2018年04月, ヨーロッパ脳卒中学会, 優秀研究賞　　　　　　　　　　　　　　　
川堀真人

2017年10月, アジア細胞治療学会, 優秀ポスター賞　　　　　　　　　　　　　　　
川堀真人

2016年03月, 北海道大学医学部, 高桑栄松奨学基金賞　　　　　　　　　　　　　　　
川堀真人

2016年02月, 北海道大学医学部同窓会, フラテ研究奨励賞　　　　　　　　　　　　　　　
川堀真人

2011年07月, 北海道大学大学院医学研究科, 音羽奨学基金　　　　　　　　　　　　　　　
川堀真人

Phase I/II trial of intracerebral transplantation of autologous bone marrow stem cells combined with recombinant peptide scaffold for patients with chronic intracerebral haemorrhage: a study protocol.
Masahito Kawabori, Hideo Shichinohe, Kaoru Kahata, Arisa Miura, Kenichiro Maeda, Yoichi M Ito, Masahiko Mukaino, Ryo Kogawa, Kentaro Nakamura, Shuho Gotoh, Kota Kurisu, Miki Fujimura
BMJ open, 14, 12, e083959, 2024年12月02日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Intracerebral haemorrhage (ICH) stands as a leading global cause of death and disability, posing a significant challenge with limited treatment options, especially for chronic patients. Recent advances in stem cell therapies have opened new avenues for therapeutic potential. Our previous preclinical research has demonstrated that intracerebral transplantation of bone marrow stromal cells (BMSCs) combined with a recombinant human collagen type I scaffold enables higher cell survival and engraftment and holds promising potential. In this article, we present the protocol for a novel clinical trial, named 'Research on Advanced Intervention using Novel Bone MarrOW stem cells for chronic intracerebral haemorrhage' (RAINBOW-Hx). METHODS AND ANALYSIS: RAINBOW-Hx is a phase I/II, open-label, uncontrolled study with the primary objective of assessing the safety and efficacy of intracerebral transplantation of autologous BMSCs combined with the scaffold (HUFF-01) in patients with chronic ICH. Eight patients, experiencing moderate to severe neurological deficits for 12 months or longer, will be enrolled. The haemorrhage location will be limited to the basal ganglia and thalamus. Approximately 50 mL of bone marrow will be extracted from the iliac bone of each patient, and BMSCs will be cultured using autologous platelet lysate. 3 days before transplantation, BMSCs will be combined with the scaffold to generate HUFF-01. Each patient will receive a 50 000 HUFF-01 dose, containing approximately 50 million BMSCs, through stereotactic transplantation into the haemorrhagic cavity. Neurological assessments, MRI, 18F-fluorodeoxyglucose positron emission tomography and 123I-Iomazenil single-photon emission CT will be performed for 1 year after administration. ETHICS AND DISSEMINATION: The trial protocols were reviewed and approved by the Institutional Review Board of the Hokkaido University Hospital (R5-11), and this study is conducted according to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The results of this trial will be submitted for publication in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: jRCT2013230053, Japan Registry of Clinical Trials.

Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury
David O. Okonkwo, Peter McAllister, Achal S. Achrol, Yasuaki Karasawa, Masahito Kawabori, Steven C. Cramer, Albert Lai, Santosh Kesari, Benjamin M. Frishberg, Leonid I. Groysman, Anthony S. Kim, Neil E. Schwartz, Jefferson W. Chen, Hideaki Imai, Takao Yasuhara, Dai Chida, Bijan Nejadnik, Damien Bates, Anthony H. Stonehouse, R. Mark Richardson, Gary K. Steinberg, Eugene C. Poggio, Alan H. Weintraub
Neurology, 103, 7, Ovid Technologies (Wolters Kluwer Health), 2024年10月08日
研究論文（学術雑誌）

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.
Masahito Kawabori, Satoshi Kuroda, Hideo Shichinohe, Kaoru Kahata, Souichi Shiratori, Satoshi Ikeda, Taisuke Harada, Kenji Hirata, Khin Khin Tha, Masato Aragaki, Shunsuke Terasaka, Yoichi M Ito, Naoki Nishimoto, Shunsuke Ohnishi, Ichiro Yabe, Kohsuke Kudo, Kiyohiro Houkin, Miki Fujimura
Med (New York, N.Y.), 2024年03月18日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p.
Yutaka Morishima, Masahito Kawabori, Kazuyoshi Yamazaki, Soichiro Takamiya, Sho Yamaguchi, Yo Nakahara, Hajime Senjo, Daigo Hashimoto, Sakiko Masuda, Yoichiro Fujioka, Yusuke Ohba, Yuki Mizuno, Yuji Kuge, Miki Fujimura
International journal of molecular sciences, 25, 4, 2024年02月18日, ［国際誌］
英語, 研究論文（学術雑誌）, Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood-brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.
Kiyohiro Houkin, Toshiya Osanai, Shinichiro Uchiyama, Kazuo Minematsu, Akihiko Taguchi, Katsuhiko Maruichi, Yoshimasa Niiya, Katsuyuki Asaoka, Yoshihiro Kuga, Katsumi Takizawa, Koichi Haraguchi, Shinichi Yoshimura, Kazumi Kimura, Koji Tokunaga, Atsuo Aoyama, Fusao Ikawa, Chikanori Inenaga, Tatsuya Abe, Atsushi Tominaga, Shinichi Takahashi, Kohsuke Kudo, Miki Fujimura, Taku Sugiyama, Masaki Ito, Masahito Kawabori, David C Hess, Sean I Savitz, Teruyuki Hirano
JAMA neurology, 2024年01月16日, ［国際誌］
英語, 研究論文（学術雑誌）, IMPORTANCE: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. OBJECTIVE: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. DESIGN, SETTING, AND PARTICIPANTS: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. EXPOSURE: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. MAIN OUTCOMES AND MEASURES: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. RESULTS: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02961504.

