Updated on 2022/03/23

写真a

 
ITO Takanori
 
Organization
Nagoya University Hospital Gastroenterology Assistant professor of hospital
Title
Assistant professor of hospital

Degree 1

  1. 博士(医学) ( 2018.3   名古屋大学 ) 

Research Interests 5

  1. 脂肪肝

  2. 肝再生

  3. 自己免疫性肝疾患

  4. 肝疾患

  5. 免疫チェックポイント阻害薬

Research Areas 1

  1. Life Science / Gastroenterology

Professional Memberships 7

  1. 日本内科学会   総合内科専門医

  2. 日本消化器病学会   専門医

  3. 日本肝臓学会   指導医

  4. 日本消化器内視鏡学会   専門医

  5. 日本超音波医学会

  6. 日本炎症・再生医学会

  7. 日本再生医療学会

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Awards 7

  1. JDDW2021若手奨励賞

    2021.11  

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    Award type:Award from Japanese society, conference, symposium, etc. 

  2. Taisho-Toyama Award

    2018  

  3. 名古屋大学大学院医学系研究科病態内科学講座研究発表会受賞(第27回)

    2017  

  4. American Association for the Study of Liver Diseases (AASLD) Basic Science Young Investigator Awards (YIA) (Boston)

    2016  

  5. American Association for the Study of Liver Diseases (AASLD) presidential poster of distinction (Boston)

    2016  

  6. 第134回 名古屋肝疾患研究会 優秀演題賞

    2015  

  7. American Association for the Study of Liver Diseases (AASLD) poster of distinction (Washington, D.C.)

    2013  

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Papers 100

  1. 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

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

    DOI: 10.1080/01635581.2022.2049322

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  2. 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

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    Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

    DOI: 10.1038/s41598-022-07810-3

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  3. Immune-related Liver Injury is a Poor Prognostic Factor in Patients with Nonsmall 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   Vol. 40 ( 2 ) page: 189 - 198   2022.2

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

    It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in nonsmall cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days postinjection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the nonliver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.

    DOI: 10.1080/07357907.2021.1994586

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

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 2 ) page: 199 - 209   2022.2

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

    Aim: Portal vein thrombosis (PVT) is a major complication in patients with liver cirrhosis (LC). In some cases, PVT decreases spontaneously, but the factors that predict this are still not fully understood. Methods: This was a retrospective, multicenter study that included 77 consecutive patients with cirrhotic PVT. Forty-eight patients did not undergo anticoagulation and 29 patients did between the time of the first diagnosis of PVT and the follow-up radiological imaging undertaken 1–6 months later. A complete disappearance and 25% shrinkage of PVT was defined as complete remission (CR) and partial remission (PR), respectively. Portosystemic collateral vessels larger than 9 mm in diameter were defined as large collateral vessels. Results: Complete remission + PR was found in 37.5% of the anticoagulation-naïve patients. On univariate analysis, the absence of large collateral vessels, absence of PVT in the main trunk of the portal vein, a high platelet count, and a low FIB-4 index were significant factors associated with CR + PR. On multivariate analysis, the absence of large collateral vessels was the unique factor associated with CR + PR of PVT (odds ratio 5.9; 95% confidence interval, 1.73–20.1). The CR + PR rate for anticoagulated patients was 44.8%. However, no predictors for a good treatment effect of anticoagulation for PVT were identified. Conclusions: Spontaneous improvement of PVT in patients with LC can be expected when large collateral vessels are absent. For these patients, the option of observing them without anticoagulation can be considered in expectation of spontaneous reduction of PVT.

    DOI: 10.1111/hepr.13725

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  5. The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with 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   2022.1

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    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

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

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 1 ) page: 81 - 92   2022.1

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

    Aims: Data on the long-term outcomes of individuals with hepatitis B virus (HBV) infection who are hepatitis envelope antigen (HBeAg)-negative inactive carriers (ICs) are limited due to small numbers. We compared the long-term prognosis of well-defined ICs with that of age- and gender-matched general population controls. Methods: A total of 526 HBeAg-negative patients who demonstrated alanine aminotransferase (ALT) level ≤40 U/L and HBV DNA level ≤4.3 log IU/ml at least three times within 1 year after the start of follow-up were enrolled as ICs. Inactive carriers were divided into two groups: Group A (n = 332), whose ALT level was ≤30 U/L and HBV DNA level was ≤3.3 log IU/ml, and Group B (remaining patients, n = 194). We determined the long-term prognosis of ICs and compared it with that of general population controls. We also analyzed factors associated with hepatitis B surface antigen (HBsAg) clearance and phase transition in ICs. Results: There were no significant differences in hepatocellular carcinoma development or all-cause, liver-related, or non–liver-related mortality between Groups A and B. There was no significant difference in all-cause mortality between ICs and the general population. Low HBsAg level (≤3.0 log IU/ml) and the presence of fatty liver were associated with HBsAg clearance and high alpha-fetoprotein level was associated with phase transition. Conclusions: The long-term prognosis of well-defined ICs was similar to that of general population controls. In addition, the ICs had a high HBsAg clearance rate and low phase transition rate.

    DOI: 10.1111/hepr.13723

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  7. Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study.

    Matsumoto K, Ohfuji S, Abe M, Komori A, Takahashi A, Fujii H, Kawata K, Noritake H, Tadokoro T, Honda A, Asami M, Namisaki T, Ueno M, Sato K, Kakisaka K, Arakawa M, Ito T, Tanaka K, Matsui T, Setsu T, Takamura M, Yasuda S, Katsumi T, Itakura J, Sano T, Tamura Y, Miura R, Arizumi T, Asaoka Y, Uno K, Nishitani A, Ueno Y, Terai S, Takikawa Y, Morimoto Y, Yoshiji H, Mochida S, Ikegami T, Masaki T, Kawada N, Ohira H, Tanaka A

    Journal of gastroenterology   Vol. 57 ( 1 ) page: 19 - 29   2022.1

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    Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case–control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case–control study to identify the environmental factors associated with the development of PBC in Japan. Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01–2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07–1.92), ever smoking (OR, 1.70; 95% CI, 1.28–2.25), and hair dye use (OR, 1.57; 95% CI, 1.15–2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99–19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077–0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52–68.0) in the model for medical and familial factors. Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.

    DOI: 10.1007/s00535-021-01836-6

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  8. Changes in the gut microbiota after hepatitis C virus eradication.

