Updated on 2023/11/23

写真a

 
ITO Takanori
 
Organization
Nagoya University Hospital Gastroenterology Assistant Professor
Graduate School
Graduate School of Medicine
Title
Assistant Professor

Degree 1

  1. 博士(医学) ( 2018.3   名古屋大学 ) 

Research Interests 5

  1. 脂肪肝

  2. 肝細胞癌

  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 9

  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・指導医

  3. 日本肝臓学会   専門医・指導医・西部会評議員

  4. 日本消化器内視鏡学会   専門医

  5. 日本炎症・再生医学会

  6. 日本超音波医学会

  7. 日本再生医療学会

  8. 日本門脈圧亢進症学会

  9. 日本臨床腫瘍学会

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Committee Memberships 1

  1. 日本内科学会   若手委員会委員(日本肝臓学会)  

       

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    Committee type:Academic society

Awards 11

  1. 令和4年度名古屋大学医学系研究科医学奨励賞

    2023  

  2. 日本肝臓学会冠Award:第8回Gilead Sciences Award

    2023  

  3. Investigator Award of APASL Oncology 2023

    2023  

  4. Best Publication in Hepatology International

    2023  

  5. JDDW2021若手奨励賞

    2021  

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

  6. Taisho-Toyama Award

    2018  

  7. 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  

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

    2016  

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

    2016  

  10. 第134回 名古屋肝疾患研究会 優秀演題賞

    2015  

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

    2013  

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Papers 156

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

    Sugiyama Y, Yamamoto K, Honda T, Kato A, Muto H, Yokoyama S, Ito T, Imai N, Ishizu Y, Nakamura M, Asano T, Enomoto A, Zaitsu K, Ishigami M, Fujishiro M, Kawashima H

    Hepatology international   Vol. 17 ( 6 ) page: 1378 - 1392   2023.12

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

    Background: Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing the serum and hepatic bile acid levels. This study aimed to investigate the impact of these factors on liver tumor. Methods: C57BL/6J mice received a one-time intraperitoneal injection of 25-mg/kg diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan). Results: Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibat treatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion: Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

    DOI: 10.1007/s12072-023-10581-2

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  2. Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

    Huang DQ, Tran A, Yeh ML, Yasuda S, Tsai PC, Huang CF, Dai CY, Ogawa E, Ishigami M, Ito T, Kozuka R, Enomoto M, Suzuki T, Yoshimaru Y, Preda CM, Marin RI, Sandra I, Tran S, Quek SXZ, Khine HHTW, Itokawa N, Atsukawa M, Uojima H, Watanabe T, Takahashi H, Inoue K, Maeda M, Hoang JK, Trinh L, Barnett S, Cheung R, Lim SG, Trinh HN, Chuang WL, Tanaka Y, Toyoda H, Yu ML, Nguyen MH

    Hepatology (Baltimore, Md.)   Vol. 78 ( 5 ) page: 1558 - 1568   2023.11

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

    Background and Aims: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. Approach and Results: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively (p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase<upper limit of normal. In multivariable Cox proportional hazards analysis adjusted for age, sex, HBeAg, HBV DNA, alanine transaminase, diabetes, and platelets, antiviral therapy remained an independent predictor of reduced HCC risk (adjusted HR = 0.3, 95% CI: 0.1-0.6, p = 0.001). Conclusions: Antiviral therapy reduces HCC risk by 70% among patients with indeterminate-phase CHB. These data have important implications for the potential expansion of CHB treatment criteria.

    DOI: 10.1097/HEP.0000000000000459

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  3. A new criterion including the aspartate aminotransferase-to-platelet ratio index and liver and spleen stiffness to rule out varices needing treatment in children with biliary atresia: Modification of the Baveno VII criteria.

    Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Muto H, Shirota C, Tainaka T, Sumida W, Makita S, Takada S, Nakagawa Y, Maeda T, Nakamura M, Ishigami M, Uchida H, Kawashima H

    Hepatology research : the official journal of the Japan Society of Hepatology     2023.10

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

    Aims: Biliary atresia (BA) is a congestive biliary disease that develops in the neonatal period or early infancy. It may present with portal hypertension and varices needing treatment (VNT) even after successful Kasai portoenterostomy. This study aimed to stratify the risk of VNT in children and adolescents with BA. Methods: In this prospective cross-sectional study, we measured liver stiffness (LS) and spleen stiffness (SS) by two-dimensional shear wave elastography and checked for VNT endoscopically in 53 patients with BA who attended for follow-up between July 2018 and September 2022. Varices needing treatment were defined as large esophageal varices, esophageal varices of any size with red color signs, and/or gastric varices along the cardia. Results: Twenty-five patients (aged 0–18 years) had VNT. Eighteen patients met the Baveno VI criteria (LS <20 kPa; platelet count >150 000/L) and were deemed to be at low risk of VNT (spared endoscopies) while three had missed VNT (16.7%). Applying the Baveno VII criteria, which combines the SS cut-off value of 40 kPa with the Baveno VI criteria, resulted in five missed VNTs among 22 spared endoscopies (22.7%). A modification of the Baveno VII criteria using the aspartate aminotransferase-to-platelet ratio index (APRI) instead of the platelet count with cut-off values of 25 kPa, 30 kPa, and 1.04 for LS, SS, and APRI, respectively, missed only one VNT (5.0%) among 20 spared endoscopies. Conclusions: A novel diagnostic criterion that combines LS, SS, and APRI reduced the risk of missing VNT to 5% in children and adolescents with BA.

    DOI: 10.1111/hepr.13976

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  4. Clinical course and prognosis of patients with hepatocellular carcinoma and haemophilia.

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

    European journal of gastroenterology & hepatology   Vol. 35 ( 10 ) page: 1211 - 1215   2023.10

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

    Introduction Although patients with haemophilia are known to develop hepatocellular carcinoma (HCC) at a lower age than patients without, there are few reports on the clinical course and prognosis of HCC. Aim We aimed to investigate the clinical course and prognosis of patients with HCC and haemophilia. Methods Twenty-two patients with haemophilia, who were initially diagnosed with HCC between 2003 and 2021, were included. Their clinical courses and prognoses were retrospectively analysed. The results were compared with those of the 24th Nationwide Follow-up Survey of Primary Liver Cancer. Results All 22 patients were male; of these, 20 patients had haemophilia A, and 2 had haemophilia B. The mean age of diagnosis was 63 years (range 45-78 years) which is lower than the mean of 72 years reported in the Nationwide Survey. The mean diameter of the largest tumour was 30 mm (range 11-70 mm), and 18 tumours (82%) were solitary at the initial diagnosis. Standard treatments for HCC were performed in all patients. Sixty-one transarterial chemoembolisation, 28 RFA, 10 hepatectomies, and 2 radiation treatments were performed, and molecular-targeted agents were administered to 5 patients during their clinical courses. No deaths were associated with complications of HCC treatments. The median survival time after initial treatment was 6.4 years (range 0.9-18.7 years) which did not differ much from the median survival time of 5.8 years in the Nationwide Survey. Conclusion Standard treatment for HCC could improve the prognosis of patients with HCC and haemophilia.

    DOI: 10.1097/MEG.0000000000002628

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  5. Identification of clinical phenotypes associated with poor prognosis in patients with nonalcoholic fatty liver disease via unsupervised machine learning.

    Ito T, Morooka H, Takahashi H, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Ishigami M, Kamada Y, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)

    Journal of gastroenterology and hepatology   Vol. 38 ( 10 ) page: 1832 - 1839   2023.10

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

    Background and Aims: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. Methods: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. Results: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3–4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. Conclusions: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

    DOI: 10.1111/jgh.16326

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  6. Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study.