Ommaya reservoir placement using ultrasound guidance via anterior fontanelle combined with frameless electromagnetic neuronavigation in patients with mucopolysaccharidosis type 2: Case reports and review of the literature.
Makoto Mizushima, Masahito Kawabori, Kazuyoshi Yamazaki, Kiyoshi Egawa, Miki Fujimura
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2024年01月02日, ［国際誌］
英語, 研究論文（学術雑誌）, Mucopolysaccharidosis type II (MPS II) results from the genetic deficiency of a lysosomal enzyme and is associated with central nervous system (CNS) dysfunction. In Japan, in addition to intravenous enzyme administration, intracerebroventricular enzyme delivery through the Ommaya reservoir has recently gained approval. Nevertheless, the ideal approach for safely implanting the reservoir into the narrow ventricles of infantile MPS II patients remains uncertain. In this report, we present two cases of successful reservoir placement in infantile MPS II patients using ultrasound guidance via the anterior fontanelle, coupled with flameless electromagnetic neuronavigation.

パーキンソン病脳深部刺激療法術後5年目における治療有効性の評価　　　　　　　　　　　　　　　
白井 慎一, 江口 克紀, 山崎 和義, 松島 理明, 川堀 真人, 平田 健司, 藤村 幹, 矢部 一郎
パーキンソン病・運動障害疾患コングレスプログラム・抄録集, 17回, 86, 86, Movement Disorder Society of Japan (MDSJ), 2023年07月
日本語

血行再建術後も再出血を繰り返す側副血行路末梢性動脈瘤を伴う成人出血型もやもや病の治療　　　　　　　　　　　　　　　
伊東 雅基, 内野 晴登, 杉山 拓, 長内 俊也, 川堀 真人, 藤村 幹
脳循環代謝, 34, 1, 124, 124, (一社)日本脳循環代謝学会, 2022年10月
日本語

亜急性期〜慢性期脳虚血病態の治療 脳血管動脈硬化性疾患に対する亜急性/慢性期EC-ICバイパスの現代的適応　　　　　　　　　　　　　　　
杉山 拓, 伊東 雅基, 内野 晴登, 長内 俊也, 川堀 真人, 藤村 幹
脳循環代謝, 34, 1, 74, 74, (一社)日本脳循環代謝学会, 2022年10月
日本語

成人もやもや病の術前MRA末梢動脈描出と間接血行発達度との関連　　　　　　　　　　　　　　　
内野 晴登, 伊東 雅基, 杉山 拓, 川堀 真人, 藤村 幹
脳循環代謝, 34, 1, 122, 122, (一社)日本脳循環代謝学会, 2022年10月
日本語

血行再建術後も再出血を繰り返す側副血行路末梢性動脈瘤を伴う成人出血型もやもや病の治療　　　　　　　　　　　　　　　
伊東 雅基, 内野 晴登, 杉山 拓, 長内 俊也, 川堀 真人, 藤村 幹
脳循環代謝, 34, 1, 124, 124, (一社)日本脳循環代謝学会, 2022年10月
日本語

Impact of RNF213 c.14576G>A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease
Masahito Kawabori, Masaki Ito, Ken Kazumata, Kikutaro Tokairin, Kanako C. Hatanaka, Susumu Ishikawa, Kiyohiro Houkin, Miki Fujimura
Cerebrovascular Diseases, 52, 2, 171, 176, S. Karger AG, 2022年09月05日
研究論文（学術雑誌）, Background: Superficial temporal artery (direct) and encephalomyosynangiosis (indirect) revascularization may develop after combined bypass surgery in pediatric patients with moyamoya disease (MMD). However, arterial development varies widely among patients, and the underlying mechanisms remain unknown. Objectives: We evaluated the relationship between the development of donor arteries after bypass surgery in pediatric patients with MMD and the MMD-susceptibility gene variant c.14576G>A of ring finger protein (RNF) 213. Methods: The data of pediatric patients with MMD (age <16 years at the time of surgery) treated with combined bypass surgery between September 2013 and April 2019 were consecutively analyzed. Quantitative measurements of the superficial temporal artery (STA), deep temporal artery (DTA), and middle meningeal artery (MMA) diameters with magnetic resonance angiography (MRA) source imaging were performed preoperatively and at 6–12 months postoperatively. The postoperative caliber change ratios (CCRs) were calculated. The relationship between CCRs and RNF213 c.14576G>A status was examined. Results: Forty-eight hemispheres from 28 pediatric patients with MMD were examined. Three hemispheres belonged to patients with the AA genotype; 33 to patients with the AG genotype (AA/AG group); and 12 to patients with the GG genotype (GG group; wild type). The CCRs for the DTA were significantly higher in patients with RNF213 variant (AA/AG group; 2.5 ± 0.1) than in the GG group (2.0 ± 0.2) (p = 0.03), whereas the CCRs for the STA were significantly higher in the GG (1.6 ± 0.1) than in the AA/AG group (1.3 ± 0.6) (p = 0.02). There was no significant difference in the CCRs for the MMA and basilar artery between the groups. Other factors, including sex, age, and MRA grading, were not associated with the development of specific bypass development. Conclusions: The extent of collateral development associated with direct or indirect bypass was found to differ between the genotypes of the RNF213 c.14576G>A associated with pediatric MMD. This genetic variant correlates with the development of the disease and affects revascularization after bypass surgery in pediatric patients with MMD.

【グローカル脳神経外科-1】もやもや病 治療の現状と研究課題について　　　　　　　　　　　　　　　
藤村 幹, 伊東 雅基, 杉山 拓, 川堀 真人, 長内 俊也
脳神経外科ジャーナル, 31, 9, 579, 585, (一社)日本脳神経外科コングレス, 2022年09月
日本語, もやもや病は東アジアに多い原因不明の頭蓋内動脈狭窄症で、小児と若年成人の脳卒中の原因として重要である。疾患感受性遺伝子RNF213の多型は発症年齢、臨床的重症度、血管病変進行との関連が知られており重要である。またRNF213遺伝子多型は血管外径狭小化、壁菲薄化を特徴とするnegative remodelingとの関連も報告され、病態解明が進んでいる。外科治療においては虚血例に加えて出血例に対するバイパス術の効果が明らかとなり、もやもや病に対する手術適応は拡大傾向にある。局所過灌流やwatershed shift現象など本疾患に特徴的な術後脳循環の診断と適切な術後管理による合併症回避が重要である。(著者抄録)