    Honda T, Ishigami M, Yamamoto K, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Kawashima H, Miyahara R, Ishikawa T, Hirooka Y, Fujishiro M

    Scientific reports   Vol. 11 ( 1 ) page: 23568   2021.12

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    The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

    DOI: 10.1038/s41598-021-03009-0

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

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

    European journal of gastroenterology & hepatology   Vol. 33 ( 1S Suppl 1 ) page: e898 - e904   2021.12

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

    BACKGROUND AND AIMS: Tenofovir alafenamide (TAF), a new tenofovir prodrug, has been developed to circumvent the less favorable safety profile of tenofovir disoproxil fumarate (TDF). We investigated reductions in hepatitis B surface antigen (HBsAg) levels in patients with HBV infection who received continuous entecavir (ETV) monotherapy or sequential therapy with ETV and TAF. METHODS: This retrospective cohort study included 286 patients who were divided into two groups: continuous ETV monotherapy (ETV group, n = 168) and sequential therapy with ETV and TAF (ETV-TAF group, n = 108). Factors associated with a 90% reduction in HBsAg levels were analyzed by a Cox proportional hazards model using a time-dependent covariate in both groups. RESULTS: In the multivariate Cox proportional hazards model, the ETV-TAF group [adjusted hazard ratio (aHR) 2.750; 95% confidence interval (CI), 1.265-3.405; P = 0.0038] and BMI ≤ 25.0 kg/m2 (aHR 0.520, 95% CI, 0.308-0.875; P = 0.0139) demonstrated a 90% reduction in HBsAg levels. HBsAg levels of patients in the TAF phase in the ETV-TAF group showed greater yearly percent reductions than those in the ETV group and those in the ETV phase in the ETV-TAF group (P = 0.0361 and P = 0.0022, respectively, Steel-Dwass test). CONCLUSION: HBsAg levels decreased more rapidly after patients switched from ETV to TAF. Switching to TAF may be an effective treatment option to reduce HBsAg levels.

    DOI: 10.1097/MEG.0000000000002292

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  10. Cationic surface charge effect on proliferation and protein production of human dental pulp stem cells cultured on diethylaminoethyl-modified cellulose porous beads

    Oki Yuichiro, Harano Kodai, Hara Yuichi, Sasajima Yoshiyuki, Sasaki Ryo, Ito Takanori, Fujishiro Mitsuhiro, Ito Taichi

    BIOCHEMICAL ENGINEERING JOURNAL   Vol. 176   2021.12

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    Human adult dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells (MSCs). Recently, DPSCs have been proposed as a new MSC source for treating immune-mediated, inflammatory, and degenerative diseases via cell-based therapy. Hence, large-scale industrial production of the required cell number will be necessary. In this study, to investigate the cationic surface charge effect on DPSC proliferation, we fabricated two types of 2-diethylaminoethyl -modified cellulose porous beads (CPB-DEAE) with different ion exchange capacities. The cationic surface charge effect increased with increase in DPSC proliferation rate for the ion exchange capacity of 0.55–1.82 meq/g. However, the DPSC proliferation rate decreased at 2.50 meq/g. Thus, the optimal ion exchange capacity was determined to be 1.82 meq/g for DPSC proliferation. Additionally, the total amount of protein produced from the DPSCs on the CPB-DEAE microcarriers was higher than that produced under the conventional monolayer culture conditions. Furthermore, the hepatocyte growth factor, which is one of the anti-inflammatory growth factors, was produced from the DPSCs on the CPB-DEAE microcarriers. Finally, the DPSCs were confirmed to maintain their proliferative and multidifferentiation ability after culture on the CPB-DEAE microcarriers. CPB-DEAE microcarriers have the potential to be used for large-scale MSC expansion and protein production.

    DOI: 10.1016/j.bej.2021.108217

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  11. Increased risk of thyroid dysfunction by PD-1 and CTLA-4 blockade in patients without thyroid autoantibodies at baseline.

    Iwama S, Kobayashi T, Yasuda Y, Okuji T, Ito M, Ando M, Zhou X, Yamagami A, Onoue T, Kawaguchi Y, Miyata T, Sugiyama M, Takagi H, Hagiwara D, Suga H, Banno R, Hase T, Morise M, Wakahara K, Yokota K, Kato M, Nishio N, Tanaka C, Miyata K, Ogura A, Ito T, Sawada T, Shimokata T, Niimi K, Ohka F, Ishigami M, Gotoh M, Hashimoto N, Saito R, Kiyoi H, Kajiyama H, Ando Y, Hibi H, Sone M, Akiyama M, Kodera Y, Arima H

    The Journal of clinical endocrinology and metabolism     2021.11

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    DOI: 10.1210/clinem/dgab829

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

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

    Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   Vol. 53 ( 11 ) page: 1443 - 1450   2021.11

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

    Background & aims: Hepatocellular carcinoma in nonalcoholic steatohepatitis is caused by the complex factors of inflammation, fibrosis and microbiomes. We used network analysis to examine the interrelationships of these factors. Methods: C57Bl/6 mice were categorized into groups: choline-sufficient high-fat (CSHF, n = 8), choline-deficient high-fat (CDHF, n = 9), and CDHF+ diethylnitrosamine (DEN, n = 8). All mice were fed CSHF or CDHF for 20 weeks starting at week 8, and mice in the CDHF + DEN group received one injection of DEN at 3 weeks of age. Bacterial gene was isolated from feces and analyzed using Miseq. Results: The CSHF group had less fibrosis than the other groups. Tumors were found in 22.2% and 87.5% of the CDHF group and CDHF + DEN groups, respectively. Gene expression in the liver of Cdkn1a (p21: tumor-suppressor) and c-jun was highest in the CDHF group. Bacteroides, Roseburia, Odoribacter, and Clostridium correlated with fibrosis. Streptococcus and Dorea correlated with inflammation and tumors. Akkermansia and Bilophila were inversely correlated with fibrosis and Bifidobacterium was inversely correlated with tumors. Conclusions: DEN suppressed the overexpression of p21 caused by CDHF. Some bacteria formed a relationship networking associated with their progression and inhibition for tumors and fibrosis.

    DOI: 10.1016/j.dld.2021.02.013

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

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

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

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    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

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  14. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis.

    Ryuge A, Kosugi T, Maeda K, Banno R, Gou Y, Zaitsu K, Ito T, Sato Y, Hirayama A, Tsubota S, Honda T, Nakajima K, Ozaki T, Kondoh K, Takahashi K, Kato N, Ishimoto T, Soga T, Nakagawa T, Koike T, Arima H, Yuzawa Y, Minokoshi Y, Maruyama S, Kadomatsu K

    JCI insight   Vol. 6 ( 20 )   2021.10

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    Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane–selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

    DOI: 10.1172/jci.insight.142464

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  15. Factors associated with bleeding after endoscopic variceal ligation in children.

    Yokoyama S, Ishizu Y, Ishigami M, Honda T, Kuzuya T, Ito T, Hinoki A, Sumida W, Shirota C, Tainaka T, Makita S, Yokota K, Uchida H, Fujishiro M

    Pediatrics international : official journal of the Japan Pediatric Society   Vol. 63 ( 10 ) page: 1223 - 1229   2021.10

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

    Background: Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension (PHT). It is used for urgent treatment and prophylactic treatment of esophagogastric varices in pediatric as well as adult patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. Methods: The subjects were children and adolescents (<18 years) with PHT who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding, or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 h to 5 days after EVL. Results: A total of 50 EVL sessions on 22 patients were eligible for this study. There were four episodes of early rebleeding. No other major adverse event has occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ), within 5 mm from the EGJ, is the independent factor for a higher risk of early rebleeding: odds ratio 18.2 (95% confidence interval: 1.40–237.0), P = 0.02. Conclusions: Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

    DOI: 10.1111/ped.14614

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  16. 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

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

    Muto Hisanori, Ito Takanori, Ishigami Masatoshi

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

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

    Ito T, Ishigami M, Yamamoto T, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Kato M, Hashimoto N, Hibi H, Kodera Y, Sone M, Ando Y, Akiyama M, Shimoyama Y, Fujishiro M

    Hepatology international   Vol. 15 ( 5 ) page: 1278 - 1287   2021.10

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    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.

