Faculty Profiles - IMAI Norihiro

Papers - IMAI Norihiro

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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 2025.1

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

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 2025.1

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

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

MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity Open Access

Liu, M; Akahori, Y; Imai, N; Wang, LN; Negishi, K; Kato, T; Fujiwara, H; Miwa, H; Shiku, H; Miyahara, Y

JOURNAL FOR IMMUNOTHERAPY OF CANCER Vol. 12 ( 11 ) 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal for ImmunoTherapy of Cancer

Background The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4 p230-239 /HLA-A∗02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity. Methods We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains. Results Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues. Conclusions These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments.

DOI： 10.1136/jitc-2024-010248

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

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

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

JOURNAL OF DIGESTIVE DISEASES Vol. 25 ( 11-12 ) page： 685 - 693 2024.11

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

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

DOI： 10.1111/1751-2980.13325

Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance.

Xie Y, Liu X, Liu W, Carr LR, Lee LP, Imai N, Ortlund EA, Cohen DE

The Journal of biological chemistry page： 107855 2024.10

EFFECT OF AGE AND DEVELOPMENT OF LIVER AND OTHER ORGAN CANCERS ON HBS ANTIGEN LOSS IN HEPATITIS B PATIENTS

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

HEPATOLOGY Vol. 80 page： S253 - S254 2024.10

RISK FACTORS ASSOCIATED WITH DECREASED BONE MINERAL DENSITY IN PATIENTS WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE: A CROSS-SECTIONAL STUDY AT A HEALTH EXAMINATION CENTER

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

HEPATOLOGY Vol. 80 page： S552 - S553 2024.10

PATHOLOGICAL SIGNIFICANCE OF INTRANUCLEAR LIPID DROPLETS AND GLYCOGENATED NUCLEI IN LIVER BIOPSY

Imai, N; Ohsaki, Y; Cheng, J; Yokoyama, S; Yamamoto, K; Ito, T; Ishizu, Y; Honda, T; Wake, H; Kawashima, H; Zhang, J

HEPATOLOGY Vol. 80 page： S615 - S615 2024.10

INTESTINE- SPECIFIC FAF2 DEPLETION AMELIORATES METABOLIC DYSFUNCTIONASSOCIATED STEATOTIC LIVER DISEASE BY IMPAIRING LIPID ABSORPTION

Zhang, JJ; Imai, N; Yokoyama, S; Yamamoto, K; Ito, T; Ishizu, Y; Honda, T; Sugiyama, A; Cohen, D; Kawashima, H

HEPATOLOGY Vol. 80 page： S45 - S46 2024.10

FEVER AFTER THE ADMINISTRATION OF ATEZOLIZUMAB AND BEVACIZUMAB PREDICTS LIVER INJURY IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA: A PROSPECTIVE OBSERVATIONAL ANALYSIS USING A MULTIPLEX BEAD-BASED IMMUNOASSAY

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

HEPATOLOGY Vol. 80 2024.10

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

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

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

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

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

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024.7

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

A 70-year-old Woman with Asymptomatic Ferroportin Disease

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

Internal Medicine Vol. advpub ( 0 ) 2024.2

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

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

DOI： 10.2169/internalmedicine.2392-23

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

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

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 2023.10

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

CHARACTERISTICS OF GUT MICROBIOTA ASSOCIATED WITH FUNCTIONAL CURE IN CHRONIC HEPATITIS B PATIENTS WITH HBEAG- NEGATIVE; POSSIBLE INHIBITION OF HEPATITIS B VIRUS BY BUTYRATE- PRODUCING BACTERIA

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

HEPATOLOGY Vol. 78 page： S594 - S594 2023.10

PREVALENCE OF INTRANUCLEAR LIPID DROPLETS IN NONALCOHOLIC FATTY LIVER DISEASE

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

HEPATOLOGY Vol. 78 page： S1125 - S1126 2023.10

INTESTINAL MICROBIOME ASSOCIATED WITH EFFICACY OF ATEZOLIZUMAB AND BEVACIZUMAB THERAPY FOR HEPATOCELLULAR CARCINOMA

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

HEPATOLOGY Vol. 78 page： S1273 - S1273 2023.10

CLINICAL OUTCOMES OF POROUS GLASS MEMBRANE PUMPING EMULSIFICATION DEVICE IN TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA

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

HEPATOLOGY Vol. 78 page： S1814 - S1814 2023.10

CLINICAL FEATURES AND OUTCOME OF LIVER INJURY INDUCED BY IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH ADVANCED MALIGNANCIES

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

HEPATOLOGY Vol. 78 page： S636 - S636 2023.10

Clinical course and prognosis of patients with hepatocellular carcinoma and haemophilia

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

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY Vol. 35 ( 10 ) page： 1211 - 1215 2023.10

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

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

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

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

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

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES Vol. 30 ( 6 ) page： 834 - 842 2023.6

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

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

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

SCIENTIFIC REPORTS Vol. 13 ( 1 ) page： 6851 2023.4

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

A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes

Rubio-Navarro, A; Gómez-Banoy, N; Stoll, L; Dündar, F; Mawla, AM; Ma, LK; Cortada, E; Zumbo, P; Li, A; Reiterer, M; Montoya-Oviedo, N; Homan, EA; Imai, N; Gilani, A; Liu, CY; Naji, A; Yang, B; Chong, ACN; Cohen, DE; Chen, SB; Cao, JL; Pitt, GS; Huising, MO; Betel, D; Lo, JC

NATURE CELL BIOLOGY Vol. 25 ( 4 ) page： 565 - + 2023.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Cell Biology

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.