Intracerebral Transplantation of Mesenchymal Stromal Cell Compounded with Recombinant Peptide Scaffold against Chronic Intracerebral Hemorrhage Model
Soichiro Takamiya, Masahito Kawabori, Tsukasa Kitahashi, Kentaro Nakamura, Yuki Mizuno, Hironobu Yasui, Yuji Kuge, Aki Tanimori, Yasuyuki Takamatsu, Kohei Yuyama, Hideo Shichinohe, Miki Fujimura
Stem Cells International, 2022, 1, 10, Hindawi Limited, 2022年07月31日
研究論文（学術雑誌）, Background. Due to the lack of effective therapies, stem cell transplantation is an anticipated treatment for chronic intracerebral hemorrhage (ICH), and higher cell survival and engraftment are considered to be the key for recovery. Mesenchymal stromal cells (MSCs) compounded with recombinant human collagen type I scaffolds (CellSaics) have a higher potential for cell survival and engraftment compared with solo-MSCs, and we investigated the validity of intracerebral transplantation of CellSaic in a chronic ICH model. Methods. Rat CellSaics (rCellSaics) were produced by rat bone marrow-derived MSC (rBMSCs). The secretion potential of neurotrophic factors and the cell proliferation rate were compared under oxygen-glucose deprivation (OGD) conditions. rCellSaics, rBMSCs, or saline were transplanted into the hollow cavity of a rat chronic ICH model. Functional and histological analyses were evaluated, and single-photon emission computed tomography for benzodiazepine receptors was performed to monitor sequential changes in neuronal integrity. Furthermore, human CellSaics (hCellSaics) were transplanted into a chronic ICH model in immunodeficient rats. Antibodies neutralizing brain-derived neurotrophic factor (BDNF) were used to elucidate its mode of action. Results. rCellSaics demonstrated a higher secretion potential of trophic factors and showed better cell proliferation in the OGD condition. Animals receiving rCellSaics displayed better neurological recovery, higher intracerebral BDNF, and better cell engraftment; they also showed a tendency for less brain atrophy and higher benzodiazepine receptor preservation. hCellSaics also promoted significant functional recovery, which was reversed by BDNF neutralization. Conclusion. Intracerebral transplantation of CellSaics enabled neurological recovery in a chronic ICH model and may be a good option for clinical application.

Outcomes of combined revascularization surgery for moyamoya disease without preoperative cerebral angiography.
Tomohiro Okuyama, Masahito Kawabori, Masaki Ito, Taku Sugiyama, Ken Kazumata, Miki Fujimura
World neurosurgery, 2022年06月21日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Cerebral angiography is the gold standard for diagnosing moyamoya disease (MMD), whereas magnetic resonance (MR) imaging/angiography is becoming more popular in the field of cerebrovascular disease due to its low invasiveness. Although there are concerns about using only MR imaging/angiography for preoperative analysis of MMD, considering the underestimation of pre-existing transdural collateral circulations and dangerous collaterals related to the risk of hemorrhage, we retrospectively reviewed our 10-year experience of MRI-first diagnosis and analyzed the perioperative outcomes. METHODS: We analyzed 160 consecutive direct/indirect combined revascularization procedures for MMD preoperatively assessed using MR imaging/angiography alone. Perioperative complications were assessed for up to 2 weeks after surgery. Locations of the lesions responsible for complications were further classified into the surgical field, the ipsilateral hemisphere outside the surgical field, and the contralateral hemisphere. RESULTS: Sixty-four revascularization procedures were performed in 38 children, and 96 procedures were performed in 68 adults. There was no difference in the incidence of perioperative ischemic complications between adults (6.3%) and pediatric patients (4.7%), but hemorrhagic complications were more frequently observed in adults (7.3%) than in children (0%) (P<0.05). There was no specific lesion deviation for ischemic complications; however, hemorrhagic complications predominantly occurred in the surgical field. CONCLUSIONS: Direct/indirect combined revascularization surgery based on our preoperative diagnostic protocol with the MR-first strategy resulted in favorable outcomes in pediatric MMD patients with relatively low complication rates. However, the validity of the MR-first diagnostic protocol should be further evaluated in adult patients with MMD.

慢性期頭部外傷患者に対する他家骨髄由来間葉系間質細胞(SB623)の脳内投与の治験成績 第二相STEMTRA試験　　　　　　　　　　　　　　　
唐沢 康暉, 篠田 裕介, 川堀 真人, 池田 聡, 生駒 一憲, 末永 潤, 中村 健, 安原 隆雄, 堅山 佳美, 千田 益生, 濱田 全紀, 千田 大
The Japanese Journal of Rehabilitation Medicine, 特別号, S528, S528, (公社)日本リハビリテーション医学会, 2022年05月
日本語

Impact of RNF213 founder polymorphism (p.R4810K) on the postoperative development of indirect pial synangiosis after direct/indirect combined revascularization surgery for adult Moyamoya disease.
Masaki Ito, Masahito Kawabori, Taku Sugiyama, Kikutaro Tokairin, Ryota Tatezawa, Haruto Uchino, Ken Kazumata, Kiyohiro Houkin, Miki Fujimura
Neurosurgical review, 45, 3, 2305, 2313, 2022年02月07日, ［国際誌］
英語, 研究論文（学術雑誌）, Direct superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis combined with indirect pial synangiosis provides favorable surgical collaterals for Moyamoya disease (MMD), especially in adults; however, factors leading to the development of each direct and indirect collateral are not well documented.We aimed to investigate the association between RNF213 founder polymorphism (p.R4810K) and each direct and indirect collateral development. By qualitative and quantitative evaluations of direct and indirect surgical collaterals using time-of-flight MR angiography, postoperative development of each type of bypass was evaluated independently into two categories. Multivariate logistic regression analysis was performed to study the contributing factors for the development of each surgical collateral. Excellent development of postoperative direct and indirect bypass was observed in 65 hemispheres (70%) by qualitative evaluation, which was confirmed by quantitative evaluation. Multivariate logistic regression analysis of excellent indirect bypass development revealed a significant positive correlation with the p.R4810K (odds ratio, OR4.0; 95%-confidence interval, CI 1.2-16), advanced MR angiographic stage (OR9.5; 95%CI 1.7-73), and preoperative middle meningeal artery caliber (OR6.8; 95%CI 1.8-35), but a significant negative correlation was found with the excellent direct bypass development (OR0.17; 95%CI 0.03-0.75). No significant correlation was observed between excellent direct bypass development and the p.R4810K (OR0.95; 95%CI 0.37-2.4).In conclusion, excellent development of indirect collaterals after STA-MCA anastomosis combined with indirect pial synangiosis occurs more frequently in adult MMD with the RNF213 founder polymorphism, suggesting a role of the p.R4810K variant for marked in-growth of indirect collaterals and the utility of preoperative genetic analysis.

Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury.
Soichiro Takamiya, Masahito Kawabori, Kazuyoshi Yamazaki, Sho Yamaguchi, Aki Tanimori, Koji Yamamoto, Shunsuke Ohnishi, Toshitaka Seki, Kotaro Konno, Khin Khin Tha, Daigo Hashimoto, Masahiko Watanabe, Kiyohiro Houkin, Miki Fujimura
PloS one, 17, 7, e0270606, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.
Masahito Kawabori, Alan H Weintraub, Hideaki Imai, Laroslav Zinkevych, Peter McAllister, Gary K Steinberg, Benjamin M Frishberg, Takao Yasuhara, Jefferson W Chen, Steven C Cramer, Achal S Achrol, Neil E Schwartz, Jun Suenaga, Daniel C Lu, Ihor Semeniv, Hajime Nakamura, Douglas Kondziolka, Dai Chida, Takehiko Kaneko, Yasuaki Karasawa, Susan Paadre, Bijan Nejadnik, Damien Bates, Anthony H Stonehouse, R Mark Richardson, David O Okonkwo
Neurology, 2021年01月04日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Corrigendum to "Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease".
Masahito Kawabori, Aki Tanimori, Shinri Kitta, Hideo Shichinohe, Kiyohiro Houkin
Stem cells international, 2021, 9796010, 9796010, 2021年, ［国際誌］
英語, [This corrects the article DOI: 10.1155/2020/4085617.].

Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Soichiro Takamiya, Kotaro Konno, Masahiko Watanabe, Kiyohiro Houkin, Miki Fujimura
Stem cells international, 2021, 9964877, 9964877, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet (7 × 104 cells, subdural), cell suspension (7 × 104 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of μ-opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.

Vascular Smooth Muscle Cell Derived from IPS Cell of Moyamoya Disease - Comparative Characterization with Endothelial Cell Transcriptome.
Kikutaro Tokairin, Shuji Hamauchi, Masaki Ito, Ken Kazumata, Taku Sugiyama, Naoki Nakayama, Masahito Kawabori, Toshiya Osanai, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 29, 12, 105305, 105305, 2020年12月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Moyamoya disease (MMD) is an occlusive cerebrovascular disease, causing stroke in children and young adults with unknown etiology. The fundamental pathology is fibrocellular intimal thickening of cerebral arteries, in which vascular smooth muscle cells (VSMCs) are observed as one of the major cell types. Although the characteristics of circulating smooth muscle progenitor cells have been previously reported, the VSMCs are poorly characterized in MMD. We aimed to characterize VSMCs in MMD using induced pluripotent stem cell (iPSC)-technology. METHODS: We differentiated VSMCs from neural crest stem cells (NCSCs) using peripheral blood mononuclear cell-derived iPSCs and compared biological and transcriptome features under naïve culture conditions between three independent healthy control (HC) subjects and three MMD patients. VSMC transcriptome profiles were also compared to those of endothelial cells (ECs) differentiated from the same iPSCs. RESULTS: Homogeneous spindle-shaped cells differentiated from iPSCs exhibited smooth muscle cell marker expressions, including α-smooth muscle actin (αSMA, 82.3 ± 6.7% and 81.0 ± 6.7%); calponin (91.3 ± 2.1% and 90.9 ± 1.3%); myosin heavy chain-11 (MYH11, 96.9 ± 0.7% and 97.1 ± 0.3%) without significance of differences between the two groups. Real-time PCR showed few PECAM1 and CD34 gene expressions in both groups, indicating features of differentiated VSMCs. There were no significant differences in cellular proliferation (p = 0.45), migration (p = 0.60), and contractile abilities (p = 0.96) between the two groups. Transcriptome analysis demonstrated similar gene expression profiles of VSMCs in HC subjects and MMD patients with six differentially expressed genes (DEGs); while ECs showed a distinct transcriptome profile in MMD patients with 120 DEGs. The Wnt-signaling pathway was a significant pathway in VSMCs. CONCLUSIONS: This is the first study that established VSMCs from NCSCs using MMD patient-derived iPSCs and demonstrated similar biological function and transcriptome profile of iPSC-derived VMSCs in MMD patients and HC subjects under naïve single culture condition. Comparative transcriptome features between iPSC-derived VSMCs and ECs, displaying distinct transcriptome in the ECs, suggested that pathological traits can be driven by naïve ECs predominantly and VSMCs may require specific environmental factors in MMD, which provides novel insight into the pathophysiology of MMD. Our iPSC derived VSMC model can contribute to further investigations of diagnostic and therapeutic target of MMD in addition to the current iPSC derived EC model.

Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke.
Masahito Kawabori, Hideo Shichinohe, Satoshi Kuroda, Kiyohiro Houkin
International journal of molecular sciences, 21, 19, 2020年10月06日, ［国際誌］
英語, 研究論文（学術雑誌）, Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.