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

    Muto H, Ito T, Tanaka T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Maeda K, Honda T, Ishikawa T, Kato A, Ohshiro T, Kano F, Yamamoto A, Sakai K, Hibi H, Ishigami M, Fujishiro M

    Scientific reports   Vol. 11 ( 1 ) page: 18778   2021.9

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    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.

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

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

    Journal of viral hepatitis   Vol. 28 ( 9 ) page: 1293 - 1303   2021.9

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    The impact of antiviral therapy on clinical outcomes in patients with hepatitis C virus (HCV) infection and mild liver fibrosis (FIB-4 score <1.45) is not well understood. We aimed to clarify the impact of viral eradication on hepatocarcinogenesis and mortality in patients with mild fibrosis.The subjects were 657 patients who achieved sustained virologic response (SVR) (Clearance group) and 586 patients who did not receive antiviral therapy or did not achieve SVR (No clearance group). We applied inverse probability weighting because the groups had different baseline characteristics. Multivariate proportional hazards models were used to analyse factors associated with hepatocarcinogenesis and mortality using a time-dependent covariate. In addition, we compared the mortality rate of the Clearance group stratified by age to the mortality rate of the general population.Clearance of HCV RNA was significantly associated with hepatocarcinogenesis and all-cause, liver-related and non–liver-related mortality (adjusted hazard ratios [95% confidence interval], 0.2653 [0.1147–0.6136, p = 0.0019], 0.3416 [0.2157–0.5409, p < 0.0001], 0.2474 [0.0802–0.8917, p = 0.0381] and 0.4118 [0.2449–0.6925, p = 0.0008], respectively). The Clearance group had significantly higher mortality than the general population matched by age, sex and follow-up duration (p < 0.0001). However, there were no significant differences between patients who achieved SVR before age 50 and the general population matched by age, sex and follow-up duration (p = 0.1570). HCV eradication in patients with mild fibrosis reduces liver-related and non–liver-related mortality. If HCV is eradicated before age 50, prognosis is likely be similar to that of the age-matched and sex-matched general population. (249 words).

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

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

    Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation   Vol. 19 ( 9 ) page: 935 - 942   2021.9

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    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.

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  22. Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study.

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

    Medicine   Vol. 100 ( 31 ) page: e26820   2021.8

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    ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

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  23. 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

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

    Kumada T, Toyoda H, Yasuda S, Sone Y, Ogawa S, Takeshima K, Tada T, Ito T, Sumida Y, Tanaka J

    Clinical and translational gastroenterology   Vol. 12 ( 4 ) page: e00337   2021.4

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    INTRODUCTION: Liver fibrosis stage is one of the most important factors in stratifying the risk of developing hepatocellular carcinoma (HCC). We evaluated the usefulness of liver stiffness measured by magnetic resonance elastography (MRE) to stratify the risk of developing HCC in patients who underwent MRE before receiving direct-acting antivirals (DAAs) and subsequently achieved sustained virological response (SVR). METHODS: A total of 537 consecutive patients with persistent hepatitis C virus who underwent initial MRE before DAA therapy and achieved SVR were enrolled. Factors associated with HCC development were analyzed by univariate and multivariate Cox proportional hazards models. RESULTS: Albumin-bilirubin score ≥ -2.60 (adjusted hazard ratio [aHR] 6.303), fibrosis-4 (FIB-4) score >3.25 (aHR 7.676), and MRE value ≥4.5 kPa (aHR 13.190) were associated with HCC development according to a univariate Cox proportional hazards model. A multivariate Cox proportional hazards model showed that an MRE value ≥4.5 kPa (aHR 7.301) was the only factor independently associated with HCC development. Even in patients with an FIB-4 score >3.25, the cumulative incidence rate of HCC development in those with an MRE value <4.5 kPa was significantly lower than that in patients with an MRE value ≥4.5 kPa. DISCUSSION: Liver stiffness measured by MRE before DAA therapy was an excellent marker for predicting subsequent HCC development in patients with hepatitis C virus infection who achieved SVR. The same results were observed in patients with high FIB-4 scores.

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

    Nishikawa T, Maeda K, Nakamura M, Yamamura T, Sawada T, Mizutani Y, Ito T, Ishikawa T, Furukawa K, Ohno E, Miyahara R, Kawashima H, Honda T, Ishigami M, Yamamoto T, Matsumoto S, Hotta Y, Fujishiro M

    Digestive diseases and sciences   Vol. 66 ( 4 ) page: 1034 - 1044   2021.4

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

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

    Clinical nutrition ESPEN   Vol. 42   page: 354 - 360   2021.4

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    Background & aims: The impact of obesity, evaluated using body mass index (BMI), on mortality in patients with cirrhosis is controversial. The prognostic impact of visceral fat accumulation, which is recommended as an indicator of obesity-related mortality, is still unknown. This study aimed to clarify the impact of visceral fat accumulation on mortality in patients with cirrhosis. Methods: A total of 335 cirrhotic patients without hepatocellular carcinoma were retrospectively evaluated. The impact of obesity, defined as a visceral fat area ≥100 cm2 at the umbilical level or BMI ≥25 kg/m2 on mortality, was evaluated using competing risk analysis. Results: Of 355 patients, visceral fat accumulation was seen in 147 patients. During the observation period (1340 ± 980 days), 84 patients died, and 17 received liver transplantation. Visceral fat accumulation was not found to be associated with mortality (hazard ratio [HR] 1.423, P = 0.180) in any of the patients. After stratification of the patients, visceral fat accumulation was observed to be associated with a poor prognosis in patients with skeletal muscle depletion (HR 3.804, P = 0.003), but not in those without (HR 1.147, P = 0.660). On the other hand, obesity defined by BMI ≥25 kg/m2 was not found to be associated with mortality in patients with (HR 0.341, P = 0.390) or without skeletal muscle depletion (HR 1.227, P = 0.500). Conclusions: Visceral fat accumulation is a useful index for evaluating obesity and aggravates mortality in cirrhotic patients with skeletal muscle depletion, but not in those without.

