研究者詳細 - 伊藤　隆徳

論文 - 伊藤　隆徳

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Diagnostic guide for immune checkpoint inhibitor-induced liver injury 査読有り

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

Hepatology Research 54 巻 ( 8 ) 頁： 719 - 726 2024年8月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hepatology Research

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

DOI： 10.1111/hepr.14078

Guide for the Diagnosis of Immune Checkpoint Inhibitor-Induced Liver Injury 査読有り

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

Kanzo/Acta Hepatologica Japonica 65 巻 ( 6 ) 頁： 268 - 276 2024年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Kanzo/Acta Hepatologica Japonica

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 査読有り国際共著

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 21 巻 ( 4 ) 頁： 1013 - 1022.e6 2023年4月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り国際共著

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 15 巻 ( 2 ) 頁： 366 - 379 2021年4月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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 55 巻 ( 6 ) 頁： 653 - 661 2020年6月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology

Background: Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury. Methods: A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined. Results: Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65–10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68–14.40, P < 0.001). Conclusions: We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.

DOI： 10.1007/s00535-020-01677-9

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

Ito, T; Ishigami, M; Matsushita, Y; Hirata, M; Matsubara, K; Ishikawa, T; Hibi, H; Ueda, M; Hirooka, Y; Goto, H; Yamamoto, A

SCIENTIFIC REPORTS 7 巻頁： 44043 2017年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Effective treatments for acute liver failure (ALF) are still lacking. We recently reported that a single intravenous administration of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) into the D-galactosamine (D-Gal)-induced rat ALF model improves the liver injury. However, the specific factors in SHED-CM that are responsible for resolving ALF remain unclear. Here we found that depleting SHED-CM of two anti-inflammatory M2 macrophage inducers-monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9)-abolished its ability to resolve rat ALF. Furthermore, treatment with MCP-1/sSiglec-9 alone dramatically improved the survival of ALF rats. This treatment induced anti-inflammatory M2, suppressed hepatocyte apoptosis, and promoted hepatocyte proliferation. Treatment with an M2-depletion reagent (mannosylated clodronate liposomes) suppressed the recovery. In addition, MCP-1 and sSiglec-9 synergistically promoted the M2 differentiation of bone marrow-derived macrophages via CCR2, accompanied by the production of multiple liver-regenerating factors. The conditioned medium from MCP-1/sSiglec-9-activated M2 macrophages, but not from interleukin-4-induced ones, suppressed the D-Gal-and LPS-induced apoptosis of primary hepatocytes and promoted their proliferation in vitro. The unique combination of MCP-1/sSiglec-9 ameliorates rat ALF by inhibiting hepatocellular apoptosis and promoting liver regeneration through the induction of anti-inflammatory/tissue-repairing M2 macrophages.

DOI： 10.1038/srep44043

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年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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 16 巻 ( 22 ) 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 129 巻頁： 62 - 70 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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 34 巻 ( 9 ) 頁： 2115 - 2123 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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

Anticancer Research 44 巻 ( 9 ) 頁： 4101 - 4111 2024年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 43 巻 ( 8 ) 頁： 1855 - 1856 2024年8月

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

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 28 巻 ( 2 ) 頁： 397 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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

Anticancer Research 44 巻 ( 7 ) 頁： 3185 - 3191 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り国際共著

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 81 巻 ( 1 ) 頁： 33 - 41 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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 44 巻 ( 7 ) 頁： 1700 - 1714 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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 54 巻 ( 6 ) 頁： 503 - 512 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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

Clinical Nutrition 43 巻 ( 6 ) 頁： 1425 - 1432 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 査読有り

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

Cancers 16 巻 ( 9 ) 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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 54 巻 ( 4 ) 頁： 347 - 357 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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