Faculty Profiles - ITO Takanori

Guide for the Diagnosis of Immune Checkpoint Inhibitor-Induced Liver Injury Reviewed

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

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

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.

DOI： 10.2957/kanzo.65.268

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

Ito T., Nguyen V.H., Tanaka T., Park H., Yeh M.L., Kawanaka M., Arai T., Atsukawa M., Yoon E.L., Tsai P.C., Toyoda H., Huang J.F., Henry L., Jun D.W., Yu M.L., Ishigami M., Nguyen M.H., Cheung R.C.

Clinical Gastroenterology and Hepatology Vol. 21 ( 4 ) page： 1013 - 1022.e6 2023.4

Authorship：Lead author 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

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

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; Barnett, SD; Stave, CD; Cheung, RC; Fujishiro, M; Eguchi, Y; Toyoda, H; Nguyen, MH

HEPATOLOGY INTERNATIONAL Vol. 15 ( 2 ) page： 366 - 379 2021.4

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

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

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

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

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

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

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 2025.2

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

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

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

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

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

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

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

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

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

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 Vol. 34 ( 9 ) page： 2115 - 2123 2024.9

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

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

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

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

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

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 Vol. 43 ( 8 ) page： 1855 - 1856 2024.8

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

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

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

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

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

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

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world Reviewed International coauthorship

Kudaravalli S., Huang D.Q., Yeh M.L., Trinh L., Tsai P.C., Hsu Y.C., Kam L.Y., Nguyen V.H., Ogawa E., Lee D.H., Ito T., Watanabe T., Enomoto M., Preda C.M., Ko M.K.L., Wan-Hin Hui R., Atsukawa M., Suzuki T., Marciano S., Barreira A., Do S., Uojima H., Takahashi H., Quek S.X.Z., Toe Wai Khine H.H., Ishigami M., Itokawa N., Go M.S., Kozuka R., Marin R.I., Sandra I., Li J., Zhang J.Q., Wong C., Yoshimaru Y., Vo D.K.H., Tseng C.H., Lee C.j., Inoue K., Maeda M., Hoang J.K., Chau A., Chuang W.L., Dai C.Y., Huang J.F., Huang C.F., Buti M., Tanaka Y., Gadano A.C., Yuen M.F., Cheung R., Lim S.G., Trinh H.N., Toyoda H., Yu M.L., Nguyen M.H.

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

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

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

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 Vol. 44 ( 7 ) page： 1700 - 1714 2024.7

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

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

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 K.i., Kagawa T.

Hepatology Research Vol. 54 ( 6 ) page： 503 - 512 2024.6

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

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 Reviewed

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

Clinical Nutrition Vol. 43 ( 6 ) page： 1425 - 1432 2024.6

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

Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma Reviewed

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

Cancers Vol. 16 ( 9 ) 2024.5

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

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

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.

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

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

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

Global incidence of adverse clinical events in nonalcoholic fatty liver disease: A systematic review and meta-analysis Reviewed International coauthorship

Le M.H., Le D.M., Baez T.C., Dang H., Nguyen V.H., Lee K., Stave C.D., Ito T., Wu Y., Yeo Y.H., Ji F., Cheung R., Nguyen M.H.

Clinical and Molecular Hepatology Vol. 30 ( 2 ) page： 235 - 246 2024.4

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

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

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

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

Chau A., Yeh M.L., Tsai P.C., Huang D.Q., Kim S.E., Trinh H., Yoon E.L., Oh H., Jeong J.Y., Ahn S.B., An J., Tseng C.H., Hsu Y.C., Jeong S.W., Cho Y.K., Shim J.J., Kim H.S., 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 J.K., Maeda M., Huang C.F., Gadano A., Dai C.Y., Huang J.F., Tanaka Y., Chuang W.L., Lim S.G., Cheung R., Yu M.L., Jun D.W., Nguyen M.H.

Clinical Gastroenterology and Hepatology Vol. 22 ( 3 ) page： 572 - 580.e5 2024.3

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

Identification of the Microbiome Associated with Prognosis in Patients with Chronic Liver Disease Reviewed

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

Microorganisms Vol. 12 ( 3 ) 2024.3

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

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

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

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

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

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

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

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

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.

DOI： 10.2169/internalmedicine.1826-23

A 70-year-old Woman with Asymptomatic Ferroportin Disease Reviewed

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

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

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 G80S mutation in SLC40A1. 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.