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  27. The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

    Ito T, Ishigami M, Zou B, Tanaka T, Takahashi H, Kurosaki M, Maeda M, Thin KN, Tanaka K, Takahashi Y, Itoh Y, Oniki K, Seko Y, Saruwatari J, Kawanaka M, Atsukawa M, Hyogo H, Ono M, Ogawa E, Barnett SD, Stave CD, Cheung RC, Fujishiro M, Eguchi Y, Toyoda H, Nguyen MH

    Hepatology international   Vol. 15 ( 2 ) page: 366 - 379   2021.4

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    Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD. Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD—8 studies) patients. Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983–2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD. Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

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

    Yamamoto K, Honda T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Miyahara R, Kawashima H, Ishigami M, Fujishiro M

    Journal of gastroenterology and hepatology   Vol. 36 ( 3 ) page: 790 - 799   2021.3

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    Background: Bacteria of oral origin (BO) in the gut are associated with prognosis in patients with cirrhosis. The Greengenes database (gg_13_8) is widely used in microbiome analysis, but the expanded Human Oral Microbiome Database (eHOMD), a specialized database for BO, can add more detailed information. We used each database to evaluate the relationship between the albumin–bilirubin grade (ALBI) and the microbiome in patients with hepatitis C. Methods: Eighty patients were classified into the low ALBI group (LA; n = 34) or high ALBI group (HA; n = 46). Isolated DNA from stool was amplified to target the V3–4 regions of 16S rRNA. The microbiomes of the two groups were compared using gg_13_8 or eHOMD. We evaluated the associations between microbiomes and prognoses using Cox proportional hazards models. Results: At the genus level, the two groups differed significantly regarding 6 (gg_13_8) and 7 (eHOMD) types of bacteria. All types except Akkermansia are classified as BO. Both databases showed an increase in Streptococcus and Veillonella. eHOMD showed a decrease in Fusobacterium and an increase in Fretibacterium; both produce various types of short-chain fatty acids. At the species level, the two groups demonstrated significant differences in 2 (gg_13_8) and 6 (eHOMD) bacterial types. Selenomonas noxia and Streptococcus salivarius were related to poor prognosis in univariate analysis. Conclusion: The HA group demonstrated increased BO, most of which produce lactic acid or acetic acid. The correlation between the microbiome and metabolism might be related to prognosis. eHOMD was a useful database for analyzing BO.

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

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

    Japanese journal of radiology   Vol. 39 ( 3 ) page: 296 - 302   2021.3

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    Purpose: This study aimed to evaluate the usefulness of a coaxial double balloon catheter for simplification of the balloon-occluded retrograde transcatheter obliteration (BRTO) procedure compared with a single-balloon catheter. Materials and methods: Thirty-three patients who underwent BRTO with a single-balloon catheter (Single-balloon group, n = 15) or a coaxial double balloon catheter (Coaxial group, n = 18) were included, retrospectively. The frequency of additional procedures for stagnation of sclerosant including ethanol injection, coil embolization, and additional balloon occlusion for collateral draining veins; the dose of ethanolamine oleate (EO); and the complication rate and the success rate of sclerosant stagnation were evaluated. Results: Additional procedures were needed in four patients in the Coaxial group, which was significantly lower than that in the Single-balloon group (nine patients, P = 0.038). The dose of EO in the Coaxial group (11.2 ± 6.6 g) was lower, but not significantly different than that in the Single-balloon group (14.4 g ± 6.1 g, P = 0.184). The complication rate and the success rate of sclerosant stagnation were not different between the two groups. Conclusion: The use of a coaxial double balloon catheter can simplify the BRTO procedure compared with a single-balloon catheter.

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

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

    Journal of viral hepatitis   Vol. 28 ( 3 ) page: 508 - 516   2021.3

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    The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non–liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non–liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non–liver-related mortality. HBV DNA ≥20,000 IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000 IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000 IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non–liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non–liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC.

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

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

    Haemophilia : the official journal of the World Federation of Hemophilia   Vol. 27 ( 1 ) page: 100 - 107   2021.1

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    Haemophilia is an X-linked inherited bleeding disorder caused by coagulation factor deficiency. Hepatocellular carcinoma (HCC) is a major complication associated with the disease. No study thus far has investigated the safety and efficacy of percutaneous radiofrequency ablation (RFA) for HCC in patients with haemophilia. Aim: This study aimed to evaluate the safety and efficacy of RFA for HCC in haemophilia patients. Methods: From July 2008 to June 2019, 217 patients with HCC underwent 300 RFA sessions. Of these, 18 sessions were performed in ten haemophilia patients (H group) and 282 in 207 non-haemophilia patients (NH group). The patients' characteristics, incidence of haemorrhagic complications and rates of local tumour recurrence were compared between the groups. Results: A majority of the haemophilia patients received clotting factor concentrate replacement therapy before and after RFA treatment, with the aim of reaching a plasma clotting factor level of higher than 60%–80%. Twelve haemorrhagic complications were observed in the NH group (4.2%; 12/282). Major bleeding requiring control procedures was observed in two patients and minor bleeding with careful observation was noted in ten patients. No bleeding complications were observed in the H group (0/18). There were no significant differences in the 5-year local tumour recurrence rates after RFA treatment between the groups (35.0% in the H group and 32.1% in the NH group). Conclusion: RFA could be an effective and a safe method for HCC treatment in patients with haemophilia.

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  32. Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure.

    Honda T, Yamada N, Murayama A, Shiina M, Aly HH, Kato A, Ito T, Ishizu Y, Kuzuya T, Ishigami M, Murakami Y, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Ishikawa T, Fujishiro M, Muramatsu M, Wakita T, Kato T

    Cellular and molecular gastroenterology and hepatology   Vol. 12 ( 5 ) page: 1583 - 1598   2021

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    Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

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

    YOKOYAMA Shinya, HONDA Takashi, KUZUYA Teiji, ISHIZU Yoji, ITO Takanori, YAMAMOTO Kenta, TANAKA Taku, MUTO Hisanori, SUGIYAMA Yoshiaki, FUJISHIRO Mitsuhiro

    GASTROENTEROLOGICAL ENDOSCOPY   Vol. 62 ( 12 ) page: 3064 - 3071   2020.12

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    <p>A 10-month-old boy with biliary atresia who had undergone the Kasai procedure, was admitted to our hospital due to tarry stool. We performed emergency esophagogastroduodenoscopy and found severe esophagogastric varices. There was a spurting bleeding site at the lower esophagus. We implemented endoscopic injection sclerotherapy (EIS) for esophagogastric variceal bleeding, since it was impossible to insert the scope through the esophagus with an endoscopic variceal ligation device attached. After performing four sessions of EIS, the patient developed esophageal ulcers and stricture related to EIS, leading to poor oral intake and body weight loss. We were able to manage these adverse events with conservative treatment. After healing of the esophageal ulcers and stricture, two additional sessions of EIS were performed. The patientʼs esophagogastric varices disappeared completely. </p><p>Intra-variceal EIS followed by para-variceal EIS by polidocanol was reported to be effective and relatively safe for the treatment of esophageal varices in adult patients. The aim of para-variceal EIS is to form ulcers at the injection sites, resulting in the development of fibrosis of the mucosa during the healing process. This mucosal fibrosis is considered important for preventing recurrence of varices. There is little evidence for the safety and efficacy of intra-variceal EIS followed by para-variceal EIS in pediatric patients. </p><p>Although we should be cautious of EIS-related stricture due to esophageal ulcer, especially in children who have a narrower esophageal lumen than adults, we have experienced a successful case of EIS for esophageal varices in an infant with biliary atresia.</p>