    Chau A, Yeh ML, Tsai PC, Huang DQ, Kim SE, Trinh H, Yoon EL, Oh H, Jeong JY, Ahn SB, An J, Tseng CH, Hsu YC, Jeong SW, Cho YK, Shim JJ, Kim HS, Ito T, Marciano S, Kawashima K, Suzuki T, Watanabe T, Nozaki A, Ishikawa T, Inoue K, Eguchi Y, Uojima H, Abe H, Takahashi H, Chuma M, Ishigami M, Hoang JK, Maeda M, Huang CF, Gadano A, Dai CY, Huang JF, Tanaka Y, Chuang WL, Lim SG, Cheung R, Yu ML, Jun DW, Nguyen MH

    Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association     2023.9

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

    Background & Aims: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. Methods: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. Results: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P <.01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P =.40) and HCC incidence rates (5.1% vs 4.4%; P =.64), but lower BR (84.0% vs 90.9%; P <.001) and CR (78.8% vs 83.4%; P =.016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17–1.46; P <.001) and CR (SHR, 1.16; 95% CI, 1.03–1.31; P =.016), but VR and HCC risks were similar. Conclusions: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

    DOI: 10.1016/j.cgh.2023.09.002

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  7. Proprioceptive reliance on trunk muscles for maintaining postural stability decreases in older patients with sagittal imbalance.

    Ito T, Sakai Y, Kawai K, Yamazaki K, Sugiura H, Morita Y

    Gait & posture   Vol. 105   page: 1 - 5   2023.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Gait and Posture  

    Background: Control of postural adjustments requires tight regulation of the spinal alignments. Sagittal imbalance may cause balance impairment and proprioceptive decline in older adults. However, the evidence on the proprioceptive mechanisms is limited, although it is known that poor proprioceptive inputs may induce spinal deformities. Thus, this study aimed to measure proprioceptive control quantifiers in older adults with sagittal imbalance to clarify the characteristic postural adjustments during proprioceptive inputs. Research question: What are the specific proprioceptive postural adjustments required to maintain balance in older adult patients with lumbar spondylosis? Methods: This was a cross-sectional, observational study. The participants were classified according to the sagittal vertical axis (SVA) lengths with 50 mm as the cut-off value. The pressure displacement center was determined in 36 patients without sagittal imbalance and 68 patients with sagittal imbalance during an upright stance on a balance board with eyes closed. Vibratory stimulations of 27–272 Hz were applied to the gastrocnemius (GS) and lumbar multifidus (LM) muscles to measure the relative contributions and center of pressures of different relative proprioceptive weighting ratios (RPWs) used on postural adjustments. Results: The RPWs of older adults with sagittal imbalance were higher than that in those without sagittal imbalance (56–100 Hz; p = 0.013). Logistic regression analysis showed that older patients with sagittal imbalance had a significant ankle proprioception control of advantage (odds ratio: 1.1, 95% confidence interval: 1.01−1.1, p = 0.012). Significance: In older patients with sagittal imbalance, the reliance on hip strategy during balance control (RPW 56–100 Hz) decreases. A quantitative assessment of postural stability during proprioceptive inputs is crucial to identify dependence on proprioception signals, including postural strategy, in older patients with sagittal imbalance. Interventions to improve proprioception can improve the postural stability and strategy of older patients with sagittal imbalance.

    DOI: 10.1016/j.gaitpost.2023.06.022

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  8. Diagnostic Performance of the Fibrosis-4 Index and Nonalcoholic Fatty Liver Disease Fibrosis Score in Lean Adults With Nonalcoholic Fatty Liver Disease.

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

    JAMA network open   Vol. 6 ( 8 ) page: e2329568   2023.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAMA Network Open  

    IMPORTANCE: The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited. OBJECTIVE: To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023. MAIN OUTCOMES AND MEASURES: The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated. RESULTS: A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age-and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P =.28) and NFS (lean, 0.790 vs nonlean, 0.755; P =.54) between the 2 groups were comparable in the age-and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend <.001), while those of the FIB-4 did not (P for trend =.05 and P =.20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P =.09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P =.03). CONCLUSIONS AND RELEVANCE: In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.

    DOI: 10.1001/jamanetworkopen.2023.29568

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  9. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons.

    Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, Lee K, Stave CD, Henry L, Barnett SD, Cheung R, Nguyen MH

    Journal of hepatology   Vol. 79 ( 2 ) page: 287 - 295   2023.8

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    Background & Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. Methods: We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD. Results: A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005). Conclusions: NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

    DOI: 10.1016/j.jhep.2023.03.040

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  10. 特集 浮腫と脱水-Q&Aで学ぶジェネラリストのための体液量異常診療 浮腫をきたす疾患の診断とそのマネジメント 肝硬変による浮腫のメカニズムとマネジメント

    伊藤 隆徳, 石上 雅敏, 川嶋 啓揮

    medicina   Vol. 60 ( 8 ) page: 1248 - 1252   2023.7

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:株式会社医学書院  

    DOI: 10.11477/mf.1402229037

    CiNii Research

  11. 特集 肝疾患-診療のチェックポイント2023 第Ⅰ部 診断のチェックポイント 第5章 肝疾患鑑別診断のチェックポイント 1.薬物性肝障害が疑われるとき

    伊藤 隆徳, 山本 崇文, 水野 和幸, 石上 雅敏, 川嶋 啓揮

    臨床消化器内科   Vol. 38 ( 7 ) page: 799 - 806   2023.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:日本メディカルセンター  

    DOI: 10.19020/cg.0000002668

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

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

    Journal of hepato-biliary-pancreatic sciences   Vol. 30 ( 6 ) page: 834 - 842   2023.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Hepato-Biliary-Pancreatic Sciences  

    Background: We aimed to investigate the factors associated with improvement of liver functional reserve after sustained virological response using interferon-free, direct-acting antiviral combination treatment in patients with compensated, severe fibrosis. Methods: Between September 2014 and April 2020, 492 patients received direct-acting antiviral combination treatment in our hospital. Among them, 173 patients who had severe fibrosis based on a fibrosis-4 index ≥3.25, showed sustained virological response after treatment. We investigated the dynamic change in albumin-bilirubin score and the baseline factors associated with its improvement, 48 weeks after treatment. Results: The baseline significant factors associated with albumin-bilirubin ≦ −0.5 were lower albumin (HR: 15.625, 95% CI: 4.273–58.824, P <.001), higher hepatitis C virus RNA (HR: 4.995, 95% CI: 1.882–13.260, P =.001), and higher alpha-fetoprotein (HR: 1.033, 95% CI: 1.011–1.055, P =.003). Patients with alpha-fetoprotein ≧10 ng/mL showed significant improvement of albumin-bilirubin score from baseline to 48 weeks after treatment compared to those with alpha-fetoprotein <10 ng/mL (P <.001). Conclusions: Baseline serum alpha-fetoprotein might be a predictive factor for improvement of liver function after sustained virological response in patients with severe fibrosis.

    DOI: 10.1002/jhbp.1309

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

    Yamamoto T, Mizuno K, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Ishikawa T, Kanamori A, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Ishii M, Sone M, Ando Y, Akiyama M, Ishigami M, Kawashima H

    Investigational new drugs   Vol. 41 ( 3 ) page: 512 - 521   2023.6

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    Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

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  14. Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

    Yamauchi R, Ito T, Yoshio S, Yamamoto T, Mizuno K, Ishigami M, Kawashima H, Yasuda S, Shimose S, Iwamoto H, Yamazoe T, Mori T, Kakazu E, Kawaguchi T, Toyoda H, Kanto T

    Journal of gastroenterology   Vol. 58 ( 6 ) page: 565 - 574   2023.6

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    Background: Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients. Methods: This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs). Results: The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8–9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100–calcium-binding protein A8/S100–calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α‐fetoprotein levels as independent predictors of PD. In the sub-analysis of Child–Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN. Conclusion: High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.

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  15. Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma.

