T, Inoue M, Ando Y, Masuda N, Kawashima H, Hashimoto N, Arima H

The Journal of clinical endocrinology and metabolism   Vol. 107 ( 10 ) page： e4115 - e4123   2022.9

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Background: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. Methods: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. Results: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. Conclusion: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

DOI： 10.1210/clinem/dgac467

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Intra-individual Comparisons of the Ultrasound-Guided Attenuation Parameter and the Magnetic Resonance Imaging-Based Proton Density Fat Fraction Using Bias and Precision Statistics.

Kumada T, Ogawa S, Goto T, Toyoda H, Yasuda S, Ito T, Yasuda E, Akita T, Tanaka J

Ultrasound in medicine & biology   Vol. 48 ( 8 ) page： 1537 - 1546   2022.8

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Ultrasound-based techniques using the attenuation coefficient, including the ultrasound-guided attenuation parameter (UGAP), have been developed for the quantification of hepatic steatosis. The magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) is considered to be more accurate than liver biopsy for liver fat quantification. The aim of this study was to perform intra-individual comparisons of UGAP and MRI-PDFF for determining hepatic steatosis grade. The study enrolled 309 patients who underwent UGAP and MRI-PDFF measurements. Bland–Altman analysis was conducted after transforming MRI-PDFF values to a normal distribution and converted to a common set of units using linear regression analysis for differing scales. The expected limits of agreement (LOA) was defined as the square root of the sum of the squares of UGAP and MRI-PDFF precision. A Bland–Altman plot revealed that the bias and upper and lower LOAs (ULOA and LLOA) were −0.0047, 0.1160 and −0.1255, respectively. The percentage difference indicated that the mean, ULOA and LLOA were −1.1434%, 18.1723% and −20.4590%, respectively. The calculated expected LOA was 18.5449%, and 283 of 309 patients (91.6%) had a percentage difference within 18.5449%. Bland–Altman analysis revealed that UGAP and MRI-PDFF were interchangeable within a clinically acceptable range.

DOI： 10.1016/j.ultrasmedbio.2022.03.019

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Effectiveness of Porous Glass Membrane Pumping Emulsification Device in Transarterial Chemoembolization for Solitary Hepatocellular Carcinoma. Open Access

Imai N, Ishigami M, Oie Y, Kumagai M, Inukai Y, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Kawashima H

Anticancer research   Vol. 42 ( 8 ) page： 3947 - 3951   2022.8

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Background/Aim: A porous glass membrane-pumping emulsification device (GMD) enables the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMD is expected to improve the locoregional therapeutic effects of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC), its effectiveness in the management of solitary HCC remains unclear. Patients and Methods: Patients treated for solitary HCCs (<5 cm) were retrospectively reviewed. A total of 46 patients who could not undergo liver resection and were unsuitable for radiofrequency ablation were included in this study. Among these, 22 patients underwent TACE using a GMD (GMD-TACE group) and 24 underwent stereotactic body radiotherapy (SBRT) using a robotic radiosurgery system (SBRT group). Local control rates were compared between the two groups. Results: The median HCC tumour size was 24 mm (range=12-50 mm) and 22 mm (range=8-39 mm) in the GMD-TACE and SBRT groups, respectively; however, the difference between the groups was not significant. Age, liver function test results, or Child-Pugh scores were not significantly different between the two groups. The rate of local control at 6 months after treatment was 100% in both groups. Although the 1-year local control rate was higher in the SBRT group (92.3%) than in the GMD-TACE group (81.8%), there was no significant difference in the log-rank test (p=0.654). No major treatment-related complications occurred in either group during the observation period. Conclusion: TACE with GMD could be considered an effective treatment option for the management of solitary HCC.

DOI： 10.21873/anticanres.15889

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A case of antiprogrammed death-ligand 1 antibody-induced multisystem immune-related adverse events with pancreatitis and steroid-resistant sclerosing cholangitis.

Yamamoto T, Ito T, Mizuno K, Shinya Y, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Matsui T, Hase T, Hashimoto N, Ishigami M

Journal of digestive diseases   Vol. 23 ( 7 ) page： 404 - 409   2022.7

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DOI： 10.1111/1751-2980.13122

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Metabolic abnormalities play a crucial role in non-obese people suffering from non-alcoholic fatty liver disease (NAFLD). Reviewed International coauthorship Open Access

Ye Q, Ito T, Henry L, Nguyen MH

Hepatobiliary surgery and nutrition   Vol. 11 ( 2 ) page： 333 - 334   2022.4

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DOI： 10.21037/hbsn-22-26

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Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline. Open Access

Iwama S, Kobayashi T, Yasuda Y, Okuji T, Ito M, Ando M, Zhou X, Yamagami A, Onoue T, Kawaguchi Y, Miyata T, Sugiyama M, Takagi H, Hagiwara D, Suga H, Banno R, Hase T, Morise M, Wakahara K, Yokota K, Kato M, Nishio N, Tanaka C, Miyata K, Ogura A, Ito T, Sawada T, Shimokata T, Niimi K, Ohka F, Ishigami M, Gotoh M, Hashimoto N, Saito R, Kiyoi H, Kajiyama H, Ando Y, Hibi H, Sone M, Akiyama M, Kodera Y, Arima H

The Journal of clinical endocrinology and metabolism   Vol. 107 ( 4 ) page： e1620 - e1630   2022.3

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Background: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. Results: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

DOI： 10.1210/clinem/dgab829

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Patients with low muscle mass have characteristic microbiome with low potential for amino acid synthesis in chronic liver disease. Open Access

Yamamoto K, Ishizu Y, Honda T, Ito T, Imai N, Nakamura M, Kawashima H, Kitaura Y, Ishigami M, Fujishiro M

Scientific reports   Vol. 12 ( 1 ) page： 3674   2022.3

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Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

DOI： 10.1038/s41598-022-07810-3

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Absence of large portal collateral vessels is associated with spontaneous improvement of cirrhotic portal vein thrombosis.

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Tsuzuki T, Ishigami M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 2 ) page： 199 - 209   2022.2

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Aim: Portal vein thrombosis (PVT) is a major complication in patients with liver cirrhosis (LC). In some cases, PVT decreases spontaneously, but the factors that predict this are still not fully understood. Methods: This was a retrospective, multicenter study that included 77 consecutive patients with cirrhotic PVT. Forty-eight patients did not undergo anticoagulation and 29 patients did between the time of the first diagnosis of PVT and the follow-up radiological imaging undertaken 1–6 months later. A complete disappearance and 25% shrinkage of PVT was defined as complete remission (CR) and partial remission (PR), respectively. Portosystemic collateral vessels larger than 9 mm in diameter were defined as large collateral vessels. Results: Complete remission + PR was found in 37.5% of the anticoagulation-naïve patients. On univariate analysis, the absence of large collateral vessels, absence of PVT in the main trunk of the portal vein, a high platelet count, and a low FIB-4 index were significant factors associated with CR + PR. On multivariate analysis, the absence of large collateral vessels was the unique factor associated with CR + PR of PVT (odds ratio 5.9; 95% confidence interval, 1.73–20.1). The CR + PR rate for anticoagulated patients was 44.8%. However, no predictors for a good treatment effect of anticoagulation for PVT were identified. Conclusions: Spontaneous improvement of PVT in patients with LC can be expected when large collateral vessels are absent. For these patients, the option of observing them without anticoagulation can be considered in expectation of spontaneous reduction of PVT.

DOI： 10.1111/hepr.13725

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Immune-related Liver Injury is a Poor Prognostic Factor in Patients with Nonsmall Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Yamamoto T, Ito T, Hase T, Ishigami M, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Shibata H, Hatta T, Yogo N, Yasuda S, Toyoda H, Abe T, Kawashima H, Hashimoto N, Fujishiro M

Cancer investigation   Vol. 40 ( 2 ) page： 189 - 198   2022.2

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It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in nonsmall cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days postinjection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the nonliver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.

DOI： 10.1080/07357907.2021.1994586

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The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with hemophilia. Open Access

Inukai Y, Imai N, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Fujishiro M

Annals of hepatology   Vol. 27 ( 1 ) page： 100545   2022.1

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Introduction and objectives: Hepatitis C virus (HCV) infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. Although recent progress in direct-acting-antivirals has facilitated a high rate of sustained virological response (SVR), the clinical influence of HCV eradication in hemophilia patients remains unclear. This study aimed to compare the clinical outcomes of SVR against HCV in patients with and without hemophilia. Patients and methods: The study enrolled 699 patients who achieved SVR after HCV antiviral treatment. Patients were divided into two groups: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). We evaluated patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR. Results: Compared with the NH group, patients in the H-group were significantly younger and had a lower hepatic fibrosis score. No difference was found in the incidence of liver-related disease or overall death between the two groups over a mean follow-up period of 7 years. Four patients in the H group and 36 patients in the NH group were diagnosed with HCC after SVR. Multivariate analysis showed that male sex, age, and cirrhosis were significant risk factors for HCC incidence. There was no significant difference in the cumulative incidence of HCC after propensity-score matching adjusting for the risk factors of HCC between the two groups. Conclusion: Hemophilia is not a significant risk factor for hepatocarcinogenesis after SVR against HCV.

DOI： 10.1016/j.aohep.2021.100545

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Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study. Reviewed

Matsumoto K, Ohfuji S, Abe M, Komori A, Takahashi A, Fujii H, Kawata K, Noritake H, Tadokoro T, Honda A, Asami M, Namisaki T, Ueno M, Sato K, Kakisaka K, Arakawa M, Ito T, Tanaka K, Matsui T, Setsu T, Takamura M, Yasuda S, Katsumi T, Itakura J, Sano T, Tamura Y, Miura R, Arizumi T, Asaoka Y, Uno K, Nishitani A, Ueno Y, Terai S, Takikawa Y, Morimoto Y, Yoshiji H, Mochida S, Ikegami T, Masaki T, Kawada N, Ohira H, Tanaka A

Journal of gastroenterology   Vol. 57 ( 1 ) page： 19 - 29   2022.1

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Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case–control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case–control study to identify the environmental factors associated with the development of PBC in Japan. Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01–2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07–1.92), ever smoking (OR, 1.70; 95% CI, 1.28–2.25), and hair dye use (OR, 1.57; 95% CI, 1.15–2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99–19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077–0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52–68.0) in the model for medical and familial factors. Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.