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  34. SAFETY AND EFFICACY OF PERCUTANEOUS RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA PATIENTS WITH HEMOPHILIA

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

    HEPATOLOGY   Vol. 72   page: 705A - 706A   2020.11

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  35. GUT MICROBIOTA ASSOCIATED WITH THE DIFFERENCE BETWEEN PATIENTS WITH AND WITHOUT HEPATOCELLULAR CARCINOMA IN CHRONIC LIVER DISEASE

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

    HEPATOLOGY   Vol. 72   page: 370A - 370A   2020.11

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  36. IMPROVEMENT OF LIVER FUNCTIONAL RESERVE AFTER SVR IN HCV-PATIENTS WITH COMPENSATED, SEVERE FIBROSIS BY IFN-FREE, DAA COMBINATION TREATMENT-IMPACT OF PRETREATMENT SERUM AFP LEVELS

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

    HEPATOLOGY   Vol. 72   page: 564A - 565A   2020.11

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  37. AMINO ACID POLYMORPHISM IN HEPATITIS B VIRUS ASSOCIATED WITH NATURAL CLEARANCE OF HBV DNA AND HBsAg

    Honda Takashi, Yamada None, Murayama Asako, Kato Asuka, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Ishigami Masatoshi, Murakami Yoshiki, Ishikawa Tetsuya, Fujishiro Mitsuhiro, Kato Takanobu

    HEPATOLOGY   Vol. 72   page: 508A - 509A   2020.11

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

    Ito T, Ishigami M, Morooka H, Yamamoto K, Imai N, Ishizu Y, Honda T, Nishimura D, Tada T, Yasuda S, Toyoda H, Kumada T, Fujishiro M

    Scientific reports   Vol. 10 ( 1 ) page: 17812   2020.10

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    The albumin–bilirubin (ALBI) score is calculated using only serum albumin and bilirubin levels, and was developed as a simple method to assess hepatic function. In this study, a total of 409 patients with primary biliary cholangitis (PBC) were enrolled between March 1990 and October 2018. The predictive performances of the ALBI score and other well-established prognostic scores were compared using time-dependent receiver operating characteristic (ROC) analysis. During the follow-up period, 60 patients died, 45 due to liver-related diseases and 15 due to non-liver-related diseases, and 16 patients underwent liver transplantation. Time-dependent ROC analysis showed that the ALBI score has higher the areas under the ROC curves (AUROCs) than the Child–Pugh (C–P) score at each time point; AUROCs at 3, 5, and 10 years after the start of follow-up were 0.94, 0.91, and 0.90 for the ALBI score, and 0.89, 0.88, and 0.82 for the C–P score, respectively. The ALBI score showed the highest AUROCs within 2 years after the start of observation; beyond 2 years, however, the Mayo score had better prognostic ability for mortality and liver transplantation. The ALBI score/grade, derived from objective blood tests, and the Mayo score were superior prognostic tools in PBC patients.

    DOI: 10.1038/s41598-020-74732-3

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

    Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Kamei H, Ogura Y, Fujishiro M

    Journal of hepato-biliary-pancreatic sciences   Vol. 27 ( 9 ) page: 655 - 662   2020.9

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    DOI: 10.1002/jhbp.777

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

    Ito T

    Alimentary pharmacology & therapeutics   Vol. 52 ( 4 ) page: 735 - 736   2020.8

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    DOI: 10.1111/apt.15911

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

    Nomura A, Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Kamei H, Onishi Y, Ogura Y, Fujishiro M

    Medicine   Vol. 99 ( 28 ) page: e21161   2020.7

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    DOI: 10.1097/MD.0000000000021161

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  42. 特集 薬剤性消化器疾患の診療 4 .その他の薬剤性消化器疾患(4)免疫チェックポイント阻害薬による消化器障害

    伊藤 隆徳, 澤田 つな騎, 中村 正直, 本多 隆, 石上 雅敏, 藤城 光弘

    臨床消化器内科   Vol. 35 ( 7 ) page: 759 - 765   2020.6

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    DOI: 10.19020/cg.0000001205

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

    Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, Inukai Y, Toyoda H, Yokota K, Hase T, Maeda O, Kiyoi H, Nagino M, Hibi H, Kodera Y, Fujimoto Y, Sone M, Gotoh M, Ando Y, Akiyama M, Hasegawa Y, Fujishiro M

    Journal of gastroenterology   Vol. 55 ( 6 ) page: 653 - 661   2020.6

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    DOI: 10.1007/s00535-020-01677-9

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

    Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

    European journal of gastroenterology & hepatology   Vol. 32 ( 6 ) page: 748 - 753   2020.6

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    DOI: 10.1097/MEG.0000000000001587

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  45. Complete response of advanced hepatocellular carcinoma achieved by sorafenib dose re-escalation after failure of long-term low-dose-sorafenib treatment combined with transcatheter arterial chemoembolization: a case report.

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

    Clinical journal of gastroenterology   Vol. 13 ( 3 ) page: 397 - 402   2020.6

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    DOI: 10.1007/s12328-019-01066-7

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

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

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

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    DOI: 10.21873/anticanres.14167

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  47. Sorafenib <i>vs</i>. Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis.

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

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

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    DOI: 10.21873/anticanres.14193

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  48. Serum soluble sialic acid-binding immunoglobulin-like lectin-7 concentration as an indicator of liver macrophage activation and advanced fibrosis in patients with non-alcoholic fatty liver disease.

    Sakamoto Y, Yoshio S, Doi H, Kawai H, Shimagaki T, Mori T, Matsuda M, Aoki Y, Osawa Y, Yoshida Y, Arai T, Itokawa N, Ito T, Seko Y, Yamaguchi K, Itoh Y, Mise Y, Saiura A, Taketomi A, Kanto T

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 4 ) page: 466 - 477   2020.4

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    DOI: 10.1111/hepr.13464

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  49. Dynamic Evaluation of Liver Fibrosis to Assess the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Who Achieved Sustained Virologic Response.

    Toyoda H, Tada T, Yasuda S, Mizuno K, Ito T, Kumada T

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   Vol. 70 ( 6 ) page: 1208 - 1214   2020.3

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    DOI: 10.1093/cid/ciz359

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

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 3 ) page: 374 - 381   2020.3

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    Aim: We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. Methods: This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results: The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions: The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.