Neuroprotective effects of combination therapy of regional cold perfusion and hemoglobin-based oxygen carrier administration on rat transient cerebral ischemia.
Yasuhiro Ito, Takeo Abumiya, Teruyuki Komatsu, Ryosuke Funaki, Masayuki Gekka, Kota Kurisu, Taku Sugiyama, Masahito Kawabori, Toshiya Osanai, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
Brain research, 1746, 147012, 147012, 2020年07月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Regional cold perfusion and hemoglobin-based oxygen carrier administration both exert neuroprotective effects against cerebral ischemia reperfusion injury. We herein investigated whether the combination of these two therapies leads to stronger neuroprotective effects. Combination therapy was performed with the regional perfusion of cold HemoAct, a core-shell structured hemoglobin-albumin cluster, in a rat transient middle cerebral artery occlusion model. The effects of combination therapy, the intra-arterial administration of 10 °C HemoAct (10H) initiated at the onset of reperfusion, were compared with those of monotherapies, the intra-arterial administration of 10 °C saline (10S) and 37 °C HemoAct (37H), and an untreated control under the condition of 2-hour ischemia/24-hour reperfusion. The durability of therapeutic effects and the therapeutic time window of combination therapy were assessed based on comparisons with the 10H and control groups. Significantly better neurological findings and smaller infarct volumes were observed in the three treated (10S, 37H, and 10H) groups than in the control group. Among the 3 treated groups, only the 10H group showed significant improvements over the control group in the other items examined, including cerebral blood flow reduction, brain edema, and protein extravasation. The significant therapeutic effects of combination therapy on neurological disabilities and infarct volumes were confirmed at least until 7 days after reperfusion. Furthermore, combination therapy ameliorated neurological disabilities and hemorrhagic transformation in rats subjected to 4- and 5-hour ischemia/24-hour reperfusion. Since therapeutic effects may be expected until at least 5 h of complete ischemia and reperfusion, this combination therapy is a promising neuroprotective strategy against severe ischemic stroke.

Clinical Trials of Stem Cell Treatment for Spinal Cord Injury.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Kiyohiro Houkin
International journal of molecular sciences, 21, 11, 2020年06月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted.

[Successful Total Resection with Preceding Arterial Coil Embolization of Intradural Extramedullary Tumor at Craniovertebral Junction Encasing Dominant-side Vertebral Artery].
Ryota Tatezawa, Motoyuki Iwasaki, Kazutoshi Hida, Toshiya Osanai, Masahito Kawabori, Rena Morita, Tomohiro Yamauchi, Yoshimasa Niiya, Koji Furukawa, Takeo Abumiya, Shoji Mabuchi
No shinkei geka. Neurological surgery, 48, 6, 509, 514, 2020年06月, ［国内誌］
日本語, 研究論文（学術雑誌）, OBJECTIVE: The surgical resection of craniovertebral junction(CVJ)meningioma is challenging because of the neighboring brainstem, lower cranial nerves, and vertebral artery(VA). Moreover, encasement of the VA by the tumor can raise the risk of complications and require cautious manipulation during surgery. CASE: A 46-year-old woman presented with a one-year history of neck pain. She had temporal hemiplegia and numbness on her left side. Magnetic resonance imaging(MRI)showed a CVJ meningioma pushing the brainstem from the right vertebral side and encasing the right VA. Digital subtraction angiography(DSA)showed two feeding arteries arising from the right VA and a sunburst sign. The right VA was the dominant side but did not have the right posterior inferior cerebellar artery(PICA). The anterior spinal artery(ASA)was dominant in the left VA. We performed a balloon test occlusion(BTO)for 20 min and it did not cause any complications;therefore, we occluded the VA using endovascular coils. After 4 days, we removed the meningioma in the prone position, using a far-lateral approach and C1-laminectomy. The laterally located meningioma pushed the brainstem. After detaching the tumor from the dura, we cut the encased VA and the tumor was resected safely(Simpson grade II). Postoperatively, she developed temporal thermal hypoalgesia on the left side of her body. Magnetic resonance imaging showed a microinfarction in the medulla. CONCLUSION: If the VA test occlusion provides a clear result, pre-operative endovascular sacrifice of the VA encased by CVJ meningioma is a feasible treatment strategy.

FTY720 Attenuates Neuropathic Pain after Spinal Cord Injury by Decreasing Systemic and Local Inflammation in a Rat Spinal Cord Compression Model.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Soichiro Takamiya, Takahiro Tateno, Kotaro Konno, Masahiko Watanabe, Kiyohiro Houkin
Journal of neurotrauma, 37, 15, 1720, 1728, 2020年05月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Neuropathic pain severely impairs rehabilitation and quality of life after spinal cord injury (SCI). The sphingosine-1-phosphate receptor agonist, FTY720, plays an important protective role in neuronal injury. This study aims to examine the effects of FTY720 in a rat acute SCI model, focusing on neuropathic pain. Female rats with SCI induced by 1-min clip compression were administered vehicle or 1.5 mg/kg of FTY720 24 h after the injury. Using the mechanical nociceptive threshold test, we monitored neuropathic pain and performed histological analysis of the pain pathway, including the μ opioid receptor (MOR), hydroxytryptamine transporter (HTT), and calcitonin gene-related peptide (CGRP). Motor score, SCI lesion volume, residual motor axons, inflammatory response, glial scar, and microvascular endothelial dysfunction were also compared between the two groups. FTY720 treatment resulted in significant attenuation of post-traumatic neuropathic pain. It also decreased systemic and local inflammation, thereby reducing the damaged areas and astrogliosis and resulting in motor functional recovery. Whereas there was no difference in the CGRP expression between the two groups, FTY720 significantly preserved the MOR in both the caudal and rostral areas of the spinal dorsal horn. Whereas HTT was preserved in the FTY720 group, it was significantly increased in the rostral side and decreased in the caudal side of the injury in the vehicle group. These results suggest that FTY720 ameliorates post-traumatic allodynia through regulation of neuroinflammation, maintenance of the blood-brain barrier, and inhibition of glial scar formation, thereby preserving the connectivity of the descending inhibitory pathway and reducing neuropathic pain.

