Researcher basic information

• 博士 (臨床薬学), 北海道大学, Mar. 2018

• https://researchmap.jp/omaehara?lang=en

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201801011126726929

• 80836338

• 201801011126726929

• 細胞外小胞
• MSC
• 肝細胞癌
• がん幹細胞

• Life Science, Gastroenterology, 再生医療 間葉系幹細胞
• Life Science, Tumor biology

• Bachelor's degree program, School of Pharmaceutical Sciences and Pharmacy
• Master's degree program, Graduate School of Life Science
• Doctoral (PhD) degree program, Graduate School of Life Science

Research activity information

• Prevalence and Prognostic Impact of the Coexistence of Cachexia and Sarcopenia in Patients With Chronic Liver Diseases.
  Takatsugu Tanaka; Goki Suda; Masatsugu Ohara; Daisuke Yokoyama; Shoichi Kitano; Osamu Maehara; Tomoka Yoda; Qingjie Fu; Zijian Yang; Naohiro Yasuura; Akimitsu Meno; Takashi Sasaki; Risako Kohya; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Shunsuke Ohnishi; Naoya Sakamoto
  Journal of cachexia, sarcopenia and muscle, 17, 3, e70305, Jun. 2026, [International Magazine]
  English, Scientific journal, BACKGROUND: Cachexia and sarcopenia are prevalent, inflammation-linked syndromes in chronic liver disease that worsen outcomes. To our knowledge, their coexistence in a single chronic liver disease cohort has not been systematically examined. In this study, we evaluated the prevalence, clinical features and prognostic impact of cachexia and sarcopenia-alone and combined-in chronic liver disease. METHODS: We retrospectively screened 776 patients with liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC) at Hokkaido University Hospital (August 2014-May 2025). The inclusion criteria were grip strength, CT-based muscle mass and complete clinical data, yielding 307 patients; 469 did not meet one of the inclusion criteria. Cachexia was determined following the Asian Working Group for Cachexia criteria, and sarcopenia was determined following Japan Society of Hepatology guidelines. Patients were grouped as no cachexia/sarcopenia, cachexia only, sarcopenia only or cachexia+sarcopenia. The outcomes were overall survival, time to liver-related events and time to readmission (Kaplan-Meier and Cox-proportional models). RESULTS: Among 776 patients, 307 were included in the final-analysis. Of 307 patients, 206 (67.1%) were male, the median age was 70 years (range, 19-90 years), 262 patients (85.3%) had LC and 188 patients (61.2%) had HCC. The patients were grouped as no cachexia/sarcopenia (213; 69.4%), cachexia only (54; 17.6%), sarcopenia only (17; 5.5%) and cachexia+sarcopenia (23; 7.5%). The combined group compared with the others had the lowest body mass index, psoas-muscle-index and grip strength (all p < 0.001). Overall survival (OS), liver-related events, LC progression and readmissions were compared between 246 patients with and without cachexia or sarcopenia, after excluding those who visited the hospital on or after July 2023 and had ≤ 3 months of follow-up. OS was shorter in the cachexia only (median 61.8 [95% CI 40.90-not reached (NR)] months, p = 0.046) and cachexia+sarcopenia (median 59.6 [95% CI 14.26-NR] months, p = 0.027) groups than in the no cachexia/sarcopenia group. Multivariable analysis showed that cachexia+sarcopenia (hazard ratio 2.48, p = 0.010), HCC (hazard ratio 3.40, p < 0.001) and diabetes mellitus (hazard ratio 1.80, p = 0.013) independently predicted mortality. The combined group compared with the other groups had a shorter time to liver-related events and readmission. CONCLUSIONS: The coexistence of cachexia and sarcopenia-rather than either alone-can be used as an indicator for identifying patients with chronic liver disease at the highest risk of poor outcomes. Concurrent assessment and early, targeted interventions may improve outcomes in this population.
• Tenofovir alafenamide prevents HBV reactivation in anticancer/immunosuppression: 24-month multicentre prospective study.
  Goki Suda; Masatsugu Ohara; Masaru Baba; Yoshiya Yamamoto; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Hidetaka Hosono; Daisuke Yokoyama; Shoichi Kitano; Takatsugu Tanaka; Akimitsu Meno; Naohiro Yasuura; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Koji Ogawa; Osamu Maehara; Shunsuke Ohnishi; Takaaki Izumi; Ren Yamada; Takashi Meguro; Katsumi Terashita; Tomofumi Takagi; Jun Ito; Tomoe Kobayashi; Izumi Tsunematsu; Naoya Sakamoto
  The Journal of infection, 92, 4, 106715, 106715, Apr. 2026, [International Magazine]
  English, Scientific journal, OBJECTIVE: Our prior interim report remains the only prospective study evaluating tenofovir alafenamide (TAF) for HBV reactivation prevention, with prophylaxis assessed up to 12 months. Herein, we report the final 24-month follow-up results. METHODS: This multicentre prospective-study enrolled HBV carriers who received prophylactic TAF before antineoplastic or immunosuppressive therapy and patients with resolved HBV infection who developed reactivation and received TAF as reactivation-related hepatitis prophylaxis. We examined TAF effectiveness at 12 and 24 months. The primary endpoints were HBV reactivation and reactivation-related hepatitis. RESULTS: Of 191 enrolled patients, 150 and 127 were evaluable at 12 and 24 months, respectively. At 12 months, no HBV reactivation, HBV reactivation-related hepatitis, or therapy interruption occurred. Between months 12-24, four patients discontinued TAF. None of the remaining patients experienced HBV reactivation, HBV reactivation-related-hepatitis, or treatment interruption. Virologic relapse occurred in one of two patients with TAF discontinuation after anticancer/immunosuppressive therapy completion; TAF re-initiation enabled biochemical hepatitis prevention and viral suppression. Neither patient who switched to entecavir experienced reactivation. No patients on high-risk regimens developed reactivation, reactivation-related hepatitis, or treatment interruption. No patient discontinued therapy for TAF-related adverse events. CONCLUSIONS: Over 24 months, TAF demonstrated effectiveness in preventing HBV reactivation and reactivation-related hepatitis.
• Serum fibroblast growth factor 21 is a novel biomarker of cachexia in chronic liver disease.
  Takatsugu Tanaka; Goki Suda; Masatsugu Ohara; Osamu Maehara; Tomoka Yoda; Qingjie Fu; Zijian Yang; Naohiro Yasuura; Akimitsu Meno; Takashi Sasaki; Risako Kohya; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Shunsuke Ohnishi; Naoya Sakamoto
  Frontiers in nutrition, 13, 1730695, 1730695, 2026, [International Magazine]
  English, Scientific journal, BACKGROUND: Cachexia is associated with poor prognosis in chronic liver disease (CLD), yet robust predictors remain poorly defined. This study examined clinical factors and serum biomarkers associated with cachexia in patients with CLD. METHODS: We analyzed 356 of 526 patients with CLD who had complete cachexia assessment and available stored serum samples. In a discovery cohort (n = 240; Aug 2014-Jun 2023), serum fibroblast growth factor 21 (FGF21), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. Multivariable logistic regression and receiver operating characteristic analyses were used to identify independent predictors and optimal cutoff values. Findings were subsequently evaluated in an independent validation cohort (n = 116; Jul 2023-May 2025). RESULTS: Median age was 68 years (range 19-90), 65.8% of participants were male, and 24.6% had cachexia, which independently predicted worse overall survival (hazard ratio 1.64; 95% CI 1.03-2.62; p = 0.038). Patients with cachexia had higher serum FGF21 concentrations than those without cachexia (median, 292 vs. 177 pg./mL; p = 0.002), whereas IL-6 and TNF-α levels did not differ significantly between groups. FGF21 was the only biomarker independently associated with cachexia (odds ratio, 1.71; 95% CI, 1.10-2.66; p = 0.016). Advanced Child-Pugh class and platelet count were identified as additional independent clinical predictors. CONCLUSION: Serum FGF21 independently predicts cachexia in CLD and may facilitate earlier identification of at-risk patients, enabling timely intervention to improve clinical outcomes.
• Three-year overall survival in unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab.
  Masatsugu Ohara; Goki Suda; Risako Kohya; Yutaka Yasui; Kaoru Tsuchiya; Masayuki Kurosaki; Joji Tani; Shinya Maekawa; Nobuyuki Enomoto; Makoto Chuma; Manabu Morimoto; Shun Kaneko; Mina Nakagawa; Yasuhiro Asahina; Atsumasa Komori; Yuki Kugiyama; Masaru Baba; Akihisa Nakamura; Jun Ito; Ren Yamada; Shunichi Hosoda; Yoshiya Yamamoto; Sonoe Yoshida; Takuya Sho; Takashi Sasaki; Tomoka Yoda; Akimitsu Meno; Naohiro Yasuura; Qingjie Fu; Zijian Yang; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Koji Ogawa; Naoya Sakamoto
  Hepatology international, 28 Aug. 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. Although the atezolizumab/bevacizumab regimen demonstrated impressive efficacy in the IMbrave150 clinical trial, long-term outcomes, particularly 3-year overall survival (OS), remain unestablished because of limited follow-up. Long-term outcomes have been reported for the tremelimumab/durvalumab combination, highlighting the need for comparable data on atezolizumab/bevacizumab. We aimed to elucidate the 3-year OS in patients with unresectable HCC (uHCC) treated with atezolizumab plus bevacizumab. METHODS: This retrospective multicenter study included patients with uHCC who received atezolizumab/bevacizumab. Among the 506 patients treated at the participating institutions, only those who initiated therapy between October 2020 and January 2022 were included. Comprehensive clinical, laboratory, and imaging data were collected, and the patients were followed up until March 2025. RESULTS: A total of 257 patients were analyzed, with a median follow-up of 48.23 months (range, 36.23-53.60 months). The 2- and 3-year OS rates were 39.2% and 25.3%, respectively. Among patients meeting the IMbrave150 criteria, the 3-year OS rate was 31.6%. Multivariate regression analysis identified baseline alpha-fetoprotein level > 116 ng/mL (odds ratio [OR] 0.41; 95% confidence interval [CI] 0.20-0.84; p = 0.015) and modified albumin-bilirubin grade 1-2a (OR 2.50; 95% CI 1.18-5.32; p = 0.017) as significant factors associated with 3-year OS. CONCLUSIONS: In a real-world setting, the 3-year OS for uHCC patients treated with atezolizumab/bevacizumab was 25.3%, rising to 31.6% among those meeting the IMbrave150 criteria. Survival outcomes underscore the clinical value of atezolizumab/bevacizumab in improving long-term prognosis and guiding first-line treatment decisions for patients with unresectable HCC.
• Cirrhotic Cardiomyopathy: Prevalence and Clinical Impact on Liver Cirrhosis Outcomes.
  Takashi Kitagataya; Goki Suda; Takatsugu Tanaka; Shoichi Kitano; Naohiro Yasuura; Akimitsu Meno; Takashi Sasaki; Risako Kohya; Qingjie Fu; Shunichi Hosoda; Sonoe Yoshida; Osamu Maehara; Shunsuke Ohnishi; Masatsugu Ohara; Masato Nakai; Takuya Sho; Kosuke Nakamura; Suguru Ishizaka; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 19 Jun. 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Cirrhotic cardiomyopathy (CCM) is a significant complication of liver cirrhosis; however, its prevalence and impact in Asian populations remain unclear. The aim of this study was to assess the prevalence of CCM in Japanese patients with liver cirrhosis and to evaluate its impact on clinical outcomes. METHODS: In this retrospective study, 80 patients with liver cirrhosis confirmed using transient elastography (liver stiffness ≥ 12.5 kPa) were included. Study was performed at Hokkaido University Hospital between January 2014 and April 2024. CCM was diagnosed using the 2019 Cirrhotic Cardiomyopathy Consortium criteria. Subsequently, patient characteristics, survival, and the incidences of decompensation and cardiovascular events were analyzed. RESULTS: The prevalence of CCM was 46.3% (37/80), with 78.4% of patients with CCM showing isolated systolic dysfunction based on global longitudinal strain. Patients with CCM were significantly older, had lower serum ammonia and bilirubin levels, and had higher platelet counts. CCM was associated with a significantly higher incidence of decompensation events (hazard ratio 3.97, 95% confidence interval 1.64-9.61, p = 0.003) and was an independent risk factor for decompensation in the multivariate analysis (hazard ratio 3.24, 95% confidence interval 1.29-8.11, p = 0.012). Patients with and without CCM showed no significant differences in overall survival or cardiovascular events. CONCLUSIONS: CCM is prevalent among Japanese patients with liver cirrhosis and is associated with an increased risk of hepatic decompensation. These findings highlight the importance of cardiac evaluation in patients with cirrhosis and suggest that CCM should be considered in the management of liver cirrhosis to improve patient outcomes.
• Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC.