DOI： 10.1007/s00535-021-01836-6

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Mortality of inactive hepatitis B virus carriers in Japan is similar to that of the general population.

Kumada T, Toyoda H, Yasuda S, Ito T, Tanaka J

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 1 ) page： 81 - 92   2022.1

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Aims: Data on the long-term outcomes of individuals with hepatitis B virus (HBV) infection who are hepatitis envelope antigen (HBeAg)-negative inactive carriers (ICs) are limited due to small numbers. We compared the long-term prognosis of well-defined ICs with that of age- and gender-matched general population controls. Methods: A total of 526 HBeAg-negative patients who demonstrated alanine aminotransferase (ALT) level ≤40 U/L and HBV DNA level ≤4.3 log IU/ml at least three times within 1 year after the start of follow-up were enrolled as ICs. Inactive carriers were divided into two groups: Group A (n = 332), whose ALT level was ≤30 U/L and HBV DNA level was ≤3.3 log IU/ml, and Group B (remaining patients, n = 194). We determined the long-term prognosis of ICs and compared it with that of general population controls. We also analyzed factors associated with hepatitis B surface antigen (HBsAg) clearance and phase transition in ICs. Results: There were no significant differences in hepatocellular carcinoma development or all-cause, liver-related, or non–liver-related mortality between Groups A and B. There was no significant difference in all-cause mortality between ICs and the general population. Low HBsAg level (≤3.0 log IU/ml) and the presence of fatty liver were associated with HBsAg clearance and high alpha-fetoprotein level was associated with phase transition. Conclusions: The long-term prognosis of well-defined ICs was similar to that of general population controls. In addition, the ICs had a high HBsAg clearance rate and low phase transition rate.

DOI： 10.1111/hepr.13723

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Changes in Body Composition Predict the Time to Treatment Failure of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma: A Pilot Retrospective Study.

Yamamoto T, Imai N, Kuzuya T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishigami M

Nutrition and cancer   Vol. 74 ( 9 ) page： 3118 - 3127   2022

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Aim: Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC. Methods: In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis. Results: Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (P = 0.004) without symptoms or changes in the other parameters. In multivariate analysis, this early change in mean-SMA after LEN treatment was a significant predictor of time to treatment failure (HR: 2.67, 95%CI: 1.338–5.081, P = 0.005) in patients with HCC. Conclusions: This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322.

DOI： 10.1080/01635581.2022.2049322

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先天性フィブリノゲン異常症患者に合併した多発動脈血栓の一例

服部 真代, 笹木 優賢, 鈴木 伸明, 石津 洋二, 荒木 芳生, 岩﨑 純子, 新島 萌, 山本 健太, 伊藤 隆徳, 川嶋 啓揮, 古澤 健司, 松下 正

超音波検査技術抄録集   Vol. 47 ( 0 ) page： S137 - S137   2022

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本超音波検査学会  

DOI： 10.11272/jssabst.47.0_s137_2

CiNii Research

Changes in the gut microbiota after hepatitis C virus eradication. Open Access

Honda T, Ishigami M, Yamamoto K, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Kawashima H, Miyahara R, Ishikawa T, Hirooka Y, Fujishiro M

Scientific reports   Vol. 11 ( 1 ) page： 23568   2021.12

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The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

DOI： 10.1038/s41598-021-03009-0

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Impact of switching to tenofovir alafenamide fumarate in patients with entecavir-treated chronic hepatitis B.

Kumada T, Toyoda H, Yasuda S, Ito T, Tanaka J

European journal of gastroenterology & hepatology   Vol. 33 ( 1S Suppl 1 ) page： e898 - e904   2021.12

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

Background and aims Tenofovir alafenamide (TAF), a new tenofovir prodrug, has been developed to circumvent the less favorable safety profile of tenofovir disoproxil fumarate (TDF). We investigated reductions in hepatitis B surface antigen (HBsAg) levels in patients with HBV infection who received continuous entecavir (ETV) monotherapy or sequential therapy with ETV and TAF. Methods: This retrospective cohort study included 286 patients who were divided into two groups: continuous ETV monotherapy (ETV group, n = 168) and sequential therapy with ETV and TAF (ETV-TAF group, n = 108). Factors associated with a 90% reduction in HBsAg levels were analyzed by a Cox proportional hazards model using a time-dependent covariate in both groups. Results In the multivariate Cox proportional hazards model, the ETV-TAF group [adjusted hazard ratio (aHR) 2.750; 95% confidence interval (CI), 1.265-3.405; P = 0.0038] and BMI ≤ 25.0 kg/m²(aHR 0.520, 95% CI, 0.308-0.875; P = 0.0139) demonstrated a 90% reduction in HBsAg levels. HBsAg levels of patients in the TAF phase in the ETV-TAF group showed greater yearly percent reductions than those in the ETV group and those in the ETV phase in the ETV-TAF group (P = 0.0361 and P = 0.0022, respectively, Steel-Dwass test). Conclusion HBsAg levels decreased more rapidly after patients switched from ETV to TAF. Switching to TAF may be an effective treatment option to reduce HBsAg levels.

DOI： 10.1097/MEG.0000000000002292

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Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis. Open Access

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

European journal of gastroenterology & hepatology   Vol. 33 ( 1S Suppl 1 ) page： e916 - e921   2021.12

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DOI： 10.1097/MEG.0000000000002303

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PubMed

Obesity and myosteatosis: The two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama Y., Ishizu Y., Ando Y., Yokoyama S., Yamamoto K., Ito T., Imai N., Nakamura M., Honda T., Kawashima H., Ishikawa T., Ishigami M.

European Journal of Gastroenterology and Hepatology   Vol. 33 ( 1 ) page： E916 - E921   2021.12

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

Objective In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. Methods We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. Results Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m²and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. Conclusion Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

DOI： 10.1097/MEG.0000000000002303

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Cationic surface charge effect on proliferation and protein production of human dental pulp stem cells cultured on diethylaminoethyl-modified cellulose porous beads Reviewed

Oki Yuichiro, Harano Kodai, Hara Yuichi, Sasajima Yoshiyuki, Sasaki Ryo, Ito Takanori, Fujishiro Mitsuhiro, Ito Taichi

BIOCHEMICAL ENGINEERING JOURNAL   Vol. 176   2021.12

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Biochemical Engineering Journal  

Human adult dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells (MSCs). Recently, DPSCs have been proposed as a new MSC source for treating immune-mediated, inflammatory, and degenerative diseases via cell-based therapy. Hence, large-scale industrial production of the required cell number will be necessary. In this study, to investigate the cationic surface charge effect on DPSC proliferation, we fabricated two types of 2-diethylaminoethyl -modified cellulose porous beads (CPB-DEAE) with different ion exchange capacities. The cationic surface charge effect increased with increase in DPSC proliferation rate for the ion exchange capacity of 0.55–1.82 meq/g. However, the DPSC proliferation rate decreased at 2.50 meq/g. Thus, the optimal ion exchange capacity was determined to be 1.82 meq/g for DPSC proliferation. Additionally, the total amount of protein produced from the DPSCs on the CPB-DEAE microcarriers was higher than that produced under the conventional monolayer culture conditions. Furthermore, the hepatocyte growth factor, which is one of the anti-inflammatory growth factors, was produced from the DPSCs on the CPB-DEAE microcarriers. Finally, the DPSCs were confirmed to maintain their proliferative and multidifferentiation ability after culture on the CPB-DEAE microcarriers. CPB-DEAE microcarriers have the potential to be used for large-scale MSC expansion and protein production.

DOI： 10.1016/j.bej.2021.108217

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Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama Yoshiaki, Ishizu Yoji, Ando Yusuke, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Nakamura Masanao, Honda Takashi, Kawashima Hiroki, Ishikawa Tetsuya, Ishigami Masatoshi

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY   Vol. 33 ( 1S ) page： E916 - E921   2021.12

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DOI： 10.1097/MEG.0000000000002303

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Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama, Y; Ishizu, Y; Ando, Y; Yokoyama, S; Yamamoto, K; Ito, T; Imai, N; Nakamura, M; Honda, T; Kawashima, H; Ishikawa, T; Ishigami, M

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY   Vol. 33   page： E916 - E921   2021.12

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DOI： 10.1097/MEG.0000000000002303

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Microbiome, fibrosis and tumor networks in a non-alcoholic steatohepatitis model of a choline-deficient high-fat diet using diethylnitrosamine.

Yamamoto K, Honda T, Yokoyama S, Ma L, Kato A, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Kawashima H, Ishigami M, Tsuji NM, Fujishiro M

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 53 ( 11 ) page： 1443 - 1450   2021.11

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

Background & aims: Hepatocellular carcinoma in nonalcoholic steatohepatitis is caused by the complex factors of inflammation, fibrosis and microbiomes. We used network analysis to examine the interrelationships of these factors. Methods: C57Bl/6 mice were categorized into groups: choline-sufficient high-fat (CSHF, n = 8), choline-deficient high-fat (CDHF, n = 9), and CDHF+ diethylnitrosamine (DEN, n = 8). All mice were fed CSHF or CDHF for 20 weeks starting at week 8, and mice in the CDHF + DEN group received one injection of DEN at 3 weeks of age. Bacterial gene was isolated from feces and analyzed using Miseq. Results: The CSHF group had less fibrosis than the other groups. Tumors were found in 22.2% and 87.5% of the CDHF group and CDHF + DEN groups, respectively. Gene expression in the liver of Cdkn1a (p21: tumor-suppressor) and c-jun was highest in the CDHF group. Bacteroides, Roseburia, Odoribacter, and Clostridium correlated with fibrosis. Streptococcus and Dorea correlated with inflammation and tumors. Akkermansia and Bilophila were inversely correlated with fibrosis and Bifidobacterium was inversely correlated with tumors. Conclusions: DEN suppressed the overexpression of p21 caused by CDHF. Some bacteria formed a relationship networking associated with their progression and inhibition for tumors and fibrosis.