DOI： 10.1038/s41556-023-01103-1

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

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

NUTRIENTS Vol. 15 ( 6 ) 2023.3

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

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

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

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 38 ( 2 ) page： 251 - 258 2023.2

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

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

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

DIGESTIVE DISEASES AND SCIENCES Vol. 68 ( 1 ) page： 155 - 163 2023.1

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

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

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

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

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

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

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

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

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

HEPATOLOGY Vol. 76 page： S1181 - S1181 2022.10

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

Honda, TH; Ishigami, M; Kato, A; Yokoyama, S; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Yasuda, S; Toyoda, H; Kumada, T; Ishikawa, T; Kawashima, H

HEPATOLOGY Vol. 76 page： S262 - S263 2022.10

CLINICAL COURSE AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEMOPHILIA

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

HEPATOLOGY Vol. 76 page： S1330 - S1330 2022.10

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

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

Nutrition and cancer page： 1 - 10 2022.3

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：European journal of gastroenterology & hepatology

OBJECTIVE: In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. METHODS: We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. RESULTS: Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m2 and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. CONCLUSION: Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

DOI： 10.1097/MEG.0000000000002303

Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis

Ritter Megan J., Amano Izuki, Imai Norihiro, De Oliveira Lorraine Soares, Vella Kristen R., Hollenberg Anthony N.

MOLECULAR METABOLISM Vol. 53 page： 101315 2021.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Molecular Metabolism

Objective: The nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT, also known as NCOR2) play critical and specific roles in nuclear receptor action. NCOR1, both in vitro and in vivo specifically regulates thyroid hormone (TH) action in the context of individual organs such as the liver, and systemically in the context of the hypothalamic-pituitary-thyroid (HPT) axis. In contrast, selective deletion of SMRT in the liver or globally has shown that it plays very little role in TH signaling. However, both NCOR1 and SMRT have some overlapping roles in hepatic metabolism and lipogenesis. Here, we determine the roles of NCOR1 and SMRT in global physiologic function and find if SMRT could play a compensatory role in the regulation of TH action, globally. Methods: We used a postnatal deletion strategy to disrupt both NCOR1 and SMRT together in all tissues at 8–9 weeks of age in male and female mice. This was performed using a tamoxifen-inducible Cre recombinase (UBC-Cre-ERT2) to KO (knockout) NCOR1, SMRT, or NCOR1 and SMRT together. We used the same strategy to KO HDAC3 in male and female mice of the same age. Metabolic parameters, gene expression, and thyroid function tests were analyzed. Results: Surprisingly, adult mice that acquired NCOR1 and SMRT deletion rapidly became hypoglycemic and hypothermic and perished within ten days of deletion of both corepressors. Postnatal deletion of either NCOR1 or SMRT had no impact on mortality. NCOR1/SMRT KO mice rapidly developed hepatosteatosis and mild elevations in liver function tests. Additionally, alterations in lipogenesis, beta oxidation, along with hepatic triglyceride and glycogen levels suggested defects in hepatic metabolism. The intestinal function was intact in the NCOR1/SMRT knockout (KO) mice. The KO of HDAC3 resulted in a distinct phenotype from the NCOR1/SMRT KO mice, whereas none of the HDAC3 KO mice succumbed after tamoxifen injection. Conclusions: The KO of NCOR1 and SMRT rapidly leads to significant metabolic abnormalities that do not survive – including hypoglycemia, hypothermia, and weight loss. Hepatosteatosis rapidly developed along with alterations in hepatic metabolism suggesting a contribution to the dramatic phenotype from liver injury. Glucose production and absorption were intact in NCOR1/SMRT KO mice, demonstrating a multifactorial process leading to their demise. HDAC3 KO mice have a distinct phenotype from the NCOR1/SMRT KO mice—which implies that NCOR1/SMRT together regulate a critical pathway that is required for survival in adulthood and is separate from HDAC3.

DOI： 10.1016/j.molmet.2021.101315

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

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

ANTICANCER RESEARCH Vol. 41 ( 11 ) page： 5817 - 5820 2021.11

Language：Japanese 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

The absence of large portal collateral vessels is concerned with spontaneous improvement of cirrhotic portal vein thrombosis.

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

Hepatology research : the official journal of the Japan Society of Hepatology 2021.10

Immune-related liver injury is a poor prognostic factor in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

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

Cancer investigation page： 1 - 31 2021.10

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

Ito Takanori, Ishigami Masatoshi, Yamamoto Takafumi, Mizuno Kazuyuki, Yamamoto Kenta, Imai Norihiro, Ishizu Yoji, Honda Takashi, Kawashima Hiroki, Yasuda Satoshi, Toyoda Hidenori, Yokota Kenji, Hase Tetsunari, Nishio Naoki, Maeda Osamu, Kato Masashi, Hashimoto Naozumi, Hibi Hideharu, Kodera Yasuhiro, Sone Michihiko, Ando Yuichi, Akiyama Masashi, Shimoyama Yoshie, Fujishiro Mitsuhiro

HEPATOLOGY INTERNATIONAL Vol. 15 ( 5 ) page： 1278 - 1287 2021.10

Language：Japanese 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

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

TakashiHonda, MasatoshiIshigami, ShinyaYokoyama, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Ishizu Yoji, Ishikawa Tetsuya, Fujishiro Mitsuhiro

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

The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with hemophiliaHCC after HCV eradication in hemophilia.