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

    Cancers   Vol. 15 ( 10 )   2023.5

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    Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

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

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

    Internal Medicine   Vol. advpub ( 0 )   2023.5

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    <p>Vanishing bile duct syndrome (VBDS) is a rare but potentially serious cholestatic liver disease caused by various etiologies, including drugs. We herein report a complicated case of VBDS with acute tubular necrosis (ATN) that improved significantly with steroid treatment. An Asian man in his 30s was admitted with the acute onset of severe jaundice and a decline in the renal function. Although initial treatment with ursodeoxycholic acid did not reduce jaundice or renal dysfunction, steroid treatment remarkably improved the VBDS and ATN to within the respective normal ranges. Steroid treatment can be considered in cases of VBDS that appear to have an immune-mediated cause. </p>

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

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

    Scientific reports   Vol. 13 ( 1 ) page: 6851   2023.4

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    Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

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  18. Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger Than 60 Diabetic NAFLD patients.

    Ito T, Nguyen VH, Tanaka T, Park H, Yeh ML, Kawanaka M, Arai T, Atsukawa M, Yoon EL, Tsai PC, Toyoda H, Huang JF, Henry L, Jun DW, Yu ML, Ishigami M, Nguyen MH, Cheung RC

    Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   Vol. 21 ( 4 ) page: 1013 - 1022.e6   2023.4

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    Background & Aims: Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized. Methods: We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM. Results: By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m2), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63–0.66). Conclusions: FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients.

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

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

    Nutrients   Vol. 15 ( 6 )   2023.3

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    The impact of a high-fat diet (HFD) on intestinal permeability has been well established. When bacteria and their metabolites from the intestinal tract flow into the portal vein, inflammation in the liver is triggered. However, the exact mechanism behind the development of a leaky gut caused by an HFD is unclear. In this study, we investigated the mechanism underlying the leaky gut related to an HFD. C57BL/6J mice were fed an HFD or control diet for 24 weeks, and their small intestine epithelial cells (IECs) were analyzed using deep quantitative proteomics. A significant increase in fat accumulation in the liver and a trend toward increased intestinal permeability were observed in the HFD group compared to the control group. Proteomics analysis of the upper small intestine epithelial cells identified 3684 proteins, of which 1032 were differentially expressed proteins (DEPs). Functional analysis of DEPs showed significant enrichment of proteins related to endocytosis, protein transport, and tight junctions (TJ). Expression of Cldn7 was inversely correlated with intestinal barrier function and strongly correlated with that of Epcam. This study will make important foundational contributions by providing a comprehensive depiction of protein expression in IECs affected by HFD, including an indication that the Epcam/Cldn7 complex plays a role in leaky gut.

    DOI: 10.3390/nu15061473

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  20. Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients

    Liu J.K., Vutien P., Huang D.Q., Ishigami M., Landis C.S., Nguyen M.H., Daniel P.C.Y.N., Ito T., Dang H., Maeda M., Leong J.

    Clinical Gastroenterology and Hepatology   Vol. 21 ( 2 ) page: 538 - 540.e4   2023.2

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    DOI: 10.1016/j.cgh.2022.01.035

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

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

    Journal of gastroenterology and hepatology   Vol. 38 ( 2 ) page: 251 - 258   2023.2

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    Background and Aim: Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis. Methods: We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters. Results: This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70–108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77–4.50, P < 0.001; HR: 2.87, 95% CI: 1.47–5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-to-lymphocyte ratio, and liver metastases between both clusters. Conclusions: The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

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

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

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

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    Background: Like esophageal varices, cardiac varices are often treated with endoscopic variceal ligation (EVL). However, we previously reported that EVL for cardiac varices may be associated with a high risk of rebleeding from the ulcer if the O-ring spontaneously drops off early. The efficacy and safety of para-variceal endoscopic injection sclerotherapy (EIS) with polidocanol for the treatment of cardiac varices in children and adolescents were evaluated. Methods: Eleven patients under 18 years of age with portal hypertension who underwent para-variceal EIS with polidocanol for cardiac varices with red signs, which were considered to be at high risk of bleeding, were retrospectively reviewed. Results: One session of para-variceal polidocanol-EIS was performed for each of the 11 patients. One patient experienced temporary hypoxia due to aspiration of saliva when the tracheal intubation tube was removed after the procedure but recovered by endotracheal suctioning; there were no other adverse events. In six of the eight cases in which efficacy could be evaluated, eradication of cardiac varices was achieved. Conclusion: Para-variceal polidocanol-EIS may be considered instead of EVL for small cardiac varices with red signs in pediatric patients with cardiac varices.

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  23. Prevalence, characteristics, and mortality outcomes of obese and nonobese MAFLD in the United States.

    Dao AD, Nguyen VH, Ito T, Cheung R, Nguyen MH

    Hepatology international   Vol. 17 ( 1 ) page: 225 - 236   2023.2

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    Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) establishes new criteria for diagnosis of fatty liver disease independent of alcohol intake. We aimed to describe the prevalence and compare characteristics and mortality outcomes of persons with nonobese and obese MAFLD. Methods: Using data from 13,640 participants from the third National Health and Nutrition Examination Survey (NHANES III) 1988–1994, we identified participants with fatty liver on ultrasound who had MAFLD and analyzed them by the presence of obesity. Results: Overall prevalence of MAFLD was 19%; amongst those, 54% were obese and 46% were nonobese. Nonobese MAFLD was more common in participants older than 65 than in younger participants (56.8% vs. 43.2%, p < 0.0001). Nonobese MAFLD was more common in males (63.2% vs. 48.3%, p < 0.0001). Obese MAFLD was more common in females (51.7% vs. 48.3%, p < 0.0001). After adjusting for several demographic factors and alcohol use, older age [adjusted odds ratio (aOR) 1.02, 95% CI 1.00–1.02, p = 0.003] and being male (aOR: 1.65, 95% CI 1.25–2.17, p = 0.001) were independent risk factors for nonobese MAFLD. Nonobese MAFLD participants had a higher 20-year cumulative incidence for all-cause mortality compared to obese MAFLD participants (33.2% vs. 28.8%, p = 0.0137). However, nonobese MAFLD was not independently associated with mortality after adjusting for relevant confounders, while FIB-4 > 1.3 and cardiovascular disease were the strongest risk factors associated with increased mortality [adjusted hazard ratio (aHR) > 2.7 for both, p < 0.0001 for both]. Conclusions: Nonobese MAFLD constitutes about half of the MAFLD in the United States, especially among males and the elderly. Notably, nonobese MAFLD carries higher mortality than obese MAFLD. Screening and diagnosis of MAFLD should be considered in nonobese populations.

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

    Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Shirota C, Tainaka T, Sumida W, Makita S, Takimoto A, Nakagawa Y, Takada S, Ishigami M, Uchida H, Kawashima H

    Pediatrics international : official journal of the Japan Pediatric Society   Vol. 65 ( 1 ) page: e15454   2023.1

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    Background: Esophagogastric varices (EGVs) may develop as a result of portal hypertension in children with biliary atresia (BA). Although endoscopic injection sclerotherapy (EIS) with ethanolamine oleate (EO) is reported useful for children, risk factors associated with the presence of high-risk EGVs after treatment remain unknown. Methods: The subjects were BA patients under 15 years of age who underwent EO-EIS. We retrospectively reviewed a total of 28 treatment sessions of EGVs with red signs and those larger than F2, which were considered to be at high risk of bleeding. Survival analysis was performed for the presence of high-risk EGVs at the time of follow-up endoscopy as the occurrence of an event. Results: Univariate analysis showed a significantly increased risk of the presence of high-risk EGVs post-EO-EIS in patients with increased liver stiffness (LS) and Mac-2 binding protein glycan isomer (M2BPGi), with hazard ratios of 1.48 and 1.15, respectively. The median presence-free period was significantly shorter in the LS ≥ 2.8 m/s patients than in those with LS <2.8 m/s (189 vs. 266 days). Similarly, the median presence-free period was significantly shorter in patients with M2BPGi ≥ 4.0 than in those with M2BPGi < 4.0 (182 vs. 203 days). The results of multivariate analysis revealed that the risk of the presence of high-risk EGVs was significantly higher only in the high-LS group, with a hazard ratio of 2.76. Conclusions: Increased LS is associated with risk of the presence of high-risk EGVs following EO-EIS in children with BA.