  Risako Kohya; Goki Suda; Masatsugu Ohara; Shunichi Hosoda; Takuya Sho; Makoto Chuma; Atsumasa Komori; Yuki Kugiyama; Yutaka Yasui; Kaoru Tsuchiya; Masayuki Kurosaki; Joji Tani; Shun Kaneko; Mina Nakagawa; Yasuhiro Asahina; Shinya Maekawa; Nobuyuki Enomoto; Yoshiya Yamamoto; Masaru Baba; Ren Yamada; Takashi Sasaki; Tomoka Yoda; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  JHEP reports : innovation in hepatology, 7, 5, 101364, 101364, May 2025, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels. METHODS: In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels. RESULTS: The median overall survival (p <0.001) and progression-free survival (p = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 vs. 8.84 months; p = 0.027) and median overall survival (14.13 vs. 22.08 months; p <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (p = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, p <0.001). CONCLUSIONS: Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab. IMPACT AND IMPLICATIONS: FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker and an indicator of treatment response in unresectable HCC treated with ICI-based therapy. These findings could be crucial for the implementation of personalised treatment strategies for unresectable HCC. However, identifying optimal therapeutic options for patients with unresectable HCC and high serum FGF21 levels remains an urgent and critical clinical issue.
• Association of proteinuria with improved prognosis in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab, and the predictive role of serum vascular endothelial growth factor D levels: A multicenter retrospective study.
  Zijian Yang; Goki Suda; Takuya Sho; Osamu Maehara; Masatsugu Ohara; Tomoka Yoda; Qingjie Fu; Takashi Sasaki; Risako Kohya; Sonoe Yoshida; Shunichi Hosoda; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Shunsuke Ohnishi; Yoshiya Yamamoto; Masaru Baba; Ren Yamada; Tomoe Kobayashi; Minhu Chen; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 25 Nov. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Atezolizumab/bevacizumab is a first-line therapy for unresectable hepatocellular carcinoma (HCC). Among several adverse events, grade ≥2 proteinuria is considered a significant adverse event that may cause bevacizumab interruption. Studies have shown that proteinuria might predict improved prognosis, although data are scarce and the association remains controversial, and the mechanisms and predictive factors remain unclear. We aimed to clarify these. METHODS: In this multicenter retrospective study, we screened patients with HCC treated with atezolizumab/bevacizumab. The prognostic impact of grade ≥2 proteinuria was examined in patients with proper clinical data and preserved serum for growth factor analysis. For biomarker analysis predicting proteinuria, baseline serum vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D levels were analyzed. RESULTS: This study included 75 patients, and 32 (42.7%) experienced grade ≥2 proteinuria. No significant differences were observed between those with or without proteinuria, except for aspartate transaminase and alanine transaminase levels. Time-dependent Cox proportional hazards analysis revealed that grade ≥2 proteinuria was significantly associated with better prognosis (hazard ratio 0.221; 95% confidence interval 0.082-0.592; p = 0.003). In biomarker analysis, low baseline serum VEGF-C and VEGF-D levels were significantly associated with proteinuria, and multivariate analysis demonstrated that baseline serum VEGF-D level was significantly associated with grade ≥2 proteinuria (hazard ratio 0.101; 95% confidence interval 0.029-0.357; p < 0.001). CONCLUSIONS: Grade ≥2 proteinuria in patients with unresectable HCC treated with atezolizumab/bevacizumab indicates a better prognosis, and baseline serum VEGF-D levels can help predict its occurrence. These findings can help in managing adverse events and prognosis in advanced HCC treated with atezolizumab/bevacizumab.
• Positivity of high-sensitivity HBsAg test, not previous HBV infection, indicates poor prognosis in patients with non-HBV-related HCC.
  Naohiro Yasuura; Goki Suda; Masatsugu Ohara; Akimitsu Meno; Takuya Sho; Risako Kohya; Takashi Sasaki; Tomoka Yoda; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Osamu Maehara; Shunsuke Ohnishi; Tomoya Saitou; Masaya Sugiyama; Takasuke Fukuhara; Masaru Baba; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Akinobu Taketomi; Naoya Sakamoto
  Alimentary pharmacology & therapeutics, 04 Sep. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND AND AIMS: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. METHODS: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC. RESULTS: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC. CONCLUSIONS: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis.
• Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.
  Takuya Sho; Goki Suda; Masatsugu Ohara; Risako Kohya; Takashi Sasaki; Sonoe Yoshida; Shunichi Hosoda; Koji Ogawa; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Masaru Baba; Yoshiya Yamamoto; Yoko Tsukuda; Takashi Meguro; Ren Yamada; Tomoe Kobayashi; Tomofumi Takagi; Naoya Sakamoto
  Targeted oncology, 19, 5, 769, 778, Sep. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. OBJECTIVES: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. PATIENTS AND METHODS: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. CONCLUSION: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.
• Potential Correlation between Changes in Serum FGF21 Levels and Lenvatinib-Induced Appetite Loss in Patients with Unresectable Hepatocellular Carcinoma.
  Risako Kohya; Goki Suda; Masatsugu Ohara; Takashi Sasaki; Tomoka Yoda; Naofumi Sakurai; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  Cancers, 15, 12, 20 Jun. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC.
• Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan.
  Takashi Sasaki; Goki Suda; Masatsugu Ohara; Shunichi Hosoda; Naoki Kawagishi; Risako Kohya; Tomoka Yoda; Osamu Maehara; Shunsuke Ohnishi; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Yoshimasa Tokuchi; Takashi Kitagataya; Kazuharu Suzuki; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Sho Komukai; Koji Ogawa; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 18 Jun. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan. METHODS: We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age. RESULTS: After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests. CONCLUSIONS: The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.
• Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.
  Shunichi Hosoda; Goki Suda; Takuya Sho; Koji Ogawa; Megumi Kimura; Zijian Yang; Sonoe Yoshida; Akinori Kubo; Yoshimasa Tokuchi; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Akihisa Nakamura; Ren Yamada; Masatsugu Ohara; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Kazuharu Suzuki; Takaaki Izumi; Takashi Meguro; Katsumi Terashita; Jun Ito; Takuto Miyagishima; Naoya Sakamoto
  Liver cancer, 12, 2, 156, 170, Jun. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, INTRODUCTION: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. METHODS: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. RESULTS: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. CONCLUSION: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
• Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.
  Yoshimasa Tokuchi; Goki Suda; Naoki Kawagishi; Masatsugu Ohara; Risako Kohya; Takashi Sasaki; Tomoka Yoda; Osamu Maehara; Shunsuke Ohnishi; Akinori Kubo; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Takashi Kitagataya; Kazuharu Suzuki; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 53, 7, 595, 606, 21 Mar. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. METHODS: This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n = 100) and 24 weeks (SVR24, n = 100), 96 weeks (SVR96, n = 100), and 144 weeks (SVR144, n = 90) after DAA. RESULTS: In 100 participants, the prevalence of fatty liver (19% vs. 32%, p = 0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p = 0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r = -0.5305, p < 0.0001 at SVR24; r = -0.3617, p = 0.0005 at SVR96; and r = -0.4735, p < 0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. CONCLUSIONS: Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.
• Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma.
  Zijian Yang; Goki Suda; Osamu Maehara; Masatsugu Ohara; Tomoka Yoda; Takashi Sasaki; Risako Kohya; Sonoe Yoshida; Shunichi Hosoda; Yoshimasa Tokuchi; Takashi Kitagataya; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Cancers, 15, 3, 18 Jan. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.
• Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C.
  Naoki Kawagishi; Goki Suda; Yoshiya Yamamoto; Masaru Baba; Ken Furuya; Osamu Maehara; Shunsuke Ohnishi; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Yoshimasa Tokuchi; Takashi Kitagataya; Masatsugu Ohara; Kazuharu Suzuki; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  Viruses, 15, 1, 07 Jan. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014-2020 were screened and evaluated for HCC occurrence or recurrence every three-six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34-6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18-6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.
• Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis.
  Goki Suda; Masaru Baba; Yoshiya Yamamoto; Takuya Sho; Koji Ogawa; Megumi Kimura; Shunichi Hosoda; Sonoe Yoshida; Akinori Kubo; Qingjie Fu; Zijian Yang; Yoshimasa Tokuchi; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Ren Yamada; Masatsugu Ohara; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Kazuharu Suzuki; Takaaki Izumi; Takashi Meguro; Katsumi Terashita; Jun Ito; Tomoe Kobayashi; Izumi Tsunematsu; Naoya Sakamoto
  Journal of medical virology, 95, 2, e28452, 04 Jan. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND: No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing HBV reactivation has yet been reported. METHODS: This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. RESULTS: Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. CONCLUSION: TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis. This article is protected by copyright. All rights reserved.
• Coexistence of muscle atrophy and high subcutaneous adipose tissue radiodensity predicts poor prognosis in hepatocellular carcinoma.
  Masatsugu Ohara; Goki Suda; Risako Kohya; Takashi Sasaki; Tomoka Yoda; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  Frontiers in nutrition, 10, 1272728, 1272728, 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, INTRODUCTION: We aimed to assess the prognostic implications of muscle atrophy and high subcutaneous adipose tissue (SAT) radiodensity in patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective study, muscle atrophy was assessed using the psoas muscle index (PMI) obtained from computed tomography. SAT radiodensity was evaluated based on radiodensity measurements. Survival and multivariate analyses were performed to identify factors associated with prognosis. The impact of muscle atrophy and high SAT radiodensity on prognosis was determined through survival analysis. RESULTS: A total of 201 patients (median age: 71 years; 76.6% male) with HCC were included. Liver cirrhosis was observed in 72.6% of patients, and the predominant Child-Pugh grade was A (77.1%). A total of 33.3% of patients exhibited muscle atrophy based on PMI values, whereas 12.9% had high SAT radiodensity. Kaplan-Meier survival analysis demonstrated that patients with muscle atrophy had significantly poorer prognosis than those without muscle atrophy. Patients with high SAT radiodensity had a significantly worse prognosis than those without it. Muscle atrophy, high SAT radiodensity, the Barcelona Clinic Liver Cancer class B, C, or D, and Child-Pugh score ≥ 6 were significantly associated with overall survival. Further classification of patients into four groups based on the presence or absence of muscle atrophy and high SAT radiodensity revealed that patients with both muscle atrophy and high SAT radiodensity had the poorest prognosis. CONCLUSION: Muscle atrophy and high SAT radiodensity are significantly associated with poor prognosis in patients with HCC. Identifying this high-risk subgroup may facilitate the implementation of targeted interventions, including nutritional therapy and exercise, to potentially improve clinical outcomes.
• Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy
  Naoki Kawagishi; Goki Suda; Ryotaro Sakamori; Takeshi Matsui; Masahiro Onozawa; Zijian Yang; Sonoe Yoshida; Masatsugu Ohara; Megumi Kimura; Akinori Kubo; Osamu Maehara; Qingjie Fu; Shunichi Hosoda; Yoshimasa Tokuchi; Kazuharu Suzuki; Masato Nakai; Takuya Sho; Kenichi Morikawa; Mitsuteru Natsuizaka; Koji Ogawa; Hajime Sakai; Shunsuke Ohnishi; Masaru Baba; Tetsuo Takehara; Naoya Sakamoto
  Scientific Reports, 12, 1, Springer Science and Business Media LLC, 07 Oct. 2022, [Peer-reviewed]
  Scientific journal, Abstract
  