Combined structural and diffusion tensor imaging detection of ischemic injury in moyamoya disease: relation to disease advancement and cerebral hypoperfusion.
Ken Kazumata, Kikutaro Tokairin, Masaki Ito, Haruto Uchino, Taku Sugiyama, Masahito Kawabori, Toshiya Osanai, Khin Khin Tha, Kiyohiro Houkin
Journal of neurosurgery, 134, 3, 1, 10, 2020年04月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: The microstructural integrity of gray and white matter is decreased in adult moyamoya disease, suggesting covert ischemic injury as a mechanism of cognitive dysfunction. Establishing a microstructural brain imaging marker is critical for monitoring cognitive outcomes following surgical interventions. The authors of the present study determined the pathophysiological basis of altered microstructural brain injury in relation to advanced arterial occlusion, cerebral hypoperfusion, and cognitive function. METHODS: The authors examined 58 patients without apparent brain lesions and 30 healthy controls by using structural MRI, as well as diffusion tensor imaging (DTI). Arterial occlusion in each hemisphere was classified as early or advanced stage based on MRA and posterior cerebral artery (PCA) involvement. Regional cerebral blood flow (rCBF) was measured with N-isopropyl-p-[123I]-iodoamphetamine SPECT. Furthermore, cognitive performance was examined using the Wechsler Adult Intelligence Scale, Third Edition and the Trail Making Test (TMT). Both voxel- and region of interest-based analyses were performed for groupwise comparisons, as well as correlation analysis, using parameters such as cognitive test scores; gray matter volume; fractional anisotropy (FA) of association fiber tracts, including the inferior frontooccipital fasciculus (IFOF) and superior longitudinal fasciculus (SLF); PCA involvement; and rCBF. RESULTS: Compared to the early stages, advanced stages of arterial occlusion in the left hemisphere were associated with a lower Performance IQ (p = 0.031), decreased anterior cingulate volumes (p = 0.0001, uncorrected), and lower FA in the IFOF, cingulum, and forceps major (all p < 0.01, all uncorrected). There was no significant difference in rCBF between the early and the advanced stage. In patients with an advanced stage, PCA involvement was correlated with a significantly lower Full Scale IQ (p = 0.036), cingulate volume (p < 0.01, uncorrected), and FA of the left SLF (p = 0.0002, uncorrected) compared to those with an intact PCA. The rCBF was positively correlated with FA of the SLF, IFOF, and forceps major (r > 0.34, p < 0.05). Global gray matter volumes were moderately correlated with TMT part A (r = 0.40, p = 0.003). FA values in the left SLF were moderately associated with processing speed (r = 0.40, p = 0.002). CONCLUSIONS: Although hemodynamic compensation may mask cerebral ischemia in advanced stages of adult moyamoya disease, the disease progression is detrimental to gray and white matter microstructure as well as cognition. In particular, additional PCA involvement in advanced disease stages may impair key neural substrates such as the cingulum and SLF. Thus, combined structural MRI and DTI are potentially useful for tracking the neural integrity of key neural substrates associated with cognitive function and detecting subtle anatomical changes associated with persistent ischemia, as well as disease progression.

【放射線科医が知っておくべき 脳血管障害診療 update】脳血管障害に対する再生医療・細胞治療の現状と今後の展望
川堀 真人, 七戸 秀夫, 黒田 敏, 寳金 清博
臨床画像, 36, 4月増刊, 141, 150, (株)メジカルビュー社, 2020年04月, ［査読有り］
日本語, ＜文献概要＞脳梗塞・頭部外傷・脊髄損傷・Parkinson病など中枢神経疾患に対する細胞治療・再生医療が,基礎研究から治験の段階(bench to bed)に入っている。これらは既存治療ではなしえなかった中枢神経を再生・回復させる治療法として大きく期待されている。本報告では,脳血管障害に対する研究結果および今後の課題について概説する。

【間葉系幹細胞の基礎と臨床応用】疾患治療 間葉系幹細胞を用いた脳・脊髄病変に対する再生医療・細胞治療
川堀 真人, 寳金 清博
医学のあゆみ, 272, 10, 1044, 1050, 医歯薬出版(株), 2020年03月, ［査読有り］
日本語, いったん障害を受けると回復することがないといわれてきた脳・脊髄の病気に対する再生医療の期待は大きい。実際、脳梗塞、頭部外傷、脊髄損傷、パーキンソン病などに対する再生医療・細胞治療が、"基礎研究"の段階から臨床応用に向けた"治験"、さらに一部は"先進医療・保険診療"の段階に入ってきている。これらの多くが間葉系幹細胞を用いており、その安全性・有用性が注目されている。2019年には、自家骨髄幹細胞の"ステミラック注"が脊髄損傷の亜急性期患者に対して期限および条件付き承認で保険適用となり、中枢神経疾患に対するはじめての"再生医療等製品"となった。また、脳梗塞に対する細胞治療も複数の治験が進行中で、その結果が待たれる。本稿では、間葉系幹細胞を用いた中枢神経疾患に対する細胞治療・再生医療の作用機序、すでに報告されている治験および現在進行中の研究内容、および残された課題について概説する。(著者抄録)

FTY720 Protects Against Ischemia-Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model.
Zifeng Wang, Kei Higashikawa, Hironobu Yasui, Yuji Kuge, Yusuke Ohno, Akio Kihara, Yenari A Midori, Kiyohiro Houkin, Masahito Kawabori
Translational stroke research, 11, 5, 1103, 1116, 2020年02月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood-brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [18F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.

Induction of large cerebral aneurysms by intraperitoneal administration of β-aminopropionitrile fumarate in male rats.
Yusuke Shimoda, Naoki Nakayama, Takuya Moriwaki, Takeo Abumiya, Masahito Kawabori, Kota Kurisu, Masayuki Gekka, Masaaki Hokari, Yasuhiro Ito, Kiyohiro Houkin
Journal of neurosurgical sciences, 2020年02月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of β-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. METHODS: Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). RESULTS: Induction rate in the high-dose groups was significantly higher (p<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 μm, vs 12 weeks; 181.7 μm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. CONCLUSIONS: High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

Reversible Cerebral Angiopathy after Viral Infection in a Pediatric Patient with Genetic Variant of RNF213.
Ikuma Echizenya, Kikutaro Tokairin, Masahito Kawabori, Ken Kazumata, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 29, 2, 104549, 104549, 2020年02月, ［査読有り］, ［国際誌］
英語, Ring finger protein (RNF) 213 is known as a susceptibility gene for moyamoya disease (MMD), which is characterized by bilateral carotid folk stenosis. Cerebral angiopathy after viral infection has been known to present angiographical appearance resembling MMD, however its pathogenesis and genetic background are not well known. We report a case of reversible cerebral angiopathy after viral infection in a pediatric patient with genetic variant of RNF213 mutation. The patient had developed a severe headache after hand, foot, and mouth disease. Magnetic resonance imaging and magnetic resonance angiography (MRA) performed 2-3 weeks after disease onset revealed bilateral carotid folk stenosis and an old cerebral infarction in the left putamen. The patient's headache spontaneously resolved and the follow-up MRA showed a complete spontaneous resolution of the arterial stenosis after 9 months. We were able to determine genetic predisposition to angiopathy by identifying the RNF213 c.14576G>A (rs112735431, p.R4859K) mutation. Based on the present case, we hypothesize that an RNF213 variant might play an important role for the onset of postviral cerebral angiopathy.