DOI： 10.2169/internalmedicine.2392-23

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

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

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

Open Access

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 Reviewed

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

Journal of Hepato-Biliary-Pancreatic Sciences 2024

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

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

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 2024

Authorship：Lead author,　Corresponding author 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

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

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

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 CD56dim 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 CD56dim NK cells in PBMCs were increased in HCC patients compared with HVs. In HCC patients, ILT2-positive CD56dim 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 CD56dim NK cells from HCC patients was inhibited by masking antibodies against MIF and CXCR4. ILT2-positive CD56dim 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 CD56dim NK cells with impaired cytolytic capacity. The MIF-CXCR4 interaction is associated with ILT2 induction on CD56dim NK cells and ILT2 serves as a target for functional NK cell restoration.

DOI： 10.3389/fimmu.2024.1389411

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 Reviewed

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 2024

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

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

ICI-induced liver injury

ITO Takanori, KAWASHIMA Hiroki

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

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

Distinct features of two lipid droplets types in cell nuclei from patients with liver diseases Reviewed

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 2023.12

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

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

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

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

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

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

Huang D.Q., Tran A., Yeh M.L., Yasuda S., Tsai P.C., Huang C.F., Dai C.Y., Ogawa E., Ishigami M., Ito T., Kozuka R., Enomoto M., Suzuki T., Yoshimaru Y., Preda C.M., Marin R.I., Sandra I., Tran S., Quek S.X.Z., Khine H.H.T.W., Itokawa N., Atsukawa M., Uojima H., Watanabe T., Takahashi H., Inoue K., Maeda M., Hoang J.K., Trinh L., Barnett S., Cheung R., Lim S.G., Trinh H.N., Chuang W.L., Tanaka Y., Toyoda H., Yu M.L., Nguyen M.H.

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

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

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 log10 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

Clinical course and prognosis of patients with hepatocellular carcinoma and haemophilia Reviewed

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 and Hepatology Vol. 35 ( 10 ) page： 1211 - 1215 2023.10

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

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

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.

Journal of Gastroenterology and Hepatology (Australia) Vol. 38 ( 10 ) page： 1832 - 1839 2023.10

Authorship：Lead author 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

Diagnostic Performance of the Fibrosis-4 Index and Nonalcoholic Fatty Liver Disease Fibrosis Score in Lean Adults with Nonalcoholic Fatty Liver Disease Reviewed International coauthorship International journal

Park H., Yoon E.L., Ito T., Jo A.J., Kim M., Lee J., Kim H.L., Arai T., Atsukawa M., Kawanaka M., Toyoda H., Ishigami M., Yu M.L., Jun D.W., Nguyen M.H.

JAMA Network Open Vol. 6 ( 8 ) page： e2329568 2023.8

Language：English Publishing type：Research paper (scientific journal) Publisher：JAMA Network Open

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

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

Le M.H., Le D.M., Baez T.C., Wu Y., Ito T., Lee E.Y., Lee K.S., Stave C.D., Henry L., Barnett S.D., Cheung R., Nguyen M.H.

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

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

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

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

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

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

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

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

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

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

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

Authorship：Lead author 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

Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma Reviewed

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

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

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

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 N.M., Ishigami M., Fujishiro M., Kawashima H.

Nutrients Vol. 15 ( 6 ) 2023.3

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

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

Dao A.D., Nguyen V.H., Ito T., Cheung R., Nguyen M.H.

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

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

Endoscopic injection sclerotherapy with polidocanol for cardiac varices in children and adolescents Reviewed

Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients Reviewed International coauthorship

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

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 Vol. 30 ( 2 ) page： 109 - 112 2023.2

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

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

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 (Australia) Vol. 38 ( 2 ) page： 251 - 258 2023.2

Authorship：Corresponding author 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

Differences in the Intestinal Microbiome Associated with Diarrhea during Lenvatinib Treatment for Hepatocellular Carcinoma Reviewed

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

Digestive Diseases Vol. 41 ( 1 ) page： 138 - 147 2023.1

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

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

The presence of high-risk varices after sclerotherapy in biliary atresia Reviewed

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 Vol. 65 ( 1 ) page： e15454 2023.1

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

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

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

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

Ito T., Nguyen M.H.

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

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 N.M., Ishigami M., Fujishiro M.

Digestive Diseases and Sciences Vol. 68 ( 1 ) page： 155 - 163 2023.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Digestive Diseases and Sciences

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

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes Invited Reviewed International coauthorship

Ito T., Nguyen M.H.

Journal of Hepatocellular Carcinoma Vol. 10 page： 413 - 428 2023

Authorship：Lead author 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

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

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

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

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

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

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

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 2022.12

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

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

Factors associated with the progression of myosteatosis in patients with cirrhosis Reviewed

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

Nutrition Vol. 103-104 page： 111777 2022.11

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

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

Decreased appetite is associated with the presence of sarcopenia in patients with cirrhosis Reviewed

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

Nutrition Vol. 103-104 page： 111807 2022.11

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

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

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

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

Hepatology Research Vol. 52 ( 11 ) page： 957 - 967 2022.11

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

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

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

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

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

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 Vol. 52 ( 11 ) page： 937 - 946 2022.11

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

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

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.