DOI： 10.1016/j.dld.2021.02.013

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Safety and Efficacy of Glass Membrane Pumping Emulsification Device in Transarterial Chemoembolization for Hepatocellular Carcinoma: First Clinical Outcomes. Open Access

Imai N, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishigami M

Anticancer research   Vol. 41 ( 11 ) page： 5817 - 5820   2021.11

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Aim: Novel glass membrane pumping emulsification devices (GMDs) enable the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMDs are expected to improve therapeutic effects in transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), clinical outcomes are not yet available. Patients and Methods: A total of 26 patients with unresectable HCC who underwent TACE using a GMD were analyzed retrospectively. Ethiodized oil was mixed with epirubicin solution using a GMD. The emulsion was injected into the tumor-feeding artery, followed by embolization. Results: The median size of HCCs was 28 (range=15-60) mm, and 15 nodules were solitary. Overall treatment effects were complete response in 18 cases (90%) and partial response in two (10%). The local recurrence rate at 6 months was 24.2%. No major complication was observed except for grade 4 elevations of liver enzymes in one case. Conclusion: TACE using a GMD is effective and safe in clinical practice.

DOI： 10.21873/anticanres.15399

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Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis. Open Access

Ryuge A, Kosugi T, Maeda K, Banno R, Gou Y, Zaitsu K, Ito T, Sato Y, Hirayama A, Tsubota S, Honda T, Nakajima K, Ozaki T, Kondoh K, Takahashi K, Kato N, Ishimoto T, Soga T, Nakagawa T, Koike T, Arima H, Yuzawa Y, Minokoshi Y, Maruyama S, Kadomatsu K

JCI insight   Vol. 6 ( 20 )   2021.10

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Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane–selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

DOI： 10.1172/jci.insight.142464

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Factors associated with bleeding after endoscopic variceal ligation in children. Open Access

Yokoyama S, Ishizu Y, Ishigami M, Honda T, Kuzuya T, Ito T, Hinoki A, Sumida W, Shirota C, Tainaka T, Makita S, Yokota K, Uchida H, Fujishiro M

Pediatrics international : official journal of the Japan Pediatric Society   Vol. 63 ( 10 ) page： 1223 - 1229   2021.10

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

Background: Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension (PHT). It is used for urgent treatment and prophylactic treatment of esophagogastric varices in pediatric as well as adult patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. Methods: The subjects were children and adolescents (<18 years) with PHT who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding, or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 h to 5 days after EVL. Results: A total of 50 EVL sessions on 22 patients were eligible for this study. There were four episodes of early rebleeding. No other major adverse event has occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ), within 5 mm from the EGJ, is the independent factor for a higher risk of early rebleeding: odds ratio 18.2 (95% confidence interval: 1.40–237.0), P = 0.02. Conclusions: Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

DOI： 10.1111/ped.14614

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Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies. Open Access

Ito T, Ishigami M, Yamamoto T, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Kato M, Hashimoto N, Hibi H, Kodera Y, Sone M, Ando Y, Akiyama M, Shimoyama Y, Fujishiro M

Hepatology international   Vol. 15 ( 5 ) page： 1278 - 1287   2021.10

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Background: The clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. Methods: We evaluated the characteristics and clinical course of immune-related liver injury in 1214 patients treated with ICIs for advanced malignancies except for hepatocellular carcinoma between August 2014 and May 2021. Results: During the follow-up period (median, 252 days), 58 patients (4.8%) had an immune-related liver injury (≥ Grade 3). The liver-injury patterns were hepatocellular (n = 26, 44.8%), mixed (n = 11, 19.0%), or cholestatic (n = 21, 36.2%), and the median time to onset of liver injury was 39, 81, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (p = 0.047). Corticosteroids were administered to 30 (51.7%) patients; while liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns, and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. Conclusion: The incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differ according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

DOI： 10.1007/s12072-021-10238-y

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CONDITIONED MEDIUM FROM STEM CELLS DERIVED FROM HUMAN EXFOLIATED DECIDUOUS TEETH AMELIORATES NASH VIA THE GUT-LIVER AXIS Open Access

Muto, H; Ito, T; Ishigami, M

HEPATOLOGY   Vol. 74   page： 1134A - 1134A   2021.10

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DOI： 10.1038/s41598-021-98254-8

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USEFULNESS OF CORE I97L IN PREDICTING THE EFFICACY OF NUCLEOS(T)IDE ANALOGUE THERAPY IN PATIENTS WITH HEPATITIS B

TakashiHonda; MasatoshiIshigami; ShinyaYokoyama; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Ishikawa, T; Fujishiro, M

HEPATOLOGY   Vol. 74   page： 468A - 469A   2021.10

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RENAL OUTCOMES IN POST-LIVER TRANSPLANT RECIPIENTS TREATED WITH TENOFOVIR ALAFENAMIDE COMPARED WITH TENOFOVIR DISOPROXIL FUMARATE AND ENTECAVIR

Liu, J; Vutien, P; Huang, D; Ishigami, M; Daniel, PCYN; Ito, T; Dang, H; Maeda, M; Leong, J; Landis, C; Nguyen, MH

HEPATOLOGY   Vol. 74   page： 492A - 493A   2021.10

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LONG-TERM OVERALL AND RECURRENCE-FREE SURVIVAL FOLLOWING CURATIVE SURGICAL RESECTION FOR HEPATOCELLULAR CARCINOMA IN THE RECENT DECADE: A META-ANALYSIS OF 110 STUDIES AND 82,392 PATIENTS

Reveron-Thornton, R; Teng, MLP; Lee, EY; Tran, AK; Vajanaphanich, S; Tan, XXE; Nerurkar, SN; Ng, RX; Teh, R; Prasad, DP; Ito, T; Tanaka, T; Miyake, N; Zou, BY; Wong, CN; Toyoda, H; Esquivel, CO; Bonham, A; Nguyen, MH; Huang, D

HEPATOLOGY   Vol. 74   page： 655A - 656A   2021.10

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META-ANALYSIS: REGIONAL DIFFERENCES IN OUTCOMES OF SURGICAL RESECTION FOR HEPATOCELLULAR CARCINOMA

Teng, M; Reveron-Thornton, R; Lee, EY; Tran, AK; Vajanaphanich, S; Tan, XXE; Nerurkar, SN; Ng, RX; Teh, R; Prasad, DP; Ito, T; Tanaka, T; Miyake, N; Zou, BY; Wong, C; Toyoda, H; Esquivel, CO; Bonham, A; Nguyen, MH; Huang, D

HEPATOLOGY   Vol. 74   page： 859A - 859A   2021.10

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CHANGE OF PREDICTIVE ABILITY IN NON-INVASIVE FIBROSIS MARKERS AMONG ASIAN NON-ALCOHOLIC FATTY LIVER DISEASE BY AGE, OBESITY, AND A PRESENCE OF TYPE 2 DIABETES

Ito, T; Nguyen, VH; Tanaka, T; Park, H; Yeh, ML; Kawanaka, M; Arai, T; Atsukawa, M; Yoon, E; Tsai, PC; Toyoda, H; Fujishiro, M; Huang, JF; Nguyen, MH; Jun, DW; Yu, ML; Ishigami, M; Cheung, RC

HEPATOLOGY   Vol. 74   page： 936A - 937A   2021.10

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Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis. Open Access

Muto H, Ito T, Tanaka T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Maeda K, Honda T, Ishikawa T, Kato A, Ohshiro T, Kano F, Yamamoto A, Sakai K, Hibi H, Ishigami M, Fujishiro M

Scientific reports   Vol. 11 ( 1 ) page： 18778   2021.9

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Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

DOI： 10.1038/s41598-021-98254-8

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Revisiting Prognosis After Liver Transplant in Patients Positive for Hepatitis C Virus: Focus on Hepatitis C Recurrence-Unrelated Complications.

Ishigami M, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Kamei H, Ogura Y, Fujishiro M

Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation   Vol. 19 ( 9 ) page： 935 - 942   2021.9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Experimental and Clinical Transplantation  

Objectives: In this study, we revisited the reasons for poorer prognosis after liver transplant in patients with hepatitis C virus, whose main causes of death were generally known to be recurrent disease. Materials and Methods: Between April 2003 and March 2017, among 132 patients who underwent liver transplant because of liver cirrhosis at our institution, 40 patients (30.3%) were positive for hepatis C virus. We retrospectively compared the overall survival after liver transplant in patients with and without hepatitis C virus infection. Furthermore, we investigated the causes of death in transplant recipients with hepatitis C virus infections. Results: In patients with hepatitis C virus infection, overall survival was 82.2%, 75.2%, and 50.8% at 1, 5, and 10 years, respectively, after liver transplant; these results were lower than those in patients without infection (94.5%, 87.0%, and 87.0% at 1, 5, and 10 years, respectively; P = .001). Among 40 patients with positive infection, 14 patients died after liver transplant. A main reason for death was hepatocellular carcinoma recurrence (3 patients). Surprisingly, only 1 patient died from hepatitis C virus-related complication (fibrosing cholestatic hepatitis); the remaining 10 patients died from reasons other than hepatitis C virus disease progression. Conclusions: Our results suggest that clinicians should not only be aware of hepatitis C virus recurrence but should also be aware of other unrelated complications in transplant recipients who are positive for this virus.

DOI： 10.6002/ect.2021.0197

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Long-term outcomes of viral eradication in patients with hepatitis C virus infection and mild hepatic fibrosis.

