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Last Updated :2024/09/05

研究者情報

マスター

アカウント（マスター）

  • 氏名

    佐藤　典宏(サトウ　ノリヒロ), サトウ　ノリヒロ

所属（マスター）

  • 北海道大学病院　医療・ヘルスサイエンス研究開発機構

所属（マスター）

  • 北海道大学病院　医療・ヘルスサイエンス研究開発機構

独自項目

syllabus

  • 2021, トランスレーショナルリサーチ概論, Introduction to Translational Research, 修士課程, 医学院, 臨床研究、トランスレーショナルリサーチ
  • 2021, 基本医学総論, Basic Principles of Medicine, 修士課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 基本公衆衛生学研究, Master's Thesis Research in Public Health, 修士課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 基本医学研究, Master's Thesis Research in Medical Sciences, 修士課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 大学院共通授業科目（教育プログラム）：外科系臨床医学研究の新展開 医療機器開発概論, Inter-Graduate School Classes:New Developments in Clinical Medical Research in Surgery - Outline of medical device development, 修士課程, 大学院共通科目, 臨床医学、臨床解剖、外科教育、献体を使用した手術手技研修 （Cadaver Surgical Training：CST）、医療機器開発
  • 2021, 大学院共通授業科目（教育プログラム）：外科系臨床医学研究の新展開 臨床医学・外科解剖セミナー, Inter-Graduate School Classes:New Developments in Clinical Medical Research in Surgery - Seminar of clinical medicine and surgical anatomy, 修士課程, 大学院共通科目, 臨床医学、臨床解剖、外科教育、献体を使用した手術手技研修（Cadaver Surgical Training: CST）、医療機器開発
  • 2021, 医理工実験・研究計画法, Research planning for Biomedical Science and Engineering Research, 修士課程, 医理工学院, 生物統計、文献検索 、疫学 、治験 、臨床研究 、論文の書き方
  • 2021, 基本実験・研究計画法, Experimental Methods and Research Designs, 修士課程, 医学院, 生物統計、文献検索 、疫学 、治験 、臨床研究 、論文の書き方
  • 2021, ゲノム情報科学特論, Genome Informatics, 修士課程, 情報科学研究科, ゲノム, 複製, 転写, 翻訳, 塩基配列決定, 分子進化解析, ゲノム配列解析, ゲノム発現解析、医療情報処理、臨床癌ゲノム研究
  • 2021, ゲノム情報科学特論, Genome Informatics, 修士課程, 情報科学院, ゲノム, 複製, 転写, 翻訳, 塩基配列決定, 分子進化解析, ゲノム配列解析, ゲノム発現解析、医療情報処理、臨床癌ゲノム研究
  • 2021, トランスレーショナルリサーチ概論, Introduction to Translational Research, 博士後期課程, 医学院, 臨床研究、トランスレーショナルリサーチ
  • 2021, 医学総論, Principles of Medicine, 博士後期課程, 医学院, 臨床研究、倫理指針、橋渡し研究 Clinical Research, Ethical Guidelines, Translational Research
  • 2021, 基盤医学研究, Dissertation Research in Medical Sciences, 博士後期課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 社会医学研究, Dissertation Research in Social Medicine, 博士後期課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 臨床医学研究, Dissertation Research in Clinical Medicine, 博士後期課程, 医学院, 臨床研究、倫理指針、橋渡し研究
  • 2021, 実験・研究計画法, Experimental Methods and Research Designs, 博士後期課程, 医学院, 生物統計、文献検索 、疫学 、治験 、臨床研究 、論文の書き方
  • 2021, ゲノム情報科学特論, Genome Informatics, 博士後期課程, 情報科学研究科, ゲノム, 複製, 転写, 翻訳, 塩基配列決定, 分子進化解析, ゲノム配列解析, ゲノム発現解析、医療情報処理、臨床癌ゲノム研究
  • 2021, ゲノム情報科学特論, Genome Informatics, 博士後期課程, 情報科学院, ゲノム, 複製, 転写, 翻訳, 塩基配列決定, 分子進化解析, ゲノム配列解析, ゲノム発現解析、医療情報処理、臨床癌ゲノム研究
  • 2021, トランスレーショナルリサーチ概論, An Introduction to Translational Research, 学士課程, 医学部, トランスレーショナルリサーチ 臨床研究

PositionHistory

  • 経営戦略室室員, 2020年10月12日, 2022年3月31日
  • 経営戦略室室員, 2022年4月1日, 2024年3月31日
  • 研究戦略室室員, 2020年10月12日, 2022年3月31日
  • 創成研究機構ワクチン研究開発拠点副拠点長, 2022年10月1日, 2024年3月31日
  • 総長補佐, 2020年10月12日, 2022年3月31日
  • 総長補佐, 2022年4月1日, 2024年3月31日