  De novo hepatitis B virus (HBV) reactivation occurs during direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-infected patients with resolved HBV infection. We evaluated the predictive factors, mechanical insight, and differences of cytokine levels during anti-cancer/immunosuppressive and DAA. Eleven, 35, and 19 HCV-infected patients with previous HBV infection with HBV reactivation during DAA treatment, previous HBV infection without HBV reactivation during DAA treatment, and without HBV infection resolution receiving DAA treatment, respectively, were enrolled. Clinical data and baseline cytokine levels were analyzed. Low baseline serum interleukin (IL)-1β levels predicted de novo HBV reactivation during DAA treatment (odds ratio: 47.6, 95% confidence interval: 6.94–333.3). HCV-infected patients with the IL-1β gene single nucleotide polymorphism rs16944 AA allele had significantly higher IL-1β levels; no HCV-infected patient with the IL-1β AA allele experienced HBV reactivation during DAA treatment. Compared to HCV-infected patients with HBV infection resolution, non-HCV infected patients with or without HBV reactivation during anti-cancer/immunosuppressive therapy or bone marrow transplantation had remarkably lower baseline IL-1β levels. Low IL-1β levels were not associated with HBV reactivation. IL-1β levels before DAA for HCV-infected patients with resolved HBV infection could predict HBV reactivation during DAA treatment.
• Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150
  Takuya Sho; Goki Suda; Yoshiya Yamamoto; Ken Furuya; Masaru Baba; Koji Ogawa; Akinori Kubo; Yoshimasa Tokuchi; Qingjie Fu; Zijian Yang; Megumi Kimura; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Akihisa Nakamura; Ren Yamada; Masatsugu Ohara; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kazuharu Suzuki; Takaaki Izumi; Takashi Meguro; Katsumi Terashita; Tomofumi Takagi; Jun Ito; Tomoe Kobayashi; Takuto Miyagishima; Naoya Sakamoto
  Cancers, 14, 16, 3938, 3938, MDPI AG, 15 Aug. 2022, [Peer-reviewed]
  Scientific journal, The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.
• Overestimated Renal Function in Patients with Liver Cirrhosis Predicts Poor Prognosis.
  Sonoe Yoshida; Goki Suda; Masatsugu Ohara; Megumi Kimura; Zijian Yang; Osamu Maehara; Qingjie Fu; Shunichi Hosoda; Kubo Akinori; Yoshimasa Tokuchi; Ren Yamada; Takashi Kitagataya; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 52, 7, 603, 613, 30 Mar. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: A high prevalence of overestimated renal function in patients with liver cirrhosis (LC) has been reported; nonetheless, its impact on prognosis remains unclear. We aimed to evaluate the impact of overestimated renal function on prognosis in patients with LC. METHODS: An overestimated renal function was defined as a >20% increase in the creatinine-based estimated glomerular filtration rate (eGFR), compared with cystatin C-based eGFR. LC patients with conserved serum, who were evaluated for muscle atrophy and had proper clinical information were included, and their prognostic factors were analyzed. RESULTS: A total of 215 consecutive patients with LC were included. The prevalence of overestimated renal function was 29.8% (64/215). Kaplan-Meier survival analysis revealed that patients with overestimated renal function had a poorer prognosis than those without overestimated renal function (hazard ratio [HR]: 2.217 95% confidence interval [CI]: 1.290-3.810; P=0.001). Subgroup analysis showed that overestimated renal function was a significant prognostic factor, irrespective of sex and the presence of hepatocellular carcinoma (HCC). Multivariate Cox regression analyses revealed that overestimated renal function was a significant and independent factor predictive of poor prognosis in the entire cohort (HR: 2.050; 95% CI: 1.041-4.037; P=0.038) and in subgroups classified by Child-Pugh class A (HR: 2.131; 95% CI: 1.019-4.458; P=0.044), Model for End-Stage Liver Disease score <9 (HR: 2.303; 95% CI: 1.038-5.109; P=0.04), and presence of HCC (HR: 2.290; 95% CI: 1.128-4.651; P=0.022). CONCLUSION: Overestimated renal function is a significant and independent prognostic factor in patients with LC. This article is protected by copyright. All rights reserved.
• Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma.
  Zijian Yang; Goki Suda; Osamu Maehara; Masatsugu Ohara; Sonoe Yoshida; Shunichi Hosoda; Megumi Kimura; Akinori Kubo; Yoshimasa Tokuchi; Qingjie Fu; Ren Yamada; Takashi Kitagataya; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Cancers, 14, 1, 04 Jan. 2022, [Peer-reviewed], [Lead author], [International Magazine]
  English, Scientific journal, Serum growth factor changes and their effect on prognosis during lenvatinib for unresectable hepatocellular carcinoma (HCC) remain underexplored. The sequential changes in serum growth factors during lenvatinib for unresectable HCC were evaluated in 58 patients using complete clinical data, and preserved serum was used to investigate changes in FGF-19, ANG-2, HGF, VEGF, and EGF. Patients with a complete response (CR), partial response (PR), and stable disease (SD) were evaluated for growth factor changes between the best response and progressive disease (PD) points, classified based on these changes, and evaluated by post progression survival (PPS). A total of 8, 24, 18, and 8 patients showed CR, PR, SD, and PD, respectively. Multivariate analysis revealed that age, relative dose intensity, and baseline ANG-2 were significantly associated with treatment response. Growth factor changes between the best response and PD points revealed that patients could be classified into four groups based on the EGF, ANG-2, and HGF changes. Although patient characteristics at baseline and PD, their response to lenvatinib, and PFS were similar among those groups, patients with an increase in all growth factors had significantly shorter PPS (median PPS was 553, 323, and 316 versus 173 days in groups 1-4 p = 0.032). We revealed that the evaluation of the changes in growth factors during lenvatinib could predict PPS.
• Autograft of Demineralized Dentin Matrix Prepared Immediately after Extraction for Horizontal Bone Augmentation of the Anterior Atrophic Maxilla: A First Case of Non-Vital Tooth-Derived Dentin
  Naoto Okubo; Masahiro Ishikawa; Mamata Shakya; Hidetaka Hosono; Osamu Maehara; Tatsuya Ohkawara; Shunsuke Ohnishi; Toshiyuki Akazawa; Masaru Murata
  Journal of Hard Tissue Biology, 31, 1, 47, 54, Society for Hard Tissue Regenerative Biology, 2022, [Peer-reviewed]
  Scientific journal
• Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on lipid profiles in patients with hepatitis B.
  Kazuharu Suzuki; Goki Suda; Yoshiya Yamamoto; Satoshi Abiko; Kenji Kinoshita; Shuichi Miyamoto; Ryo Sugiura; Megumi Kimura; Osamu Maehara; Ren Yamada; Takashi Kitagataya; Taku Shigesawa; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  PloS one, 17, 1, e0261760, 2022, [International Magazine]
  English, Scientific journal, For long-term treatment of hepatitis B virus (HBV) infection, switching from tenofovir-disoproxil-fumarate (TDF) to tenofovir-alafenamide (TAF) may prevent renal dysfunction and bone loss. However, the precise effects of this switch on the blood lipid profile remain to be clarified. This is an important issue as TDF is known to have effects on both low- and high-density lipids. Therefore, our retrospective multi-center study aimed to evaluate the effects of switching from TDF to TAF on the lipid profile of patients with HBV infection. Samples were obtained prior to the switch from TDF to TAF and at 6-12 months after TAF initiation. In some cases, additional samples obtained pre- and post-TDF administration were available for analysis. Serum cholesterol levels, including oxidized-low-density lipoprotein (LDL) and non-high-density lipoprotein-cholesterol (HDL-c), and the rate of dyslipidemia, according to the NCEP-ATP III lipid risk classification, were analyzed. The data from 69 patients were analyzed, including 33 patients with pre- and post-TDF-initiation serum samples. Total cholesterol (T-chol), HDL-c, LDL-c, non-HDL-c, and oxidized LDL levels increased significantly after switching to TAF. With regard to sequential changes pre- to post-TAF, TDF was associated with significantly lower serum T-chol, HDL-c, and oxidized LDL-c levels, with T-chol, HDL-c, LDL-c, and oxidized LDL-c levels increasing significantly after the switch. The switch from TDF to TAF was also associated with an increase in the rate of dyslipidemia, from 33% to 39%, with an increase in the rate of severe dyslipidemia of 1.4% and 5.8%, based on T-chol and LDL-c levels. Of note, no cases of severe dyslipidemia were detected pre-TAF treatment. As oxidized LDL-c and non-HDL-c are strongly associated with atherosclerosis development, careful monitoring of lipid is needed after switching from TDF to TAF in this clinical population.
• Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.
  Takuya Sho; Goki Suda; Koji Ogawa; Megumi Kimura; Akinori Kubo; Yoshimasa Tokuchi; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Taku Shigesawa; Akihisa Nakamura; Ren Yamada; Masatsugu Ohara; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Kazuharu Suzuki; Takaaki Izumi; Takashi Meguro; Katsumi Terashita; Jun Ito; Takuto Miyagishima; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 51, 9, 979, 989, Sep. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.
• Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals.
  Yoshimasa Tokuchi; Goki Suda; Megumi Kimura; Osamu Maehara; Takashi Kitagataya; Akinori Kubo; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Masatsugu Ohara; Ren Yamada; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Scientific reports, 11, 1, 16616, 16616, 16 Aug. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, We aimed to evaluate factors associated with changes in skeletal muscle mass in hepatitis C virus (HCV)-infected patients after treatment with direct-acting antivirals (DAAs). Consecutive HCV-infected patients after treatment with DAA were recruited into the study. Patients who achieved sustained virological response (SVR); and had complete clinical information, preserved serum samples at baseline and SVR48, and skeletal muscle mass evaluations based on the psoas muscle mass index (PMI) on computed tomography at baseline and ≥ 12 months were included. Altogether, 70.7% of patients (41/58) showed increased PMI after DAA therapy, and mean relative PMI was significantly higher after DAA therapy than at baseline. There were no significant associations between baseline clinical factors routinely examined in clinical practice and increased PMI. Among factors reported to be associated with skeletal muscle loss in patients with chronic liver disease, serum zinc levels and total and free carnitine levels increased significantly after DAA therapy and only changes in serum free carnitine levels were significantly associated with an increased PMI (r = 0305, P = 0.020). In conclusion, increased skeletal muscle mass after successful HCV eradication by DAAs was significantly associated with increased serum-free carnitine levels. L-carnitine supplementation may be beneficial in patients with low skeletal muscle mass after DAA.
• Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI.
  Akinori Kubo; Goki Suda; Megumi Kimura; Osamu Maehara; Yoshimasa Tokuchi; Takashi Kitagataya; Masatsugu Ohara; Ren Yamada; Taku Shigesawa; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Cancers, 13, 14, 20 Jul. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study analyzed the prevalence, characteristics, response to lenvatinib, and CTNNB-1 mutation frequency in unresectable HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. In 52 patients with unresectable HCC treated with lenvatinib, the prevalence of iso-high intensity in the hepatobiliary phase of EOB-MRI was 13%. All patients had multiple HCCs, and 3 patients had multiple HCCs with iso-high intensity in the hepatobiliary phase of EOB-MRI. Lenvatinib response to progression-free survival and overall survival were similar between patients with or without iso-high intensity in the hepatobiliary phase of EOB-MRI. Seven patients (three and four patients who had unresectable HCC with or without iso-high intensity in the hepatobiliary phase of EOB-MRI, respectively) underwent genetic analyses. Among these, two (67%, 2/3) who had HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI carried a CTNNB-1 mutation, while all four patients who had HCC without iso-high intensity in the hepatobiliary phase of EOB-MRI did not carry the CTNNB-1 mutation. This study's findings have clinical implications for the detection and treatment of HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI.
• Frequency and Characteristics of Overestimated Renal Function in Japanese Patients with Chronic Liver Disease and Its Relation to Sarcopenia.
  Sonoe Yoshida; Goki Suda; Masatsugu Ohara; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Megumi Kimura; Kubo Akinori; Yoshimasa Tokuchi; Ren Yamada; Takashi Kitagataya; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Osamu Maehara; Shunsuke Ohnishi; Naoya Sakamoto
  Nutrients, 13, 7, 14 Jul. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a >20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis (p = 0.004) and psoas muscle mass index (p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered; furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.
• FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma.
  Osamu Maehara; Goki Suda; Mitsuteru Natsuizaka; Taku Shigesawa; Gouki Kanbe; Megumi Kimura; Masaya Sugiyama; Masashi Mizokami; Masato Nakai; Takuya Sho; Kenichi Morikawa; Koji Ogawa; Shinya Ohashi; Shingo Kagawa; Hideaki Kinugasa; Seiji Naganuma; Naoto Okubo; Shunsuke Ohnishi; Hiroshi Takeda; Naoya Sakamoto
  Cancer biology & therapy, 22, 5-6, 372, 380, 03 Jun. 2021, [Peer-reviewed], [Lead author], [International Magazine]
  English, Scientific journal, Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial-mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.
• Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass.
  Yoshimasa Tokuchi; Goki Suda; Megumi Kimura; Osamu Maehara; Takashi Kitagataya; Masatsugu Ohara; Ren Yamada; Taku Shigesawa; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  Journal of viral hepatitis, 28, 5, 755, 763, May 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Hepatitis C virus (HCV) infection can cause renal dysfunction, expected to improve upon HCV eradication. However, adverse effects of HCV eradication using direct-acting antiviral agents (DAAs) on renal function have been recently reported. This retrospective study aimed to evaluate renal function with glomerular filtration rate (eGFR) estimated using creatinine (eGFRcre) and cystatin C (eGFRcys). Complete clinical information and preserved serum samples were collected from 207 patients with HCV infection treated with interferon-free DAA at baseline and SVR48 (SVR48). Patients who underwent paired computed tomography (CT) at baseline and ≥12 months after DAA were evaluated for changes in skeletal muscle mass using the psoas muscle mass index (PMI). eGFRcre significantly worsened at SVR48, while eGFRcys was similar at baseline and SVR48. At baseline, eGFRcre was significantly higher than eGFRcys; eGFRcre and eGFRcys were similar at SVR48. Multivariate analysis revealed that the presence of liver cirrhosis and low-albumin level, as well as cirrhosis and age, was significantly associated with the overestimation of renal function by eGFRcre at baseline and SVR48, respectively. In the 57 patients who underwent paired CT at baseline and ≥12 months after DAA, relative values of PMI significantly increased after DAA. After DAA, in patients with increased PMI (65% 37/57), eGFRcre significantly worsened but did not change in patients without increased PMI. eGFRcre significantly worsened after DAAs; however, this might not reflect accurate changes in renal function, partially because of changes in skeletal muscle mass. eGFRcys did not change after DAAs, and it is a potential alternative to eGFRcre.
• Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C.
  Naoki Kawagishi; Goki Suda; Megumi Kimura; Osamu Maehara; Ren Yamada; Yoshimasa Tokuchi; Akinori Kubo; Takashi Kitagataya; Taku Shigesawa; Kazuharu Suzuki; Masatsugu Ohara; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Yusuke Kudo; Mutsumi Nishida; Naoya Sakamoto
  Scientific reports, 11, 1, 9207, 9207, 28 Apr. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, We previously revealed that Angiopoietin-2 (Ang2) predicts non-regression of liver fibrosis based on liver stiffness measurement (LSM) at 24 weeks after anti-hepatitis C virus (HCV) treatment. In this study, we extended the observational period to 96 weeks to investigate the factors associated with non-regression after treatment with direct-acting-antivirals (DAAs). Patients treated with DAAs who underwent transient elastography at baseline and 24 and 96 weeks after DAA therapy were included. Baseline and post-treatment serum Ang2 levels were measured. Liver fibrosis stages were defined based on LSM. Multivariate regression was used to evaluate factors associated with non-regression of liver fibrosis between various time points. In total, 110 patients were included. Of these, 11% showed non-regression of LSM-based fibrosis stage at 96 weeks after DAA therapy. In multivariate analysis, advanced liver fibrosis stage and high baseline Ang2 levels were significantly associated with non-regression at 96 weeks. In patients with advanced liver fibrosis (F3/4), baseline Ang2 levels were associated with non-regression of liver fibrosis stage. Between SVR24 and SVR96, post-treatment Ang2 levels and controlled attenuation parameter values at SVR24 were significantly associated with non-regression of liver fibrosis stage in patients with F3/4. Thus, serum Ang2 levels are an important target for monitoring and therapy.
• Protective effect of ISO-1 with inhibition of RIPK3 up-regulation and neutrophilic accumulation on acetaminophen-induced liver injury in mice.
  Tatsuya Ohkawara; Naoto Okubo; Osamu Maehara; Jun Nishihira; Hiroshi Takeda
  Toxicology letters, 339, 51, 59, 15 Mar. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Overdose use of acetaminophen (APAP) often occurs a severe liver injury, and its liver injury is lethal in some cases. Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and has multifunctional roles. However, the role of MIF in APAP-induced liver injury has not been fully investigated. In this study, we investigated whether treatment with (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a MIF inhibitor, protected mice from acute APAP-induced liver injury. Acute liver injury was induced by injection of APAP (300 mg/kg body weight). Mice were treated with a single injection of ISO-1(15 mg/kg body weight) 1 h (h) before APAP administration. Histological, biochemical and molecular analyses were performed in liver of mice 12 h after APAP administration. ISO-1 remarkably improved the histological findings of APAP-induced liver injury in mice. The increases in serum levels of alanine aminotransferase (ALT), and macrophage inflammatory protein-2 (MIP-2) by APAP were inhibited by ISO-1. In addition, ISO-1 reduced the increased number of the myeloperoxidase-staining cells and that of TUNEL-positive staining cells in the liver of mice with APAP-induced liver injury. Up-regulation of hepatic receptor interacting protein kinase (RIPK)3 and heat shock protein70 by APAP was suppressed in the liver of mice given ISO-1. These results provide the additional evidence that inhibition of MIF activity may be clinically effective for treatment of acute APAP-induced liver injury.
• Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection.
  Kazuharu Suzuki; Goki Suda; Yoshiya Yamamoto; Ken Furuya; Masaru Baba; Akinobu Nakamura; Hideaki Miyoshi; Megumi Kimura; Osamu Maehara; Ren Yamada; Takashi Kitagataya; Koji Yamamoto; Taku Shigesawa; Akihisa Nakamura; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  Journal of gastroenterology, 56, 2, 168, 180, Feb. 2021, [Peer-reviewed], [Domestic magazines]
  English, Scientific journal, BACKGROUND: Entecavir and tenofovir-disoproxil-fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. METHODS: A retrospective study was performed on HBV patients administered entecavir or tenofovir-disoproxil-fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6-12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir-disoproxil-fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. RESULTS: Administration of tenofovir-disoproxil-fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir-disoproxil-fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir-disoproxil-fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir-disoproxil-fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir-disoproxil-fumarate on CD36. CONCLUSIONS: Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.
• Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma.
  Taku Shigesawa; Goki Suda; Megumi Kimura; Osamu Maehara; Yoshimasa Tokuchi; Akinori Kubo; Ren Yamada; Ken Furuya; Masaru Baba; Takashi Kitagataya; Kazuharu Suzuki; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  PloS one, 16, 3, e0247728, 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, A deteriorated liver functional reserve during systemic therapy for unresectable hepatocellular carcinoma (HCC) causes poor patient outcomes. We aimed to identify predictive factors associated with the deterioration of Child-Pugh score at 8 weeks after lenvatinib initiation. Patients with adequate clinical data and baseline preserved serum samples available were included. Baseline fibroblast growth factor (FGF)19 and 21, angiopoietin (ANG)2, and vascular endothelial growth factor (VEGF) levels were evaluated. Thirty-seven patients were included, and 6, 15, 14, and 2 experienced complete response, partial response, stable disease, and progressive disease, respectively. Twenty-four (65%) and 13 (35%) patients showed a maintained/improved and deteriorated Child-Pugh-score, respectively. While baseline clinical data, treatment response, and laboratory data were similar between these two patient groups, baseline ANG2 and VEGF levels were significantly higher (P = 0.0017) and lower (P = 0.0231), respectively, in patients with deteriorated Child-Pugh score than in those without. Based on receiver operating characteristic curve analysis, cut-off values for ANG2 and VEGF were found to be 3,108 pg/mL and 514.9 pg/mL, respectively. Among patients with low VEGF and high ANG2, 89% (8/9) exhibited a deteriorated Child-Pugh score, whereas none of the patients (0/9) with high VEGF and low ANG2 did. The deterioration of the Child-Pugh score in patients with unresectable HCC who are treated with lenvatinib may be predictable based on combined baseline serum ANG2 and VEGF levels.
• Time-dependent changes in the seroprevalence of COVID-19 in asymptomatic liver disease outpatients in an area in Japan undergoing a second wave of COVID-19.
  Goki Suda; Koji Ogawa; Megumi Kimura; Osamu Maehara; Takashi Kitagataya; Masatsugu Ohara; Yoshimasa Tokuchi; Akinori Kubo; Ren Yamada; Taku Shigesawa; Kazuharu Suzuki; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 50, 10, 1196, 1200, Oct. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Coronavirus disease 2019 (COVID-19) is a serious public health concern, with unclarified prevalence in Japan. Concomitant liver disease could increase the severity of COVID-19 disease, and chronic liver disease patients sometimes require frequent admission and gastrointestinal endoscopy. Thus, clarifying the prevalence of asymptomatic COVID-19 in outpatients with liver disease is essential for preventing nosocomial infections. We aimed to clarify the time-dependent changes in COVID-19 seroprevalence in liver disease outpatients, who were asymptomatic for COVID-19, in an area of Japan experiencing a second wave of COVID-19. METHODS: We included the preserved sera of 100, 300, and 300 consecutive liver disease outpatients, who were asymptomatic for COVID-19, from May 2019, March 2020, and May 2020, respectively. The sera were analyzed immunochromatographically to detect immunoglobulin G against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (KURABO) and by Elecsys Anti-SARS-CoV-2-assay (Roche Diagnostics). RESULTS: Analysis of 100 cases from May 2019, before COVID-19 became pandemic, revealed that the specificity of immunochromatographic tests and Elecsys were 98% (95% confidence interval [CI], 93-99.8%) and 100% (95% CI, 97-100%), respectively. Analysis of 300 cases from March 2020 revealed a seroprevalence of 0.3% (1/300; 95% CI, 0-1.8%) for COVID-19 by Elecsys Anti-SARS-CoV-2 assay. Analysis of 300 cases from May 2020 revealed a seroprevalence of 0% (0/300; 95% CI, 0-1.0%). CONCLUSIONS: The Elecsys Anti-SARS-CoV-2 assay has high specificity. The cumulative seroprevalence of COVID-19 by the Elecsys Anti-SARS-CoV-2 assay in outpatients with liver disease in Sapporo, who were asymptomatic for COVID-19, was 0.17% (1/600; 95% CI, 0.0-0.9%) until May 2020.
• Computed tomography, not bioelectrical impedance analysis, is the proper method for evaluating changes in skeletal muscle mass in liver disease
  Masatsugu Ohara; Goki Suda; Megumi Kimura; Osamu Maehara; Tomoe Shimazaki; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  JCSM Rapid Communications, 3, 2, 103, 114, Wiley, Jul. 2020
  Scientific journal
• High serum angiopoietin-2 level predicts non-regression of liver stiffness measurement-based liver fibrosis stage after direct-acting antiviral therapy for hepatitis C.
  Naoki Kawagishi; Goki Suda; Megumi Kimura; Osamu Maehara; Tomoe Shimazaki; Ren Yamada; Takashi Kitagataya; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Yusuke Kudo; Mutsumi Nishida; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 50, 6, 671, 681, Jun. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Factors associated with improvement of liver fibrosis after successful hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting antiviral agents (DAAs) have been not clarified well. Angiopoietin-2 (Ang2) is reported to be associated with vascular leak and inflammation observed in patients with advanced liver fibrosis. METHODS: In this retrospective study, patients treated with IFN-free DAAs who underwent transient elastography before and at 24-weeks post-treatment and achieved sustained viral response were enrolled. Baseline serum Ang2 was measured, and its relationship with other clinical factors was analyzed. Liver fibrosis stage was defined based on liver stiffness according to a previous report. Predictive factors for regression of liver fibrosis stage after DAA therapy were evaluated. RESULTS: Overall, 116 patients were analyzed. Baseline serum Ang2 levels were significantly associated with liver stiffness, spleen index, and liver stiffness-based liver fibrosis stage. Moreover, 75% of patients experienced regression of liver fibrosis stage after DAA therapy. Multivariate analysis revealed that advanced liver fibrosis stage and Ang2 levels were significantly associated with regression of liver fibrosis stage after DAA therapy. In patients with advanced liver fibrosis (F3/4), baseline Ang2 level alone could predict regression of liver fibrosis stage. A baseline Ang2 cut-off value (354 pg/ML) could predict regression of liver fibrosis stage after DAA therapy with high accuracy (sensitivity 0.882, specificity 0.733). CONCLUSIONS: Evaluation of serum Ang2 levels before DAA therapy is important. Our results provide a novel mechanistic insight into non-regression of liver stiffness after DAA therapy. Long-term and larger studies are required.
• Analysis of the optimal psoas muscle mass index cut-off values, as measured by computed tomography, for the diagnosis of loss of skeletal muscle mass in Japanese people.
  Masatsugu Ohara; Goki Suda; Megumi Kimura; Osamu Maehara; Tomoe Shimazaki; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Tomoe Kobayashi; Minoru Uebayashi; Ryo Takagi; Isao Yokota; Tsuyoshi Shimamura; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 50, 6, 715, 725, Jun. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, This study aimed to determine the optimal psoas muscle mass index (PMI) cut-off values for diagnosis of skeletal muscle mass loss. METHODS: We evaluated PMI in two groups of normal controls: a medical check-up group and a liver donation candidate group. We analyzed two novel PMI cut-off values, one based on the mean - two standard deviations (2SD) and one based on the lower 5%. Skeletal muscle mass index (SMI) evaluations using computed tomography (sliceOmatic; TomoVision) and bioelectrical impedance analysis and PMI evaluation were undertaken simultaneously. We analyzed the correlation between our PMI cut-off values and the Japan Society of Hepatology-defined SMI cut-off values. The prevalence of skeletal muscle mass loss in patients with liver disease was assessed using the novel PMI cut-off values. RESULTS: In 504 normal controls aged ≤50 years, the PMI cut-off values based on mean -2SD and the lower 5% were set at 3.30 cm2 /m2 for men and 1.69 cm2 /m2 for women and 3.74 cm2 /m2 for men and 2.29 cm2 /m2 for women, respectively. The PMI cut-off values based on the lower 5% alone showed that skeletal muscle mass loss increased with age. Furthermore, they correlated well with Japan Society of Hepatology-defined SMI (sliceOmatic) cut-off values and showed a significantly higher prevalence of skeletal muscle mass loss in patients with liver cirrhosis than those without liver cirrhosis. CONCLUSIONS: We propose the following PMI cut-off values: 3.74 cm2 /m2 for male individuals and 2.29 cm2 /m2 for female individuals. These cut-off values can facilitate accurate diagnosis and management of sarcopenia in patients with chronic liver disease.
• Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR 1-3 signaling, but not FGFR4 signaling.
  Taku Shigesawa; Osamu Maehara; Goki Suda; Mitsuteru Natsuizaka; Megumi Kimura; Tomoe Shimazaki; Koji Yamamoto; Ren Yamada; Takashi Kitagataya; Akihisa Nakamura; Kazuharu Suzuki; Masatsugu Ohara; Naoki Kawagishi; Machiko Umemura; Masato Nakai; Takuya Sho; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Masaya Sugiyama; Masashi Mizokami; Hiroshi Takeda; Naoya Sakamoto
  Carcinogenesis, 42, 1, 58, 69, 25 May 2020, [Peer-reviewed], [Lead author], [International Magazine]
  English, In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multi-kinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and RT-PCR analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1 to 4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.
• Baseline angiopoietin-2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma
  Taku Shigesawa; Goki Suda; Megumi Kimura; Tomoe Shimazaki; Osamu Maehara; Ren Yamada; Takashi Kitagataya; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  JGH OPEN, Apr. 2020, [Peer-reviewed]
  English, Scientific journal
• Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.