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 2021.9

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

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

Muto Hisanori, Ito Takanori, Tanaka Taku, Yokoyama Shinya, Yamamoto Kenta, Imai Norihiro, Ishizu Yoji, Maeda Keiko, Honda Takashi, Ishikawa Tetsuya, Kato Asuka, Ohshiro Taichi, Kano Fumiya, Yamamoto Akihito, Sakai Kiyoshi, Hibi Hideharu, Ishigami Masatoshi, Fujishiro Mitsuhiro

SCIENTIFIC REPORTS Vol. 11 ( 1 ) page： 18778 2021.9

Language：Japanese 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

Ishigami Masatoshi, Honda Takashi, Ishizu Yoji, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Kamei Hideya, Ogura Yasuhiro, Fujishiro Mitsuhiro

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

Language：Japanese 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

Upregulation of Thioesterase Superfamily Member 2 in Skeletal Muscle Promotes Hepatic Steatosis and Insulin Resistance.

Imai N, Nicholls HT, Alves-Bezerra M, Li Y, Ivanova AA, Ortlund EA, Cohen DE

Hepatology (Baltimore, Md.) 2021.8

The impact of hepatitis C virus eradication on hepatocarcinogenesis in haemophiliacs

Inukai Yosuke, Imai Norihiro, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishigami Masatoshi

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

Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice

Li Yue, Imai Norihiro, Nicholls Hayley T., Roberts Blaine R., Goyal Samaksh, Krisko Tibor I., Ang Lay-Hong, Tillman Matthew C., Roberts Anne M., Baqai Mahnoor, Ortlund Eric A., Cohen David E., Hagen Susan J.

NATURE COMMUNICATIONS Vol. 12 ( 1 ) page： 3493 2021.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nature Communications

In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure.

DOI： 10.1038/s41467-021-23595-x

Prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhosis with fasting plasma glucose level of <126mg/dL

MATSUMOTO Naoki, ARASE Yasuji, SEKO Yuya, IMAI Norihiro, KAWAMURA Yusuke, SEZAKI Hitomi, HOSAKA Tetsuya, AKUTA Norio, KOBAYASHI Mariko, KOBAYASHI Masahiro, SUZUKI Yoshiyuki, SAITO Satoshi, SUZUKI Fumitaka, IKEDA Kenji, KUMADA Hiromitsu, AIDA Kaoru, KOBAYASHI Tetsuro

Vol. 42 ( 6 ) page： 558 - 563 2012.6

PROLONGED NEW ONSET OF HEPATOCELLULAR CARCINOMA FROM NON-ALCOHOLIC FATTY LIVER DISEASE IN JAPANESE LARGE POPULATION

Kawamura, Y; Arase, Y; Ikeda, K; Seko, Y; Imai, N; Hosaka, T; Kobayashi, M; Saitoh, S; Sezaki, H; Akuta, N; Suzuki, F; Suzuki, Y; Ohmoto, Y; Amakawa, K; Tsuji, H; Kumada, H

HEPATOLOGY Vol. 54 page： 1364A - 1364A 2011.10

STAGE PROGRESSION OF SMALL HEPATOCELLULAR CARCINOMA AFTER POTENTIALLY RADICAL THERAPY - COMPARISONS OF RADIOFREQUENCY ABLATION AND SURGERY USING MARKOV MODEL

Ikeda, K; Seko, Y; Imai, N; Hirakawa, M; Kawamura, Y; Sezaki, H; Hosaka, T; Akuta, N; Kobayashi, M; Saitoh, S; Suzuki, F; Suzuki, Y; Arase, Y; Kumada, H

HEPATOLOGY Vol. 52 ( 4 ) page： 1184A - 1184A 2010.10

TUMOR SIZE OF HEPATOCELLULAR CARCINOMA AT DETECTION IS LARGER IN PATIENTS WITH HBV THAN THOSE WITH HCV

Imai, N; Ikeda, K; Seko, Y; Hirakawa, M; Kawamura, Y; Kobayashi, M; Hosaka, T; Sezaki, H; Akuta, N; Saitoh, S; Suzuki, F; Suzuki, Y; Arose, Y; Kumada, H

HEPATOLOGY Vol. 52 ( 4 ) page： 1180A - 1180A 2010.10

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

Fumitaka Mizuno, Norihiro Imai, Kazuyuki Mizuno, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Hiroki Kawashima

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

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

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

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. International journal

Shinya Yokoyama, Takashi Honda, Yoji Ishizu, Norihiro Imai, Takanori Ito, Kenta Yamamoto, Kazuyuki Mizuno, Tetsuhito Kojima, Naoyoshi Kariya, Masanao Nakamura, Hiroki Kawashima

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

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

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

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

Takanori Ito, Kazuyuki Mizuno, Takafumi Yamamoto, Tsukasa Yasuda, Shinya Yokoyama, Kenta Yamamoto, Norihiro Imai, Yoji Ishizu, Takashi Honda, Masayo Hama, Tomomi Kataoka, Tomoya Shimokata, Yuichi Ando, Hiroki Kawashima

Hepatology research : the official journal of the Japan Society of Hepatology 2024.4

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

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

Identification of the Microbiome Associated with Prognosis in Patients with Chronic Liver Disease. International journal