researchmap

プロフィール情報

学位

  • 医学博士（北海道大学）

プロフィール情報

  • 姓

    佐藤

  • 名

    典宏

  • ID各種

    201201066910729378

業績リスト

研究分野

  • その他 / その他

論文

  • Monami Tarisawa, Masaaki Matsushima, Akihiko Kudo, Ken Sakushima, Yasuhiro Kanatani, Naoki Nishimoto, Jun Sawada, Takeshi Matsuoka, Shin Hisahara, Haruo Uesugi, Naoya Minami, Kazuya Sako, Asako Takei, Akiko Tamakoshi, Norihiro Sato, Hidenao Sasaki, Ichiro Yabe
    Internal medicine (Tokyo, Japan) 2024年03月18日 
    Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.
  • Takuya Maeda, Teruki Yanagi, Keiko Tokuchi, Takeru Funakoshi, Nao Horie, Toshiyuki Isoe, Yoichi M Ito, Norihiro Sato, Hideyuki Ujiie
    Experimental dermatology 33 1 e14993  2024年01月 
    Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.
  • 北海道における多系統萎縮症レジストリ研究 HoRC-MSA2014-2023
    松島 理明, 足澤 萌奈美, 工藤 彰彦, 佐久嶋 研, 金谷 泰宏, 西本 尚樹, 澤田 潤, 松岡 健, 上杉 春雄, 南 尚哉, 佐光 一也, 武井 麻子, 久原 真, 玉腰 暁子, 佐藤 典宏, 佐々木 秀直, 矢部 一郎
    臨床神経学 63 11 780 - 780 (一社)日本神経学会 2023年11月
  • Takashi Miyakoshi, Shuhei Ishikawa, Ryo Okubo, Naoki Hashimoto, Norihiro Sato, Ichiro Kusumi, Yoichi M Ito
    Journal of psychiatric research 168 149 - 156 2023年10月27日 
    Antipsychotic medications increase the risk of abnormal glucose metabolism. However, in clinical practice, it is difficult to predict this risk because it is affected by medication-related and background factors. This study aimed to identify the risk factors for abnormal glucose metabolism during antipsychotic treatment. We conducted a multicenter, prospective, cohort study in patients with schizophrenia, schizoaffective disorder, or bipolar disorder. Of these patients, those with prediabetes or possible diabetes were excluded. Finally, 706 patients were included in the analysis. The hazard ratio (HR) for each factor was calculated for events of progression to hyperglycemia using time-dependent Cox regression analysis stratified according to facility type and adjusted for available background and drug-related factors. Treatments with olanzapine (HR = 2.06, 95% confidence interval [CI] = 1.05-4.05), clozapine (HR = 4.25, 95% CI = 1.56-11.60), and chlorpromazine (HR = 4.48, 95% CI = 1.21-16.57), overweight and obesity (HR = 1.57, 95% CI = 1.02-2.41), and hypertriglyceridemia (HR = 1.72, 95% CI = 1.02-2.88) were associated with a significantly higher occurrence of hyperglycemic progression. The number and daily dose of antipsychotics were not associated with their occurrence. Our study demonstrated that more careful monitoring is necessary during olanzapine, clozapine, and chlorpromazine treatment because of the higher occurrence of abnormalities in glucose metabolism. Furthermore, patients with obesity or hypertriglyceridemia warrant monitoring for the occurrence of abnormal glucose metabolism, regardless of the type of antipsychotic medication.
  • 多系統萎縮症新診断基準の有用性の検討
    市之川 萌奈美, 松島 理明, 工藤 彰彦, 佐久嶋 研, 西本 尚樹, 澤田 潤, 松岡 健, 南 尚哉, 佐光 一也, 武井 麻子, 久原 真, 佐藤 典宏, 佐々木 秀直, 矢部 一郎
    臨床神経学 63 Suppl. S249 - S249 (一社)日本神経学会 2023年09月
  • Satoshi Kuroda, Shusuke Yamamoto, Takeshi Funaki, Miki Fujimura, Hiroharu Kataoka, Tomohito Hishikawa, Jun Takahashi, Hidenori Endo, Tadashi Nariai, Toshiaki Osato, Nobuhito Saito, Norihiro Sato, Emiko Hori, Yoichi M Ito, Susumu Miyamoto
    Stroke 54 6 1494 - 1504 2023年06月 
    BACKGROUND: Long-term outcomes are unknown in patients with asymptomatic moyamoya disease. In this report, we aimed to clarify their 5-year risk of stroke and its predictors. METHODS: We are conducting a multicenter, prospective cohort study (Asymptomatic Moyamoya Registry) in Japan. Participants were eligible if they were 20 to 70 years, had bilateral or unilateral moyamoya disease, experienced no episodes suggestive of TIA and stroke; and were functionally independent (modified Rankin Scale score 0-1). Demographic and radiological information was collected at enrollment. In this study, they are still followed up for 10 years. In this interim analysis, we defined the primary end point as a stroke occurring during a 5-year follow-up period. Independent predictors for stroke were also determined, using a stratification analysis method. RESULTS: Between 2012 and 2015, we enrolled 109 patients, of whom 103 patients with 182 involved hemispheres completed the 5-year follow-up. According to the findings on DSA and MRA, 143 hemispheres were judged as moyamoya disease and 39 hemispheres as questionable manifestations (isolated middle cerebral artery stenosis). The patients with questionable hemispheres were significantly older, more often male, and more frequently had hypertension than those with moyamoya hemisphere. Moyamoya hemispheres developed 7 strokes, including 6 hemorrhagic and 1 ischemic stroke, during the first 5 years. The annual risk of stroke was 1.4% per person, 0.8% per hemisphere, and 1.0% per moyamoya hemisphere. Independent predictor for stroke was Grade-2 choroidal anastomosis (hazard ratio, 5.05 [95% CI, 1.24-20.6]; P=0.023). Furthermore, microbleeds (hazard ratio, 4.89 [95% CI, 1.13-21.3]; P=0.0342) and Grade-2 choroidal anastomosis (hazard ratio, 7.05 [95% CI, 1.62-30.7]; P=0.0093) significantly predicted hemorrhagic stroke. No questionable hemispheres developed any stroke. CONCLUSIONS: The hemispheres with asymptomatic moyamoya disease may carry a 1.0% annual risk of stroke during the first 5 years, the majority of which are hemorrhagic stroke. Grade-2 choroidal anastomosis may predict stroke, and the microbleeds and Grade-2 choroidal anastomosis may carry the risk for hemorrhagic stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: UMIN000006640.
  • Hideaki Shiraishi, Tsuyoshi Teramoto, Saki Yokoshiki, Jun Tohyama, Yuki Ueda, Kiyoshi Egawa, Norihiro Sato, Atsushi Manabe, Mitsuhiro Kato
    BRAIN & DEVELOPMENT 45 6 343 - 347 2023年06月 
    Objective: The efficacy of the mechanistic target of rapamycin inhibitor, sirolimus, was recently reported for patients more than 6 years of age by Kato et al. We evaluated the efficacy and safety of sirolimus in a 2-year-old patient with recurrent focal seizures with impaired consciousness after focal cortical dysplasia (FCD) type IIa resection. Methods: The patient was a 2-year-old girl who had recurrent seizures after undergoing FCD resection at 4 months of age. The initial dose of sirolimus was 0.5 mg/day and was gradually increased using the trough blood concentration before oral administration as an index, and evaluation was performed at 92 weeks. Results: The trough blood level of sirolimus was increased to 6.1 ng/mL and maintenance therapy was started at 40 weeks. Focal seizures with impairment of consciousness with tonic extension of the limbs decreased. No critically serious adverse events occurred. Conclusion: Sirolimus was effective against epileptic seizures from FCD type II even for a child under 5 years of age. There were no critically serious adverse events and administration could be continued. (c) 2023 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Hideki Sudo, Takashi Miyakoshi, Yudai Watanabe, Yoichi M Ito, Kaoru Kahata, Khin Khin Tha, Nozomi Yokota, Hiroe Kato, Tomoko Terada, Norimasa Iwasaki, Teruyo Arato, Norihiro Sato, Toshiyuki Isoe
    BMJ open 13 2 e065476  2023年02月02日 
    INTRODUCTION: In patients with combined lumbar spinal canal stenosis (LSCS), a herniated intervertebral disc (IVD) that compresses the dura mater and nerve roots is surgically treated with discectomy after laminoplasty. However, defects in the IVD after discectomy may lead to inadequate tissue healing and predispose patients to the development of IVD degeneration. Ultrapurified stem cells (rapidly expanding clones (RECs)), combined with an in situ-forming bioresorbable gel (dMD-001), have been developed to fill IVD defects and prevent IVD degeneration after discectomy. We aim to investigate the safety and efficacy of a new treatment method in which a combination of REC and dMD-001 is implanted into the IVD of patients with combined LSCS. METHODS AND ANALYSIS: This is a multicentre, prospective, double-blind randomised controlled trial. Forty-five participants aged 20-75 years diagnosed with combined LSCS will be assessed for eligibility. After performing laminoplasty and discectomy, participants will be randomised 1:1:1 into the combination of REC and dMD-001 (REC-dMD-001) group, the dMD-001 group or the laminoplasty and discectomy alone (control) group. The primary outcomes of the trial will be the safety and effectiveness of the procedure. The effectiveness will be assessed using visual analogue scale scores of back pain and leg pain as well as MRI-based estimations of morphological and compositional quality of the IVD tissue. Secondary outcomes will include self-assessed clinical scores and other MRI-based estimations of compositional quality of the IVD tissue. All evaluations will be performed at baseline and at 1, 4, 12, 24 and 48 weeks after surgery. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the institutions involved. We plan to conduct dissemination of the outcome data by presenting our data at national and international conferences, as well as through formal publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCT2013210076.
  • 北海道における多系統萎縮症レジストリ研究 HoRC-MSA2014-2022
    松島 理明, 足澤 萌奈美, 工藤 彰彦, 佐久嶋 研, 金谷 泰宏, 西本 尚樹, 澤田 潤, 松岡 健, 久原 真, 上杉 春雄, 南 尚哉, 佐光 一也, 武井 麻子, 玉腰 暁子, 佐藤 典宏, 佐々木 秀直, 矢部 一郎, 北海道保健福祉部健康安全局地域保健課感染症・特定疾患グループ
    臨床神経学 62 12 976 - 976 (一社)日本神経学会 2022年12月
  • 北海道における多系統萎縮症レジストリ研究 HoRC-MSA2014-2022
    松島 理明, 足澤 萌奈美, 工藤 彰彦, 佐久嶋 研, 金谷 泰宏, 西本 尚樹, 澤田 潤, 松岡 健, 久原 真, 上杉 春雄, 南 尚哉, 佐光 一也, 武井 麻子, 玉腰 暁子, 佐藤 典宏, 佐々木 秀直, 矢部 一郎, 北海道保健福祉部健康安全局地域保健課感染症・特定疾患グループ
    臨床神経学 62 12 976 - 976 (一社)日本神経学会 2022年12月
  • 北海道における多系統萎縮症レジストリ研究:HoRC-MSA2014-2021
    松島 理明, 佐久嶋 研, 金谷 泰宏, 西本 尚樹, 澤田 潤, 松岡 健, 久原 真, 上杉 春雄, 南 尚哉, 佐光 一也, 武井 麻子, 玉腰 暁子, 佐藤 典宏, 佐々木 秀直, 矢部 一郎
    臨床神経学 62 4 333 - 333 (一社)日本神経学会 2022年04月
  • Ryo Sawagashira, Ryodai Yamamura, Ryo Okubo, Naoki Hashimoto, Shuhei Ishikawa, Yoichi M Ito, Norihiro Sato, Ichiro Kusumi
    The Journal of clinical psychiatry 83 3 2022年03月30日 
    Objective: The risk of diabetes development has been reported to differ among second-generation antipsychotics (SGAs). However, few studies have focused on the subthreshold change in glycated hemoglobin (HbA1c). Therefore, this study examined the subthreshold change in HbA1c and change in body mass index (BMI) 3 months after patients initiated one of 6 SGAs widely prescribed in Japan. Methods: This is a prospective cohort study of patients followed up based on the Japanese blood glucose monitoring guidelines for patients with schizophrenia. We collected eligible patients' demographic data, medication history, blood tests, and weight measurements both at baseline and 3 months after recruitment, between April 2013 and March 2015. In the 378 patients with schizophrenia, schizoaffective disorder, and bipolar disorder based on ICD-10, we compared the subthreshold change in HbA1c and the change in BMI 3 months after antipsychotic initiation by using multivariate regression analysis. Results: The subthreshold change in HbA1c 3 months after initiating blonanserin was significantly lower compared with olanzapine (B = -0.17, 95% CI = -0.31 to -0.04). In addition, the change in BMI 3 months after initiating blonanserin and aripiprazole was significantly lower compared with olanzapine (B = -0.93, 95% CI = -1.74 to -0.12; B = -0.71, 95% CI = -1.30 to -0.12, respectively). Conclusions: This is the first study to clarify the differences in the subthreshold change in HbA1c among SGAs. Our results suggest that blonanserin is likely to be a favorable treatment for patients with high risk of diabetes. Trial Registration: UMIN Clinical Trial Registry identifier: UMIN000009868.
  • Shuhei Ishikawa, Ryodai Yamamura, Naoki Hashimoto, Ryo Okubo, Ryo Sawagashira, Yoichi M Ito, Norihiro Sato, Ichiro Kusumi
    Progress in neuro-psychopharmacology & biological psychiatry 113 110453 - 110453 2022年03月08日 
    There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H1, M1, M3, and 5-HT2C receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed.
  • Kenichi Nakamura, Hitoshi Ozawa, Taro Shibata, Nobuko Ushirozawa, Tomomi Hata, Natsuko Okita, Nozomu Fuse, Norihiro Sato, Koji Ikeda, Hideki Hanaoka, Tatsuya Maruyama, Michihiko Wada, Shinobu Shimizu, Hiroi Kasai, Yoichi Yamamoto, Jun Sakurai, Koji Todaka, Shimon Tashiro, Haruko Yamamoto
    Therapeutic innovation & regulatory science 56 2 220 - 229 2022年03月 
    BACKGROUND: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. METHODS: A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. RESULTS: The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP's scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. CONCLUSION: The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.
  • Katsuhisa Yamada, Maeda Kenichiro, Yoichi M Ito, Fujio Inage, Toshiyuki Isoe, Nozomi Yokota, Osamu Sugita, Norihiro Sato, Khin Khin Tha, Norimasa Iwasaki, Teruyo Arato, Hideki Sudo
    Contemporary clinical trials communications 23 100805 - 100805 2021年09月 [査読有り]
     
