Faculty Profiles - IMAI Norihiro

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

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

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

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

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

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

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

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

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

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