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

Microorganisms Vol. 12 ( 3 ) 2024.3

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

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

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

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

Internal medicine (Tokyo, Japan) Vol. 63 ( 1 ) page： 57 - 61 2024

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

当院における免疫チェックポイント阻害薬投与によるHBV再活性化リスクの検討

水野和幸, 伊藤隆徳, 山本崇文, 横山晋也, 山本健太, 今井則博, 石津洋二, 本多隆, 石上雅敏, 川嶋啓揮

日本消化器病学会雑誌 Vol. 120 ( 臨増総会 ) page： A309 - A309 2023.3

Endoscopic injection sclerotherapy with polidocanol for cardiac varices in children and adolescents. International journal

Shinya Yokoyama, Yoji Ishizu, Takashi Honda, Norihiro Imai, Takanori Ito, Kenta Yamamoto, Akinari Hinoki, Wataru Sumida, Chiyoe Shirota, Takahisa Tainaka, Satoshi Makita, Kazuki Yokota, Hiroo Uchida, Masatoshi Ishigami

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

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

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

Decreased appetite is associated with the presence of sarcopenia in patients with cirrhosis. International journal

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

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

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

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

Factors associated with the progression of myosteatosis in patients with cirrhosis. International journal

Yoji Ishizu, Masatoshi Ishigami, Takashi Honda, Norihiro Imai, Takanori Ito, Kenta Yamamoto, Shinya Yokoyama, Tetsuya Ishikawa, Mitsuhiro Fujishiro

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

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

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

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

Norihiro Imai, Masatoshi Ishigami, Yumi Oie, Motoki Kumagai, Yosuke Inukai, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Hiroki Kawashima

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

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

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. International journal

Takafumi Yamamoto, Takanori Ito, Kazuyuki Mizuno, Yokoyama Shinya, Kenta Yamamoto, Norihiro Imai, Yoji Ishizu, Takashi Honda, Hiroki Kawashima, Toshinori Matsui, Tetsunari Hase, Naozumi Hashimoto, Masatoshi Ishigami

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

非小細胞肺癌に対する抗Programmed Death-Ligand 1抗体治療で発症した免疫関連硬化性胆管炎の1例

山本崇文, 伊藤隆徳, 松田宜賢, 犬飼庸介, 杉山由晃, 吉岡直輝, 水野和幸, 武藤久哲, 横山晋也, 山本健太, 今井則博, 石津洋二, 本多隆, 石上雅敏

日本消化器病学会東海支部例会プログラム抄録集 Vol. 136回 page： 56 - 56 2022.5

肝硬変患者の予後予測における脂肪成分の少ない骨格筋を用いた骨格筋量の有用性

石津洋二, 松田宜賢, 犬飼庸介, 山本崇文, 杉山由晃, 水野和幸, 吉岡直輝, 武藤久哲, 横山晋也, 山本健太, 伊藤隆徳, 今井則博, 本多隆, 石上雅敏

肝臓 Vol. 63 ( Suppl.1 ) page： A348 - A348 2022.4

肝疾患における核内脂肪滴の2つの異なる役割

今井則博, 横山晋也, 山本健太, 伊藤隆徳, 石津洋二, 本多隆, 石上雅敏

肝臓 Vol. 63 ( Suppl.1 ) page： A354 - A354 2022.4

肝硬変患者における質を考慮したより適切な骨格筋量評価の提案

杉山由晃, 石津洋二, 山本崇文, 犬飼庸介, 吉岡直輝, 水野和幸, 武藤久哲, 横山晋也, 山本健太, 伊藤隆徳, 今井則博, 本多隆, 石上雅敏, 藤城光弘

肝臓 Vol. 62 ( Suppl.2 ) page： A576 - A576 2021.9

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

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

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

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

Ishizu Yoji, Ishigami Masatoshi, Honda Takashi, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Fujishiro Mitsuhiro

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

核酸アナログ治療中止可能予測因子とHBVコア変異の関係

本多隆, 石上雅敏, 山本崇文, 犬飼庸介, 杉山由晃, 吉岡直輝, 水野和幸, 武藤久哲, 横山晋也, 山本健太, 伊藤隆徳, 今井則博, 石津洋二, 石川哲也, 藤城光弘

肝臓 Vol. 62 ( Suppl.1 ) page： A344 - A344 2021.4

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

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

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

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

Yamamoto Takafumi, Imai Norihiro, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Honda Takashi, Okamoto Shuichi, Kanematsu Takeshi, Suzuki Nobuaki, Matsushita Tadashi, Ishigami Masatoshi, Fujishiro Mitsuhiro

HAEMOPHILIA Vol. 27 ( 1 ) page： 100 - 107 2021.1

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

Ito Takanori, Ishigami Masatoshi, Morooka Hikaru, Yamamoto Kenta, Imai Norihiro, Ishizu Yoji, Honda Takashi, Nishimura Daisaku, Tada Toshifumi, Yasuda Satoshi, Toyoda Hidenori, Kumada Takashi, Fujishiro Mitsuhiro

SCIENTIFIC REPORTS Vol. 10 ( 1 ) page： 17812 2020.10

Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine

Tillman Matthew C., Imai Norihiro, Li Yue, Khadka Manoj, Okafor C. Denise, Juneja Puneet, Adhiyaman Akshitha, Hagen Susan J., Cohen David E., Ortlund Eric A.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 117 ( 36 ) page： 22080 - 22089 2020.9

Them1 Binds to Free Fatty Acids and is Allosterically Regulated by Lysophosphatidylcholine to Control Fatty Acyl-CoA Hydrolysis in Brown Adipose Tissue

Tillman Matthew, Li Yue, Khadka Manoj, Imai Norihiro, Adhiyaman Akshitha, Juneja Puneet, Hagen Susan, Cohen David, Ortlund Eric

FASEB JOURNAL Vol. 34 2020.4

Thioesterase Superfamily Member 1 Undergoes Stimulus-coupled Reorganization to Regulate Metabolic Activity in Brown Adipose Tissue

Li Yue, Imai Norihiro, Goyal Samaksh, Nicholls Hayley, Krisko Tibor, Baqai Mahnoor, Ang Lay-Hong, Tillman Matthew, Ortlund Eric, Cohen David, Hagen Susan

FASEB JOURNAL Vol. 34 2020.4

Hepatology Highlights.