    Herniated nucleus pulposus (NP), one of the most common diseases of the spine, is surgically treated by removing the sequestered NP. However, intervertebral disc (IVD) defects may remain after discectomy, leading to inadequate tissue healing and predisposing patients to IVD degeneration. An acellular, bioresorbable, ultra-purified alginate (UPAL) gel (dMD-001) implantation system can be used to fill any IVD defects in order to prevent IVD degeneration after discectomy. This first-in-human pilot study aims to determine the feasibility, safety, and perceived patient response to a combined treatment involving discectomy and UPAL gel implantation for herniated NP. We designed a one-arm, double-centre, open-label, pilot trial. The study started in November 2018 and will run until a sample of 40 suitable participants is established. Patients aged 20-49 years, diagnosed with isolated lumbar IVD herniation and scheduled for discectomy represent suitable candidates. All eligible participants who provide informed consent undergo standard discectomy followed by UPAL gel implantation. The primary outcomes of the trial will be the feasibility and safety of the procedure. Secondary outcomes will include self-assessed clinical scores and magnetic resonance imaging-based measures of morphological and compositional quality of the IVD tissue. Initial outcomes will be published at 24 weeks. Analysis of feasibility and safety will be performed using descriptive statistics. Both intention-to-treat and per-protocol analyses of treatment trends of effectiveness will be conducted.
  • Masaaki Matsushima, Ichiro Yabe, Ken Sakushima, Yasuhiro Kanatani, Naoki Nishimoto, Takeshi Matsuoka, Jun Sawada, Haruo Uesugi, Kazuya Sako, Asako Takei, Akiko Tamakoshi, Shun Shimohama, Norihiro Sato, Seiji Kikuchi, Hidenao Sasaki
    BMJ open 11 2 e045100  2021年02月08日 [査読有り]
     
    OBJECTIVES: Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA. SETTING: Patient recruitment started in November 2014 and is ongoing at the time of submission. The number of participating facilities was 66. Postal surveys were sent to medical facilities and patients with MSA in Hokkaido, Japan. PARTICIPANTS: After obtaining written consent from 196 participants, 184 overview surveys and 115 detailed surveys were conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: An overview survey evaluated conformity to diagnostic criteria and a detailed survey implemented an annual assessment based on the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: At the time of registration, 58.2% of patients were diagnosed with cerebellar symptoms predominant type MSA (MSA-C) and 29.9% were diagnosed with parkinsonism predominant type MSA (MSA-P). UMSARS Part Ⅳ score of 4 or 5 accounted for 53.8% of participants. The higher the UMSARS Part Ⅳ score, the higher the proportion of MSA-P. At baseline, levodopa was used by 69 patients (37.5%) and the average levodopa dose was 406.7 mg/day. The frequency of levodopa use increased over time. Eleven cases changed from MSA-C to MSA-P during the study, but the opposite was not observed. Information about survival and causes of death was collected on 54 cases. Half of deaths were respiratory-related. Sudden death was recorded even in the group with UMSARS Part Ⅳ score of 1. CONCLUSIONS: This study is the first large-scale prospective MSA cohort study in Asia. MSA-C was dominant, but the use of antiparkinsonian drugs increased over the study period. Changes from MSA-C to MSA-P occurred, but not vice versa.
  • Hideaki Shiraishi, Kenji Yamada, Kiyoshi Egawa, Mika Ishige, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Keiko Kobayashi, Takashi Miyakoshi, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, Norihiro Sato
    Brain & development 43 2 214 - 219 2021年02月 [査読有り]
     
    BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. PATIENTS AND METHODS: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. RESULTS: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment. CONCLUSION: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
  • 医師主導治験における症例登録促進のための課題調査と登録改善策の検討
    堀江 奈穂, 袴田 遥, 三浦 亜利紗, 磯江 敏幸, 佐藤 典宏, 野尻 崇, 山本 晴子, 樋田 泰浩
    臨床薬理 51 Suppl. S273 - S273 (一社)日本臨床薬理学会 2020年10月
  • Clinical trials act and ethical guidelines for medical and health research in Japan
    Yusuke Watanabe, Satoshi Hirano, Norihito Sato
    THE INTERNATIONAL JOURNAL OF MICRODENTISTRY 11 2 60 - 67 2020年04月 [査読有り]
  • Yoshiya Tanaka, Koji Oba, Takao Koike, Nobuyuki Miyasaka, Tsuneyo Mimori, Tsutomu Takeuchi, Shintaro Hirata, Eiichi Tanaka, Hidekata Yasuoka, Yuko Kaneko, Kosaku Murakami, Tomohiro Koga, Kazuhisa Nakano, Koichi Amano, Kazuyasu Ushio, Tatsuya Atsumi, Masayuki Inoo, Kazuhiro Hatta, Shinichi Mizuki, Shouhei Nagaoka, Shinichiro Tsunoda, Hiroaki Dobashi, Nao Horie, Norihiro Sato
    Annals of the rheumatic diseases 79 1 94 - 102 2020年01月 [査読有り][通常論文]
     
    OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.
  • Haruko Yamamoto, Toshimitsu Hamasaki, Kaori Onda, Takashi Nojiri, Masato Aragaki, Nao Horie, Norihiro Sato, Yasuhiro Hida
    Trials 20 1 715 - 715 2019年12月11日 [査読有り][通常論文]
     
    BACKGROUND: Recurrence of cancer after curative surgery is a major problem after most cancer treatments. Increased sympathetic activity during the perioperative period could promote cancer cell invasion to blood vessels and angiogenesis, resulting in cancer metastasis. Recent studies showed that use of beta blockers can be associated with the prolonged survival of patients with cancer. The objective of this study is to evaluate the preventive effects of landiolol hydrochloride, which is an ultra-short-acting beta-1-selective blocker that has been developed in Japan, on reducing recurrence of cancer after curative surgery for patients with lung cancer. METHODS: The present study is a phase III, multicenter, randomized trial with two parallel groups of patients with lung cancer, comparing surgery alone and surgery with landiolol administration for three days during the perioperative period. A total of 400 patients will be enrolled from 12 Japanese institutions. The primary endpoint is two-year relapse-free survival and overall survival after curative surgery for lung cancer. The secondary endpoints are additional treatment after recurrence of cancer, safety events, and the incidence of postoperative complications. DISCUSSION: The principal question addressed in this trial is whether landiolol can reduce recurrence of cancer after curative surgery for lung cancer. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT2011180004. Registered 17 January 2019.
  • Wakana Matsumura, Yasuyuki Fujita, Satoru Shinkuma, Shotaro Suzuki, Saki Yokoshiki, Hideki Goto, Hiroshi Hayashi, Kota Ono, Masukazu Inoie, Shota Takashima, Chihiro Nakayama, Toshifumi Nomura, Hideki Nakamura, Riichiro Abe, Norihiro Sato, Hiroshi Shimizu
    The Journal of investigative dermatology 139 10 2115 - 2124 2019年10月 [査読有り][通常論文]
     