Kumada T, Toyoda H, Yasuda S, Tada T, Ito T, Tanaka J

Journal of viral hepatitis   Vol. 28 ( 9 ) page： 1293 - 1303   2021.9

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

The impact of antiviral therapy on clinical outcomes in patients with hepatitis C virus (HCV) infection and mild liver fibrosis (FIB-4 score <1.45) is not well understood. We aimed to clarify the impact of viral eradication on hepatocarcinogenesis and mortality in patients with mild fibrosis.The subjects were 657 patients who achieved sustained virologic response (SVR) (Clearance group) and 586 patients who did not receive antiviral therapy or did not achieve SVR (No clearance group). We applied inverse probability weighting because the groups had different baseline characteristics. Multivariate proportional hazards models were used to analyse factors associated with hepatocarcinogenesis and mortality using a time-dependent covariate. In addition, we compared the mortality rate of the Clearance group stratified by age to the mortality rate of the general population.Clearance of HCV RNA was significantly associated with hepatocarcinogenesis and all-cause, liver-related and non–liver-related mortality (adjusted hazard ratios [95% confidence interval], 0.2653 [0.1147–0.6136, p = 0.0019], 0.3416 [0.2157–0.5409, p < 0.0001], 0.2474 [0.0802–0.8917, p = 0.0381] and 0.4118 [0.2449–0.6925, p = 0.0008], respectively). The Clearance group had significantly higher mortality than the general population matched by age, sex and follow-up duration (p < 0.0001). However, there were no significant differences between patients who achieved SVR before age 50 and the general population matched by age, sex and follow-up duration (p = 0.1570). HCV eradication in patients with mild fibrosis reduces liver-related and non–liver-related mortality. If HCV is eradicated before age 50, prognosis is likely be similar to that of the age-matched and sex-matched general population. (249 words).

DOI： 10.1111/jvh.13562

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Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study. Open Access

Muto H, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Medicine   Vol. 100 ( 31 ) page： e26820   2021.8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medicine United States  

AbstractReal-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6weeks.Overall survival was significantly longer in patients with partial response (PR)+stable disease (SD) (13.7months) than in patients with progressive disease (PD) (1.7months, P<.001) in the ≥50% group. Patients with antitumor response of PR+SD at 6weeks in the ≥50% group showed more marked deterioration of ALBI score at 2weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. Focusing on patients with PD at 6weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR+SD patients, a significant increase in CRP levels at 1 and 2weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR+SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

DOI： 10.1097/MD.0000000000026820

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The impact of hepatitis C virus eradication on hepatocarcinogenesis in haemophiliacs

Inukai, Y; Imai, N; Yamamoto, K; Ito, T; Ishizu, Y; Honda, T; Ishigami, M

JOURNAL OF HEPATOLOGY   Vol. 75   page： S787 - S788   2021.7

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Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty

Ozawa N., Sato K., Sugimura A., Maki S., Tanaka T., Yamamoto K., Ito T., Ishizu Y., Kuzuya T., Honda T., Ishigami M., Fujishiro M., Ishikawa T., Ando S.

Japan Journal of Nursing Science   Vol. 18 ( 3 )   2021.7

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Aim: Patients with nonalcoholic fatty liver disease (NAFLD) have a low quality of life (QOL) and illness uncertainty. This study examined the structure of QOL and associated factors, including illness uncertainty, among individuals with NAFLD. Methods: A cross-sectional survey was conducted using a self-administered questionnaire for outpatients with NAFLD. QOL was measured using the Short Form-8. Dietary habits, physical activity level, illness uncertainty, health locus of control, and knowledge of NAFLD were assessed. Path analysis was used to study the associated factors of QOL and their structure, including uncertainty of disease. Results: Path analysis of 168 NAFLD patients indicated that a high Physical Component Summary score on the Short Form-8—representing physical QOL—was predicted by a body mass index <25 kg/m² and high educational level. A high Mental Component Summary score—representing mental QOL—was predicted by being male, good dietary habits, low illness uncertainty, and presence of consultants. The model showed satisfactory goodness-of-fit without being rejected by the chi-square test (goodness-of-fit index =.947, adjusted goodness-of-fit index =.917, comparative fit index =.967, root mean square error of approximation = 0.023). Conclusions: Nurses need to work closely with NAFLD patients as consultants, providing adequate information about the causes, treatments, and dietary habits, and focusing on the individual's perception of health. This could reduce illness uncertainty and contribute to the improvement of QOL.

DOI： 10.1111/jjns.12415

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Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty

Ozawa, N; Sato, K; Sugimura, A; Maki, S; Tanaka, T; Yamamoto, K; Ito, T; Ishizu, Y; Kuzuya, T; Honda, T; Ishigami, M; Fujishiro, M; Ishikawa, T; Ando, S

JAPAN JOURNAL OF NURSING SCIENCE   Vol. 18 ( 3 )   2021.7

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DOI： 10.1111/jjns.12415

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Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty

Ozawa Naoki, Sato Kazuki, Sugimura Ayumi, Maki Shigeyoshi, Tanaka Taku, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Ishigami Masatoshi, Fujishiro Mitsuhiro, Ishikawa Tetsuya, Ando Shoko

JAPAN JOURNAL OF NURSING SCIENCE   Vol. 18 ( 3 )   2021.7

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DOI： 10.1111/jjns.12415

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Tolerability of Molecular-targeted Agents for Hepatocellular Carcinoma Treatment in Haemophiliacs. Open Access

Yamamoto T, Imai N, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Fujishiro M

Anticancer research   Vol. 41 ( 5 ) page： 2569 - 2573   2021.5

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Background: Hepatocellular carcinoma (HCC) is considered a leading cause of death in patients with haemophilia. Recent advances in the treatment of unresectable HCC with molecular-Targeted agents (MTAs) have led to better clinical outcomes. However, the tolerability of MTAs by haemophilic patients with HCC remains unclear. Aim: This study aimed to compare the tolerability of MTAs in such patients. Patients and Methods: From January 2011 to October 2020, five haemophilic patients with HCC were treated with MTAs. Adverse events were assessed in comparison with 265 non-haemophilic patients with HCC. Results: The prevalence of hand foot skin reaction was not higher in the haemophiliacs than in the non-haemophiliacs, whereas the rate of haemorrhagic events was higher in the haemophiliacs (6.0% versus 40.0%, p=0.037). Conclusion: Haemophiliacs tolerate long-Term MTA use, without the occurrence of life-Threatening complications. However, careful observation and prevention are needed for MTA-related gastrointestinal bleeding in haemophiliacs.

DOI： 10.21873/anticanres.15035

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Prediction of Hepatocellular Carcinoma by Liver Stiffness Measurements Using Magnetic Resonance Elastography After Eradicating Hepatitis C Virus. Open Access

Kumada T, Toyoda H, Yasuda S, Sone Y, Ogawa S, Takeshima K, Tada T, Ito T, Sumida Y, Tanaka J

Clinical and translational gastroenterology   Vol. 12 ( 4 ) page： e00337   2021.4

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INTRODUCTION:Liver fibrosis stage is one of the most important factors in stratifying the risk of developing hepatocellular carcinoma (HCC). We evaluated the usefulness of liver stiffness measured by magnetic resonance elastography (MRE) to stratify the risk of developing HCC in patients who underwent MRE before receiving direct-acting antivirals (DAAs) and subsequently achieved sustained virological response (SVR).METHODS:A total of 537 consecutive patients with persistent hepatitis C virus who underwent initial MRE before DAA therapy and achieved SVR were enrolled. Factors associated with HCC development were analyzed by univariate and multivariate Cox proportional hazards models.RESULTS:Albumin-bilirubin score ≥ -2.60 (adjusted hazard ratio [aHR] 6.303), fibrosis-4 (FIB-4) score >3.25 (aHR 7.676), and MRE value ≥4.5 kPa (aHR 13.190) were associated with HCC development according to a univariate Cox proportional hazards model. A multivariate Cox proportional hazards model showed that an MRE value ≥4.5 kPa (aHR 7.301) was the only factor independently associated with HCC development. Even in patients with an FIB-4 score >3.25, the cumulative incidence rate of HCC development in those with an MRE value <4.5 kPa was significantly lower than that in patients with an MRE value ≥4.5 kPa.DISCUSSION:Liver stiffness measured by MRE before DAA therapy was an excellent marker for predicting subsequent HCC development in patients with hepatitis C virus infection who achieved SVR. The same results were observed in patients with high FIB-4 scores.

DOI： 10.14309/ctg.0000000000000337

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Filtrated Adipose Tissue-Derived Mesenchymal Stem Cell Lysate Ameliorates Experimental Acute Colitis in Mice.

Nishikawa T, Maeda K, Nakamura M, Yamamura T, Sawada T, Mizutani Y, Ito T, Ishikawa T, Furukawa K, Ohno E, Miyahara R, Kawashima H, Honda T, Ishigami M, Yamamoto T, Matsumoto S, Hotta Y, Fujishiro M

Digestive diseases and sciences   Vol. 66 ( 4 ) page： 1034 - 1044   2021.4

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DOI： 10.1007/s10620-020-06359-3

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Impact of visceral fat accumulation on the prognosis of patients with cirrhosis.