Journal of Clinical Endocrinology and Metabolism Vol. 107 ( 10 ) page： E4115 - E4123 2022.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Endocrinology and Metabolism

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

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

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

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

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

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

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

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

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

American Journal of Roentgenology Vol. 219 ( 4 ) page： 604 - 613 2022.10

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 (LSM2D SWE) for evaluation of liver fibrosis with LSM from MRE (LSMMRE) 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 LSM2D SWE was evaluated by Kruskal-Wallis tests with post hoc tests and ROC analysis. RESULTS. LSM2D SWE 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). LSM2D SWE 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, LSM2D SWE 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 LSM2D SWE 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 LSM2D SWE 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

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

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

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

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

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

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

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

Ultrasound in Medicine and Biology Vol. 48 ( 8 ) page： 1537 - 1546 2022.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Ultrasound in Medicine and Biology

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

Effectiveness of Porous Glass Membrane Pumping Emulsification Device in Transarterial Chemoembolization for Solitary Hepatocellular Carcinoma Reviewed

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

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

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

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

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

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.

Journal of Clinical Endocrinology and Metabolism Vol. 107 ( 4 ) page： E1620 - E1630 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Endocrinology and Metabolism

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

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

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

Ye Q, Ito T, Henry L, Nguyen MH

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

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

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

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

The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with hemophilia HCC after HCV eradication in hemophilia Reviewed

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

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

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

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

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

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

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

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

HEPATOLOGY RESEARCH Vol. 52 ( 1 ) page： 81 - 92 2022.1

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

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

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

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Investigation

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

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

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

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

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

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

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

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

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.

DOI： 10.2169/internalmedicine.9404-22

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

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

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

European Journal of Gastroenterology and Hepatology Vol. 33 ( 1 ) page： E898 - E904 2021.12

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

Changes in the gut microbiota after hepatitis C virus eradication Reviewed

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

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

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

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

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

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

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

DIGESTIVE AND LIVER DISEASE Vol. 53 ( 11 ) page： 1443 - 1450 2021.11

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

Safety and efficacy of glass membrane pumping emulsification device in transarterial chemoembolization for hepatocellular carcinoma: First clinical outcomes Reviewed

IMAI N., YOKOYAMA S., YAMAMOTO K., ITO T., ISHIZU Y., HONDA T., ISHIGAMI M.

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

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

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

Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis Reviewed

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

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

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

Factors associated with bleeding after endoscopic variceal ligation in children Reviewed

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 Vol. 63 ( 10 ) page： 1223 - 1229 2021.10

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

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

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies Reviewed

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

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Hepatology International

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

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

Muto, H; Ito, T; Ishigami, M

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

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

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

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

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

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

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

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

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

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

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

EXPERIMENTAL AND CLINICAL TRANSPLANTATION Vol. 19 ( 9 ) page： 935 - 942 2021.9

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

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

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

JOURNAL OF VIRAL HEPATITIS Vol. 28 ( 9 ) page： 1293 - 1303 2021.9

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

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 Reviewed

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

MEDICINE Vol. 100 ( 31 ) page： e26820 2021.8

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

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

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

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

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

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

CLINICAL NUTRITION ESPEN Vol. 42 page： 354 - 360 2021.4

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

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

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

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

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

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

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

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

JOURNAL OF VIRAL HEPATITIS Vol. 28 ( 3 ) page： 508 - 516 2021.3

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

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

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

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

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

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

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

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

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

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 Vol. 27 ( 1 ) page： 100 - 107 2021.1

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

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

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

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

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

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 2020.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

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. 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. 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.

DOI： 10.11280/gee.62.3064

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

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

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

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

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

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

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

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

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

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

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

Oncology Vol. 98 ( 9 ) page： 621 - 629 2020.9

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

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

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

Ito, T

ALIMENTARY PHARMACOLOGY & THERAPEUTICS Vol. 52 ( 4 ) page： 735 - 736 2020.8

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

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

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

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 2020.7

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

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. Reviewed

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

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

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

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

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

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

Sorafenib vs. Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis. Reviewed

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

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

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. Reviewed

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

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

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

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

HEPATOLOGY RESEARCH Vol. 50 ( 3 ) page： 374 - 381 2020.3

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

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

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

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

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

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

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

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

HEPATOLOGY RESEARCH Vol. 50 ( 1 ) page： 47 - 56 2020.1

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

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