Cell therapy against cns diseases：current status and future perspectives
Masahito Kawabori, Hideo Shichinohe, Satoshi Kuroda, Kiyohiro Houkin
Japanese Journal of Neurosurgery, 29, 11, 777, 783, Japanese Congress of Neurological Surgeons, 2020年
日本語, 研究論文（学術雑誌）, Cell therapy for central nervous system (CNS) diseases including stroke, traumatic brain injury, spinal cord injury, and Parkinson’s disease are now shifting from“basic research”to“clinical trials and approved therapies”. The results obtained from the clinical research promise to alleviate CNS damage which have long been considered as unrecoverable. Autologous bone marrow derived mesenchymal stem cell product “Stemirac”was approved for insurance‒covered therapy against acute spinal cord injury under the new Japanese regulation, and many more clinical trials focused especially on ischemic stroke are currently executed in Japan. However, there persist several unsolved issues including ideal cell types, transplantation routes, transplantation timing, and types of disease, which need to be clarified to maximize the effect of cell therapy. Hence, it is important for neurosurgeons to understand the current status of stem cell therapy as a treatment for patients suffering from CNS diseases. (Received July 26, 2019；accepted August 9, 2019)

Long-Term Clinical Outcome and Prognosis After Thrombectomy in Patients With Concomitant Malignancy.
Sogo Oki, Masahito Kawabori, Sumire Echizenya, Yusuke Shimoda, Daisuke Shimbo, Toshiya Osanai, Kazuki Uchida, Kiyohiro Houkin
Frontiers in neurology, 11, 572589, 572589, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Endovascular thrombectomy (EVT) is the preferred treatment strategy for patients with acute ischemic stroke (AIS). However, clinical outcome and prognosis in patients who undergo EVT in response to AIS with concomitant malignancy have not been fully elucidated. Data of patients with malignancy who underwent EVT at participating institutions between January 2015 and April 2019 were retrospectively analyzed. Patient characteristics, treatment methods, posttreatment strategy, and long-term prognosis were evaluated in 12 patients with prediagnoses of malignancy. Good revascularization (TICI 2b or higher) was achieved in 10 of 12 patients. Among the eight patients who survived more than 2 weeks from onset, four patients showed good clinical outcome [modified Rankin Scale (mRS) <2] at 60 days posttreatment and were able to continue treatment for malignancy. However, seven of eight patients died within a year of EVT (median survival, 83 days) due to progression of malignancy. One-year survival was achieved in only one patient whose etiology of stroke was determined as infectious endocarditis and not Trousseau syndrome. Even after successful revascularization and good short-term clinical outcome, the long-term prognosis after thrombectomy in patients with malignancy was poor. Thrombectomy for concomitant malignancy requires judicious decision, and further studies are necessary to fully elucidate its efficacy.

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease.
Masahito Kawabori, Aki Tanimori, Shinri Kitta, Hideo Shichinohe, Kiyohiro Houkin
Stem cells international, 2020, 4085617, 4085617, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Cell therapy for central nervous system (CNS) disorders is beginning to prove its safety and efficiency. Intraparenchymal transplantation can be an option for cell delivery; however, one concern regarding this method is that the transplantation cannula may cause additional brain injuries. These include vessel damage, which results in brain hemorrhage, and clogging of the cannula by brain debris and/or cell clusters, which requires replacement of the cannula or forced injection causing jet flow of the cell suspension. We compared cannulas for cell delivery used in clinical trials, the Pittsburg and Mizuho cannulas, to a newly designed one, MK01, to assess their usability. MK01 has a spherical-shaped tip with a fan-like open orifice on the side of the cannula, which prevents vessel damage, clogging of brain debris, and jet flow phenomenon. We compared the extent of rat cervical and abdominal arterial damage with the cannula, the amount of debris in the cannula, the force needed to cause jet flow, and cell viability. While the viability of cells passed through the cannulas was almost the same among cannulas (approximately 95%), the Pittsburg cannula caused cervical arterial injury and subsequent hemorrhage, as it required a significantly smaller force to penetrate the arterial wall. Moreover, the Pittsburg cannula, but not the Mizuho and MK01 cannulas, showed high frequency of brain debris in the needle tip (approximately 80%) after brain puncture. While jet flow of the injection liquid was observed even when using smaller forces in the Pittsburg and Mizuho cannulas, MK01 constantly showed low jet flow occurrence. Thus, MK01 seems to be safer than the previously reported cannulas, although further investigation is necessary to validate its safety for clinical use.

FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment.
Zifeng Wang, Masahito Kawabori, Kiyohiro Houkin
Current medicinal chemistry, 27, 18, 2979, 2993, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional "antagonist" and "agonist" mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.

脳梗塞亜急性期に対する自家骨髄間質細胞の脳内投与 第一相治験:RAINBOW研究　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 黒田 敏, 寳金 清博
脳循環代謝, 31, 1, 83, 83, (一社)日本脳循環代謝学会, 2019年11月, ［査読有り］
日本語

Brain Structure, Connectivity, and Cognitive Changes Following Revascularization Surgery in Adult Moyamoya Disease.
Ken Kazumata, Khin Khin Tha, Kikutaro Tokairin, Masaki Ito, Haruto Uchino, Masahito Kawabori, Taku Sugiyama
Neurosurgery, 85, 5, E943-E952, 2019年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The effect of the combined direct/indirect revascularization surgery in Moyamoya disease has not been evaluated sufficiently with regard to cognitive function, brain microstructure, and connectivity. OBJECTIVE: To investigate structural and functional changes following revascularization surgery in patients with moyamoya disease (MMD) through a combined analysis of brain morphology, microstructure, connectivity, and neurobehavioral data. METHODS: Neurobehavioral and neuroimaging examinations were performed in 25 adults with MMD prior to and >12 mo after revascularization surgery. Cognitive function was investigated using the Wechsler Adult Intelligence Scale-III, Trail-Making Test, Wisconsin Card Sorting Test, Continuous Performance Test, Stroop test, and Wechsler Memory Scale. We assessed white matter integrity using diffusion tensor imaging, brain morphometry using magnetization-prepared rapid gradient-echo sequences, and brain connectivity using resting-state functional magnetic resonance imaging (MRI). RESULTS: Cognitive examinations revealed significant changes in the full-scale intelligence quotient (IQ), performance IQ (PIQ), perceptual organization (PO), processing speed, and Stroop test scores after surgery (P < .05). Enlargement of the lateral ventricle, volume reductions in the corpus callosum and subcortical nuclei, and cortical thinning in the prefrontal cortex were also observed (P < .05). Fractional anisotropy in the white matter tracts, including the superior longitudinal fasciculus, increased 2 to 4 yr after surgery, relative to that observed in the presurgical state (P < .05). Resting-state brain connectivity was increased predominantly in the fronto-cerebellar circuit and was positively correlated with improvements in PIQ and PO (P < .05). CONCLUSION: Revascularization surgery may improve processing speed and attention in adult patients with MMD. Further, multimodal MRI may be useful for detecting subtle postsurgical brain structural changes, reorganization of white matter tracts, and brain connectivity alterations.