    Inherited skin disorders have been reported recently to have sporadic normal-looking areas, where a portion of the keratinocytes have recovered from causative gene mutations (revertant mosaicism). We observed a case of recessive dystrophic epidermolysis bullosa treated with cultured epidermal autografts (CEAs), whose CEA-grafted site remained epithelized for 16 years. We proved that the CEA product and the grafted area included cells with revertant mosaicism. Based on these findings, we conducted an investigator-initiated clinical trial of CEAs from clinically revertant skin for recessive dystrophic epidermolysis bullosa. The donor sites were analyzed by genetic analysis, immunofluorescence, electron microscopy, and quantification of the reverted mRNA with deep sequencing. The primary endpoint was the ulcer epithelization rate per patient at 4 weeks after the last CEA application. Three patients with recessive dystrophic epidermolysis bullosa with 8 ulcers were enrolled, and the epithelization rate for each patient at the primary endpoint was 87.7%, 100%, and 57.0%, respectively. The clinical effects were found to persist for at least 76 weeks after CEA transplantation. One of the three patients had apparent revertant mosaicism in the donor skin and in the post-transplanted area. CEAs from clinically normal skin are a potentially well-tolerated treatment for recessive dystrophic epidermolysis bullosa.
  • Hideaki Shiraishi, Kenji Yamada, Eishin Oki, Mika Ishige, Toshiyuki Fukao, Yusuke Hamada, Norio Sakai, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Takashi Miyakoshi, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, Norihiro Sato
    Molecular genetics and metabolism reports 20 100496 - 100496 2019年09月 [査読有り][通常論文]
     
    Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8-26.4 years). The bezafibrate administration was continued for a further 102-174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases. Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs.
  • Hiroyuki Tsutsui, Shin-ichi Momomura, Tohru Masuyama, Yoshihiko Saito, Issei Komuro, Toyoaki Murohara, Shintaro Kinugawa, Koji Oba, Norihiro Sato, Yoshio Yasumura, Shinya Hiramitsu, Yukihito Satou, Takayuki Inomata, Katsuya Onishi, Yasushi Sakata, Kyoichi Mizuno, Kenji Sunagawa, Hisao Ogawa, Mitsuaki Isobe, Hiroyuki Daida, Masahiko Kurabayashi, Shintaro Kinugawa, Tetsuro Kohya, Yuji Ogawa, Naofumi Itoh, Shigeo Kakinoki, Kenji Aoki, Akihito Tsuchida, Hiroshi Ito, Osamu Yamaguchi, Yutaka Eki, Shigeru Toyoda, Akihiko Nakano, Norimichi Koitabashi, Toshihiro Muramatsu, Hideo Nakahara, Hiroyuki Tanaka, Akira Yamashina, Kiyoshi Takasu, Yasuhiro Maejima, Yukihiko Momiyama, Iwao Nakamura, Keisuke Kida, Takashi Naruke, Hideshi Takenobu, Tohru Minamino, Masahiko Nakamura, Masatoshi Ikeda, Kazuhiro Ashida, Shigekiyo Takahashi, Shinya Minatoguchi, Satoru Suwa, Hiroshi Satoh, Hideo Izawa, Hidekatsu Fukuta, Naoya Tsuboi, Hiroyasu Uzui, Atsuyuki Wada, Takeshi Kimura, Ken Takenaka, Takao Kato, Masaaki Okutsu, Tomohito Ohtani, Shinji Hasegawa, Toshihisa Anzai, Kenshi Fujii, Ichiro Shiojima, Yoshinori Yasaka, Tohru Masuyama, Ken-ichi Hirata, Yoshihiko Saito, Takashi Akasaka, Hiroshi Ito, Yasuki Kihara, Ritsu Tamura, Hiroki Teragawa, Kotaro Yasuda, Koichiro Okuhara, Eiji Karashima, Masataka Sata, Akira Ota, Takahisa Noma, Jun Suzuki, Kouki Watanabe, Hiroaki Kitaoka, Ryuichi Matsukawa, Takeshi Yoshihiro, Nobuhide Tanaka, Kiyoshi Ozumi, Masaru Takahashi, Koji Maemura, Nobuhiko Atsuchi
    CIRCULATION JOURNAL 83 6 1269 - + 2019年06月 
    Background: The comparative tolerability, efficacy, and safety of bisoprolol and carvedilol have not been established in Japanese patients with heart failure and reduced ejection fraction (HFrEF).Methods and Results: The CIBIS-J trial is a multicenter, open-label, non-inferiority randomized controlled trial of bisoprolol vs. carvedilol in 217 patients with HFrEF (EF <= 40%). The primary endpoint was tolerability, defined as reaching and maintaining the maximum maintenance dose (bisoprolol 5 mg/day or carvedilol 20 mg/day) during 48 weeks of treatment. The primary endpoint was achieved in 41.4% of patients in bisoprolol (n=111) and 42.5% in carvedilol (n=106) groups. The non-inferiority of tolerability of bisoprolol compared with carvedilol was not supported, however, neither beta-blocker was superior with regard to tolerability. Heart rate (HR) decreased in both groups and its decrease from baseline was significantly greater in the bisoprolol group (20.3 vs. 15.4 beats/min at 24 week, P<0.05). Plasma B-type natriuretic peptide (BNP) levels decreased in both groups and the decrease was significantly greater in the carvedilol group (12.4 vs. 39.0 % at 24 weeks, P<0.05).Conclusions: There were no significant differences between bisoprolol and carvedilol in the tolerability of target doses in Japanese HFrEF patients. The clinical efficacy and safety were also similar despite the greater reduction in HR by bisoprolol and plasma BNP by carvedilol.
  • Junichi Hashiguchi, Masahiro Onozawa, Kohei Okada, Toraji Amano, Kanako C. Hatanaka, Hiroshi Nishihara, Norihiro Sato, Takanori Teshima
    International Journal of Laboratory Hematology 41 2 e38 - e40 2019年04月
  • Masanori Fukushima, Christopher Austin, Norihiro Sato, Tatsuya Maruyama, Eileen Navarro, Mitra Rocca, Jacques Demotes, Melissa Haendel, Samuel L Volchenboum, Matthew Cowperthwaite, Jonathan C Silverstein, Chris Webb, Ida Sim, Marianne Chase, John Speakman, Erika Augustine, Daniel E Ford, Rebecca Kush
    Learning health systems 3 1 e10073  2019年01月 [査読有り][通常論文]
     
    Introduction: Global data sharing is essential. This is the premise of the Academic Research Organization (ARO) Council, which was initiated in Japan in 2013 and has since been expanding throughout Asia and into Europe and the United States. The volume of data is growing exponentially, providing not only challenges but also the clear opportunity to understand and treat diseases in ways not previously considered. Harnessing the knowledge within the data in a successful way can provide researchers and clinicians with new ideas for therapies while avoiding repeats of failed experiments. This knowledge transfer from research into clinical care is at the heart of a learning health system. Methods: The ARO Council wishes to form a worldwide complementary system for the benefit of all patients and investigators, catalyzing more efficient and innovative medical research processes. Thus, they have organized Global ARO Network Workshops to bring interested parties together, focusing on the aspects necessary to make such a global effort successful. One such workshop was held in Austin, Texas, in November 2017. Representatives from Japan, Taiwan, Singapore, Europe, and the United States reported on their efforts to encourage data sharing and to use research to inform care through learning health systems. Results: This experience report summarizes presentations and discussions at the Global ARO Network Workshop held in November 2017 in Austin, TX, with representatives from Japan, Korea, Singapore, Taiwan, Europe, and the United States. Themes and recommendations to progress their efforts are explored. Standardization and harmonization are at the heart of these discussions to enable data sharing. In addition, the transformation of clinical research processes through disruptive innovation, while ensuring integrity and ethics, will be key to achieving the ARO Council goal to overcome diseases such that people not only live longer but also are healthier and happier as they age. Conclusions: The achievement of global learning health systems will require further exploration, consensus-building, funding aligned with incentives for data sharing, standardization, harmonization, and actions that support global interests for the benefit of patients.
  • Kusumi I, Arai Y, Okubo R, Honda M, Matsuda Y, Matsuda Y, Tochigi A, Takekita Y, Yamanaka H, Uemura K, Ito K, Tsuchiya K, Yamada J, Yoshimura B, Mitsui N, Matsubara S, Segawa T, Nishi N, Sugawara Y, Kako Y, Shinkawa I, Shinohara K, Konishi A, Iga J, Hashimoto N, Inomata S, Tsukamoto N, Ito H, Ito YM, Sato N
    BJPsych open 4 6 454 - 460 2018年11月 [査読有り][通常論文]
     