    DOI: 10.1111/hepr.13452

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

    Yamamoto K, Kuzuya T, Honda T, Ito T, Ishizu Y, Nakamura M, Miyahara R, Kawashima H, Ishigami M, Fujishiro M

    Anticancer research   Vol. 40 ( 2 ) page: 665 - 676   2020.2

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    DOI: 10.21873/anticanres.13996

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

    Yoshioka N, Ishigami M, Watanabe Y, Sumi H, Doisaki M, Yamaguchi T, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Haruta JI, Fujishiro M

    Scientific reports   Vol. 10 ( 1 ) page: 481   2020.1

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    DOI: 10.1038/s41598-019-57369-9

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

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 50 ( 1 ) page: 47 - 56   2020.1

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    DOI: 10.1111/hepr.13426

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

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

    Oncology   Vol. 98 ( 9 ) page: 621 - 629   2020

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    DOI: 10.1159/000507051

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

    Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

    Nutrition and cancer   Vol. 72 ( 5 ) page: 884 - 891   2020

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    DOI: 10.1080/01635581.2019.1653474

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  56. Sarcopenia impairs health-related quality of life in cirrhotic patients.

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

    European journal of gastroenterology & hepatology   Vol. 31 ( 12 ) page: 1550 - 1556   2019.12

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    DOI: 10.1097/MEG.0000000000001472

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  57. Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity

    Yoshioka Naoki, Kuzuya Teiji, Ito Takanori, Ishizu Yoji, Honda Takashi, Ishikawa Tetsuya, Ishigami Masatoshi, Fujishiro Mitsuhiro

    Internal Medicine   Vol. 58 ( 19 ) page: 2803 - 2808   2019.10

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    <p>Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity. </p>

    DOI: 10.2169/internalmedicine.2812-19

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  58. CHANGES OF MICROBIOTA AFTER HEPATITIS C VIRUS ERADICATION

    Honda Takashi, Ishigami Masatoshi, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

    HEPATOLOGY   Vol. 70   page: 1160A - 1161A   2019.10

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  59. Spleen stiffness by 2-D shear wave elastography is the most accurate predictor of high-risk esophagogastric varices in children with biliary atresia.

    Yokoyama S, Ishigami M, Honda T, Kuzuya T, Ishizu Y, Ito T, Hirooka Y, Tanaka Y, Tainaka T, Shirota C, Chiba K, Uchida H, Fujishiro M

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 49 ( 10 ) page: 1162 - 1168   2019.10

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    DOI: 10.1111/hepr.13381

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  60. NON-INVASIVE SCREENING FOR DETECTING ESOPHAGOGASTRIC VARICES IN CHILDREN WITH BILIARY ATRESIA

    Yokoyama Shinya, Ishigami Masatoshi, Honda Takashi, Kuzuya Teiji, Ishizu Yoji, Ito Takanori, Shirota Chiyoe, Uchida Hiroo, Fujishiro Mitsuhiro

    HEPATOLOGY   Vol. 70   page: 200A - 200A   2019.10

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  61. INDICATION FOR HCC TREATMENT IN RECENT ERA-PROPOSAL OF THE NEW PRIORITY FOR LIVER TRANSPLANTATION IN PATIENTS WITH HCC

    Ishigami Masatoshi, Honda Takashi, Kuzuya Teiji, Ishizu Yoji, Ito Takanori, Fujishiro Mitsuhiro

    HEPATOLOGY   Vol. 70   page: 543A - 544A   2019.10

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  62. UTILITY OF THE ALBUMIN-BILIRUBIN SCORE FOR PREDICTING PROGNOSIS IN JAPANESE PATIENTS WITH PRIMARY BILIARY CHOLANGITIS: AN ANALYSIS USING TIME-DEPENDENT RECEIVER OPERATING CHARACTERISTICS

    Ito Takanori, Ishigami Masatoshi, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Yasuda Satoshi, Toyoda Hidenori, Kumada Takashi, Fujishiro Mitsuhiro

    HEPATOLOGY   Vol. 70   page: 789A - 790A   2019.10

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  63. Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment.

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 49 ( 9 ) page: 1054 - 1065   2019.9

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    DOI: 10.1111/hepr.13358

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  64. The relationship between portal hypertension and the microbiome

    Yamamoto K., Honda T., Hattori S., Pu L. Zorron Cheng Tao, Ito T., Yamamura T., Ishizu Y., Kuzuya T., Ishigami M., Fujishiro M.

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 34   page: 106 - 107   2019.9

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  65. Association between core mutations and annual decline rate of HBVDNA and HBsAg in chronic hepatitis B patients treated with nucleoside analogue

    Honda Takashi, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

    JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page: E258 - E258   2019.4

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  66. The optimal cut-off points of FIB-4 index for predicting the incidences of HCC and extra-hepatic malignancies in biopsyproven Japanese NAFLD patients

    Ito Takanori, Ishigami Masatoshi, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Fujishiro Mitsuhiro

    JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page: E775 - E775   2019.4

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  67. The early clinical response at 2 weeks of lenvatinib therapy for patients with advanced HCC

    Kuzuya Teiji, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Honda Takashi, Fujishiro Mitsuhiro

    JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page: E611 - E611   2019.4

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  68. Serum Zinc levels as a prognostic factor for extra-hepatic carcinogenesis in Japanese patients with non-alcoholic liver disease

    Ito Takanori, Ishigami Masatoshi, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Fujishiro Mitsuhiro

    JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page: E298 - E298   2019.4

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  69. Association between gut microbiota and hepatocellular carcinoma in patients with chronic liver disease

    Honda Takashi, Ishigami Masatoshi, Yamamoto Kenta, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Fujishiro Mitsuhiro

    JOURNAL OF HEPATOLOGY   Vol. 70 ( 1 ) page: E512 - E513   2019.4

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  70. Influence of proton pump inhibitors on microbiota in chronic liver disease patients.

    Yamamoto K, Ishigami M, Honda T, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Hayashi K, Goto H, Hirooka Y

    Hepatology international   Vol. 13 ( 2 ) page: 234 - 244   2019.3

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    DOI: 10.1007/s12072-019-09932-9

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  71. Utility and limitations of noninvasive fibrosis markers for predicting prognosis in biopsy-proven Japanese non-alcoholic fatty liver disease patients.

    Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Nishimura D, Toyoda H, Kumada T, Goto H, Hirooka Y

    Journal of gastroenterology and hepatology   Vol. 34 ( 1 ) page: 207 - 214   2019.1

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    DOI: 10.1111/jgh.14448

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  72. Association between Core Mutations Induced By Interferon Therapy and Annual Decline Rate of Hbvdna in Chronic Hepatitis B Patients

    Honda Takashi, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Hirooka Yoshiki

    HEPATOLOGY   Vol. 68   page: 1233A-1234A   2018.10

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  73. Interferon-Free Antiviral Therapy Rapidly Improves Thrombocytopenia in Patients with Advanced Chronic Hepatitis C

    Ishizu Yoji, Ishigami Masatoshi, Ito Takanori, Kuzuya Teiji, Honda Takashi, Hirooka Yoshiki

    HEPATOLOGY   Vol. 68   page: 1157A-1158A   2018.10

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  74. Comparison of Gut Microbiota and Predicted Functional Metagenome in Hepatitis C Patients with and without Advanced Fibrosis Categorized By FIB4-Index

    Yamamoto Kenta, Ishigami Masatoshi, Ito Takanori, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Hirooka Yoshiki

    HEPATOLOGY   Vol. 68   page: 590A-590A   2018.10

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  75. Successful treatment of esophageal bleeding due to rupture of major aortopulmonary collateral arteries by transcatheter arterial embolization. Reviewed

    Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Matsushima M, Kato T, Hirooka Y

    Clinical journal of gastroenterology     2018.8

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    DOI: 10.1007/s12328-018-0895-8

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  76. Secreted ectodomain of SIGLEC-9 and MCP-1 ameliorate acute liver failure in rats by altering bone marrow macrophage polarity

    Ito T., Ishigami M., Yamamoto A., Ishizu Y., Kazuya T., Honda T., Hayashi K., Ishikawa T., Hirooka Y., Goto H.