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

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

    Digestive diseases and sciences   Vol. 68 ( 1 ) page: 155 - 163   2023.1

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    Background: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. Aims: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. Methods: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. Results: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. Conclusions: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH. Graphical Abstract: [Figure not available: see fulltext.].

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  26. Bulevirtide and tenofovir combination therapy for hepatitis D virus infection: longer treatment and more diverse trial populations are needed.

    Ito T, Nguyen MH

    The Lancet. Infectious diseases   Vol. 23 ( 1 ) page: 14 - 16   2023.1

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    DOI: 10.1016/S1473-3099(22)00412-1

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  27. Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes.

    Ito T, Nguyen MH

    Journal of hepatocellular carcinoma   Vol. 10   page: 413 - 428   2023

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    Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

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

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

    Digestive diseases (Basel, Switzerland)   Vol. 41 ( 1 ) page: 138 - 147   2023

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    Introduction: Lenvatinib has been widely used for the treatment of advanced hepatocellular carcinoma (HCC). Some adverse events, including diarrhea, have been reported for lenvatinib. Diarrhea may be associated with the changes in the intestinal microbiome; however, the underlying mechanism has not been elucidated. Aim: In this study, we aimed to investigate the relationship between the intestinal microbiome and diarrhea caused by lenvatinib via analysis of fecal samples collected before treatment. Methods: A total of 21 patients with advanced HCC who were treated with lenvatinib were enrolled. Fecal samples were collected from patients. The patients were divided into diarrhea (n = 8) and nondiarrhea groups (n = 12). We compared the characteristics of patients, incidence of adverse events, composition of the intestinal microbiome, and enrichment of functional pathways between both groups using QIIME2 and PICRUSt2. Results: The median age of the two groups was 73 years. The nondiarrhea group comprised a relatively higher number of male patients than the diarrhea group; however, there were no significant differences in patient characteristics between both groups. The proportion of the microbiome was similar, and alpha and beta diversities were not significantly different between both groups. The relative abundance of order Bacteroidales, including Parabacteroides and Prevotella, was higher in the diarrhea group than in the nondiarrhea group. PICRUSt2 analysis showed some metabolic pathways, including butanoate (butyrate) metabolism, were enriched in the nondiarrhea group when compared with those in the diarrhea group. Conclusion: Differences in the intestinal microbiomes and their functions may influence the incidence of diarrhea during lenvatinib treatment.

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  29. Relationship between low-back pain and flexibility in children: A cross-sectional study.

    Ito T, Sugiura H, Ito Y, Narahara S, Natsume K, Takahashi D, Noritake K, Yamazaki K, Sakai Y, Ochi N

    PloS one   Vol. 18 ( 11 ) page: e0293408   2023

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    Low-back pain is common among school-aged children. Decreased trunk flexibility in childhood influences low-back pain in adulthood. Previous studies examining the association between low-back pain and trunk flexibility in children are insufficient. Examining this association among elementary school children may help to better understand trunk flexibility in children with low-back pain and to modify the management of inflexibility. Therefore, this study aimed to identify the prevalence of low-back pain and its relationship with physical function among elementary school students. School-aged children aged 6–12 years were recruited in Japan between May 2018 and March 2023. Fingertip-to-floor distance, back muscle strength, pelvic tilt angle during gait, and the visual analog scale for low-back pain were measured. In addition, factors independently related to low-back pain were determined through logistic regression analysis. Low-back pain was reported in 9.6% of the 394 participants (boys, 191; girls, 203). All children with low-back pain presented with back pain when they moved; however, the pain was non-specific. Logistic regression analysis showed that the fingertip-to-floor distance was an independent risk factor for low-back pain (odds ratio, 0.921; p = 0.007). The odds ratios calculated in the logistic regression analysis confirmed that low-back pain frequency increased as the fingertip-to-floor distance decreased. The risk of low-back pain was associated with inflexibility, regardless of sex and muscle strength. These findings suggest that children with low-back pain must increase their trunk and lower extremity flexibility.

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  30. 寄生虫感染による孤立性壊死性結節の一例

    服部 真代, 伊藤 隆徳, 山本 健太, 水野 史崇, 佐藤 浩司, 松原 宏紀, 石津 洋二, 石川 卓哉, 古澤 健司, 服部 昌志, 川嶋 啓揮

    超音波検査技術抄録集   Vol. 48 ( 0 ) page: S207 - S207   2023

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    DOI: 10.11272/jssabst.48.0_s207

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  31. Pipeline Esophagogastric Varices Secondary to Extrahepatic Portal Vein Obstruction Treated Endoscopically with the Assistance of Transileocolic Obliteration

    Yokoyama Shinya, Ishizu Yoji, Honda Takashi, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Komada Tomohiro, Hayashi Masamichi, Ishigami Masatoshi

    Internal Medicine   Vol. 61 ( 23 ) page: 3503 - 3511   2022.12

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    <p>Endoscopic injection sclerotherapy (EIS) for esophagogastric varices (EGV) was attempted for a 29-year-old man with extrahepatic portal vein obstruction. However, pipeline varices characterized by a large blood flow volume were present, and the sclerosant did not accumulate sufficiently in them. Transileocolic obliteration (TIO) using coils was performed, but some EGVs and palisading veins remained. Thus, EIS was performed once again immediately after TIO. Since a reduction in the intravariceal blood flow was achieved by preceding TIO, effective injection of sclerosant into the vessels was possible. For pipeline varices difficult to treat endoscopically, combination therapy with TIO may be effective. </p>

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  32. Factors associated with the progression of myosteatosis in patients with cirrhosis.

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

    Nutrition (Burbank, Los Angeles County, Calif.)   Vol. 103-104   page: 111777   2022.11

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    Objectives: The presence of myosteatosis is one factor associated with poor prognosis for patients with cirrhosis; however, the factors contributing to worsening myosteatosis are, to our knowledge, unknown. The aim of this study was to clarify the changes in myosteatosis, and the factors involved in these changes. Methods: The present study enrolled 178 patients with cirrhosis who underwent computed tomography twice to measure changes in skeletal muscle attenuation (SMA) at the L3 level. Factors associated with SMA and those associated with changes in SMA were examined. Results: Using linear multiple regression analysis, age (β = –0.22), skeletal muscle index (SMI; skeletal muscle area divided by height squared; β = 0.25), and visceral and subcutaneous fat indices (VFI and SFI; the visceral and subcutaneous fat areas at the umbilical level divided by height squared; β = –0.08, β = –0.06, respectively) were identified as associated with SMA. The 100-d change in SMA was –0.21 ± 1.29 Hounsfield units (HU). Changes in SMI and SMA were positively associated (R = 0.183, P = 0.014), whereas those in VFI and SMA were negatively associated (R = –0.172, P = 0.022). No association was noted between the 100-d changes in SFI and SMA. In patients whose SMI increased and VFI decreased, the 100-d change in SMA was 0.24 ± 1.82 HU, which was marginally different from that in patients whose SMI decreased and VFI increased (–0.44 ± 1.32 HU, P = 0.077). Conclusions: In patients with cirrhosis, myosteatosis progressed, and decreases in SMI and increases in VFI were correlated with its progression.