    Background: Patients with schizophrenia or bipolar disorder have a high risk of developing type 2 diabetes. Aims: To identify predictive factors for hyperglycaemic progression in individuals with schizophrenia or bipolar disorder and to determine whether hyperglycaemic progression rates differ among antipsychotics in regular clinical practice. Method: We recruited 1166 patients who initially had normal or prediabetic glucose levels for a nationwide, multisite, l-year prospective cohort study to determine predictive factors for hyperglycaemic progression. We also examined whether hyperglycaemic progression varied among patients receiving monotherapy with the six most frequently used antipsychotics. Results: High baseline serum triglycerides and coexisting hypertension significantly predicted hyperglycaemic progression. The six most frequently used antipsychotics did not significantly differ in their associated hyperglycaemic progression rates over the 1-year observation period. Conclusions: Clinicians should carefully evaluate baseline serum triglycerides and coexisting hypertension and perform strict longitudinal monitoring irrespective of the antipsychotic used. Declaration of interest: The authors report no financial or other relationship that is relevant to the subject of this article. Relevant financial activities outside the submitted work are as follows. I.K. has received honoraria from Astellas, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Nippon Chemiphar, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; has received research/grant support from AbbVie GK, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; and is a member of the advisory boards of Dainippon Sumitomo Pharma and Tanabe Mitsubishi Pharma. Y.T. has received speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Janssen Pharmaceutical, Daiichi-Sankyo Company, UCB Japan and Ono Pharmaceutical. K.U. has received honoraria from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin. B.Y. has received speaker's honoraria from Otsuka Pharmaceutical and Janssen Pharmaceutical. J. I. has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical and Mochida Pharma.
  • Tanaka Yoshiya, Oba Koji, Koike Takao, Miyasaka Nobuyuki, Mimori Tsuneyo, Takeuchi Tsutomu, Hirata Shintaro, Tanaka Eiichi, Yasuoka Hidekata, Kaneko Yuko, Murakami Kosaku, Koga Tomohiro, Nakano Kazuhisa, Amano Koichi, Ushio Kazuyasu, Atsumi Tatsuya, Inoo Masayuki, Hatta Kazuhiro, Mizuki Shinichi, Nagaoka Shohei, Tsunoda Shinichiro, Dobashi Hiroaki, Horie Nao, Sato Norihiro
    ARTHRITIS & RHEUMATOLOGY 70 2018年09月 [査読有り][通常論文]
  • Kenji Yamada, Hideaki Shiraishi, Eishin Oki, Mika Ishige, Toshiyuki Fukao, Yusuke Hamada, Norio Sakai, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Takashi Miyakoshi, Kota Ono, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, Norihiro Sato
    Molecular genetics and metabolism reports 15 55 - 63 2018年06月 [査読有り][通常論文]
     
    Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires). Results: The frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed. Conclusion: In this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations.
  • Hideyuki Ujiie, Ken Muramatsu, Taisei Mushiroda, Takeshi Ozeki, Hideaki Miyoshi, Hiroaki Iwata, Akinobu Nakamura, Hiroshi Nomoto, Kyu Yong Cho, Norihiro Sato, Machiko Nishimura, Takamasa Ito, Kentaro Izumi, Wataru Nishie, Hiroshi Shimizu
    The Journal of investigative dermatology 138 5 1201 - 1204 2018年05月 [査読有り][通常論文]
  • Kazumasa Ohmura, Masaru Kato, Toshiyuki Watanabe, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Yoichi M Ito, Norihiro Sato, Tatsuya Atsumi
    Arthritis research & therapy 20 1 72 - 72 2018年04月17日 [査読有り][通常論文]
     
    BACKGROUND: Premature atherosclerosis is one of the major complications of systemic lupus erythematosus (SLE). Recently, the biological linkage between atherosclerosis and osteoporosis has garnered much attention. The aim of this study is to explore correlation between the development of atherosclerosis and anti-osteoporotic treatment. METHODS: Consecutive patients with SLE (n = 117) who underwent carotid ultrasonography were retrospectively analyzed using propensity scoring. RESULTS: Of the 117 patients, 42 (36%), 27 (23%), and 30 (26%) were receiving bisphosphonates and vitamin D (BP + VD), bisphosphonates alone, or vitamin D alone, respectively. Low bone mineral density was more frequent, and carotid plaque was less prevalent in the BP + VD group compared with other treatment groups. Age (OR = 1.57) and BP + VD treatment (OR = 0.24) were shown by multivariate analysis to be associated with the presence of carotid plaque. In all strata divided using the propensity score, carotid plaque was statistically significantly less prevalent (p = 0.015, Mantel-Haenszel test) in the BP + VD group relative to the other treatment groups. CONCLUSION: Combined treatment with bisphosphonate and vitamin D may have a role in preventing atherosclerosis in patients with SLE.
  • Kiyohiro Houkin, Hideo Shichinohe, Koji Abe, Teruyo Arato, Mari Dezawa, Osamu Honmou, Nobutaka Horie, Yasuo Katayama, Kohsuke Kudo, Satoshi Kuroda, Tomohiro Matsuyama, Ichiro Miyai, Izumi Nagata, Kuniyasu Niizuma, Ken Sakushima, Masanori Sasaki, Norihiro Sato, Kenji Sawanobori, Satoshi Suda, Akihiko Taguchi, Teiji Tominaga, Haruko Yamamoto, Toru Yamashita, Toshiki Yoshimine
    Stroke 49 4 e145-e152 - e152 2018年04月 [査読有り][通常論文]
  • Shinsuke Otagiri, Shunsuke Ohnishi, Arisa Miura, Hiroshi Hayashi, Izumi Kumagai, Yoichi M Ito, Takehiko Katsurada, Shiro Nakamura, Rika Okamoto, Kenichi Yamahara, Kyu Yong Cho, Toshiyuki Isoe, Norihiro Sato, Naoya Sakamoto
    BMJ open gastroenterology 5 1 e000206  2018年 [査読有り][通常論文]
     
    Introduction: The medical treatment options for patients with Crohn's disease (CD) are limited and patients resistant to those therapies are left requiring surgical operations that usually only achieve some symptomatic relief. Mesenchymal stem cells (MSC) have been shown to be effective for the treatment of CD, and we have demonstrated in animal experiments that human amnion-derived MSCs (AMSC) are a potential new therapeutic strategy. Therefore, we designed this study to investigate the safety and efficacy of AMSCs in patients with treatment-resistant CD. Methods and analysis: This is the protocol for an ongoing phase I/II, dual-centre, open-label, uncontrolled, dose-response study. The estimated enrolment is 6-12 patients with treatment-resistant, moderate CD. A dose of 1.0×106 cells/kg will be administered intravenously in the low-dose group at days 0 and 7. After confirming the safety of low-dose administration, a dose of 4.0×106 cells/kg will be administered intravenously in the high-dose group on days 0 and 7. The primary endpoint will measure the occurrence of adverse events related to acute infusion toxicity, and secondary endpoints will include long-term adverse events and efficacy of AMSC administration. Ethics and dissemination: The Institutional Review Board of Hokkaido University Hospital approved this study protocol (approval number H29-6). A report releasing study results will be submitted to an appropriate journal. Discussion: This study is the first to investigate the safety and efficacy of AMSC use for CD treatment. Our results will advance studies on more efficient and convenient methods to overcome the limits of available CD treatments. Trial registration number: UMIN000029841.
  • Koji Oba, Nao Horie, Norihiro Sato, Kazuyoshi Saito, Tsutomu Takeuchi, Tsuneyo Mimori, Nobuyuki Miyasaka, Takao Koike, Yoshiya Tanaka
    Contemporary clinical trials communications 8 49 - 54 2017年12月 [査読有り][通常論文]
     
    Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017.
  • Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Yukayo Terashita, Tadashi Ariga, Yosuke Hosoya, Shinsuke Hirabayashi, Atsushi Manabe, Keisuke Hara, Tetsuya Aiba, Tsugumi Shiokawa, Hiroko Tada, Norihiro Sato
    INTERNATIONAL JOURNAL OF HEMATOLOGY 106 2 291 - 298 2017年08月 [査読有り][通常論文]
     