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Fujishiro M

Clinical nutrition ESPEN   Vol. 42   page： 354 - 360   2021.4

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Background & aims: The impact of obesity, evaluated using body mass index (BMI), on mortality in patients with cirrhosis is controversial. The prognostic impact of visceral fat accumulation, which is recommended as an indicator of obesity-related mortality, is still unknown. This study aimed to clarify the impact of visceral fat accumulation on mortality in patients with cirrhosis. Methods: A total of 335 cirrhotic patients without hepatocellular carcinoma were retrospectively evaluated. The impact of obesity, defined as a visceral fat area ≥100 cm² at the umbilical level or BMI ≥25 kg/m² on mortality, was evaluated using competing risk analysis. Results: Of 355 patients, visceral fat accumulation was seen in 147 patients. During the observation period (1340 ± 980 days), 84 patients died, and 17 received liver transplantation. Visceral fat accumulation was not found to be associated with mortality (hazard ratio [HR] 1.423, P = 0.180) in any of the patients. After stratification of the patients, visceral fat accumulation was observed to be associated with a poor prognosis in patients with skeletal muscle depletion (HR 3.804, P = 0.003), but not in those without (HR 1.147, P = 0.660). On the other hand, obesity defined by BMI ≥25 kg/m² was not found to be associated with mortality in patients with (HR 0.341, P = 0.390) or without skeletal muscle depletion (HR 1.227, P = 0.500). Conclusions: Visceral fat accumulation is a useful index for evaluating obesity and aggravates mortality in cirrhotic patients with skeletal muscle depletion, but not in those without.

DOI： 10.1016/j.clnesp.2021.01.008

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The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040. International coauthorship

Ito T, Ishigami M, Zou B, Tanaka T, Takahashi H, Kurosaki M, Maeda M, Thin KN, Tanaka K, Takahashi Y, Itoh Y, Oniki K, Seko Y, Saruwatari J, Kawanaka M, Atsukawa M, Hyogo H, Ono M, Ogawa E, Barnett SD, Stave CD, Cheung RC, Fujishiro M, Eguchi Y, Toyoda H, Nguyen MH

Hepatology international   Vol. 15 ( 2 ) page： 366 - 379   2021.4

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Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD. Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD—8 studies) patients. Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983–2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD. Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

DOI： 10.1007/s12072-021-10143-4

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Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty.

Ozawa N, Sato K, Sugimura A, Maki S, Tanaka T, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishigami M, Fujishiro M, Ishikawa T, Ando S

Japan journal of nursing science : JJNS     page： e12415   2021.3

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DOI： 10.1111/jjns.12415

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Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty

Naoki Ozawa, Kazuki Sato, Ayumi Sugimura, Shigeyoshi Maki, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Masatoshi Ishigami, Mitsuhiro Fujishiro, Tetsuya Ishikawa, Shoko Ando

Japan Journal of Nursing Science     2021.3

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

DOI： 10.1111/jjns.12415

CiNii Research

Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty

Ozawa Naoki, Sato Kazuki, Sugimura Ayumi, Maki Shigeyoshi, Tanaka Taku, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Ishigami Masatoshi, Fujishiro Mitsuhiro, Ishikawa Tetsuya, Ando Shoko

Japan Journal of Nursing Science     2021.3

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DOI： 10.1111/jjns.12415

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Long-term prognosis with or without nucleot(s)ide analogue therapy in hepatitis B virus-related decompensated cirrhosis.

Kumada T, Toyoda H, Yasuda S, Miyake N, Ito T, Tanaka J

Journal of viral hepatitis   Vol. 28 ( 3 ) page： 508 - 516   2021.3

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

The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non–liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non–liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non–liver-related mortality. HBV DNA ≥20,000 IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000 IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000 IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non–liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non–liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC.

DOI： 10.1111/jvh.13457

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Simplification of balloon-occluded retrograde transcatheter obliteration procedure using a coaxial double balloon catheter compared with a single-balloon catheter.

Ishizu Y, Ishigami M, Honda T, Kuzuya T, Ito T, Komada T, Fujishiro M

Japanese journal of radiology   Vol. 39 ( 3 ) page： 296 - 302   2021.3

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Purpose: This study aimed to evaluate the usefulness of a coaxial double balloon catheter for simplification of the balloon-occluded retrograde transcatheter obliteration (BRTO) procedure compared with a single-balloon catheter. Materials and methods: Thirty-three patients who underwent BRTO with a single-balloon catheter (Single-balloon group, n = 15) or a coaxial double balloon catheter (Coaxial group, n = 18) were included, retrospectively. The frequency of additional procedures for stagnation of sclerosant including ethanol injection, coil embolization, and additional balloon occlusion for collateral draining veins; the dose of ethanolamine oleate (EO); and the complication rate and the success rate of sclerosant stagnation were evaluated. Results: Additional procedures were needed in four patients in the Coaxial group, which was significantly lower than that in the Single-balloon group (nine patients, P = 0.038). The dose of EO in the Coaxial group (11.2 ± 6.6 g) was lower, but not significantly different than that in the Single-balloon group (14.4 g ± 6.1 g, P = 0.184). The complication rate and the success rate of sclerosant stagnation were not different between the two groups. Conclusion: The use of a coaxial double balloon catheter can simplify the BRTO procedure compared with a single-balloon catheter.

DOI： 10.1007/s11604-020-01060-x

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The relationship between oral-origin bacteria in the fecal microbiome and albumin-bilirubin grade in patients with hepatitis C.

Yamamoto K, Honda T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Miyahara R, Kawashima H, Ishigami M, Fujishiro M

Journal of gastroenterology and hepatology   Vol. 36 ( 3 ) page： 790 - 799   2021.3

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

Background: Bacteria of oral origin (BO) in the gut are associated with prognosis in patients with cirrhosis. The Greengenes database (gg_13_8) is widely used in microbiome analysis, but the expanded Human Oral Microbiome Database (eHOMD), a specialized database for BO, can add more detailed information. We used each database to evaluate the relationship between the albumin–bilirubin grade (ALBI) and the microbiome in patients with hepatitis C. Methods: Eighty patients were classified into the low ALBI group (LA; n = 34) or high ALBI group (HA; n = 46). Isolated DNA from stool was amplified to target the V3–4 regions of 16S rRNA. The microbiomes of the two groups were compared using gg_13_8 or eHOMD. We evaluated the associations between microbiomes and prognoses using Cox proportional hazards models. Results: At the genus level, the two groups differed significantly regarding 6 (gg_13_8) and 7 (eHOMD) types of bacteria. All types except Akkermansia are classified as BO. Both databases showed an increase in Streptococcus and Veillonella. eHOMD showed a decrease in Fusobacterium and an increase in Fretibacterium; both produce various types of short-chain fatty acids. At the species level, the two groups demonstrated significant differences in 2 (gg_13_8) and 6 (eHOMD) bacterial types. Selenomonas noxia and Streptococcus salivarius were related to poor prognosis in univariate analysis. Conclusion: The HA group demonstrated increased BO, most of which produce lactic acid or acetic acid. The correlation between the microbiome and metabolism might be related to prognosis. eHOMD was a useful database for analyzing BO.

DOI： 10.1111/jgh.15206

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Progression After Molecular Targeted Agents: Hepatic Arterial Changes and Transarterial Chemoembolization in Hepatocellular Carcinoma. Open Access

Matsuda N, Imai N, Kuzuya T, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishigami M, Fujishiro M

In vivo (Athens, Greece)   Vol. 35 ( 2 ) page： 1185 - 1189   2021.3

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DOI： 10.21873/invivo.12367

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Safety and efficacy of percutaneous radiofrequency ablation for hepatocellular carcinoma patients with haemophilia.

Yamamoto T, Imai N, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Fujishiro M

Haemophilia : the official journal of the World Federation of Hemophilia   Vol. 27 ( 1 ) page： 100 - 107   2021.1

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Haemophilia is an X-linked inherited bleeding disorder caused by coagulation factor deficiency. Hepatocellular carcinoma (HCC) is a major complication associated with the disease. No study thus far has investigated the safety and efficacy of percutaneous radiofrequency ablation (RFA) for HCC in patients with haemophilia. Aim: This study aimed to evaluate the safety and efficacy of RFA for HCC in haemophilia patients. Methods: From July 2008 to June 2019, 217 patients with HCC underwent 300 RFA sessions. Of these, 18 sessions were performed in ten haemophilia patients (H group) and 282 in 207 non-haemophilia patients (NH group). The patients' characteristics, incidence of haemorrhagic complications and rates of local tumour recurrence were compared between the groups. Results: A majority of the haemophilia patients received clotting factor concentrate replacement therapy before and after RFA treatment, with the aim of reaching a plasma clotting factor level of higher than 60%–80%. Twelve haemorrhagic complications were observed in the NH group (4.2%; 12/282). Major bleeding requiring control procedures was observed in two patients and minor bleeding with careful observation was noted in ten patients. No bleeding complications were observed in the H group (0/18). There were no significant differences in the 5-year local tumour recurrence rates after RFA treatment between the groups (35.0% in the H group and 32.1% in the NH group). Conclusion: RFA could be an effective and a safe method for HCC treatment in patients with haemophilia.

DOI： 10.1111/hae.14220

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Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure. Open Access

Honda T, Yamada N, Murayama A, Shiina M, Aly HH, Kato A, Ito T, Ishizu Y, Kuzuya T, Ishigami M, Murakami Y, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Ishikawa T, Fujishiro M, Muramatsu M, Wakita T, Kato T

Cellular and molecular gastroenterology and hepatology   Vol. 12 ( 5 ) page： 1583 - 1598   2021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cellular and Molecular Gastroenterology and Hepatology  

Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

DOI： 10.1016/j.jcmgh.2021.07.013

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Increased Frequency of Dysfunctional Siglec-7(-)CD57(+)PD-1(+) Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease. Open Access

Sakamoto Y, Yoshio S, Doi H, Mori T, Matsuda M, Kawai H, Shimagaki T, Yoshikawa S, Aoki Y, Osawa Y, Yoshida Y, Arai T, Itokawa N, Atsukawa M, Ito T, Honda T, Mise Y, Ono Y, Takahashi Y, Saiura A, Taketomi A, Kanto T

Frontiers in immunology   Vol. 12   page： 603133   2021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56⁺ NK cell and CD56^dim NK cell populations compared with HVs, and the CD56^dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7⁺CD56^dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56^dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7⁻CD57⁺PD-1⁺CD56^dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.