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

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

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 11 ) page: 937 - 946   2022.11

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    Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat-infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low-fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low-fat SMI was significantly correlated with handgrip strength (males, R = 0.393, p = 0.002; females, R = 0.423, p < 0.001) and LFI (males, R = −0.535, p = 0.035; females, R = −0.368, p = 0.039), whereas conventional SMI was not. When using low-fat SMI, patients with low skeletal muscle mass had significantly low handgrip strength, LFI, SPPB, and physical and social-related QOL score than those without. By contrast, no significant differences were found for any items when using conventional SMI. Conclusions: Low-fat SMI is a good index of skeletal muscle mass that appropriately reflects skeletal muscle function.

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  34. Combined ultrasound and magnetic resonance elastography predict hepatocellular carcinoma after hepatitis C virus eradication.

    Kumada T, Toyoda H, Yasuda S, Ogawa S, Gotoh T, Tada T, Ito T, Sumida Y, Tanaka J

    Hepatology research : the official journal of the Japan Society of Hepatology   Vol. 52 ( 11 ) page: 957 - 967   2022.11

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    Aim: Elastography is an established, noninvasive method for measuring liver stiffness using to 2-D shear-wave elastography (2D-SWE) or magnetic resonance elastography (MRE). The aim of this study was to determine the usefulness of combined measurement using 2D-SWE and MRE to stratify the risk of developing hepatocellular carcinoma (HCC) in patients who achieved hepatitis C virus eradication. Methods: Five hundred and twenty-five patients who underwent 2D-SWE and MRE before antiviral therapy and who achieved eradication were enrolled. The optimal 2D-SWE and MRE cutoff values were determined using time-dependent receiver operating characteristic (ROC) curves for predicting HCC development. Inverse probability of treatment weighting (IPTW) and a Cox proportional hazards model were used to adjust the cumulative incidence rate of HCC development for potential imbalances. Results: Time-dependent ROC analysis showed that the optimal cut-off values of 2D-SWE and MRE for predicting HCC development were 11.7 and 4.5 kPa, respectively. The IPTW-adjusted cumulative incidence rate of HCC development in patients with both an 2D-SWE value ≥ 11.7 kPa and an MRE value ≥ 4.5 kPa had a higher hazard ratio (28.080; 95% confidence interval, 5.527–132.600; p < 0.001) than those with either an 2D-SWE value < 11.7 kPa or an MRE value < 4.5 kPa. Conclusions: The combined measurement of 2D-SWE and MRE was very effective for identifying patients at high risk of HCC development. US-based elastography should be performed first, and if the 2D-SWE value is high, MRE should then be carried out to confirm the degree of liver stiffness.

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

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

    Nutrition (Burbank, Los Angeles County, Calif.)   Vol. 103-104   page: 111807   2022.11

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    Objectives: To our knowledge, the relationship between appetite and sarcopenia in patients with cirrhosis is unknown. The aims of this study were to examine the factors associated with decreased appetite and to clarify the relationship between appetite and sarcopenia. Methods: This study included 61 patients with cirrhosis. The patients were asked to describe their appetite using a numerical rating scale (NRS) from 0 (none at all) to 10 (most), with ≤5 defined as decreased appetite. The clinical characteristics, gastrointestinal symptoms as assessed using the Gastrointestinal Symptom Rating Scale, handgrip strength, and skeletal muscle area at the third vertebra were collected retrospectively. Sarcopenia was diagnosed according to the criteria of the Japan Society of Hepatology. The differences in these factors between patients with and without decreased appetite, and the factors associated with the presence of sarcopenia were examined. Results: Alcoholic liver disease was the most common etiology. The median Model for End-Stage Liver Disease score was 8 (interquartile range = 7 - 10) and hepatocellular carcinoma was present in 35 patients. Overall, 36% of the patients with cirrhosis had decreased appetite. Patients with decreased appetite had a higher frequency of abdominal pain and acid reflux–related symptoms and significantly lower handgrip strength than patients without, among both men (P = 0.034) and women (P = 0.017). The multivariate analysis identified a decrease in appetite as a significant factor associated with the presence of sarcopenia (NRS one increase, odds ratio, 0.701; 95% confidence interval, 0.502–0.977; P = 0.036). Conclusion: Decreased appetite was associated with the presence of sarcopenia.

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  36. Additional survival follow-up of TACTICS-L: Transcatheter arterial chemoembolization therapy (TACE) in combination strategy with lenvatinib in (LEN) patients with unresectable hepatocellular carcinoma in Japan

    Inaba Y., Ueshima K., Ishikawa T., Saeki I., Morimoto N., Aikata H., Tanabe N., Wada Y., Kondo Y., Tsuda M., Nakao K., Ikeda M., Moriguchi M., Ito T., Hosaka T., Koga H., Hino K., Kawamura Y., Yoshimura K., Kudo M.

    ANNALS OF ONCOLOGY   Vol. 33   page: S1472 - S1472   2022.11

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    DOI: 10.1016/j.annonc.2022.10.131

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

    Honda Takashi Honda, Ishigami Masatoshi, Kato Asuka, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Ishizu Yoji, Yasuda Satoshi, Toyoda Hidenori, Kumada Takashi, Ishikawa Tetsuya, Kawashima Hiroki

    HEPATOLOGY   Vol. 76   page: S262 - S263   2022.10

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

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

    HEPATOLOGY   Vol. 76   page: S1181 - S1181   2022.10

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  39. ANTIVIRAL THERAPY REDUCES HEPATOCELLULAR CARCINOMA RISK AMONG HBV PATIENTS IN THE INDETERMINATE PHASE

    Huang Daniel, Tran Andrew Khoa, Yeh Ming-Lun, Tsai Pei-Chien, Chuang Wan-Long, Huang Chung-Feng, Dai Chia-Yen, Toyoda Hidenori, Yasuda Satoshi, Trinh Huy, Ogawa Eiichi, Ishigami Masatoshi, Ito Takanori, Kozuka Ritsuzo, Enomoto Masaru, Tanaka Yasuhito, Suzuki Takanori, Yoshimaru Yoko, Preda Carmen, Marin Raluca, Sandra Irina, Quek Sabrina, Khine Htet Htet Toe Wai, Itokawa Norio, Atsukawa Masanori, Uojima Haruki, Watanabe Tsunamasa, Takahashi Hirokazu, Inoue Kaori, Maeda Mayumi, Hoang Joseph, Trinh Lindsey, Cheung Ramsey, Lim Seng Gee, Yu Ming-Lung, Nguyen Mindie H.

    HEPATOLOGY   Vol. 76   page: S34 - S35   2022.10

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  40. CIRRHOSIS INCIDENCE AND LONG-TERM MORTALITY RATE AMONG LEAN, OVERWEIGHT, AND OBESE PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN THE UNITED STATES

    Nguyen Vy H., Ha Audrey, Park Jung Eun, Rouillard Nicholas, Le Richard H. X., Fong Ashley, Maeda Mayumi, Ito Takanori, Nguyen Mindie H.

    HEPATOLOGY   Vol. 76   page: S742 - S743   2022.10

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  41. CLINICAL COURSE AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEMOPHILIA

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

    HEPATOLOGY   Vol. 76   page: S1330 - S1330   2022.10

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  42. Factors linked to hepatocellular carcinoma development beyond 10 years after viral eradication in patients with hepatitis C virus.

    Kumada T, Toyoda H, Yasuda S, Ito T, Tsuji K, Fujioka S, Hiraoka A, Kariyama K, Nouso K, Ishikawa T, Tamai T, Tada T, Tanaka J

    Journal of viral hepatitis   Vol. 29 ( 10 ) page: 919 - 929   2022.10

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    The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p = 0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508–5.693, p = 0.0015), fibrosis-4 (FIB-4) score > 3.25 (aHR 4.364; 95%CI 2.206–8.633, p < 0.0001) and alpha-fetoprotein ≥5.0 ng/ml (aHR 2.381; 95%CI 1.325–4.280, p = 0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366–16.190, p = 0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240–6.935, p = 0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400–12.350, p = 0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words).