  Takashi Kitagataya; Goki Suda; Kazunori Nagashima; Takehiko Katsurada; Koji Yamamoto; Megumi Kimura; Osamu Maehara; Ren Yamada; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Shunsuke Ohnishi; Yoshito Komatsu; Hiroo Hata; Satoshi Takeuchi; Takashige Abe; Jun Sakakibara-Konishi; Takanori Teshima; Akihiro Homma; Naoya Sakamoto
  Journal of gastroenterology and hepatology, 35, 10, 1782, 1788, 18 Mar. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal, BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.
• Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting
  Takuya Sho; Goki Suda; Koji Ogawa; Megumi Kimura; Tomoe Shimazaki; Osamu Maehara; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Tomoe Kobayashi; Takashi Meguro; Akiyoshi Saga; Takuto Miyagishima; Hideki Yokoo; Toshiya Kamiyama; Akinobu Taketomi; Naoya Sakamoto
  JGH OPEN, 4, 1, 54, 60, Feb. 2020, [Peer-reviewed]
  English, Scientific journal
• Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting.
  Takuya Sho; Goki Suda; Koji Ogawa; Megumi Kimura; Tomoe Shimazaki; Osamu Maehara; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Kenichi Morikawa; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Tomoe Kobayashi; Takashi Meguro; Akiyoshi Saga; Takuto Miyagishima; Hideki Yokoo; Toshiya Kamiyama; Akinobu Taketomi; Naoya Sakamoto
  JGH open : an open access journal of gastroenterology and hepatology, 4, 1, 54, 60, Feb. 2020, [Peer-reviewed], [International Magazine]
  English, Scientific journal
• FGFR阻害剤およびMEK阻害剤は食道扁平上皮癌(ESCC)がん幹細胞を減少させる
  前原 経; 夏井坂 光輝; 須田 剛生; 大西 俊介; 坂本 直哉; 武田 宏司
  日本消化管学会雑誌, 4, Suppl., 301, 301, (一社)日本消化管学会, Jan. 2020
  Japanese
• Entecavir treatment of hepatitis B virus-infected patients with severe renal impairment and those on hemodialysis.
  Kazuharu Suzuki; Goki Suda; Yoshiya Yamamoto; Ken Furuya; Masaru Baba; Megumi Kimura; Osamu Maehara; Tomoe Shimazaki; Koji Yamamoto; Taku Shigesawa; Akihisa Nakamura; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 49, 11, 1294, 1304, Nov. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are first-line nucleos(t)ide analogues for hepatitis B virus (HBV)-infected patients. However, consecutive TDF treatment causes renal dysfunction, and the safety and efficacy of TAF have not been established in severe renal dysfunction patients, including hemodialysis patients. The efficacy and safety of ETV in these populations has not been clarified. The study aimed to clarify this. METHODS: In this retrospective multicenter study, between 2006 and 2018, a total of 567 HBV-infected patients treated with ETV monotherapy were screened. Patients were included if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical information. The efficacy of ETV and changes in renal function were evaluated according to renal function. RESULTS: A total of 273 patients were included: 9.2% (25/273), 1.8% (5/273), and 3.7% (10/273) had chronic kidney disease (CKD) stage G3, CKD stage G4/5, and were on hemodialysis, respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV-DNA disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with CKD stage G3-5, estimated glomerular filtration rate tended to restore with time, which was in contrast to patients without renal dysfunction. The rate of disappearance in serum HBV-DNA, alanine transaminase normalization, and virological breakthrough was similar between patients with or without renal dysfunction. ETV showed high efficacy for all 10 hemodialysis patients without virological breakthrough. CONCLUSIONS: Entecavir for HBV-infected patients with severe renal dysfunction, including hemodialysis patients, is highly effective and does not affect renal function.
• Effects of resistance-associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs.
  Goki Suda; Megumi Kimura; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Osamu Maehara; Tomoe Shimazaki; Kenichi Morikawa; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 49, 11, 1275, 1285, Nov. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIMS: Development of direct-acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant-associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non-structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. METHODS: We utilized HCV-2b/2a (JFH-1) chimeric virus (genotype 2a), which replicates more robustly than JFH-1. We constructed various genotype 2a JFH-1-based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti-HCV reagents. RESULTS: Genotype 2a-based HCV with NS5A-P32 deletion could not replicate even in long-term cultures. Genotype 2a-based HCV with NS5A-F28S/M31I showed significantly higher replication ability than the wild-type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000-10 000 fold-resistance compared with the wild-type strain). However, genotype 2a-based HCV with NA5A-F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon-α, and ribavirin. Genotype 2a-based HCV with NS5B-S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. CONCLUSIONS: When undertaking retreatment for genotype 2a HCV-infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti-HCV drugs.
• 肝細胞癌細胞株においてメトホルミンはAMPK-CEBPβ経路を介してCD133の発現を制御する(Metformin regulates the expression of CD133 through the AMPK-CEBPβ pathway in hepatocellular carcinoma cell lines)
  前原 経; 大西 俊介; 夏井坂 光輝; 坂本 直哉
  日本癌学会総会記事, 78回, P, 3258, 日本癌学会, Sep. 2019
  English
• The Successful Retreatment with Glecaprevir and Pibrentasvir of Genotype 1 or 2 HCV-infected Hemodialysis Patients who Failed to Respond to NS5A and Protease Inhibitor Treatment.
  Goki Suda; Masato Nakai; Takuya Sho; Megumi Kimura; Tomoe Shimazaki; Osamu Maehara; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Naoki Kawagishi; Masaru Baba; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  Internal medicine (Tokyo, Japan), 58, 7, 943, 947, 01 Apr. 2019, [Peer-reviewed], [Domestic magazines]
  English, Scientific journal, Clinical trials and real-world data have proven that hepatitis C virus (HCV) in most infected patients can be eradicated by direct-acting antivirals (DAAs). However, the proper retreatment regimen for hemodialysis patients with HCV infection who have previously failed to respond to DAAs has not been clarified. We herein report, for the first time, the successful retreatment with glecaprevir and pibrentasvir, of three hemodialysis patients with genotype 1 or 2 HCV infection, who had previously failed to respond to combination therapy with an HCV-NA5A inhibitor (daclatasvir) and an HCV protease inhibitor (asunaprevir).
• Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines.
  Maehara O; Ohnishi S; Asano A; Suda G; Natsuizaka M; Nakagawa K; Kobayashi M; Sakamoto N; Takeda H
  Neoplasia (New York, N.Y.), 21, 6, 545, 556, Apr. 2019, [Peer-reviewed], [Lead author]
• Glecaprevir and Pibrentasvir for Japanese Patients with Human Immunodeficiency Virus and Genotype 3 Hepatitis C Virus Coinfection: A Report of Three Cases.
  Takuya Sho; Goki Suda; Megumi Kimura; Tomoe Shimazaki; Osamu Maehara; Taku Shigesawa; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Machiko Umemura; Takaaki Izumi; Naoki Kawagishi; Masaru Baba; Masato Nakai; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  Internal medicine (Tokyo, Japan), 58, 6, 797, 802, 15 Mar. 2019, [Peer-reviewed], [Domestic magazines]
  English, Scientific journal, The efficacy and safety of glecaprevir and pibrentasvir in Japanese patients with human immunodeficiency virus (HIV) and/or genotype 3 hepatitis C virus (HCV) infection is yet to be clarified. This is because no or only a few patients have been included in Japanese phase 3 trials. We herein report for the first time the successful treatment of glecaprevir and pibrentasvir in three Japanese patients with HIV and genotype 3 HCV coinfection as well as hemophilia. Glecaprevir and pibrentasvir treatment is safe and effective for Japanese patients with genotype 3 HCV and HIV coinfection.
• L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis.
  Masatsugu Ohara; Koji Ogawa; Goki Suda; Megumi Kimura; Osamu Maehara; Tomoe Shimazaki; Kazuharu Suzuki; Akihisa Nakamura; Machiko Umemura; Takaaki Izumi; Naoki Kawagishi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Shunsuke Ohnishi; Naoya Sakamoto
  Hepatology communications, 2, 8, 906, 918, Aug. 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Liver cirrhosis (LC) is a major cause of secondary sarcopenia. Sarcopenia makes the prognosis worse; thus, novel therapeutic options for sarcopenia in patients with LC are urgently required as they are currently limited. In this retrospective study, 158 patients with LC were screened, and 35 of those patients who were treated with L-carnitine for more than 6 months and for whom skeletal muscle mass changes could be evaluated by computer tomography were enrolled. Of the 158 patients, 79 patients who did not receive L-carnitine supplementation served as controls. Cases and controls were propensity score matched for age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration, and changes in skeletal muscle mass and clinical data were compared. The 35 patients who received L-carnitine supplementation and 35 propensity score-matched patients who did not receive carnitine supplementation comprised the final enrollment. Compared with control patients, patients who received L-carnitine had significantly worse liver function, which is associated with rapid progress of skeletal muscle depletion. However, loss of skeletal muscle mass was significantly suppressed in patients receiving L-carnitine, and a significant effect was observed in patient subgroups stratified by age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration. The change ratios of most laboratory data, including vitamin D and insulin-like growth factor 1 levels, were similar in the two groups, but ammonia levels were significantly less in those receiving L-carnitine. However, even in patients receiving L-carnitine but not showing an ammonia decrease, loss of skeletal muscle was significantly suppressed. Conclusion: L-carnitine suppresses loss of skeletal muscle mass and may therefore be a novel therapeutic option for sarcopenia in patients with LC. (Hepatology Communications 2018; 00:000-000).
• Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats.
  Ohara M; Ohnishi S; Hosono H; Yamamoto K; Fu Q; Maehara O; Suda G; Sakamoto N
  Frontiers in pharmacology, 9, 709, 709, 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.
• Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis.
  Naoki Kawagishi; Goki Suda; Akinobu Nakamura; Megumi Kimura; Osamu Maehara; Kazuharu Suzuki; Akihisa Nakamura; Masatsugu Ohara; Takaaki Izumi; Machiko Umemura; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Yusuke Kudo; Mutsumi Nishida; Hideaki Miyoshi; Naoya Sakamoto
  PloS one, 13, 12, e0209615, 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, AIM: We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk. METHODS: Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed. RESULTS: A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels. CONCLUSIONS: Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.
• Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats.
  Ohara M; Ohnishi S; Hosono H; Yamamoto K; Yuyama K; Nakamura H; Fu Q; Maehara O; Suda G; Sakamoto N
  Stem cells international, 2018, 3212643, 3212643, 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Background: There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods: NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 μg/kg) and at week 3 in rats with liver fibrosis (20 μg/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results: AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) α, interleukin- (Il-) 1β and Il-6, and transforming growth factor- (Tgf-) β. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions: AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.
• Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C
  N. Kawagishi; G. Suda; M. Onozawa; M. Kimura; O. Maehara; M. Ohara; T. Izumi; M. Umemura; J. Ito; M. Nakai; T. Sho; M. Natsuizaka; K. Morikawa; K. Ogawa; N. Sakamoto
  JOURNAL OF VIRAL HEPATITIS, 24, 12, 1098, 1106, Dec. 2017, [Peer-reviewed]
  English, Scientific journal
• Hepatitis B virus reactivation during hepatitis C direct-acting antiviral therapy in patients with previous HBV infection
  Naoki Kawagishi; Goki Suda; Masahiro Onozawa; Megumi Kimura; Osamu Maehara; Jun Ito; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto
  JOURNAL OF HEPATOLOGY, 67, 5, 1106, 1108, Nov. 2017, [Peer-reviewed]
  English
• Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma
  Osamu Maehara; Goki Suda; Mitsuteru Natsuizaka; Shunsuke Ohnishi; Yoshito Komatsu; Fumiyuki Sato; Masato Nakai; Takuya Sho; Kenichi Morikawa; Koji Ogawa; Tomoe Shimazaki; Megumi Kimura; Ayaka Asano; Yoshiyuki Fujimoto; Shinya Ohashi; Shingo Kagawa; Hideaki Kinugasa; Seiji Naganuma; Kelly A. Whelan; Hiroshi Nakagawa; Koji Nakagawa; Hiroshi Takeda; Naoya Sakamoto
  CARCINOGENESIS, 38, 11, 1073, 1083, Nov. 2017, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Anti-Adipogenic and Antiviral Effects of L-Carnitine on Hepatitis C Virus Infection
  Yoko Tsukuda; Goki Suda; Seiji Tsunematsu; Jun Ito; Fumiyuki Sato; Katsumi Terashita; Masato Nakai; Takuya Sho; Osamu Maehara; Tomoe Shimazaki; Megumi Kimura; Kenichi Morikawa; Mitsuteru Natsuizaka; Koji Ogawa; Shunsuke Ohnishi; Makoto Chuma; Naoya Sakamoto
  JOURNAL OF MEDICAL VIROLOGY, 89, 5, 857, 866, May 2017, [Peer-reviewed]
  English, Scientific journal
• A pivotal role of Kruppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma
  Osamu Maehara; Fumiyuki Sato; Mitsuteru Natsuizaka; Ayaka Asano; Yoshimasa Kubota; Jun Itoh; Seiji Tsunematsu; Katsumi Terashita; Yoko Tsukuda; Masato Nakai; Takuya Sho; Goki Suda; Kenichi Morikawa; Koji Ogawa; Makoto Chuma; Koji Nakagawa; Shunsuke Ohnishi; Yoshito Komatsu; Kelly A. Whelan; Hiroshi Nakagawa; Hiroshi Takeda; Naoya Sakamoto
  CANCER BIOLOGY & THERAPY, 16, 10, 1453, 1461, Oct. 2015, [Peer-reviewed], [Lead author]
  English, Scientific journal
• EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition
  Fumiyuki Sato; Yoshimasa Kubota; Mitsuteru Natsuizaka; Osamu Maehara; Yutaka Hatanaka; Katsuji Marukawa; Katsumi Terashita; Goki Suda; Shunsuke Ohnishi; Yuichi Shimizu; Yoshito Komatsu; Shinya Ohashi; Shingo Kagawa; Hideaki Kinugasa; Kelly A. Whelan; Hiroshi Nakagawa; Naoya Sakamoto
  CANCER BIOLOGY & THERAPY, 16, 6, 933, 940, Jun. 2015, [Peer-reviewed]
  English, Scientific journal
• KLF5 Promotes Tumorigenicity of Hepatocellular Carcinoma by Upregulation of Cancer Stem-Like Cells
  Sato Fumiyuki; Natsuizaka Mitsuteru; Maehara Osamu; Asano Ayaka; Kubota Yoshimasa; Itoh Jun; Tsunematsu Seiji; Tsukuda Yoko; Terashita Katsumi; Nakai Masato; Sho Takuya; Suda Goki; Morikawa Kenichi; Ogawa Koji; Ohnishi Shunsuke; Sakamoto Naoya
  GASTROENTEROLOGY, 148, 4, S43, Apr. 2015, [Peer-reviewed]
• A pivotal role of KLF5 in regulation of cancer stem-like cells in hepatocellular carcinoma
  Mitsuteru Natsuizaka; Osamu Maehara; Fumiyuki Sato; Yoshimasa Kubota; Goki Suda; Jun Itoh; Seiji Tsunematsu; Yoko Tsukuda; Katsumi Terashita; Masato Nakai; Takuya Sho; Koji Ogawa; Shunsuke Ohnishi; Naoya Sakamoto
  HEPATOLOGY, 60, 825A, 825A, 2014, [Peer-reviewed]
  English
• Hypoxia-Inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors
  Shunsuke Ohnishi; Osamu Maehara; Koji Nakagawa; Ayano Kameya; Kanako Otaki; Hirotoshi Fujita; Ryosuke Higashi; Kikuko Takagi; Masahiro Asaka; Naoya Sakamoto; Masanobu Kobayashi; Hiroshi Takeda
  PLoS ONE, 8, 6, e66255, 20 Jun. 2013, [Peer-reviewed]
  English, Scientific journal

