Faculty Profiles - ITO Takanori

Papers - ITO Takanori

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

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

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

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

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

DOI： 10.1111/apt.70194

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

Suzuki T, Mizuno K, Ito T

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

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

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

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

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

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

DOI： 10.1111/hepr.14200

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

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

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

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

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

DOI： 10.1111/hepr.14195

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

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

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

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

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

DOI： 10.3350/cmh.2024.1070

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

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

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

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

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

DOI： 10.1007/s00535-025-02232-0

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

Suzuki T, Mizuno K, Ito T

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

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

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

The oncologist Vol. 30 ( 6 ) 2025.6

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

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

DOI： 10.1093/oncolo/oyaf120

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

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

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

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

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

DOI： 10.1016/j.dld.2025.02.027

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

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

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

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

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

DOI： 10.1007/s12072-025-10776-9

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

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

Metabolites Vol. 15 ( 6 ) 2025.5

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

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

DOI： 10.3390/metabo15060366

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

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

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

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

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

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

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

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

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

DOI： 10.1111/hepr.14151

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

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

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

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

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

DOI： 10.1111/hepr.14152

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

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

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

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

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

DOI： 10.1016/j.dld.2025.01.037

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Coronary Artery Disease

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

DOI： 10.1097/MCA.0000000000001431

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

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

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

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

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

DOI： 10.1097/MEG.0000000000002912

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

横山晋也, 石津洋二, 本多隆, 今井則博, 伊藤隆徳, 山本健太, 川嶋啓揮

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

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

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

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

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

ICIによる肝障害　 Invited Reviewed

伊藤　隆徳、川嶋　啓揮

日消誌121巻12号『薬物性肝障害』　 2024.12

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