    Bortezomib has been shown to be effective and well-tolerated in patients with refractory acute lymphoblastic leukemia (ALL) in the Therapeutic Advances in Childhood Leukemia trial. However, the safety and efficacy of bortezomib have not been evaluated in Japanese pediatric patients. Here, we report the results of a clinical trial designed to evaluate the safety of bortezomib combined with induction chemotherapy in Japanese children with refractory ALL. A total of six patients with B-precursor ALL were enrolled in this study. Four-dose bortezomib (1.3 mg/m(2)/dose) combined with two standard induction chemotherapies was used. Prolonged pancytopenia (grade 4) was observed in all patients. Four of the six patients developed severe infectious complications. Peripheral neuropathy (grade 2) occurred in five patients. The individual plasma bortezomib concentration-time profiles were not related to toxicity and efficacy. Five patients were evaluable for response, and four patients achieved complete response (CR) or CR without platelet recovery (80%). In conclusion, four-dose bortezomib (1.3 mg/m(2)/dose) combined with standard re-induction chemotherapy was associated with a high risk of infectious complications induced by prolonged neutropenia, although high efficacy has been achieved for Japanese pediatric patients with refractory ALL. Attention must be given to severe infectious complications when performing re-induction chemotherapy including bortezomib.
  • Satoru Todo, Kenichiro Yamashita, Ryoichi Goto, Masaaki Zaitsu, Akihisa Nagatsu, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura, Toshiya Kamiyama, Norihiro Sato, Junichi Sugita, Kanako Hatanaka, Hisashi Bashuda, Sonoko Habu, Anthony J. Demetris, Ko Okumura
    HEPATOLOGY 64 2 632 - 643 2016年08月 [査読有り][通常論文]
     
    Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. Conclusions: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases.
  • A clinical trial of cell therapy-based tolerance induction in living donor liver transplantation: Long-term follow-up results
    Yamashita Kenichiro, Zaitsu Masaaki, Goto Ryoichi, Nagatsu Akihisa, Oura Tetsu, Watanabe Masaaki, Aoyagi Takeshi, Suzuki Tomomi, Shimamura Tsuyoshi, Kamiyama Toshiya, Sato Norihiro, Sugita Junichi, Hatanaka Kanako, Bashuda Hisashi, Okumura Ko, Todo Satoru
    TRANSPLANTATION 100 7 S244  2016年07月 [査読有り][通常論文]
  • Sayaka Yuzawa, Hiroshi Nishihara, Shigeru Yamaguchi, Hiromi Mohri, Lei Wang, Taichi Kimura, Masumi Tsuda, Mishie Tanino, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin, Norihiro Sato, Shinya Tanaka
    MODERN PATHOLOGY 29 7 708 - 716 2016年07月 [査読有り][通常論文]
     
    Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgenefixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.
  • Ichiro Kusumi, Yuki Arai, Junichi Iga, Yasuhiro Matsuda, Nobuyuki Mitsui, Hiroyuki Muraoka, Kota Ohno, Ryo Okubo, Norihiro Sato, Takayuki Segawa, Kaoru Shinohara, Akihiko Tohigi, Keiichi Uemura, Hiroyoshi Yamanaka
    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 19 59 - 59 2016年06月 [査読無し][通常論文]
  • Ken Sakushima, Naoki Nishimoto, Masanori Nojima, Masaaki Matsushima, Ichiro Yabe, Norihiro Sato, Mitsuru Mori, Hidenao Sasaki
    CEREBELLUM 14 6 682 - 687 2015年12月 [査読有り][通常論文]
     
    Multiple system atrophy (MSA) is an intractable neurodegenerative disorder that is characterized by various combinations of autonomic failure, cerebellar ataxia, and parkinsonism. We conducted an epidemiological study of MSA using the combined data of a national registry system and a postal survey in Hokkaido, Japan. A postal survey was conducted in 2013 based on national registry data from 2006 to 2011. This survey contained the current status of each patient with MSA that had been collected from attending physicians and recorded into a national registry. Survey items included date, outcomes, primary symptoms, and activities of daily living at the last medical examination. Confirmation data of the diagnosis by a board-certified neurologist was also collected. Based on the national registry data, 1,092 patients with MSA were selected as our target population. The response rate of the postal survey was 81 % (885/1,092). After excluding inappropriate responses, 839 patients with MSA were analyzed. Forty-nine percent of the patients were male, and the mean onset age was 62.1 +/- 10.4 years. A Kaplan-Meier survival curve revealed that patients with onset symptoms of cerebellar ataxia had a better prognosis than those with onset of parkinsonism or autonomic failure (p < 0.01). Additionally, we found that a higher onset age was associated with poor prognosis. We found that patients with cerebellar ataxia at onset had a better survival prognosis than those with parkinsonism or autonomic failure at onset and that patients with an older age at onset had a worse survival prognosis.
  • Kenichiro Yamashita, Ryoichi Goto, Masaaki Zaitsu, Akihisa Nagatsu, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura, Toshiya Kamiyama, Norihiro Sato, Junichi Sugita, Kanako Hatanaka, Anthony Demetris, Hisashi Bashuda, Ko Okumura, Satoru Todo
    TRANSPLANT INTERNATIONAL 28 57 - 57 2015年11月 [査読有り][通常論文]
  • Takano H, Nakamura T, Tsuchikawa T, Kushibiki T, Hontani K, Inoko K, Takahashi M, Sato S, Abe H, Takeuchi S, Sato N, Hiraoka K, Nishihara H, Shichinohe T, Hirano S
    Oncotarget 6 38 41063 - 41076 Oncotarget 2015年 [査読無し][通常論文]
     
    Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion,compound 1 has a high potential as a therapeutic agent for patients with PDAC.
  • Successful Withdrawal of Immunosuppression by a Cell Therapy Using Donor Ag-pulsed Tregs in Living Donor Liver Transplantation: An Update on Clinical Trial.
    Yamashita Kenichiro, Zaitsu Masaaki, Nagatsu Akihisa, Goto Ryoichi, Oura Tetsu, Watanabe Masaaki, Aoyagi Takeshi, Suzuki Tomomi, Shimamura Tsuyoshi, Kamiyama Toshiya, Sato Norihiro, Sugita Junichi, Hatanaka Kanako, Bashuda Hisashi, Okumura Ko, Todo Satoru
    LIVER TRANSPLANTATION 20 S125 - S126 2014年06月 [査読有り][通常論文]
  • 山下 健一郎, 財津 雅昭, 長津 明久, 後藤 了一, 大浦 哲, 渡辺 正明, 青柳 武史, 江本 愼, 鈴木 友己, 嶋村 剛, 佐藤 典宏, 杉田 純一, 畑中 佳奈子, 場集田 寿, 奥村 康, 藤堂 省
    移植 49 1 106 - 106 (一社)日本移植学会 2014年05月 [査読有り][通常論文]
  • Kenichiro Yamashita, Masaaki Zaitsu, Akihisa Nagatsu, Ryoichi Goto, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura, Norihiro Sato, Junichi Sugita, Kanako Hatanaka, Hisashi Bashuda, Ko Okumura, Satoru Todo
    TRANSPLANT INTERNATIONAL 26 98 - 98 2013年11月 [査読有り][通常論文]
  • Kenichiro Yamashita, Masaaki Zaitsu, Akihisa Nagatsu, Ryoichi Goto, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura, Norihiro Sato, Junichi Sugita, Kanako Hatanaka, Hisashi Bashuda, Ko Okumura, Satoru Todo
    LIVER TRANSPLANTATION 19 S130 - S130 2013年06月 [査読有り][通常論文]
  • Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Masato Obara, Keisuke Yamaguchi, Yukari Takeda, Hideki Goto, Ikumi Kasahara, Norihiro Sato, Takao Koike
    INTERNATIONAL JOURNAL OF HEMATOLOGY 90 5 601 - 604 2009年12月 [査読有り][通常論文]
     
    A 44-year-old female presented with asymptomatic leukocytosis and moderate splenomegaly. The diagnosis of splenic marginal zone lymphoma (SMZL) was made by a splenectomy. A virological examination revealed the patient to be a hepatitis B virus (HBV) carrier. The lymphocyte count in her peripheral blood decreased after splenectomy, but remained high for 2 years and bone marrow infiltration was obvious. Two years after the splenectomy, she was admitted for an acute flare-up of hepatitis B. The liver dysfunction improved without any medication and thereafter returned to the normal range within a few weeks. At the same time, the lymphocyte count in her peripheral blood rapidly decreased to normal levels. Atypical lymphocytes disappeared from the peripheral blood and bone marrow aspirates and biopsy specimen revealed complete remission of SMZL, including the disappearance of the clonal rearrangement of IgH-JH. There has been no recurrence of acute hepatitis and she has been in complete remission for SMZL for more than 6 years. The clinical course of this patient suggests that an immune response against HBV also affects the clearance of lymphoma cells. This is the first report that a complete remission was achieved in a patient with SMZL after a hepatitis B flare-up.
  • Ikumi Kasahara, Mitsufumi Nishio, Satoshi Yamamoto, Tomoyuki Endo, Katsuya Fujimoto, Keisuke Yamaguchi, Yukari Takeda, Hideki Goto, Norihiro Sato, Takao Koike
    INTERNATIONAL JOURNAL OF HEMATOLOGY 90 3 413 - 415 2009年10月 [査読有り][通常論文]
     