• 羊膜間葉系幹細胞由来液性因子HSPB6の抗炎症効果についての検討
  太田友里奈; 前原経; 酒井真央; 小林美春; 武井則雄; 柘植厚志; 大久保直登; 林真広; 中石智之; 大西俊介, 日本再生医療学会総会(Web), 24th, 2025
• TGF-β-decoy EVを用いた線維化シグナル抑制
  山之内海心; 細野秀崇; 中嶋楓; 前原経; 柘植厚志; 大久保直登; 大西俊介, 日本再生医療学会総会(Web), 24th, 2025
• クローン病に伴う痔瘻モデル作製の試み
  小松葉月; 柘植厚志; 杉浦弘周; 飯田千菜; 川村芳江; 河南雅成; 前原経; 大久保直登; 大西俊介, 日本再生医療学会総会(Web), 24th, 2025
• 肝細胞癌幹細胞維持に関連する遺伝子の解析
  須田剛生; 前原経; 坂本直哉, 日本消化器病学会雑誌(Web), 119, 2022
• Synthesis and evaluation of ⁶⁸Ga-labeled probes based on transferrin receptor targeting linear peptides
  水野雄貴; 水野雄貴; 三浦春香; 安井博宣; 柴田悠貴; 大久保直登; 前原経; 武田宏司; 大西俊介; 久下裕司; 久下裕司, 日本薬学会年会要旨集(Web), 142nd, 2022
• FGFR阻害剤およびMEK阻害剤は食道扁平上皮癌(ESCC)がん幹細胞を減少させる
  前原経; 夏井坂光輝; 須田剛生; 大西俊介; 坂本直哉; 武田宏司, 日本消化管学会雑誌, 4, Supplement, 2020
• 糖尿病治療薬メトホルミンによるAMPK-CEBPβ経路を介したがん幹細胞マーカーCD133の発現制御
  大西俊介; 前原経; 浅野彩華; 須田剛生; 夏井坂光輝; 中川宏治; 小林正伸; 坂本直哉; 武田宏司, 日本分子生物学会年会プログラム・要旨集(Web), 42nd, 2019
• 羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果
  大原正嗣; 大西俊介; 山本幸司; 付慶傑; 前原経; 須田剛生; 坂本直哉, 日本再生医療学会総会(Web), 18th, 2019
• Prevalence and risk factors of hepatitis B virus reactivation in interferon-free direct-acting antiviral therapies for hepatitis C
  N. Kawagishi; G. Suda; M. Onozawa; M. Kimura; O. Maehara; M. Ohara; T. Izumi; M. Umemura; J. Ito; M. Nakai; T. Sho; M. Natsuizka; K. Morikawa; K. Ogawa; N. Sakamoto, JOURNAL OF HEPATOLOGY, 66, 1, S725, S726, 2017
  English, Summary international conference
• 食道扁平上皮がん(ESCC)がん幹細胞に対するFGFR阻害剤の効果
  前原経; 夏井坂光輝; 佐藤史幸; 中川宏治; 大西俊介; 坂本直哉; 武田宏司, 再生医療, 15, 2016
• 肝細胞癌におけるKLF5による癌幹細胞制御機構
  佐藤 史幸; 夏井坂 光輝; 前原 経; 浅野 彩華; 久保田 良政; 出水 孝章; 梅村 真知子; 伊藤 淳; 常松 聖司; 中井 正人; 荘 拓也; 須田 剛生; 森川 賢一; 小川 浩司; 大西 俊介; 坂本 直哉, 肝臓, 56, Suppl.3, A1002, A1002, Nov. 2015
  (一社)日本肝臓学会, Japanese

• Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines
  Ohnishi Shunsuke; Maehara Osamu; Sakamoto Naoya; Takeda Hiroshi
  Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2021, Japanese Pharmacological Society, Japanese
  2021 - 2021, CD133 is a cellular surface protein, which has been reported to be a cancer stem cell marker, and thus is considered a potential target for cancer treatment. Metformin is also known to reduce the risk of cancer development and cancer stem cells (CSCs), including the expression of CD133. However, the mechanism underlying the reduction of the expression of CD133 by metformin is not yet understood. This study shows that metformin suppressed CD133 expression mainly by affecting the CD133 P1 promoter via AMPK signaling. AMPK inhibition rescued the reduction of CD133 by metformin. Further experiments demonstrated that CEBPβ was upregulated by metformin and that two isoforms of CEBPβ reciprocally regulated the expression of CD133. Specifically, the liver-enriched activator protein (LAP) isoform increased the expression of CD133 by directly binding to the P1 promoter region, whereas the liver-enriched inhibitory protein (LIP) isoform suppressed the expression of CD133. Consistent with these findings, a 3D culture assay and drug sensitivity assay demonstrated that LAP-overexpressing cells formed large spheroids and were more resistant to 5-FU treatment, whereas LIP-overexpressing cells were more sensitive to 5-FU and showed combined effects with metformin. Our results indicated that metformin-AMPK-CEBPb signaling plays a crucial role in regulating the gene expression of CD133. Additionally, regulating the ratio of LAP/LIP may be a novel strategy for targeting CSCs for the treatment of cancer.
• Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR 1-3 signaling, but not FGFR4 signaling
  前原経; 夏井坂光輝; 大西俊介; 坂本直哉
  日本癌学会学術総会抄録集(Web), 2020
  2020 - 2020
• FGFR阻害剤およびMEK阻害剤は食道扁平上皮癌(ESCC)がん幹細胞を減少させる
  前原経; 夏井坂光輝; 須田剛生; 大西俊介; 坂本直哉; 武田宏司
  日本消化管学会雑誌, 2020
  2020 - 2020
• Metformin regulates the expression of CD133 through the AMPK-CEBP β pathway in hepatocellular carcinoma cell lines
  前原経; 大西俊介; 夏井坂光輝; 坂本直哉
  日本癌学会学術総会抄録集(Web), 2019
  2019 - 2019
• 羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果
  大原正嗣; 大西俊介; 山本幸司; 付慶傑; 前原経; 須田剛生; 坂本直哉
  日本再生医療学会総会(Web), 2019, Japanese
• 食道扁平上皮がん(ESCC)がん幹細胞に対するFGFR阻害剤の効果
  前原経; 夏井坂光輝; 佐藤史幸; 中川宏治; 大西俊介; 坂本直哉; 武田宏司
  再生医療, 01 Feb. 2016, Japanese
• 肝細胞癌におけるKLF5による癌幹細胞制御機構
  佐藤 史幸; 夏井坂 光輝; 前原 経; 浅野 彩華; 久保田 良政; 出水 孝章; 梅村 真知子; 伊藤 淳; 常松 聖司; 中井 正人; 荘 拓也; 須田 剛生; 森川 賢一; 小川 浩司; 大西 俊介; 坂本 直哉
  肝臓, Nov. 2015, Japanese
• KLF5 Promotes Tumorigenicity of Hepatocellular Carcinoma by Upregulation of Cancer Stem-Like Cells
  Sato Fumiyuki; Natsuizaka Mitsuteru; Maehara Osamu; Asano Ayaka; Kubota Yoshimasa; Itoh Jun; Tsunematsu Seiji; Tsukuda Yoko; Terashita Katsumi; Nakai Masato; Sho Takuya; Suda Goki; Morikawa Kenichi; Ogawa Koji; Ohnishi Shunsuke; Sakamoto Naoya
  GASTROENTEROLOGY, Apr. 2015