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  43. GLOBAL INCIDENCE OF NON-ALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

    Le Michael, Le David M., Baez Thomas, Wu Yuankai, Lee Eunice Y., Ito Takanori, Nguyen Mindie H.

    HEPATOLOGY   Vol. 76   page: S850 - S850   2022.10

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  44. HIGHER HEPATOCELLULAR CARCINOMA (HCC) INCIDENCE IN CHRONIC HEPATITIS C (CHC) PATIENTS AFTER HEPATITIS C VIRUS (HCV) CURE COMPARED TO TREATED CHRONIC HEPATITIS B (CHB): RESULTS FROM A MULTINATIONAL REAL-WORLD COHORT OF PATIENTS WITH CIRRHOSIS

    Park Jiyoon, Tran Sally, Ogawa Eiichi, Huang Chung-Feng, Toyoda Hidenori, Chen Chien Hung, Yeh Ming-Lun, Tseng Cheng-Hao, Hsu Yao-Chun, Kawashima Keigo, Preda Carmen, Istratescu Doina, Yasuda Satoshi, Nozaki Akito, Chuma Makoto, Oh Hyunwoo, Shim Jae-Jun, Jeong Soung Won, An Jihyun, Ahn Sang Bong, Kim Sung Eun, Yoon Eileen, Lee Han Ah, Kim Hyoung Su, Cho Yong Kyun, Uojima Haruki, Trinh Huy, Atsukawa Masanori, Itokawa Norio, Okubo Tomomi, Abe Hiroshi, Lee Dong Hyun, Jun Mi Jung, Landis Charles, Liu Joanne, Enomoto Masaru, Watanabe Tsunamasa, Ji Fanpu, Wang Wenjun, Yu Li, Xie Qing, Fukunishi Shinya, Asai Akira, Yokohama Keisuke, Ishikawa Toru, Liu Li, Li Junyi, Takahashi Hirokazu, Inoue Kaori, Eguchi Yuichiro, Ishigami Masatoshi, Ito Takanori, Huang Daniel, Wong Grace L., Wong Vincent, Lu Chengzhen, Zang Wenqian, Li Jia, Ueno Yoshiyuki, Haga Hiroaki, Marciano Sebastian, Jing Liang, Ye Qing, Lam Carla, Ho Dang Kh, Do Son T., Huang Rui, Takaguchi Koichi, Senoh Tomonori, Chien Nicholas, Maeda Mayumi, Kudaravalli Sahith, Henry Linda, Chuang Wan-Long, Dai Chia-Yen, Huang Jee-Fu, Gadano Adrian C., Yuen Man-Fung, Lim Seng Gee, Cheung Ramsey, Tanaka Yasuhito, Jun Dae Won, Yu Ming-Lung, Nguyen Mindie H.

    HEPATOLOGY   Vol. 76   page: S377 - S379   2022.10

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  45. Liver Stiffness Measurements by 2D Shear-Wave Elastography: Effect of Steatosis on Fibrosis Evaluation.

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

    AJR. American journal of roentgenology   Vol. 219 ( 4 ) page: 604 - 612   2022.10

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    BACKGROUND. Hepatic steatosis has been found not to affect liver stiffness measurements (LSM) from MR elastography (MRE). However, the effect of steatosis on LSM from 2D shear-wave elastography (SWE) remains controversial. OBJECTIVE. The purpose of this study was to evaluate the effect of hepatic steatosis on the diagnostic performance of LSM from 2D SWE (LSM2D SWE) for evaluation of liver fibrosis with LSM from MRE (LSMMRE) as the reference standard. METHODS. This retrospective study included 888 patients (442 women, 446 men; median age, 67 years) with chronic liver disease who underwent LSM by both 2D SWE and MRE within a 3-month window. Steatosis was also assessed on ultrasound examinations by ultrasound-guided attenuation parameter (UGAP) and on MRI examinations by proton density fat fraction (PDFF). Fibrosis stages and steatosis grades were classified according to previously established thresholds. The effect of steatosis on LSM2D SWE was evaluated by Kruskal-Wallis tests with post hoc tests and ROC analysis. RESULTS. LSM2D SWE were significantly higher in patients with severe steatosis than those without steatosis by MRI PDFF among patients with F0 fibrosis (5.5 kPa [IQR, 4.7–6.0 kPa] vs 4.7 kPa [IQR, 4.2–5.5 kPa], p = .009) and F1 fibrosis (6.3 kPa [IQR, 6.0–7.2 kPa] vs 5.9 kPa [IQR, 5.0–6.6 kPa], p = .009). LSM2D SWE were significantly higher in patients with severe steatosis than those without steatosis by UGAP among patients with F1 fibrosis (6.6 kPa [IQR, 5.9–7.3 kPa] vs 5.9 kPa [IQR, 5.1–6.5 kPa], p = .008). Otherwise, LSM2D SWE did not vary significantly across steatosis grades at a given fibrosis stage (all p > .05). Sensitivity and specificity for ≥ F1 fibrosis were 63.8% and 91.5% in patients without versus 60.4% and 80.9% in patients with severe steatosis by MRI PDFF and were 62.4% and 91.5% in patients without versus 72.1% and 78.3% in patients with severe steatosis by UGAP. CONCLUSION. Severe hepatic steatosis may result in overestimation of LSM2D SWE in patients without or with mild steatosis, reducing the specificity of liver fibrosis detection. CLINICAL IMPACT. Assessment of UGAP at 2D SWE may help identify patients in whom LSM2D SWE should be assessed with caution. In patients with no or mild steatosis by 2D SWE and severe steatosis by UGAP, MRE helps provide a more reliable measure of liver fibrosis.

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  46. Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade.

    Kobayashi T, Iwama S, Yamagami A, Yasuda Y, Okuji T, Ito M, Zhou X, Ando M, Onoue T, Miyata T, Sugiyama M, Hagiwara D, Suga H, Banno R, Hase T, Morise M, Ito T, Kikumori T, Inoue M, Ando Y, Masuda N, Kawashima H, Hashimoto N, Arima H

    The Journal of clinical endocrinology and metabolism   Vol. 107 ( 10 ) page: e4115 - e4123   2022.9

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    Background: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. Methods: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. Results: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. Conclusion: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

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  47. Intra-individual Comparisons of the Ultrasound-Guided Attenuation Parameter and the Magnetic Resonance Imaging-Based Proton Density Fat Fraction Using Bias and Precision Statistics.

    Kumada T, Ogawa S, Goto T, Toyoda H, Yasuda S, Ito T, Yasuda E, Akita T, Tanaka J

    Ultrasound in medicine & biology   Vol. 48 ( 8 ) page: 1537 - 1546   2022.8

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    Ultrasound-based techniques using the attenuation coefficient, including the ultrasound-guided attenuation parameter (UGAP), have been developed for the quantification of hepatic steatosis. The magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) is considered to be more accurate than liver biopsy for liver fat quantification. The aim of this study was to perform intra-individual comparisons of UGAP and MRI-PDFF for determining hepatic steatosis grade. The study enrolled 309 patients who underwent UGAP and MRI-PDFF measurements. Bland–Altman analysis was conducted after transforming MRI-PDFF values to a normal distribution and converted to a common set of units using linear regression analysis for differing scales. The expected limits of agreement (LOA) was defined as the square root of the sum of the squares of UGAP and MRI-PDFF precision. A Bland–Altman plot revealed that the bias and upper and lower LOAs (ULOA and LLOA) were −0.0047, 0.1160 and −0.1255, respectively. The percentage difference indicated that the mean, ULOA and LLOA were −1.1434%, 18.1723% and −20.4590%, respectively. The calculated expected LOA was 18.5449%, and 283 of 309 patients (91.6%) had a percentage difference within 18.5449%. Bland–Altman analysis revealed that UGAP and MRI-PDFF were interchangeable within a clinically acceptable range.