    Two multiple myeloma patients relapsed after autologous stem cell transplantation (ASCT). Conventional chemotherapy, including thalidomide, showed very little effect, but both patients responded well to a standard dose of bortezomib. One patient was treated with two additional cycles of bortezomib, but his clinical course suddenly deteriorated. Unrelated cord blood transplantation (CBT) with reduced-intensity conditioning regimen (RIC) was performed in refractory disease. After CBT, the clinical course was aggravated by tumor lysis syndrome and other conditions, thus resulting in patient death on day 34. Thereafter, we administered CBT with RIC on the second patient after just one course of bortezomib therapy since she was in partial remission. The second patient developed acute and chronic GVHD, and both responded to the steroid therapy. She has been in complete remission for more than 48 months after CBT. These results suggested that the timing of CBT with RIC may be very important, and cytoreduction with not only ASCT but also bortezomib could give a promising chance for a successful CBT.
  • Tomoyuki Endo, Katsuya Fujimoto, Mitsufumi Nishio, Satoshi Yamamoto, Masato Obara, Norihiro Sato, Takao Koike
    JOURNAL OF MEDICAL VIROLOGY 81 6 979 - 982 2009年06月 [査読有り][通常論文]
     
    The effect of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) infection remains uncertain. This report describes the case of a man with hemophilia with HIV-HCV coinfection with persistent disappearance of HCV RNA after changing the HAART regimen. He had been treated with zidovudine, lamivudine, and indinavir for initial HAART and the HIV RNA level had been undetectable for more than 8 years. He had Suffered from chronic active hepatitis. The HAART regimen was changed to emtricitabine/tenofovir, atazanavir, and ritonavir because the patient preferred a once daily regimen. The HCV RNA level fell immediately and thereafter became undetectable by quantitative and qualitative assay at 5 and 7 months after the change of the HAART regimen, respectively. In contrast to other reported cases, he experienced neither increase of CD4+ T cells Count nor ALT flare-ups before HCV RNA clearance. The HCV RNA disappearance in this case may be due to the direct effect of HAART against HCV rather than restoration of cellular immunity to HCV. J. Med. Virol. 81:979-982, 2009. (c) 2009 Wiley-Liss Inc.
  • Akio Shigematsu, Atsushi Yasumoto, Satoshi Yamamoto, Junichi Sugita, Takeshi Kondo, Masahiro Onozawa, Kaoru Kahata, Tomoyuki Endo, Shuichi Ota, Norihiro Sato, Mutsumi Takahata, Kohei Okada, Junji Tanaka, Satoshi Hashino, Mitsufumi Nishio, Takao Koike, Masahiro Asaka, Masahiro Imamura
    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 15 6 679 - 685 2009年06月 [査読有り][通常論文]
     
    Cytomegalovirus (CMV) infection is I of the major causes of morbidity in patients undergoing allogeneic stem cell transplantation (allo-SCT). The incidences of CMV antigenemia and CMV disease in 43 patients who received allogeneic bone marrow trans plantation (BMT) using a reduced-intensity conditioning (RIC) regimen, which mainly consisted of fluclarabine (Flu), busulfan (Bu), and total body irradiation (TBI), were compared with those in 68 patients who received a myeloablative conditioning (MAC) regimen, and risk factors for CMV antigenemia and CMV disease were identified. Before engraftment, grade 3-4 mucosal injury because of the conditioning regimen was significantly decreased in RIC patients (stomatitis: P=.02; diarrhea: P<.01). Rate of engraftment, incidences of acute graft-versus-host disease (aGVHD), and rate of corticosteroid administration were not different in RIC patients and MAC patients. Although the incidences of CMV antigenemia were not significantly different in RIC patients and MAC patients (64.1% versus 57.8%, log rank, P=.59), the incidence of CMV disease was significantly decreased in RIC patients (5.4% versus 20.3%, log rank, P=.04). CMV seropositivity in the patients (P<.01) and corticosteroid administration (P<.01) were revealed by multivariate analysis to be significant risk factors for CMV antigenemia. Grade II-IV aGVHD (P=.02) and grade 3-4 diarrhea before engraftment (P=.04) were revealed to be risk factors for CMV disease. The present study is the first study to show that severe diarrhea before engraftment is a significant risk factor for CMV disease. In summary, risk of CMV disease was significantly decreased in patients without severe mucosal injury of the gut because of the conditioning regimen before engraftment. Biol Blood Marrow Transplant 15: 679-685 (2009) (C) 2009 American Society for Blood and Marrow Transplantation
  • Mitsufumi Nishio, Tomoyuki Endo, Katsuya Fujimoto, Satoshi Yamamoto, Masato Obara, Keisuke Yamaguchi, Yukari Takeda, Hideki Goto, Ikumi Kasahara, Norihiro Sato, Takao Koike
    EUROPEAN JOURNAL OF HAEMATOLOGY 82 2 143 - 147 2009年02月 [査読有り][通常論文]
     
    Recent studies have indicated that patients who receive stem cell transplantation (SCT) and rituximab demonstrate an increased risk of developing hypogammaglobulinemia. Such hypogammaglobulinemia has been found to be due to delayed recovery of memory B cells with an abnormal cell marker expression and impaired immunoglobulin production in vitro. However, no predictive factors for the levels of immunoglobulin after autologous SCT and rituximab therapy have been reported. The aim of this study is to clarify the relationships between the FCGR3A-158V/F genotype and the levels of serum immunoglobulin after SCT. A total of 24 non-Hodgkin's lymphoma (NHL) patients received autologous SCT with an adjuvant rituximab. The FCGR3A-158V/F genotype was determined in these patients. We also included ten NHL patients who received an identical conditioning regimen and autologous SCT but no rituximab as control patients. The levels of IgG were significantly lower in FCGR3A-158F homozygous patients (n = 9) in comparison to those in FCGR3A-158V carriers (n = 15). Moreover, the levels of IgG and IgA of FCGR3A-158F homozygous patients, but not those of FCGR3A-158V carriers, were significantly lower than those of control patients. The genotype of FCGR3A determines not only the response to rituximab, but also the levels of immunoglobulin after SCT and an adjuvant rituximab.
  • Mitsufumi Nishio, Katsuya Fujimoto, Satoshi Yamamoto, Tomoyuki Endo, Toshiya Sakai, Masato Obara, Kohki Kumano, Keisuke Yamaguchi, Yukari Takeda, Hideki Goto, Norihiro Sato, Kazuki Koizumi, Masaya Mukai, Takao Koike
    BRITISH JOURNAL OF HAEMATOLOGY 137 4 349 - 354 2007年05月 [査読有り][通常論文]
     
    Recent studies have indicated that patients who received rituximab as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinaemia, which was found to be a result of delayed recovery of CD27 positive memory B cells and impaired isotype expression. It appears that rituximab influences both the quantity and quality of B-cell redistribution. Precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with non-Hodgkin lymphoma (NHL) remains to be elucidated. This study performed a phenotypical analysis of B cells in 17 NHL patients who received rituximab as an adjuvant to autologous SCT. The median period after final administration of rituximab was 36 months (range, 12-43 months). Surface antigen expression of CD27, CD40 and CD80 in NHL patients was statistically significantly different from healthy controls (n = 14). Moreover, B cells from NHL patients showed significantly impaired IgG and IgA production upon engagement of surface immunoglobulin receptors in the presence of interleukin (IL)-2, IL-10 and CD40 ligand in comparison with samples from healthy controls. The delayed recovery of memory B cells with an abnormal cell marker expression and function demonstrates that naive B cells may fail to differentiate into plasma cells, resulting in hypogammaglobulinaemia after autologous SCT and rituximab therapy.
  • Mitsufumi Nishio, Katsuya Fujimoto, Satoshi Yamamoto, Tomoyuki Endo, Toshiya Sakai, Masato Obara, Kohki Kumano, Koichiro Minauchi, Keisuke Yamaguchi, Yukari Takeda, Norihiro Sato, Kazuki Koizumi, Masaya Mukai, Takao Koike
    EUROPEAN JOURNAL OF HAEMATOLOGY 77 3 226 - 232 2006年09月 [査読有り][通常論文]
     
    Objectives: Some studies have indicated patients who received rituximab as adjuvant to stem cell transplantation had an increased risk of developing severe hypogammaglobulinemia. The mechanism of this hypogammaglobulinemia is unknown, although investigators have hypothesized a further delay in the B-cell recovery as one potential etiology. The aim of this study is to clarify the mechanism(s) of this hypogammaglobulinemia. Methods: A total of 14 patients with high-risk CD20(+) lymphoma underwent an autologous peripheral blood stem cell transplantation (APBSCT). After a hematological recovery, rituximab was given weekly for up to four doses as an adjuvant therapy. Results: After a median follow up of 33.5 months, we found six patients (group A) who had hypogammaglobulinemia, while the eight other patients (group B) had normal serum immunoglobulin levels. A phenotypical analysis revealed that group A patients had already achieved B-cell recovery. However, we found a severe delay in the recovery of CD27(+) memory B cells, especially in the IgD(-)/CD27(+) switched populations in group A, but CD27 negative naive B-cells reverted to a normal range in both groups. Consistent with this, reverse transcriptase-polymerase chain reaction studies with peripheral blood mononuclear cells revealed that most patients in group A lacked more than two classes of isotype transcripts. Conclusions: Abnormal repertoires and impaired isotype expression are seen in patients with common variable immunodeficiency, these data suggested that rituximab after APBSCT can affect not only the B-cell quantities, but also the recovery of the B-cell repertoires.