• 実務実習事前実習, 2024年, 学士課程, 薬学部
• OSCE対応演習, 2024年, 学士課程, 薬学部

• CD73/CD166共陽性肝細胞癌幹細胞の特性解明と治療抵抗性克服に向けた分子基盤の探索
  科学研究費助成事業
  01 Apr. 2026 - 31 Mar. 2029
  前原 経; 須田 剛生; 大原 正嗣
  日本学術振興会, 基盤研究(C), 北海道大学, 26K10893
• 肝細胞癌幹細胞における免疫チェックポイント分子の発現機構の解明
  科学研究費助成事業
  01 Apr. 2023 - 31 Mar. 2026
  前原 経
  本年度(令和5年度)は基本的に申請書に記載した研究内容に従って実験を行った。①HCC細胞株(Huh7やHep3B等)を用いてlenvatinib耐性細胞を作成し、2次元培養および3次元培養を行った。その細胞における免疫チェックポイント関連遺伝子の発現変動をRNAseqを用いて網羅的に解析を行い、複数の関連遺伝子の発現変動を確認し候補遺伝子とした。続いて、候補遺伝子の発現調節機構を文献情報から検索し、実際のRNAseqのデータと照合した。②発現変動が確認された関連遺伝子の安定発現細胞を作成し(作成中のものも含む)、細胞増殖や浸潤能、遊走能等に違いが起こるかin vitroの系で検証した。③マウス同種腫瘍移植モデルのモデル作成を検討した。具体的には、マウス肝癌細胞株Hep55細胞およびBNL-1ME A.7R.1細胞をそれぞれの母系マウスに皮下移植および直接肝移植し、腫瘍形成を検討したところ、いづれの方法でも腫瘍の生着および増大を確認できた。現在はピックアップした複数の関連遺伝子について、ノックダウンおよびノックアウト過剰細胞を作成中である。また、CSCsマーカー(CD44high/CD133high)でソーティングした細胞における関連遺伝子の発現についても検討し、レンバチニブ耐性細胞との比較検討を実施していく予定である。
  日本学術振興会, 若手研究, 北海道大学, 23K14999
• 食道扁平上皮癌がん幹細胞における免疫逃避機構の解明
  科学研究費助成事業
  Apr. 2022 - Mar. 2025
  夏井坂 光輝; 須田 剛生; 前原 経
  日本学術振興会, 基盤研究(C), 北海道大学, Coinvestigator, 22K08000
• 肝細胞癌幹細胞におけるレンバチニブ耐性機構の解明
  科学研究費助成事業 若手研究
  Apr. 2020 - Mar. 2023
  前原 経
  本年度(令和3年度)も基本的には申請書に記載した研究内容に従って実験を行った。
  昨年度作成した耐性細胞を用いて①3次元培養(浮遊培養、biomaterialを用いた培養)の条件検討を行い、最適な培養条件を確認できた。本来は3次元培養による細胞塊の性質を詳細に検討する予定であったが、条件検討に想定以上に時間を要してしまったため、詳細の検討は来年度に持ち越す予定である。②昨年度実施したマイクロアレイの候補遺伝子の恒常的過剰発現・ノックダウン細胞を作成し、lenvatinib,sorafenib耐性への影響をin vitroで検討した。その結果、候補遺伝子Aはlenvatinib,sorafenib耐性に直接関与する可能性が示唆された。さらに、候補遺伝子のCSCsマーカーの発現への影響を検討したところ、コントロール群と比較して有意な変化が確認できた。③耐性細胞株と親細胞株をヌードマウスの皮下に移植後、実際にlenvatinib,sorafenibをゾンデを用いて経口投与し、薬剤投与量の最適化とin vivoレベルでの耐性について確認検討した。その結果、想定通り親細胞株移植群に対しては薬剤の効果が見られたものの、耐性細胞株ではin vivoにおいても薬剤耐性が確認できた。④候補遺伝子と薬剤耐性・CSCsに関わる遺伝子の発現のHCC検体での相関解析をTCGAデータを用いて行った。その結果、一部の候補遺伝子において、本研究で用いている耐性細胞株での結果と類似する結果が得られた。
  現在は、3次元培養での各種検討、候補遺伝子の恒常的過剰発現・ノックダウン細胞を用いたin vivoでの検討を行っている。
  日本学術振興会, 若手研究, 北海道大学, Principal investigator, 20K17039
• メトホルミンによるがん幹細胞マーカーＣＤ１３３発現抑制機構の解明
  科学研究費助成事業 特別研究員奨励費
  Apr. 2017 - Mar. 2019
  前原 経
  本年度も昨年度に引き続き基本的には申請書に記載した実験内容に従って実験を行った。
  ①メトホルミンによるCD133の発現抑制にAMPK下流経路が関与するか否かの検討.昨年度の実験でメトホルミンによるCD133の発現抑制がAMPKを介していることが明らかとなったため、本年度はその下流経路の解析を行った。その結果、mTOR経路の関与は認められなかったが、STAT3経路の関与が認められた。②候補遺伝子の発現がCD133の発現に影響を与えるか否かの検討.昨年度の実験でマイクロアレイの結果からCEBPβ遺伝子に注目した。CEBPβは機能の相反するisoformが存在するため(LAP, LIP)、それぞれの遺伝子がP1プロモーター活性に与える影響を検討した。その結果、LAPの過剰発現によってP1プロモーター活性が上昇し、LIPの過剰発現では減少した。③メトホルミンによるLIP/LAP発現比の変化の検討.メトホルミンによってLAPとLIPの発現が変化するか否かを検討したところ、メトホルミンによってLAPの発現は変化していないもののLIPの発現の上昇が確認された。この結果からLIP/LAP比の上昇が示唆された。④LIP,LAPの安定発現細胞のin vitroにおける腫瘍形成能および抗がん剤感受性の検討.LAP,LIPそれぞれの安定発現細胞を用いて三次元培養を行い、スフィア形成能を検討した。その結果、形成されたスフィアの数に変化は認められなかったものの、スフィア1個あたりの大きさはLAP安定発現細胞で有意に増大していた。また、LAP,LIPそれぞれの安定発現細胞を用いて5-FUの抗腫瘍効果、さらにはメトホルミンとの併用効果についても検討した。その結果、LAP安定発現細胞は5-FUへの耐性を示した。一方、LIP発現細胞では5-FUとメトホルミンの併用効果が認められた。
  日本学術振興会, 特別研究員奨励費, 北海道大学, Principal investigator, 17J00434
• FGFR inhibitors eliminate cancer stem-like cells in esophageal squamous cell carcinoma
  Grants-in-Aid for Scientific Research
  01 Apr. 2015 - 31 Mar. 2018
  Natsuizaka Mitsuteru; MAEHARA Osamu
  In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to be cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor sharply diminishes CSCs via induction of mesenchymal-epithelial transition (MET). Further experiments revealed that Mek/Erk pathway is crucial for FGF-2-mediated CSC regulation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 15K08943