Shah PA, Lau DTY, Russo NW, Brown RS Jr, Maiers JL, Schwartz RE, Imai N, Krisko TI, Navarro-Corcuera A, Jalan-Sakrikar N, Pisa JF, Jesudian AB, Tafesh ZH, Fortune BE, Kostallari E

Hepatology (Baltimore, Md.) Vol. 71 ( 1 ) page： 1 - 3 2020.1

Trimming the Fat: Acetyl-CoA Carboxylase Inhibition for the Management of NAFLD.

Imai N, Cohen DE

Hepatology (Baltimore, Md.) Vol. 68 ( 6 ) page： 2062 - 2065 2018.12

Hepatocyte-specific depletion of ubiquitin regulatory X domain containing protein 8 accelerates fibrosis in a mouse non-alcoholic steatohepatitis model

Imai Norihiro, Suzuki Michitaka, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Hayashi Kazuhiko, Ishigami Masatoshi, Hirooka Yoshiki, Ishikawa Tetsuya, Goto Hidemi, Fujimoto Toyoshi

HISTOCHEMISTRY AND CELL BIOLOGY Vol. 148 ( 3 ) page： 219 - 227 2017.9

Hepatocyte-Specific Depletion of UBXD8 Induces Periportal Steatosis in Mice Fed a High-Fat Diet

Imai Norihiro, Suzuki Michitaka, Hayashi Kazuhiko, Ishigami Masatoshi, Hirooka Yoshiki, Abe Takaya, Shioi Go, Goto Hidemi, Fujimoto Toyoshi

PLOS ONE Vol. 10 ( 5 ) page： e0127114 2015.5

Transarterial chemoembolization for hepatocellular carcinoma: A review of techniques.

Imai N, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Goto H

World journal of hepatology Vol. 6 ( 12 ) page： 844 - 50 2014.12

当院におけるHBV感染と肝発癌の検討

荒川恭宏, 加藤幸一郎, 新家卓郎, 今井則博, 阿知波宏一, 山田恵一, 石津洋二, 葛谷貞二, 本多隆, 林和彦, 石上雅敏, 後藤秀実

肝臓 Vol. 55 ( Suppl.2 ) page： A599 - A599 2014.9

The relationship between the fever and the disappearance or decrease of lesion contrast on contrast enhanced CT images after 2 weeks of sorafenib treatment for patients with advanced hepatocellular carcinoma

KUZUYA Teiji, ISHIGAMI Masatoshi, NIINOMI Takurou, IMAI Norihiro, ACHIWA Kouichi, ARAKAWA Takahiro, YAMADA Keiichi, NAKANO Satoshi, ISHIZU Yoji, HONDA Takashi, HAYASHI Kazuhiko, ISHIKAWA Tetsuya, NAKANO Isao, KATANO Yoshiaki, ITOH Akihiro, HIROOKA Yoshiki, GOTO Hidemi

Kanzo Vol. 54 ( 7 ) page： 505 - 506 2013.5

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

We investigated the relationship between the fever and the disappearance or decrease of lesion contrast on contrast enhanced CT images after 2 weeks of sorafenib treatment for patients with advanced hepatocellular carcinoma (HCC). Subjects were 64 patients who began sorafenib therapy. Contrast enhanced CT images were taken at baseline and after 2 weeks of sorafenib treatment. In patients with fever, the ratio of patients demonstrating the disappearance or decrease of lesion contrast on contrast enhanced CT images was significantly higher than in those without fever (91.3% and 61.0%, respectively, p=0.010, Fisher's exact probability test). The results suggested the relationship between the fever and contrast change on contrast enhanced CT.<br>

DOI： 10.2957/kanzo.54.505

Transcatheter arterial chemotherapy with miriplatin for hepatocellular carcinoma patients with chronic renal failure: report of three cases.

Imai N, Ikeda K, Seko Y, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Kumada H

Gut and liver Vol. 7 ( 2 ) page： 246 - 51 2013.3

Clinical trial of percutaneous radio frequency ablation therapy by two-step insertion method using VirtuTRAX<sup>TM</sup> instrument navigator

Kuzuya Teiji, Hayashi Kazuhiko, Ishigami Masatoshi, Ishikawa Tetsuya, Nakano Isao, Katano Yoshiaki, Itoh Akihiro, Hirooka Yoshiki, Izumi Namiki, Goto Hidemi, Ishizu Yoji, Niinomi Takurou, Imai Norihiro, Achiwa Kouichi, Arakawa Takahiro, Yamada Keiichi, Nakano Satoshi, Honda Takashi

Kanzo Vol. 54 ( 12 ) page： 850 - 853 2013

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

We performed percutaneous radio frequency ablation (RFA) therapy by two-step insertion method using VirtuTRAX<sup>TM</sup> (GE Healthcare, USA) instrument navigator. Subjects were 16 patients (23 nodules) with hepatocellular carcinoma. VirtuTRAX<sup>TM</sup> position sensor was attached to the hilt of 14-gauge outer needle. In all cases, we could perform 17- gauge Cool-tip RFA without the positional gap between the virtual tract and the actual needle which was caused by the deflection of the needle. The reasons without causing the positional gap were that the outer needle was more rigid than Cool-tip needle, and that it was inserted using initial insertion of a 21-gauge guided needle. RFA by two-step insertion method using VirtuTRAX<sup>TM</sup> is suggested to be more safe and effective than conventional RFA.