DOI： 10.3389/fimmu.2021.603133

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SAFETY AND EFFICACY OF PERCUTANEOUS RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA PATIENTS WITH HEMOPHILIA

Yamamoto, T; Ishigami, M; Yamamoto, K; Ito, T; Imai, N; Lshizu, Y; Honda, T; Fujishiro, M

HEPATOLOGY   Vol. 72   page： 705A - 706A   2020.11

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GUT MICROBIOTA ASSOCIATED WITH THE DIFFERENCE BETWEEN PATIENTS WITH AND WITHOUT HEPATOCELLULAR CARCINOMA IN CHRONIC LIVER DISEASE

Honda, T; Ishigami, M; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Fujishiro, M

HEPATOLOGY   Vol. 72   page： 370A - 370A   2020.11

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IMPROVEMENT OF LIVER FUNCTIONAL RESERVE AFTER SVR IN HCV-PATIENTS WITH COMPENSATED, SEVERE FIBROSIS BY IFN-FREE, DAA COMBINATION TREATMENT-IMPACT OF PRETREATMENT SERUM AFP LEVELS

Ishigami, M; Honda, T; Ishizu, Y; Imai, N; Ito, T; Yamamoto, K; Fujishiro, M

HEPATOLOGY   Vol. 72   page： 564A - 565A   2020.11

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AMINO ACID POLYMORPHISM IN HEPATITIS B VIRUS ASSOCIATED WITH NATURAL CLEARANCE OF HBV DNA AND HBsAg

Honda, T; Yamada, N; Murayama, A; Kato, A; Ito, T; Ishizu, Y; Kuzuya, T; Ishigami, M; Murakami, Y; Ishikawa, T; Fujishiro, M; Kato, T

HEPATOLOGY   Vol. 72   page： 508A - 509A   2020.11

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THE EPIDEMIOLOGY OF NAFLD AND LEAN NAFLD IN JAPAN: A SYSTEMATIC REVIEW AND META-ANALYSIS WITH INDIVIDUAL PATIENT LEVEL DATA AND FORECASTING, 1995-2040

Ito, T; Ishigami, M; Zou, BY; Tanaka, T; Takahashi, H; Kurosaki, M; Maeda, M; Thin, KN; Tanaka, K; Takahashi, Y; Itoh, Y; Oniki, K; Seko, Y; Saruwatari, J; Kawanaka, M; Atsukawa, M; Hyogo, H; Ono, M; Ogawa, E; Barnette, SD; Stave, CD; Cheung, R; Fujishiro, M; Eguchi, Y; Toyoda, H; Nguyen, MH

HEPATOLOGY   Vol. 72   page： 999 - 999   2020.11

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The albumin-bilirubin score as a predictor of outcomes in Japanese patients with PBC: an analysis using time-dependent ROC. Open Access

Ito T, Ishigami M, Morooka H, Yamamoto K, Imai N, Ishizu Y, Honda T, Nishimura D, Tada T, Yasuda S, Toyoda H, Kumada T, Fujishiro M

Scientific reports   Vol. 10 ( 1 ) page： 17812   2020.10

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The albumin–bilirubin (ALBI) score is calculated using only serum albumin and bilirubin levels, and was developed as a simple method to assess hepatic function. In this study, a total of 409 patients with primary biliary cholangitis (PBC) were enrolled between March 1990 and October 2018. The predictive performances of the ALBI score and other well-established prognostic scores were compared using time-dependent receiver operating characteristic (ROC) analysis. During the follow-up period, 60 patients died, 45 due to liver-related diseases and 15 due to non-liver-related diseases, and 16 patients underwent liver transplantation. Time-dependent ROC analysis showed that the ALBI score has higher the areas under the ROC curves (AUROCs) than the Child–Pugh (C–P) score at each time point; AUROCs at 3, 5, and 10 years after the start of follow-up were 0.94, 0.91, and 0.90 for the ALBI score, and 0.89, 0.88, and 0.82 for the C–P score, respectively. The ALBI score showed the highest AUROCs within 2 years after the start of observation; beyond 2 years, however, the Mayo score had better prognostic ability for mortality and liver transplantation. The ALBI score/grade, derived from objective blood tests, and the Mayo score were superior prognostic tools in PBC patients.

DOI： 10.1038/s41598-020-74732-3

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Revisiting the indications for liver transplantation in cirrhotic patients considering the long-term outcomes of cirrhotic patients.

Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Kamei H, Ogura Y, Fujishiro M

Journal of hepato-biliary-pancreatic sciences   Vol. 27 ( 9 ) page： 655 - 662   2020.9

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DOI： 10.1002/jhbp.777

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Editorial: impact of the introduction of direct-acting anti-viral drugs on hepatocarcinogenesis-a prospective serial follow-up MRI study.

Ito T

Alimentary pharmacology & therapeutics   Vol. 52 ( 4 ) page： 735 - 736   2020.8

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DOI： 10.1111/apt.15911

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Limitation of non-transplant treatment and proper timing for liver transplantation in patients with hepatocellular carcinoma considering long-term survival. Open Access

Nomura A, Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Kamei H, Onishi Y, Ogura Y, Fujishiro M

Medicine   Vol. 99 ( 28 ) page： e21161   2020.7

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DOI： 10.1097/MD.0000000000021161

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特集 薬剤性消化器疾患の診療 4 .その他の薬剤性消化器疾患(4)免疫チェックポイント阻害薬による消化器障害

伊藤 隆徳, 澤田 つな騎, 中村 正直, 本多 隆, 石上 雅敏, 藤城 光弘

臨床消化器内科   Vol. 35 ( 7 ) page： 759 - 765   2020.6

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DOI： 10.19020/cg.0000001205

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Complete response of advanced hepatocellular carcinoma achieved by sorafenib dose re-escalation after failure of long-term low-dose-sorafenib treatment combined with transcatheter arterial chemoembolization: a case report.

Muto H, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Clinical journal of gastroenterology   Vol. 13 ( 3 ) page： 397 - 402   2020.6

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DOI： 10.1007/s12328-019-01066-7

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Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies.

Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, Inukai Y, Toyoda H, Yokota K, Hase T, Maeda O, Kiyoi H, Nagino M, Hibi H, Kodera Y, Fujimoto Y, Sone M, Gotoh M, Ando Y, Akiyama M, Hasegawa Y, Fujishiro M

Journal of gastroenterology   Vol. 55 ( 6 ) page： 653 - 661   2020.6

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DOI： 10.1007/s00535-020-01677-9

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Correlation of serum zinc levels with pathological and laboratory findings in patients with nonalcoholic fatty liver disease.

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

European journal of gastroenterology & hepatology   Vol. 32 ( 6 ) page： 748 - 753   2020.6

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DOI： 10.1097/MEG.0000000000001587

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Initial Experience of Ramucirumab Treatment After Lenvatinib Failure for Patients With Advanced Hepatocellular Carcinoma. Open Access

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Anticancer research   Vol. 40 ( 4 ) page： 2089 - 2093   2020.4

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DOI： 10.21873/anticanres.14167

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Sorafenib <i>vs</i>. Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis. Open Access

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Anticancer research   Vol. 40 ( 4 ) page： 2283 - 2290   2020.4

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DOI： 10.21873/anticanres.14193

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Serum soluble sialic acid-binding immunoglobulin-like lectin-7 concentration as an indicator of liver macrophage activation and advanced fibrosis in patients with non-alcoholic fatty liver disease.

Sakamoto Y, Yoshio S, Doi H, Kawai H, Shimagaki T, Mori T, Matsuda M, Aoki Y, Osawa Y, Yoshida Y, Arai T, Itokawa N, Ito T, Seko Y, Yamaguchi K, Itoh Y, Mise Y, Saiura A, Taketomi A, Kanto T

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 4 ) page： 466 - 477   2020.4

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DOI： 10.1111/hepr.13464

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Dynamic Evaluation of Liver Fibrosis to Assess the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Who Achieved Sustained Virologic Response. Reviewed

Toyoda H, Tada T, Yasuda S, Mizuno K, Ito T, Kumada T

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   Vol. 70 ( 6 ) page： 1208 - 1214   2020.3

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DOI： 10.1093/cid/ciz359

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Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma.

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 3 ) page： 374 - 381   2020.3

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Aim: We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. Methods: This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results: The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions: The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.

DOI： 10.1111/hepr.13452

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Relationship Between Adverse Events and Microbiomes in Advanced Hepatocellular Carcinoma Patients Treated With Sorafenib. Open Access

Yamamoto K, Kuzuya T, Honda T, Ito T, Ishizu Y, Nakamura M, Miyahara R, Kawashima H, Ishigami M, Fujishiro M

Anticancer research   Vol. 40 ( 2 ) page： 665 - 676   2020.2

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DOI： 10.21873/anticanres.13996

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Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease: sex-specific analysis. Open Access

Yoshioka N, Ishigami M, Watanabe Y, Sumi H, Doisaki M, Yamaguchi T, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Haruta JI, Fujishiro M

Scientific reports   Vol. 10 ( 1 ) page： 481   2020.1

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DOI： 10.1038/s41598-019-57369-9

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Rapid increase of platelet counts during antiviral therapy in patients with hepatitis C virus infection.