    JOURNAL OF HEPATOLOGY   Vol. 68   page: S614-S614   2018.4

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  77. Utility and limitation of non-invasive fibrosis markers for predicting the prognosis in biopsy-proven Japanese NAFLD patients

    Ito T., Ishigami M., Ishizu Y., Kazuya T., Honda T., Hayashi K., Ishikawa T., Hirooka Y., Goto H.

    JOURNAL OF HEPATOLOGY   Vol. 68   page: S561-S561   2018.4

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

    Ito Takanori, Ishigami Masatoshi, Matsushita Yoshihiro, Hirata Marina, Matsubara Kohki, Ishikawa Tetsuya, Hibi Hideharu, Ueda Minoru, Hirooka Yoshiki, Goto Hidemi, Yamamoto Akihito

    SCIENTIFIC REPORTS   Vol. 7   page: 44043   2017.3

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    DOI: 10.1038/srep44043

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  79. Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.

    Kobayashi N, Kumada T, Toyoda H, Tada T, Ito T, Kage M, Okanoue T, Kudo M

    Digestive diseases (Basel, Switzerland)   Vol. 35 ( 6 ) page: 521-530   2017

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    DOI: 10.1159/000480142

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  80. Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis. Reviewed

    Hirata M, Ishigami M, Matsushita Y, Ito T, Hattori H, Hibi H, Goto H, Ueda M, Yamamoto A

    Stem cells translational medicine   Vol. 5 ( 10 ) page: 1416-1424   2016.10

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    DOI: 10.5966/sctm.2015-0353

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  81. Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 identified from Dental Pulp Stem Cells Synergistically Resolve Acute Liver Failure in Rats by Altering Macrophage Polarity

    Ito Takanori, Yamamoto Akihito, Ishizu Yoji, Kuzuya Teiji, Honda Takashi, Ishikawa Tetsuya, Ishigami Masatoshi, Hirooka Yoshiki, Goto Hidemi

    HEPATOLOGY   Vol. 64   page: 515A-515A   2016.10

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  82. Extra-hepatic feeding arteries of hepatocellular carcinoma: An investigation based on intra-arterial CT aortography images using an angio-MDCT system. Reviewed

    Takada K, Ito T, Kumada T, Toyoda H, Tada T, Sone Y, Endo T, Tanaka K, Kitagawa H, Ichikawa K

    European journal of radiology   Vol. 85 ( 8 ) page: 1400-6   2016.8

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    DOI: 10.1016/j.ejrad.2016.05.007

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  83. Accurate and rapid identification of feeding arteries with multidetector-row angiography-assisted computed tomography for transarterial chemoembolization for hepatocellular carcinoma. Reviewed

    Takada K, Toyoda H, Tada T, Ito T, Hasegawa R, Gotoh T, Ichikawa H, Sone Y, Kumada T

    Journal of gastroenterology   Vol. 50 ( 12 ) page: 1190-6   2015.12

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    DOI: 10.1007/s00535-015-1065-0

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  84. Utility of Contrast-enhanced Ultrasonography with Perflubutane for Determining Histologic Grade in Hepatocellular Carcinoma. Reviewed

    Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Kaneoka Y, Maeda A, Okuda S, Otobe K, Takahashi K

    Ultrasound in medicine & biology   Vol. 41 ( 12 ) page: 3070-8   2015.12

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    DOI: 10.1016/j.ultrasmedbio.2015.07.023

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  85. Utility of the FIB-4 Index for hepatocarcinogenesis in hepatitis C virus carriers with normal alanine aminotransferase levels. Reviewed

    Ito T, Kumada T, Toyoda H, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S

    Journal of viral hepatitis   Vol. 22 ( 10 ) page: 777-83   2015.10

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    DOI: 10.1111/jvh.12389

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  86. Utility of real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C infection without cirrhosis: Comparison of liver fibrosis indices. Reviewed

    Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Okuda S, Tsuji N, Imayoshi Y, Yasuda E

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 45 ( 10 ) page: E122-9   2015.10

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    DOI: 10.1111/hepr.12476

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  87. Long-term prognosis of patients with hepatitis B infection: causes of death and utility of nucleos(t)ide analogue therapy. Reviewed

    Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabtake S, Ito T

    Journal of gastroenterology   Vol. 50 ( 7 ) page: 795-804   2015.7

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    DOI: 10.1007/s00535-014-1011-6

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  88. Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. Reviewed

    Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T

    Journal of gastroenterology and hepatology   Vol. 30 ( 7 ) page: 1183-9   2015.7

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    DOI: 10.1111/jgh.12915

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  89. FIB-4 index for assessing the prognosis of hepatocellular carcinoma in patients with Child-Pugh class A liver function. Reviewed

    Ito T, Kumada T, Toyoda H, Tada T

    Journal of cancer research and clinical oncology   Vol. 141 ( 7 ) page: 1311-9   2015.7

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    DOI: 10.1007/s00432-015-1922-5

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  90. Diagnostic accuracy for macroscopic classification of nodular hepatocellular carcinoma: comparison of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging and angiography-assisted computed tomography. Reviewed

    Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Okuda S, Ogawa S, Igura T, Imai Y

    Journal of gastroenterology   Vol. 50 ( 1 ) page: 85-94   2015.1

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    DOI: 10.1007/s00535-014-0947-x

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  91. Utility of contrast-enhanced ultrasound with perflubutane for diagnosing the macroscopic type of small nodular hepatocellular carcinomas. Reviewed

    Tada T, Kumada T, Toyoda H, Ito T, Sone Y, Kaneoka Y, Maeda A, Okuda S, Otobe K, Takahashi K

    European radiology   Vol. 24 ( 9 ) page: 2157-66   2014.9

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    DOI: 10.1007/s00330-014-3254-2

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  92. Changes in highly sensitive alpha-fetoprotein for the prediction of the outcome in patients with hepatocellular carcinoma after hepatectomy. Reviewed

    Toyoda H, Kumada T, Tada T, Ito T, Maeda A, Kaneoka Y, Kagebayashi C, Satomura S

    Cancer medicine   Vol. 3 ( 3 ) page: 643-51   2014.6

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    DOI: 10.1002/cam4.218

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  93. Oral supplementation with branched-chain amino acid granules prevents hepatocarcinogenesis in patients with hepatitis C-related cirrhosis: A propensity score analysis.

    Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Niinomi T, Ito T, Hasegawa R, Ando Y, Yamamoto K, Tanaka T

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 44 ( 3 ) page: 288-95   2014.3

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    DOI: 10.1111/hepr.12120

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  94. [An autopsy of G-CSF-producing anaplastic carcinoma of the pancreas with impaired accumulation on FDG-PET after S-1 chemotherapy].

    Ikeda S, Okubo K, Shibahara H, Narita M, Morita K, Takeuchi A, Kanazawa H, Ito T, Nishimura D, Katada N

    Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 40 ( 6 ) page: 789-92   2013.6

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  95. Non-hypervascular hypointense nodules detected by Gd-EOB-DTPA-enhanced MRI are a risk factor for recurrence of HCC after hepatectomy.

    Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Sone Y, Kaneoka Y, Maeda A

    Journal of hepatology   Vol. 58 ( 6 ) page: 1174-80   2013.6

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    DOI: 10.1016/j.jhep.2013.01.030

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  96. A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil

    ITO Takanori, OKUBO Kenji, SHIOMI Masaya, NARITA Michihiko, MORITA Kiyoshi, TAKEUCHI Atsufumi, KANAZAWA Hironobu, SHIMIZU Junichi, TAKEYAMA Tomoaki, HASHIZUME Kiyotaka, SHIBAHARA Hiroaki, NISHIMURA Daisaku, KATADA Naoyuki, KATANO Yoshiaki, GOTO Hidemi

    Nippon Shokakibyo Gakkai Zasshi   Vol. 109 ( 12 ) page: 2088-2096   2012.12

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    A 37-year-old man underwent lobectomy of the right liver for granulocyte colony-stimulating factor (G-CSF) producing hepatocellular carcinoma accompanying type B hepatitis. Within two months after the surgery, lung metastases were revealed and administration of sorafenib was begun, however, the lung metastases continued to enlarge. Changing the patient's medication to tegafur-uracil provided remarkable reduction of the lung metastases. The patient is alive two years after diagnosis and receives outpatient chemotherapy. We concluded that this case is valuable with regard to the extreme rarity of G-CSF producing hepatocellular carcinoma and its successful treatment in this case.<br>

    DOI: 10.11405/nisshoshi.109.2088

  97. [A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil].

    Ito T, Okubo K, Shiomi M, Narita M, Morita K, Takeuchi A, Kanazawa H, Shimizu J, Takeyama T, Hashizume K, Shibahara H, Nishimura D, Katada N, Katano Y, Goto H

    Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology   Vol. 109 ( 12 ) page: 2088-96   2012.12

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  98. A case of successful treatment of granulocyte colony-stimulating factor producing hepatocellular carcinoma accompanying type B hepatitis with tegafur-uracil

    Ito T.

    Journal of Japanese Society of Gastroenterology   Vol. 109 ( 12 ) page: 2088-2096   2012.12

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  99. Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy.

    Toyoda H, Kumada T, Tada T, Niinomi T, Ito T, Kaneoka Y, Maeda A

    Journal of hepatology   Vol. 57 ( 6 ) page: 1251-7   2012.12

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    DOI: 10.1016/j.jhep.2012.07.018

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  100. [Low-dose mirtazapine improved nausea and appetite loss during S-1 therapy].

    Shibahara H, Ito T, Uematsu N, Imai E, Nishimura D

    Gan to kagaku ryoho. Cancer & chemotherapy   Vol. 39 ( 1 ) page: 143-5   2012.1

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KAKENHI (Grants-in-Aid for Scientific Research) 1

  1. 歯髄幹細胞産生因子による腸肝臓器相関に着目した新規NASH治療法の開発

    Grant number:19K17457  2019.4 - 2022.3

    科学研究費助成事業  若手研究

    伊藤 隆徳

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    現在、非アルコール性脂肪性肝炎(NASH)に対しての基礎研究や治験薬の開発が国内外を問わず行われているが、肝硬変に至った場合、その治療法は確立されていない。われわれはヒト乳歯歯髄幹細胞が産生する抗炎症・再生因子をNASHモデルに投与し、重要な免疫細胞の一つであるマクロファージを調節することで、脂肪・炎症・線維化を抑制しNASH進展を抑制することができるかどうかの検討を行う。さらにNASHの原因のひとつとされる腸内環境にも注目し、詳細なメカニズム解析を行うことで、将来の治療応用を見据えた基礎データを取得したいと考える。
    本年度は、本研究2年目に当たり、申請書記載の「研究実施予定」に従って、1) in vitro系におけるSHED-CMの治療効果、2) 非アルコール性脂肪肝炎(NASH)モデルのin vivoにおける腸管循環に着目したメカニズム解析を中心に検討・解析した。
    初年度にウェスタンダイエット食と高濃度糖水、週1の少量四塩化炭素腹腔内投与を用いたヒトNASH類似肝線維化マウスモデルに対して、SHED-CMが抗炎症・線維化抑制効果を示すことがわかっていた。具体的にはSHED-CM治療群における血清トランスアミナーゼの改善、中性脂肪・遊離脂肪酸の低下、また肝組織におけるα-SMA陽性線維化面積の有意な減少を認めた。しかしながら今回追加検討にて、NAFLD Activity Score(NAS)における炎症因子は改善あるものの、脂肪沈着の程度には変化を認めなかった。つまり、SHED-CM治療は肝内脂肪代謝には関与せずに抗炎症・線維化抑制効果を示していると考えられた。
    続いてNASH発症の原因の一つと考えられている腸肝相関を検討するために、肝組織におけるLPS受容体TLR4発現、また腸管透過性に関与する遺伝子であるZo-1の回腸末端における発現を解析するとqPCRにおいてSHED-CM群におけるTLR4の有意な発現低下、また蛍光免疫染色においてZo-1陽性細胞の有意な増加を認めた。
    最後にin vitroにおいて腸管透過性へのSHED-CMの効果を検討するために、IFNγ・TNFαを用いてCaco-2細胞のtight junctionを破壊したのちにSHED-CM置換を行い、その影響を検討した。SHED-CM治療群では、Zo-1陽性細胞の増加、ならびにFITC-デキストランを用いた腸管透過性確認試験においても、SHED-CMの透過性維持効果が確認された。
    概ね研究実施予定通りに進んでいる。一部、in vitroにおいて星細胞(Lx-2)のviabilityやTGF-βによる活性化が安定しないため、SHED-CMによる星細胞への影響は検討しきれていない。しかし、SHED-CMのマクロファージを介した肝内炎症・線維化抑制や腸管透過性への影響など、これまでに予定した主なメカニズム解析は完了しており、これまでのデータをまとめて論文化を進めている。
    次年度は、SHED-CM内のどの因子が治療効果発現メカニズムに直接的に関与しているか、特に腸肝相関に焦点を当てて、検討したいと考えている。また腸管透過性に直接的に影響しうる、腸内細菌叢に関してもSHED-CMとコントロール群において、次世代シークエンサーを用いて解析を行う予定である。