DOI： 10.2957/kanzo.54.850

An Increase in Lesion Density can Predict Lower Local Recurrence after Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

Imai Norihiro, Katano Yoshiaki, Kuzuya Teiji, Honda Takashi, Hayashi Kazuhiko, Ishigami Masatoshi, Itoh Akihiro, Hirooka Yoshiki, Goto Hidemi

HEPATO-GASTROENTEROLOGY Vol. 60 ( 125 ) page： 965 - 970 2013

Efficacy of reduction therapy of natural human β-interferon and ribavirin in elderly patients with chronic hepatitis C, genotype 2 and high virus load

ARASE Yasuji, SUZUKI Yoshiyuki, SUZUKI Fumitaka, AKUTA Norio, SEZAKI Hitomi, KAWAMURA Yusuke, KOBAYASHI Masahiro, IMAI Norihiro, SEKO Yuya, HOSAKA Tetsuya, MATSUMOTO Naoki, SAITO Satoshi, IKEDA Kenji, KOBAYASHI Mariko, KUMADA Hiromitsu

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 42 ( 8 ) page： 750 - 756 2012.8

Combination therapy with transcatheter arterial infusion chemotherapy using miriplatin and percutaneous radiofrequency ablation for hepatocellular carcinoma

IMAI Norihiro, IKEDA Kenji, SEKO Yuya, HARA Tasuku, OHNO Atsushi, MATSUMOTO Naoki, KAWAMURA Yusuke, HOSAKA Tetsuya, KOBAYASHI Masahiro, SAITOH Satoshi, SEZAKI Hitomi, AKUTA Norio, SUZUKI Fumitaka, SUZUKI Yoshiyuki, ARASE Yasuji, KUMADA Hiromitsu

Kanzo Vol. 53 ( 6 ) page： 351-354 - 354 2012.6

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

Miriplatin is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We retrospectively evaluated the efficacy of combination therapy with transcatheter arterial infusion chemotherapy using miriplatin and percutaneous radiofrequency ablation for HCC in 11 patients. Immediately after transcatheter arterial infusion chemotherapy using miriplatin, we performed radiofrequency ablation. The greatest long-axis and short-axis dimensions of the area coagulated after combination therapy were 42 mm (35-80 mm) and 34 mm (32-60 mm), respectively. During follow-up (median 12 months), there was no recurrence from the same subsegment. No serious adverse events were observed. These results suggested that using the combination therapy, it is possible to finish one treatment session for patient with HCC.<br>

DOI： 10.2957/kanzo.53.351

Prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhosis with fasting plasma glucose level of <126 mg/dL

Matsumoto, N; Arase, Y; Seko, Y; Imai, N; Kawamura, Y; Sezaki, H; Hosaka, T; Akuta, N; Kobayashi, M; Kobayashi, M; Suzuki, Y; Saito, S; Suzuki, F; Ikeda, K; Kumada, H; Aida, K; Kobayashi, T

HEPATOLOGY RESEARCH Vol. 42 ( 6 ) page： 558 - 563 2012.6

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

Aim: The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of <126mg/dL. Methods: A total of 263 patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) positive liver cirrhosis, FPG level of <126mg/dL, and had diabetes status evaluated by the use of 75-g oral glucose tolerance test (OGTT), were enrolled in this study. Plasma glucose and insulin levels were analyzed periodically for 3h after oral glucose loading. Diabetes was defined as a 2-h post-load glucose on the OGTT of ≥200mg/dL. The prevalence of diabetes by use of OGTT and predictive factors for diabetes were evaluated by the use of the Mann-Whitney U-test, Fisher's exact probability test or multivariate analysis by logistic regression. Hypoalbuminemia was defined as serum albumin level of <3.9g/dL. Elevated indocyanine green retention rate at 15min (ICG R15) was regarded as ≥ 25%. Results: Out of 263 patients, 44 (16.7%) were diagnosed as having diabetes. Multivariate analysis showed that diabetes occurred when patients had hypoalbuminemia of <3.9g/dL (odds ratio [OR] 2.33; 95% confidential interval [CI]=1.04-5.24; P=0.040) and ICG R15 of <25% (OR 2.36; 95%CI=1.01-5.58). Conclusions: Hypoalbuminemia and elevated ICG R15 in hepatitis virus related cirrhotic patients with FPG level of <126mg/day enhance diabetes pattern after OGTT with significant difference. © 2012 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2011.00957.x

Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderlv patients

ARASE Yasuji, KOBAYASHI Mariko, SUZUKI Fumitaka, SUZUKI Yoshiyuki, KAWAMURA Yusuke, AKUTA Norio, IMAI Norihiro, KOBAYASHI Masahiro, SEZAKI Hitomi, MATSUMOTO Naoki, SAITO Satoshi, HOSAKA Tetsuya, IKEDA Kenji, KUMADA Hiromitsu, OHMOTO Yuki, AMAKAWA Kazuhisa, HSIEH Shiun Dong, OGAWA Kyoko, TANABE Maho, TSUJI Hiroshi, KOBAYASHI Tetsuro

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 42 ( 3 ) page： 264 - 272 2012.3

Transcatheter arterial chemotherapy using miriplatin-lipiodol suspension with or without embolization for unresectable hepatocellular carcinoma.