Ishizu Y, Ishigami M, Hayashi K, Honda T, Kuzuya T, Ito T, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 1 ) page： 47 - 56   2020.1

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Aim: The cause of thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is multifactorial: hypersplenism, decreased thrombopoietin levels, and myelosuppression induced by HCV. Platelet counts increase after eradication of HCV; however, this mechanism is not fully understood. Therefore, the aim of this study was to determine the influence of these three factors on platelet counts. Methods: We retrospectively analyzed data from 109 HCV-infected patients with platelet counts ≤150 × 10³/μL who achieved viral eradication using interferon-free anti-HCV therapy. Changes in hematological parameters, thrombopoietin levels, HCV titers, and spleen volumes, and the correlations among them were evaluated. Results: HCV RNA levels significantly decreased at 4 weeks after initiating antiviral therapy. Platelet counts rapidly increased at 4 weeks from baseline (120 ± 35 vs. 106 ± 28 × 10³/μL, P < 0.001), and remained at a plateau until 48 weeks after initiating antiviral therapy. Neutrophil counts showed the same pattern. Spleen volume was evaluated in 32 patients and, among them, it decreased in 21 patients, but remained unchanged in seven and increased in four. In addition to patients with decreased spleen volume, patients with unchanged spleen volume showed marginally increased platelet counts. Thrombopoietin levels did not correlate with platelet counts. Conclusions: Platelet counts increased at 4 weeks after starting anti-HCV treatment. Our results suggest that this rapid change was possibly caused by improvement of hypersplenism and HCV-induced myelosuppression resulting from anti-HCV therapy.

DOI： 10.1111/hepr.13426

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Efficacy and Safety of Sorafenib in Unresectable Hepatocellular Carcinoma with Bile Duct Invasion.

Tanaka T, Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Oncology   Vol. 98 ( 9 ) page： 621 - 629   2020

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DOI： 10.1159/000507051

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Serum Nutritional Markers as Prognostic Factors for Hepatic and Extrahepatic Carcinogenesis in Japanese Patients with Nonalcoholic Fatty Liver Disease.

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

Nutrition and cancer   Vol. 72 ( 5 ) page： 884 - 891   2020

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DOI： 10.1080/01635581.2019.1653474

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SUCCESSFUL REPEATED ENDOSCOPIC INJECTION SCLEROTHERAPY FOR SEVERE ESOPHAGOGASTRIC VARICES IN AN INFANT WITH BILIARY ATRESIA: A CASE REPORT

YOKOYAMA Shinya, HONDA Takashi, KUZUYA Teiji, ISHIZU Yoji, ITO Takanori, YAMAMOTO Kenta, TANAKA Taku, MUTO Hisanori, SUGIYAMA Yoshiaki, FUJISHIRO Mitsuhiro

GASTROENTEROLOGICAL ENDOSCOPY   Vol. 62 ( 12 ) page： 3064 - 3071   2020

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<p>A 10-month-old boy with biliary atresia who had undergone the Kasai procedure, was admitted to our hospital due to tarry stool. We performed emergency esophagogastroduodenoscopy and found severe esophagogastric varices. There was a spurting bleeding site at the lower esophagus. We implemented endoscopic injection sclerotherapy (EIS) for esophagogastric variceal bleeding, since it was impossible to insert the scope through the esophagus with an endoscopic variceal ligation device attached. After performing four sessions of EIS, the patient developed esophageal ulcers and stricture related to EIS, leading to poor oral intake and body weight loss. We were able to manage these adverse events with conservative treatment. After healing of the esophageal ulcers and stricture, two additional sessions of EIS were performed. The patientʼs esophagogastric varices disappeared completely. </p><p>Intra-variceal EIS followed by para-variceal EIS by polidocanol was reported to be effective and relatively safe for the treatment of esophageal varices in adult patients. The aim of para-variceal EIS is to form ulcers at the injection sites, resulting in the development of fibrosis of the mucosa during the healing process. This mucosal fibrosis is considered important for preventing recurrence of varices. There is little evidence for the safety and efficacy of intra-variceal EIS followed by para-variceal EIS in pediatric patients. </p><p>Although we should be cautious of EIS-related stricture due to esophageal ulcer, especially in children who have a narrower esophageal lumen than adults, we have experienced a successful case of EIS for esophageal varices in an infant with biliary atresia.</p>

DOI： 10.11280/gee.62.3064

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Sarcopenia impairs health-related quality of life in cirrhotic patients.

Ando Y, Ishigami M, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Fujishiro M

European journal of gastroenterology & hepatology   Vol. 31 ( 12 ) page： 1550 - 1556   2019.12

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DOI： 10.1097/MEG.0000000000001472

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Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity Open Access

Yoshioka Naoki, Kuzuya Teiji, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishikawa Tetsuya, Ishigami Masatoshi, Fujishiro Mitsuhiro

Internal Medicine   Vol. 58 ( 19 ) page： 2803 - 2808   2019.10

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<p>Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity. </p>

DOI： 10.2169/internalmedicine.2812-19

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CHANGES OF MICROBIOTA AFTER HEPATITIS C VIRUS ERADICATION

Honda Takashi, Ishigami Masatoshi, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

HEPATOLOGY   Vol. 70   page： 1160A - 1161A   2019.10

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Spleen stiffness by 2-D shear wave elastography is the most accurate predictor of high-risk esophagogastric varices in children with biliary atresia.

Yokoyama S, Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Hirooka Y, Tanaka Y, Tainaka T, Shirota C, Chiba K, Uchida H, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 49 ( 10 ) page： 1162 - 1168   2019.10

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DOI： 10.1111/hepr.13381

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NON-INVASIVE SCREENING FOR DETECTING ESOPHAGOGASTRIC VARICES IN CHILDREN WITH BILIARY ATRESIA

Yokoyama Shinya, Ishigami Masatoshi, Honda Takashi, Kuzuya Teiji, Ishizu Yoji, Ito Takanori, Shirota Chiyoe, Uchida Hiroo, Fujishiro Mitsuhiro

HEPATOLOGY   Vol. 70   page： 200A - 200A   2019.10

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INDICATION FOR HCC TREATMENT IN RECENT ERA-PROPOSAL OF THE NEW PRIORITY FOR LIVER TRANSPLANTATION IN PATIENTS WITH HCC

Ishigami Masatoshi, Honda Takashi, Kuzuya Teiji, Ishizu Yoji, Ito Takanori, Fujishiro Mitsuhiro

HEPATOLOGY   Vol. 70   page： 543A - 544A   2019.10

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UTILITY OF THE ALBUMIN-BILIRUBIN SCORE FOR PREDICTING PROGNOSIS IN JAPANESE PATIENTS WITH PRIMARY BILIARY CHOLANGITIS: AN ANALYSIS USING TIME-DEPENDENT RECEIVER OPERATING CHARACTERISTICS

Ito, T; Ishigami, M; Ishizu, Y; Kuzuya, T; Honda, T; Yasuda, S; Toyoda, H; Kumada, T; Fujishiro, M

HEPATOLOGY   Vol. 70   page： 789A - 790A   2019.10

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Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment.

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Hirooka Y, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 49 ( 9 ) page： 1054 - 1065   2019.9

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DOI： 10.1111/hepr.13358

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The relationship between portal hypertension and the microbiome

Yamamoto K., Honda T., Hattori S., Pu L. Zorron Cheng Tao, Ito T., Yamamura T., Ishizu Y., Kuzuya T., Ishigami M., Fujishiro M.

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 34   page： 106 - 107   2019.9

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Association between core mutations and annual decline rate of HBVDNA and HBsAg in chronic hepatitis B patients treated with nucleoside analogue

Honda Takashi, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page： E258 - E258   2019.4

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DOI： 10.1016/S0618-8278(19)30488-8

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The optimal cut-off points of FIB-4 index for predicting the incidences of HCC and extra-hepatic malignancies in biopsyproven Japanese NAFLD patients

Ito Takanori, Ishigami Masatoshi, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Fujishiro Mitsuhiro

JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page： E775 - E775   2019.4

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The early clinical response at 2 weeks of lenvatinib therapy for patients with advanced HCC

Kuzuya Teiji, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Honda Takashi, Fujishiro Mitsuhiro

JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page： E611 - E611   2019.4

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DOI： 10.1016/S0618-8278(19)31220-4

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Serum Zinc levels as a prognostic factor for extra-hepatic carcinogenesis in Japanese patients with non-alcoholic liver disease

Ito Takanori, Ishigami Masatoshi, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Fujishiro Mitsuhiro

JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page： E298 - E298   2019.4

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DOI： 10.1016/S0618-8278(19)30577-8

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Association between gut microbiota and hepatocellular carcinoma in patients with chronic liver disease

Honda Takashi, Ishigami Masatoshi, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page： E512 - E513   2019.4

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DOI： 10.1016/S0618-8278(19)31015-1

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Influence of proton pump inhibitors on microbiota in chronic liver disease patients.

Yamamoto K, Ishigami M, Honda T, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Hayashi K, Goto H, Hirooka Y

Hepatology international   Vol. 13 ( 2 ) page： 234 - 244   2019.3

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DOI： 10.1007/s12072-019-09932-9

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Successful treatment of esophageal bleeding due to rupture of major aortopulmonary collateral arteries by transcatheter arterial embolization.

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Matsushima M, Kato T, Hirooka Y

Clinical journal of gastroenterology   Vol. 12 ( 1 ) page： 20 - 24   2019.2

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DOI： 10.1007/s12328-018-0895-8

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Utility and limitations of noninvasive fibrosis markers for predicting prognosis in biopsy-proven Japanese non-alcoholic fatty liver disease patients. Open Access

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Nishimura D, Toyoda H, Kumada T, Goto H, Hirooka Y

Journal of gastroenterology and hepatology   Vol. 34 ( 1 ) page： 207 - 214   2019.1

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DOI： 10.1111/jgh.14448

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Association between Core Mutations Induced By Interferon Therapy and Annual Decline Rate of Hbvdna in Chronic Hepatitis B Patients

Honda Takashi, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Hirooka Yoshiki

HEPATOLOGY   Vol. 68   page： 1233A - 1234A   2018.10

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Interferon-Free Antiviral Therapy Rapidly Improves Thrombocytopenia in Patients with Advanced Chronic Hepatitis C

Ishizu Yoji, Ishigami Masatoshi, Ito Takanori, Kuzuya Teiji, Honda Takashi, Hirooka Yoshiki

HEPATOLOGY   Vol. 68   page： 1157A - 1158A   2018.10

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Comparison of Gut Microbiota and Predicted Functional Metagenome in Hepatitis C Patients with and without Advanced Fibrosis Categorized By FIB4-Index

Yamamoto Kenta, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Hirooka Yoshiki

HEPATOLOGY   Vol. 68   page： 590A - 590A   2018.10

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Secreted ectodomain of SIGLEC-9 and MCP-1 ameliorate acute liver failure in rats by altering bone marrow macrophage polarity

Ito T., Ishigami M., Yamamoto A., Ishizu Y., Kazuya T., Honda T., Hayashi K., Ishikawa T., Hirooka Y., Goto H.