MISC

講演・口頭発表等

  • 北海道における多系統萎縮症のレジストリ研究HoRC-MSA 2014-2019  [通常講演]
    松島理明, 佐久嶋研, 矢部一郎, 金谷泰宏, 西本尚樹, 松岡健, 澤田潤, 上杉春雄, 佐光一也, 武井麻子, 玉腰暁子, 下濱俊, 佐藤典宏, 菊地誠志, 佐々木秀直
    第105回日本神経学会北海道地方会 2019年09月
  • 第三回 臨床研究の法的規制時代到来－過去から学ぶ臨床研究法施行への不安と期待 －  [招待講演]
    佐藤 典宏
    第211回レギュラトリーサイエンス エキスパート研修会 2017年10月
  • 脂肪酸代謝異常症に対するベザフィブラートのオープンラベル臨床治験結果  [通常講演]
    山田健治, 白石秀明, 朝比奈直子, 横式沙紀, 宮腰崇, 大野浩太, 磯江敏幸, 林宏至, 山口清次, 佐藤典宏
    第59回日本先天代謝異常学会総会 2017年10月
  • FDAが提案したICH-GCPrenovation-日本でどこまでできるか？-  [招待講演]
    佐藤 典宏
    第210回レギュラトリーサイエンス エキスパート研修会 2017年10月
  • 臨床研究の規制に関する最新の動き  [通常講演]
    佐藤 典宏
    第1回日本臨床薬理学会 北海道・東北地方会 2017年07月
  • 臨床研究法に備える～今から打てる一手を考える～  [招待講演]
    佐藤 典宏
    レギュラトリーサイエンス学会シンポジウム～臨床研究法の実施に向けた課題とその対応～ 2017年06月
  • Strategy for Global Clinical Trials by Japan ARO Council  [通常講演]
    2nd Global ARO Network Workshop 2017年
  • rogress Report of the Registry Study for Multiple System Atrophy in Hokkaido, Japan  [通常講演]
    Masaaki Matsushima, Ken Sakushima, Ichiro Yabe, Yasuhiro Kanatani, Yoichi M. Ito, Takeshi Matsuoka, Takayuki Katayama, Haruo Uesugi, Kazuya Sako, Asako Takei, Shun Shimohama, Norihiro Sato, Seiji Kikuchi, Hidenao Sasaki, Department of Health, Welfare, Hokkaido Government, HoRC-MSA study group
    HoRC-MSA Project 2017年
  • Adaptive randomization for balancing over continuous covariates in multi-arm trials with equal and unequal allocation  [通常講演]
    Ono K, Iijima H, Sato N
    CEN-ISBS 2017年

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2021年04月 -2024年03月 
    代表者 : 七戸 俊明, 平野 聡, 渡辺 雅彦, 佐藤 典宏, 渡邊 祐介, 岡本 吉弘
     
    要約：本年度は下記の2つの研究を行った。来年度はこれらの内容をまとめて報告する予定である。１．医療機器開発における献体使用のパイロットスタディの実施（3回）２．有識者によるディスカッションの場としてカダバーワークショップの開催（2回） 概要：１．カダバーラボを使用した医療機器開発の共同研究（実施担当：北海道大学病院医療機器開発推進センター） 〇実施内容：①耳鼻科領域の経口的咽頭手術機器の医療機器開発を行った。研究では献体を使用した性能試験を行った。同時にダビンチとの比較試験を含む性能試験（ドライラボ）も実施した。②内視鏡を使用した心臓血管外科手術に使用する医療機器の性能試験を行った。同時にダビンチとの比較試験を含む性能試験（ドライラボ）も実施した。③呼吸器内科領域の医療機器開発として献体を使用した性能試験を行った。 ２．有識者によるワークショップとして「カダバーワークショップ」をwebで2回実施した。（共催：AMED次世代医療機器連携拠点整備等事業「国内唯一：カダバーラボで医療機器開発が可能な拠点」、文科省課題解決型高度医療人材養成プログラム「臨床医学の献体利用を促進する専門人材養成」）①2021年10月29日「医療機器開発における献体利用のあるべき姿：実例から考える」内容：北大での実施例の報告を行い、コメンテーターと参加者がカダバーラボの実施における課題を明らかにすべく、ディスカッションを行った。参加者：26名、参加企業：2社。②2022年1月14日「医療機器開発における献体利用のあるべき姿：理想を語る」内容：国内外のカダバーを使用した医療機器開発の動向の報告を行い、引き続き厚労省、経産省、PMDA等の行政と、企業関係者、臨床医、解剖学者、コーディネータ等が参加し、国内でカダバーラボを推進するためのディスカッションを行った。参加者：33名、参加企業：7社。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2019年04月 -2024年03月 
    代表者 : 伊東 雅基, 内野 晴登, 杉山 拓, 藤村 幹, 佐藤 典宏, 矢部 一郎, 寳金 清博, 中山 若樹, 数又 研, 東海林 菊太郎, 浜内 祝嗣
     
    研究年度の3年目にあたる2021（R3）年度は、前年度末に完了した全対象者160名（もやもや病患者82名、健常比較対照者78名）の末梢血循環血漿から抽出精製した、血漿microRNAの発現量データの解析を行なった。すなわち、ハイスループットreal-time定量PCRアレイにより、関心microRNA17種類と内部および外部標準7種類（全24種）のmicroRNAのPCR測定値を、比較定量法により発現分析した。全160検体、24microRNAのうち、全被験者でCt値を検出可能であったのは、15microRNA（関心miRNA 8種類と内部および外部標準7種類）であったため、これら15microRNAの全発現量を用いてglobal normalizationによりdataの正規化をおこなった。続いて、15種の血漿microRNA発現profileを主成分分析により解析した結果、発現変動は第一主成分と第二主成分で二郡に分かれ、疾患群と比較対照群間で発現プロファイルに差があることが判明した。続いて、疾患群と対照群で関心microRNAの発現変動解析を実施した結果、3種類の関心microRNAで、二郡間での有意な発現変動を認めた。そのほかの関心microRNAについては、全体として発現量が極めて少ないためか、先行研究で認めた発現変動を確認できなかった。続いてmicroRNA発現量と、もやもや病の臨床的特徴との関連解析を開始した。その結果、microRNA発現量に関わらず、RNF213創始者変異（p.R4810K）を有する成人もやもや病患者では、直接・間接複合血行再建術後に、間接血行再建路が有意に発達することを見出した。間接血行再建路を介した血管新生反応には、microRNAによるエピゲノム制御ではなく、感受性遺伝子の遺伝的多型が関与していることが示唆された。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 1991年 -1993年 
    代表者 : 澤田 賢一, 佐藤 典宏
     
    骨髄不全を呈する疾患、特に骨髄異形成症候群(myelodysplastic syndrome;MDS)における血液幹細胞と芽球の細胞病態学的異常を明らかにするために、患者骨髄からCD34^+細胞を純化し、無血清培地を用いて以下の点を解明した。 1)芽球の純化率は形態学的にほぼ100%、表面形質による検討では87〜98%がCD34^+であり、MDSにおいてもCD34モノクローナル抗体を用いた幹細胞・芽球の純化が可能であった。 2)純化MDS・CD34^+細胞の回収絶対量は、77%の症例で増加していた。 3)MDS・CD34^+細胞のコロニー形成率は、不応性貧血(refractory anemia;RA)など臨床的に軽症の症例で正常コントロールの約50%、芽球増加型(RAEB)などの重症例で約25%と低下ししていた。 4)形成されるコロニーの細胞系列の検討から、MDSにおいては、臨床的重症度が高くなるに従って赤芽球系幹細胞が減少し、顆粒球系幹細胞が増加した。 5)約40%のMDS症例で、G-CSFに対する純化芽球の反応性低下が認められた。 6)以上のMDSにおいて認められた幹細胞・芽球の細胞生物学的異常は、骨髄の微少環境の異常に起因するのではなく、MDS芽球そのものの異常に基づくものであった。

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