Imai N, Ikeda K, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Kumada H

Japanese journal of clinical oncology Vol. 42 ( 3 ) page： 175 - 82 2012.3

Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients.

Arase Y, Kobayashi M, Suzuki F, Suzuki Y, Kawamura Y, Akuta N, Imai N, Kobayashi M, Sezaki H, Matsumoto N, Saito S, Hosaka T, Ikeda K, Kumada H, Ohmoto Y, Amakawa K, Hsieh SD, Ogawa K, Tanabe M, Tsuji H, Kobayashi T

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 42 ( 3 ) page： 264 - 272 2012.3

Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma.

Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, Kobayashi M, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ohmoto Y, Amakawa K, Tsuji H, Kumada H

The American journal of gastroenterology Vol. 107 ( 2 ) page： 253 - 61 2012.2

Transcatheter arterial chemotherapy with miriplatin for patients with hepatocellular carcinoma and chronic renal failure

IMAI Norihiro, IKEDA Kenji, SEKO Yuya, MATSUMOTO Naoki, KAWAMURA Yusuke, HOSAKA Tetsuya, KOBAYASHI Masahiro, SAITOH Satoshi, SEZAKI Hitomi, AKUTA Norio, SUZUKI Fumitaka, SUZUKI Yoshiyuki, ARASE Yasuji, KUMADA Hiromitsu

Nippon Shokakibyo Gakkai Zasshi Vol. 108 ( 11 ) page： 1872-1878 - 1878 2011.11

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

Miriplatin is a novel lipophilic platinum complex developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, there is no reliable data regarding clinical toxicity of miriplatin in HCC patients with chronic renal failure. We retrospectively evaluated the safety and efficacy of transcatheter arterial chemotherapy with miriplatin in 67 HCC patients with chronic renal failure (estimated glomerular filtration rate [GFR] by the Cockcroft-Gault equation <60m<i>l</i>/min). Estimated GFR within 2 months after miriplatin administration did not decrease significantly by the Wilcoxon signed rank test (pretreatment;46m<i>l</i>/min, 1 month;48m<i>l</i>/min;<i>P</i>=0.019, 2 months;45m<i>l</i>/min;<i>P</i>=0.619 [<i>P</i><0.003 was significant by the Bonferroni correction]). Complete response in terms of tumor necrosis was achieved in 14 of 67 patients and no serious adverse events were observed. These results suggested that transcatheter arterial chemotherapy with miriplatin can be used safely for HCC patients with chronic renal failure.<br>

DOI： 10.11405/nisshoshi.108.1872

Transcatheter arterial chemotherapy with miriplatin for patients with hepatocellular carcinoma and chronic renal failure

Imai N.

Journal of Japanese Society of Gastroenterology Vol. 108 ( 11 ) page： 1872-1878 2011.11

Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy

ARASE Yasuji, SUZUKI Fumitaka, KAWAMURA Yusuke, SUZUKI Yoshiyuki, KOBAYASHI Masahiro, MATSUMOTO Naoki, AKUTA Norio, SEZAKI Hitomi, HOSAKA Tetsuya, OGAWA Kyoko, IMAI Norihiro, SEKO Yuya, SAITO Satoshi, IKEDA Kenji, KOBAYASHI Mariko, KUMADA Hiromitsu

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 41 ( 10 ) page： 946 - 954 2011.10

A case of intractable hepatic encephalopathy successfully treated by oral administration of vancomycin hydrochloride, with subsequent improvement of hepatic function reserve enabling transcatheter arterial chemoembolization against hepatocellular carcinoma

Kuzuya T.

Japanese Journal of Cancer and Chemotherapy Vol. 38 ( 6 ) page： 995 - 997 2011.6

Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analogues treatment in chronic hepatitis B

HOSAKA Tetsuya, SUZUKI Fumitaka, KOBAYASHI Masahiro, SEKO Yuya, IMAI Norihiro, HIRAKAWA Miharu, KAWAMURA Yusuke, SEZAKI Hitomi, AKUTA Norio, SUZUKI Yoshiyuki, SAITOH Satoshi, ARASE Yasuji, IKEDA Kenji, KOBAYASHI Mariko, KUMADA Hiromitsu

Kanzo Vol. 52 ( 4 ) page： 255 - 257 2011.6

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

Clearance of HBsAg is considered the ultimate goal in the treatment for chronic hepatitis B. We analyzed clinical factors associated with HBsAg clearance during long-term nucleot(s)ide analogue treatment. By univariate analysis, HBV genotype, family history of HBV infection, previous IFN therapy, HBeAg clearance at 6 months, and undetectable HBV DNA at 6 months were significant predictive factors. By multivariate analysis, HBV genotype, previous IFN therapy, HBeAg clearance at 6 months, and undetectable HBV DNA at 6 months were independent and significant predictive factors of HBsAg clearance. We conclude that patients with genotype A have high probability of HBsAg clearance, and it seems that not only the antiviral potential of nucleot(s)ide analogue but host immune response is needed to achieve HBsAg clearance.<br>

DOI： 10.2957/kanzo.52.255

Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus

Arase Y

Hepatology Research Vol. 41 ( 6 ) page： 524 - 529 2011.6

Stage progression of small hepatocellular carcinoma after radical therapy: comparisons of radiofrequency ablation and surgery using the Markov model.