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

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

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

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    Background/Aim: A porous glass membrane-pumping emulsification device (GMD) enables the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMD is expected to improve the locoregional therapeutic effects of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC), its effectiveness in the management of solitary HCC remains unclear. Patients and Methods: Patients treated for solitary HCCs (<5 cm) were retrospectively reviewed. A total of 46 patients who could not undergo liver resection and were unsuitable for radiofrequency ablation were included in this study. Among these, 22 patients underwent TACE using a GMD (GMD-TACE group) and 24 underwent stereotactic body radiotherapy (SBRT) using a robotic radiosurgery system (SBRT group). Local control rates were compared between the two groups. Results: The median HCC tumour size was 24 mm (range=12-50 mm) and 22 mm (range=8-39 mm) in the GMD-TACE and SBRT groups, respectively; however, the difference between the groups was not significant. Age, liver function test results, or Child-Pugh scores were not significantly different between the two groups. The rate of local control at 6 months after treatment was 100% in both groups. Although the 1-year local control rate was higher in the SBRT group (92.3%) than in the GMD-TACE group (81.8%), there was no significant difference in the log-rank test (p=0.654). No major treatment-related complications occurred in either group during the observation period. Conclusion: TACE with GMD could be considered an effective treatment option for the management of solitary HCC.

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  49. A case of antiprogrammed death-ligand 1 antibody-induced multisystem immune-related adverse events with pancreatitis and steroid-resistant sclerosing cholangitis.

    Yamamoto T, Ito T, Mizuno K, Shinya Y, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Matsui T, Hase T, Hashimoto N, Ishigami M

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

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    DOI: 10.1111/1751-2980.13122

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  50. Metabolic abnormalities play a crucial role in non-obese people suffering from non-alcoholic fatty liver disease (NAFLD).

    Ye Q, Ito T, Henry L, Nguyen MH

    Hepatobiliary surgery and nutrition   Vol. 11 ( 2 ) page: 333 - 334   2022.4

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    DOI: 10.21037/hbsn-22-26

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  51. 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   Vol. 107 ( 4 ) page: e1620 - e1630   2022.3

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    Background: Previous studies showed that although the risk of thyroid dysfunction [thyroid immune-related adverse events (irAEs)] induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2% to 7% in patients negative for anti-thyroid antibodies (ATAs) at baseline, it was much higher (30%-50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods: A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab and CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then observed until the last clinical visit. Results: Of the 451 patients, 51 developed thyroid irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) treated with CTLA-4-Ab, and 10 of 27 (37.0%) treated with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid irAEs was significantly higher in patients who were positive vs negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs 13/329 (4.0%), P < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs 4/17 (23.5%), P < 0.05] treatments. The risk of thyroid irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions: This study showed that the incidence of thyroid irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

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  52. 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.

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  53. 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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    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.

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  54. 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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    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.

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  55. 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.

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  56. 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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    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.

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  57. 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.

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  58. 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   Vol. 74 ( 9 ) page: 3118 - 3127   2022

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    Aim: Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC. Methods: In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis. Results: Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (P = 0.004) without symptoms or changes in the other parameters. In multivariate analysis, this early change in mean-SMA after LEN treatment was a significant predictor of time to treatment failure (HR: 2.67, 95%CI: 1.338–5.081, P = 0.005) in patients with HCC. Conclusions: This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322.

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  59. 先天性フィブリノゲン異常症患者に合併した多発動脈血栓の一例

    服部 真代, 笹木 優賢, 鈴木 伸明, 石津 洋二, 荒木 芳生, 岩﨑 純子, 新島 萌, 山本 健太, 伊藤 隆徳, 川嶋 啓揮, 古澤 健司, 松下 正

    超音波検査技術抄録集   Vol. 47 ( 0 ) page: S137 - S137   2022

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    DOI: 10.11272/jssabst.47.0_s137_2

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  60. 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.

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  61. 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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    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.

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  62. 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.

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  63. 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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    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.

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  64. 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.

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  65. 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.

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  66. 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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    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.

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

    TakashiHonda; MasatoshiIshigami; ShinyaYokoyama; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Ishikawa, T; Fujishiro, M

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

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  68. 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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  69. 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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  70. RENAL OUTCOMES IN POST-LIVER TRANSPLANT RECIPIENTS TREATED WITH TENOFOVIR ALAFENAMIDE COMPARED WITH TENOFOVIR DISOPROXIL FUMARATE AND ENTECAVIR

    Liu, J; Vutien, P; Huang, D; Ishigami, M; Daniel, PCYN; Ito, T; Dang, H; Maeda, M; Leong, J; Landis, C; Nguyen, MH

    HEPATOLOGY   Vol. 74   page: 492A - 493A   2021.10

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  71. CHANGE OF PREDICTIVE ABILITY IN NON-INVASIVE FIBROSIS MARKERS AMONG ASIAN NON-ALCOHOLIC FATTY LIVER DISEASE BY AGE, OBESITY, AND A PRESENCE OF TYPE 2 DIABETES

    Ito, T; Nguyen, VH; Tanaka, T; Park, H; Yeh, ML; Kawanaka, M; Arai, T; Atsukawa, M; Yoon, E; Tsai, PC; Toyoda, H; Fujishiro, M; Huang, JF; Nguyen, MH; Jun, DW; Yu, ML; Ishigami, M; Cheung, RC

    HEPATOLOGY   Vol. 74   page: 936A - 937A   2021.10

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  72. LONG-TERM OVERALL AND RECURRENCE-FREE SURVIVAL FOLLOWING CURATIVE SURGICAL RESECTION FOR HEPATOCELLULAR CARCINOMA IN THE RECENT DECADE: A META-ANALYSIS OF 110 STUDIES AND 82,392 PATIENTS

    Reveron-Thornton, R; Teng, MLP; Lee, EY; Tran, AK; Vajanaphanich, S; Tan, XXE; Nerurkar, SN; Ng, RX; Teh, R; Prasad, DP; Ito, T; Tanaka, T; Miyake, N; Zou, BY; Wong, CN; Toyoda, H; Esquivel, CO; Bonham, A; Nguyen, MH; Huang, D

    HEPATOLOGY   Vol. 74   page: 655A - 656A   2021.10

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  73. META-ANALYSIS: REGIONAL DIFFERENCES IN OUTCOMES OF SURGICAL RESECTION FOR HEPATOCELLULAR CARCINOMA

    Teng, M; Reveron-Thornton, R; Lee, EY; Tran, AK; Vajanaphanich, S; Tan, XXE; Nerurkar, SN; Ng, RX; Teh, R; Prasad, DP; Ito, T; Tanaka, T; Miyake, N; Zou, BY; Wong, C; Toyoda, H; Esquivel, CO; Bonham, A; Nguyen, MH; Huang, D

    HEPATOLOGY   Vol. 74   page: 859A - 859A   2021.10

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  74. 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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  75. 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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  76. 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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  77. 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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    AbstractReal-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 6weeks.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 6weeks.Overall survival was significantly longer in patients with partial response (PR)+stable disease (SD) (13.7months) than in patients with progressive disease (PD) (1.7months, P<.001) in the ≥50% group. Patients with antitumor response of PR+SD at 6weeks in the ≥50% group showed more marked deterioration of ALBI score at 2weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. Focusing on patients with PD at 6weeks, 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 2weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2weeks.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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  78. The impact of hepatitis C virus eradication on hepatocarcinogenesis in haemophiliacs

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

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

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  79. 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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  80. 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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  81. 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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  82. 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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  83. 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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  84. 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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  85. 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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  86. 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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  87. 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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  88. 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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  89. SAFETY AND EFFICACY OF PERCUTANEOUS RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA PATIENTS WITH HEMOPHILIA

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

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

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

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

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

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  91. 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, M; Honda, T; Ishizu, Y; Imai, N; Ito, T; Yamamoto, K; Fujishiro, M

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

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

    Honda, T; Yamada, N; Murayama, A; Kato, A; Ito, T; Ishizu, Y; Kuzuya, T; Ishigami, M; Murakami, Y; Ishikawa, T; Fujishiro, M; Kato, T

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

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  93. THE EPIDEMIOLOGY OF NAFLD AND LEAN NAFLD IN JAPAN: A SYSTEMATIC REVIEW AND META-ANALYSIS WITH INDIVIDUAL PATIENT LEVEL DATA AND FORECASTING, 1995-2040

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

    HEPATOLOGY   Vol. 72   page: 999 - 999   2020.11

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  94. 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.