JOURNAL OF HEPATOLOGY   Vol. 68   page： S614 - S614   2018.4

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DOI： 10.1016/S0168-8278(18)31483-1

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Utility and limitation of non-invasive fibrosis markers for predicting the prognosis in biopsy-proven Japanese NAFLD patients

Ito T., Ishigami M., Ishizu Y., Kazuya T., Honda T., Hayashi K., Ishikawa T., Hirooka Y., Goto H.

JOURNAL OF HEPATOLOGY   Vol. 68   page： S561 - S561   2018.4

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DOI： 10.1016/S0168-8278(18)31379-5

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Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity Open Access

Ito Takanori, Ishigami Masatoshi, Matsushita Yoshihiro, Hirata Marina, Matsubara Kohki, Ishikawa Tetsuya, Hibi Hideharu, Ueda Minoru, Hirooka Yoshiki, Goto Hidemi, Yamamoto Akihito

SCIENTIFIC REPORTS   Vol. 7   page： 44043   2017.3

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DOI： 10.1038/srep44043

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PubMed

Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.

Kobayashi N, Kumada T, Toyoda H, Tada T, Ito T, Kage M, Okanoue T, Kudo M

Digestive diseases (Basel, Switzerland)   Vol. 35 ( 6 ) page： 521-530   2017

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

DOI： 10.1159/000480142

PubMed

Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis. Reviewed Open Access

Hirata M, Ishigami M, Matsushita Y, Ito T, Hattori H, Hibi H, Goto H, Ueda M, Yamamoto A

Stem cells translational medicine   Vol. 5 ( 10 ) page： 1416-1424   2016.10

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

DOI： 10.5966/sctm.2015-0353

Open Access

PubMed

Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 identified from Dental Pulp Stem Cells Synergistically Resolve Acute Liver Failure in Rats by Altering Macrophage Polarity

Ito Takanori, Yamamoto Akihito, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Ishikawa Tetsuya, Ishigami Masatoshi, Hirooka Yoshiki, Goto Hidemi

HEPATOLOGY   Vol. 64   page： 515A - 515A   2016.10

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Web of Science

Extra-hepatic feeding arteries of hepatocellular carcinoma: An investigation based on intra-arterial CT aortography images using an angio-MDCT system. Reviewed Open Access

Takada K, Ito T, Kumada T, Toyoda H, Tada T, Sone Y, Endo T, Tanaka K, Kitagawa H, Ichikawa K

European journal of radiology   Vol. 85 ( 8 ) page： 1400-6   2016.8

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DOI： 10.1016/j.ejrad.2016.05.007

PubMed

Accurate and rapid identification of feeding arteries with multidetector-row angiography-assisted computed tomography for transarterial chemoembolization for hepatocellular carcinoma. Reviewed

Takada K, Toyoda H, Tada T, Ito T, Hasegawa R, Gotoh T, Ichikawa H, Sone Y, Kumada T

Journal of gastroenterology   Vol. 50 ( 12 ) page： 1190-6   2015.12

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

DOI： 10.1007/s00535-015-1065-0

PubMed

Utility of Contrast-enhanced Ultrasonography with Perflubutane for Determining Histologic Grade in Hepatocellular Carcinoma. Reviewed

Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Kaneoka Y, Maeda A, Okuda S, Otobe K, Takahashi K

Ultrasound in medicine & biology   Vol. 41 ( 12 ) page： 3070-8   2015.12

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DOI： 10.1016/j.ultrasmedbio.2015.07.023

PubMed

Utility of the FIB-4 Index for hepatocarcinogenesis in hepatitis C virus carriers with normal alanine aminotransferase levels. Reviewed

Ito T, Kumada T, Toyoda H, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S

Journal of viral hepatitis   Vol. 22 ( 10 ) page： 777-83   2015.10

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

DOI： 10.1111/jvh.12389

PubMed

Utility of real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C infection without cirrhosis: Comparison of liver fibrosis indices. Reviewed Open Access

Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Okuda S, Tsuji N, Imayoshi Y, Yasuda E

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 45 ( 10 ) page： E122-9   2015.10

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

DOI： 10.1111/hepr.12476

PubMed

Long-term prognosis of patients with hepatitis B infection: causes of death and utility of nucleos(t)ide analogue therapy. Reviewed Open Access

Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabtake S, Ito T

Journal of gastroenterology   Vol. 50 ( 7 ) page： 795-804   2015.7

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DOI： 10.1007/s00535-014-1011-6

PubMed

Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. Reviewed

Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T

Journal of gastroenterology and hepatology   Vol. 30 ( 7 ) page： 1183-9   2015.7

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

DOI： 10.1111/jgh.12915

PubMed

FIB-4 index for assessing the prognosis of hepatocellular carcinoma in patients with Child-Pugh class A liver function. Reviewed Open Access

Ito T, Kumada T, Toyoda H, Tada T

Journal of cancer research and clinical oncology   Vol. 141 ( 7 ) page： 1311-9   2015.7

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

DOI： 10.1007/s00432-015-1922-5

PubMed

Diagnostic accuracy for macroscopic classification of nodular hepatocellular carcinoma: comparison of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging and angiography-assisted computed tomography. Reviewed

Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Okuda S, Ogawa S, Igura T, Imai Y

Journal of gastroenterology   Vol. 50 ( 1 ) page： 85-94   2015.1

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DOI： 10.1007/s00535-014-0947-x

PubMed

Utility of contrast-enhanced ultrasound with perflubutane for diagnosing the macroscopic type of small nodular hepatocellular carcinomas. Reviewed

Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Kaneoka Y, Maeda A, Okuda S, Otobe K, Takahashi K

European radiology   Vol. 24 ( 9 ) page： 2157-66   2014.9

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DOI： 10.1007/s00330-014-3254-2

PubMed

Changes in highly sensitive alpha-fetoprotein for the prediction of the outcome in patients with hepatocellular carcinoma after hepatectomy. Reviewed Open Access

Toyoda H, Kumada T, Tada T, Ito T, Maeda A, Kaneoka Y, Kagebayashi C, Satomura S

Cancer medicine   Vol. 3 ( 3 ) page： 643-51   2014.6

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

DOI： 10.1002/cam4.218

Open Access

PubMed

Oral supplementation with branched-chain amino acid granules prevents hepatocarcinogenesis in patients with hepatitis C-related cirrhosis: A propensity score analysis.

Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Niinomi T, Ito T, Hasegawa R, Ando Y, Yamamoto K, Tanaka T

Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 44 ( 3 ) page： 288-95   2014.3

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

DOI： 10.1111/hepr.12120

PubMed

[An autopsy of G-CSF-producing anaplastic carcinoma of the pancreas with impaired accumulation on FDG-PET after S-1 chemotherapy].

Ikeda S, Okubo K, Shibahara H, Narita M, Morita K, Takeuchi A, Kanazawa H, Ito T, Nishimura D, Katada N

Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 40 ( 6 ) page： 789-92   2013.6

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PubMed

Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy. Reviewed

Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Sone Y, Kaneoka Y, Maeda A

Journal of hepatology   Vol. 58 ( 6 ) page： 1174-80   2013.6

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DOI： 10.1016/j.jhep.2013.01.030

PubMed

A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil

ITO Takanori, OKUBO Kenji, SHIOMI Masaya, NARITA Michihiko, MORITA Kiyoshi, TAKEUCHI Atsufumi, KANAZAWA Hironobu, SHIMIZU Junichi, TAKEYAMA Tomoaki, HASHIZUME Kiyotaka, SHIBAHARA Hiroaki, NISHIMURA Daisaku, KATADA Naoyuki, KATANO Yoshiaki, GOTO Hidemi

Nippon Shokakibyo Gakkai Zasshi   Vol. 109 ( 12 ) page： 2088-2096   2012.12

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A 37-year-old man underwent lobectomy of the right liver for granulocyte colony-stimulating factor (G-CSF) producing hepatocellular carcinoma accompanying type B hepatitis. Within two months after the surgery, lung metastases were revealed and administration of sorafenib was begun, however, the lung metastases continued to enlarge. Changing the patient's medication to tegafur-uracil provided remarkable reduction of the lung metastases. The patient is alive two years after diagnosis and receives outpatient chemotherapy. We concluded that this case is valuable with regard to the extreme rarity of G-CSF producing hepatocellular carcinoma and its successful treatment in this case.<br>

DOI： 10.11405/nisshoshi.109.2088

CiNii Research

[A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil]. Open Access

Ito T, Okubo K, Shiomi M, Narita M, Morita K, Takeuchi A, Kanazawa H, Shimizu J, Takeyama T, Hashizume K, Shibahara H, Nishimura D, Katada N, Katano Y, Goto H

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology   Vol. 109 ( 12 ) page： 2088-96   2012.12

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

DOI： 10.11405/nisshoshi.109.2088

Open Access

PubMed

A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil

Ito T.

Journal of Japanese Society of Gastroenterology   Vol. 109 ( 12 ) page： 2088 - 2096   2012.12

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Scopus

Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy. Reviewed

Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Kaneoka Y, Maeda A

Journal of hepatology   Vol. 57 ( 6 ) page： 1251-7   2012.12

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

DOI： 10.1016/j.jhep.2012.07.018

PubMed

[Low-dose mirtazapine improved nausea and appetite loss during S-1 therapy].

Shibahara H, Ito T, Uematsu N, Imai E, Nishimura D

Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 39 ( 1 ) page： 143-5   2012.1

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PubMed