Ikeda K, Kobayashi M, Kawamura Y, Imai N, Seko Y, Hirakawa M, Hosaka T, Sezaki H, Akuta N, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Kumada H

Liver international : official journal of the International Association for the Study of the Liver Vol. 31 ( 5 ) page： 692 - 9 2011.5

Effect of early antiviral agent therapy (NS3 and NS5A inhibitors) in chronic hepatitis C null responders

SUZUKI Yoshiyuki, SEZAKI Hitomi, AKUTA Norio, SUZUKI Fumitaka, SEKO Hiroya, IMAI Norihiro, HIRAKAWA Miharu, KAWAMURA Yuusuke, HOSAKA Tetsuya, KOBAYASHI Masahiro, SAITOH Satoshi, ARASE Yasuji, IKEDA Kenji, KOBAYASHI Mariko, KUMADA Hiromitsu

Kanzo Vol. 52 ( 2 ) page： 147 - 149 2011.4

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

To further improve therapeutic effect on chronic hepatitis C, we have administered NS3 inhibitor and NS5A inhibitor together, and examined effects of early antiviral agent therapy. The subjects were five cases where interferon is ineffective (null responders). The NS5A and NS3 inhibitors are oral drugs and were daily administered for 24 weeks. Figure 1 shows time-dependent change of the number of viruses after the therapy started, and rapid decrease of viruses is recognized. Within 12 hours, HCV-RNA decreased by more than 2 log IU/m<i>l</i> in every patient. Two patients became negative for the virus by the 15th day after the therapy started. Furthermore, 80% of cases by the 28th day and all the cases by the 56th day became negative. The new therapy has manifested excellent early antiviral effect.<br>

DOI： 10.2957/kanzo.52.147

Efficacy and safety of combination therapy of natural human interferon beta and ribavirin in chronic hepatitis C patients.

Arase Y, Suzuki Y, Suzuki F, Matsumoto N, Akuta N, Imai N, Seko Y, Sezaki H, Kawamura Y, Kobayashi M, Hosaka T, Saito S, Ikeda K, Kobayashi M, Kumada H

Internal medicine (Tokyo, Japan) Vol. 50 ( 19 ) page： 2083 - 8 2011

Previous chemoembolization response after transcatheter arterial chemoembolization (TACE) can predict the anti-tumor effect of subsequent TACE with miriplatin in patients with recurrent hepatocellular carcinoma.

Imai N, Ikeda K, Seko Y, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Arase Y, Kumada H

Oncology Vol. 80 ( 3-4 ) page： 188 - 94 2011

Administration of interferon for two or more years decreases early stage hepatocellular carcinoma recurrence rate after radical ablation : A retrospective study of hepatitis C virus-related liver cancer

IKEDA Kenji, KOBAYASHI Masahiro, SEKO Yuya, IMAI Norihiro, HIRAKAWA Miharu, KAWAMURA Yusuke, SEZAKI Hitomi, HOSAKA Tetsuya, AKUTA Norio, SAITOH Satoshi, SUZUKI Fumitaka, SUZUKI Yoshiyuki, ARASE Yasuji, KUMADA Hiromitsu

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 40 ( 12 ) page： 1168-1175 2010.12

Transcatheter arterial chemotherapy with miriplatin for patients with hepatocellular carcinoma and Child-Pugh B liver cirrhosis

IMAI Norihiro, IKEDA Kenji, SEKO Yuya, HIRAKAWA Miharu, KAWAMURA Yusuke, HOSAKA Tetsuya, KOBAYASHI Masahiro, SAITOH Satoshi, SEZAKI Hitomi, AKUTA Norio, SUZUKI Fumitaka, SUZUKI Yoshiyuki, ARASE Yasuji, KUMADA Hiromitsu

Kanzo Vol. 51 ( 12 ) page： 758 - 760 2010.12

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

Miriplatin is a novel lipophilic platinum complex developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting severe liver cirrhosis, there is no prospective data regarding clinical toxicity of miriplatin in HCC patients with severe cirrhosis. We retrospectively evaluated the safety and efficacy of transcatheter arterial chemotherapy with miriplatin in 34 HCC patients with severe liver cirrhosis (Child-Pugh grade B). An anti-tumor effect of complete response was achieved in 8 of 34 patients and no serious adverse events were observed. These results suggested that transcatheter arterial chemotherapy with miriplatin can be used safety for HCC patients with Child-Pugh B liver cirrhosis.<br>

DOI： 10.2957/kanzo.51.758

A case of metastatic pancreatic cancer with a remarkable response to combination therapy of gemcitabine and adoptive immune cell therapy

Imai N.

Japanese Journal of Cancer and Chemotherapy Vol. 37 ( 3 ) page： 527 - 529 2010.3

High Incidence of Colonic Perforation During Colonoscopy in Hemodialysis Patients With End-Stage Renal Disease

Imai Norihiro, Takeda Kinichi, Kuzuya Teiji, Utsunomiya Setsuo, Takahashi Hiroshi, Kasuga Hirotake, Asai Masami, Yamada Michiko, Tanikawa Yutaka, Goto Hidemi

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8 ( 1 ) page： 55 - 59 2010.1

A case of hepatitis b-related multiple hepatocellular carcinomas, most of which lead to necrosis possibly due to the implantation of an arterial infusion catheter

Kuzuya T.

Japanese Journal of Cancer and Chemotherapy Vol. 36 ( 12 ) page： 2377 - 2379 2009.11

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