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  95. 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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  96. 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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  97. 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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  98. 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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  99. 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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  100. 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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  101. 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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  102. 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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  103. 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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  104. 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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  105. 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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  106. 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.

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  107. 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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  108. 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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  109. 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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    Aim: The cause of thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is multifactorial: hypersplenism, decreased thrombopoietin levels, and myelosuppression induced by HCV. Platelet counts increase after eradication of HCV; however, this mechanism is not fully understood. Therefore, the aim of this study was to determine the influence of these three factors on platelet counts. Methods: We retrospectively analyzed data from 109 HCV-infected patients with platelet counts ≤150 × 103/μL who achieved viral eradication using interferon-free anti-HCV therapy. Changes in hematological parameters, thrombopoietin levels, HCV titers, and spleen volumes, and the correlations among them were evaluated. Results: HCV RNA levels significantly decreased at 4 weeks after initiating antiviral therapy. Platelet counts rapidly increased at 4 weeks from baseline (120 ± 35 vs. 106 ± 28 × 103/μL, P < 0.001), and remained at a plateau until 48 weeks after initiating antiviral therapy. Neutrophil counts showed the same pattern. Spleen volume was evaluated in 32 patients and, among them, it decreased in 21 patients, but remained unchanged in seven and increased in four. In addition to patients with decreased spleen volume, patients with unchanged spleen volume showed marginally increased platelet counts. Thrombopoietin levels did not correlate with platelet counts. Conclusions: Platelet counts increased at 4 weeks after starting anti-HCV treatment. Our results suggest that this rapid change was possibly caused by improvement of hypersplenism and HCV-induced myelosuppression resulting from anti-HCV therapy.

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  110. 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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  111. 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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  112. 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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  113. 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>

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  114. 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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  115. 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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  116. 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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  117. 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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  118. 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, T; Ishigami, M; Ishizu, Y; Kuzuya, T; Honda, T; Yasuda, S; Toyoda, H; Kumada, T; Fujishiro, M

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

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  119. 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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  120. 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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  121. 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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    DOI: 10.1016/S0618-8278(19)30488-8

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  122. 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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  123. 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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  124. 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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  125. 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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  126. 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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  127. 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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  128. 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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  129. 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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  130. 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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  131. 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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  132. 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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    DOI: 10.1016/S0168-8278(18)31483-1

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  133. 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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    DOI: 10.1016/S0168-8278(18)31379-5

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  134. 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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  135. 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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  136. 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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  137. 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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  138. 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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  139. 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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  140. 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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  141. 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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  142. 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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  143. 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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  144. 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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  145. 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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  146. 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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  147. 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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  148. 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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  149. 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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  150. [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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  151. 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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  152. 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

  153. [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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  154. 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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  155. 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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  156. [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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Books 6

  1. 輸液グリーンノート 中外医学社

    伊藤隆徳,藤城光弘( Role: Joint author ,  23 肝硬変)

    2021 

  2. 臨牀消化器内科 Vol.35 薬剤性消化器疾患の診療

    伊藤隆徳、澤田つな騎、中村正直、本多隆、石上雅敏、藤城光弘(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)

    2020 

  3. 消化器・肝臓内科 特集II 肝癌分子標的治療と今後の展望

    伊藤 隆徳,葛谷 貞二,石上 雅敏,廣岡 芳樹(「TACEなど既存治療のポジショニング-新薬の登場でいかに変わるか-)

    2018 

  4. 日本臨床増刊号 最新肝癌学 2015年73巻増刊号 基礎と臨床の最新研究動向

    伊藤 隆徳,熊田 卓,豊田 秀徳,多田 俊史(Ⅷ. 発癌予測因子としての線維化進展度診断 血清線維化マーカー(FIB-4 indexなど))

    2015 

  5. 日本医事新報No. 4940

    伊藤隆徳(非アルコール性脂肪性肝疾患(NAFLD)における肝線維化診断の重要性について)

  6. 日本医事新報 No. 4931

    伊藤隆徳、石上雅敏、後藤秀実(難渋症例から学ぶ診療のエッセンス「妊娠後期に破裂した巨大肝細胞腺腫」)

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Research Project for Joint Research, Competitive Funding, etc. 1

  1. 難治性irAE肝障害の予後改善を目指した肝内病理学的解析と治療効果予測バイオマーカーの検討

    2023.4 - 2025.3

    国際医療研究開発費 

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    Authorship:Coinvestigator(s) 

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 肝内マクロファージ極性と類洞内皮障害に着目したirAE肝障害の発症機序の解明

    Grant number:22K15962  2022.4 - 2025.3

    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:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    免疫チェックポイント阻害薬(immune checkpoint inhibitor: ICI)による免疫関連有害事象(Immune-related adverse event: irAE)irAE肝障害について、発症患者における肝生検組織検体の遺伝子学的解析とともに、肝内マクロファージ浸潤と類洞内皮障害との関連に着目し、解析を行う。in vitroにてICI投与による免疫細胞の変化や肝細胞・類洞内皮細胞への影響を解析する。本研究ではirAE肝障害の病態生理を、臨床・基礎両面からアプローチ・解明し、irAE肝障害の発症・治療効果予測バイオマーカーを検索することを目的とする。

  2. 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 - 2023.3

    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3年目に当たり、2年目に引き続き、SHED-CMの腸管相関における影響を解析した。まずは、ELISA法により血中LPS-binding protein濃度の低下を確認した。さらに、vivoにおけるNASH肝線維化マウスモデルにおいて、FITC-dextranを用いた腸管透過性評価によって、SHED-CM治療は腸管バリア機能を保護することが確認された。回腸におけるZO-1の発現はSHED-CM群で有意に増強しており、tight junctionを保護する作用が示唆された。またSHED-CMによる腸内細菌叢への影響を確認するために、SHED-CM投与群とコントロールにおいて、次世代シークエンサーを用いて解析を行ったが、それらには有意差を認めなかった。つまり、SHED-CMは腸内細菌を変化させるということではなく、CM内のHGFをはじめとした再生因子が腸管上皮に直接的に働いて腸管透過性亢進を抑制することが明らかになった。ここまでの結果より、SHED-CMが、肝細胞の保護作用や炎症性マクロファージの活性化の抑制に加えて、腸肝軸を介して、マウスNASHモデルの線維化を抑制することを明らかにした。しかしM2マクロファージマーカーはCM投与群でも変化はなかった。これらのデータは、SHED-CMがNASHに対して多面的な治療効果を発揮する可能性を示すと考えた。以上の結果をAASLD(アメリカ肝臓学会)2021、肝臓学会総会2021にて発表し、Scientific Reports. 2021 Sep 21;11(1):18778. doi: 10.1038/s41598-021-98254-8(PMID: 34548598)に論文報告することができた。
    本年度は目標としていた論文作成、受理を得ることができた。SHED-CM内のメカニズムの中心となる因子同定は今後の検討が必要である。
    今後はhepatocyteやマクロファージを用いたin vitroの系よりSHED-CM効果の中心となる因子の同定を行うためにRNA seqを中心とした解析を進める予定である。

 

Academic Activities 1

  1. 薬物性肝障害診断指針:RECAM-J 2023、免疫チェックポイント阻害薬による肝障害診断指針作成ワーキンググループ委員(総括)