Association of cognitive function with cerebral blood flow in children with moyamoya disease.
Ken Kazumata, Kikutaro Tokairin, Taku Sugiyama, Masaki Ito, Haruto Uchino, Toshiya Osanai, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin
Journal of neurosurgery. Pediatrics, 1, 7, 2019年10月11日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: The cognitive effects of main cerebral artery occlusive lesions are unclear in children with moyamoya disease (MMD). The authors aimed to investigate cognitive function in the presurgical phase of pediatric patients with MMD with no apparent brain lesions. METHODS: In this prospective, observational, single-center study, 21 children (mean age 10 ± 3.0 years, range 5-14 years) diagnosed with MMD at Hokkaido University Hospital between 2012 and 2018 were enrolled. A cross-sectional evaluation of intellectual ability was performed using the Wechsler Intelligence Scale for Children-Fourth Edition at the initial diagnosis. rCBF was measured using [123I] N-isopropyl p-iodoamphetamine/SPECT. The associations among clinical factors, disease severity, regional cerebral blood flow (rCBF), and intelligence test scores were also examined. RESULTS: The mean full-scale intelligence quotient (FIQ) was 101.8 ± 12.5 (range 76-125) in children with no apparent brain lesions. A significant difference in the intelligence scale index score was observed, most frequently (42.9%) between working memory index (WMI) and verbal comprehension index (VCI; VCI - WMI > 11 points). Regional CBF was significantly reduced both in the left and right medial frontal cortices (left: 61.3 ± 5.3 ml/100 g/min, right 65.3 ± 5.3 ml/100 g/min; p < 0.001) compared to the cerebellum (77.8 ± 6.8 ml/100 g/min). There was a significant association of rCBF in the left dorsolateral prefrontal cortex (DLPFC) with FIQ (r = 0.46, p = 0.034), perceptual reasoning index (PRI; r = 0.44, p = 0.045), and processing speed index (PSI; r = 0.44, p = 0.045). There was an association between rCBF of the left medial frontal cortex and PSI (r = 0.49, p = 0.026). Age of onset, family history, ischemic symptoms, and angiographic severity were not associated with poor cognitive performance. CONCLUSIONS: Although average intellectual ability was not reduced in children with MMD, the association of reduced rCBF in the left DLPFC and medial frontal cortex with FIQ, PRI, and PSI suggests mild cognitive dysfunction due to cerebral hypoperfusion.

脳卒中におけるトランスレーショナル・リサーチ 脳梗塞亜急性期に対する自家骨髄幹細胞の直接投与(第一相治験:RAINBOW研究)
川堀 真人, 七戸 秀人, 黒田 敏, 寳金 清博
神経治療学, 36, 6, S128, S128, (一社)日本神経治療学会, 2019年10月, ［査読有り］
日本語

A Rare Case of Idiopathic Temporal Muscle Abscess in a Nine-month-old Infant.
Sogo Oki, Masahito Kawabori, Hiroaki Motegi, Shigeru Yamaguchi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Internal medicine (Tokyo, Japan), 58, 18, 2699, 2702, 2019年09月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Temporal muscle abscess in children usually occurs from acute otitis media, and rapid progression and concomitant infectious disease often make it easy to diagnose. We report a rare case of a nine-month-old infant who showed right temporal mass with no evidence of infection. Computed tomography showed an osteolytic round mass, and magnetic resonance imaging revealed heterogenous enhancement with a high apparent diffusion coefficient. Malignant tumor was first suspected, but an open biopsy revealed the swelling to be temporal muscle abscess. It should be noted that temporal abscess may mimic the features of a malignant tumor, and multiple examinations should be performed for an accurate diagnosis.

脳梗塞に対する再生医療の現状と展望は?
川堀 真人, 寳金 清博
脳血管病Trend Review, 1, 1, 28, 31, (株)先端医学社, 2019年09月, ［査読有り］
日本語, 脳梗塞に対する幹細胞を用いた再生医療の現状とその課題および将来像について概説した。現在多くの基礎および臨床研究が進められている細胞種として、胚性幹細胞(ES細胞)、人工多能性幹細胞(iPS細胞)、体性幹細胞(間葉系幹細胞、神経幹細胞等)などがあげられるが、特に臨床応用が進んでいるのが骨髄由来の間葉系幹細胞(BMSC)である。幹細胞の作用機序として、分化による直接効果と保護効果による間接効果が考えられる。現在、脳梗塞に対して幹細胞を用いた臨床試験がおこなわれているが、最適な細胞種類、細胞数、投与ルート、投与時期、患者群など解決されていない問題も残されている。

Efficacy of 'drive and retrieve' as a cooperative method for prompt endovascular treatment for acute ischemic stroke.
Toshiya Osanai, Yasuhiro Ito, Satoshi Ushikoshi, Takeshi Aoki, Masahito Kawabori, Kensuke Fujiwara, Katsuhiko Ogasawara, Kikutaro Tokairin, Katsuhiko Maruichi, Naoki Nakayama, Ken Kazumata, Kota Ono, Kiyohiro Houkin
Journal of neurointerventional surgery, 11, 8, 757, 761, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Outcomes of endovascular treatment for acute ischemic stroke depend on the time interval from onset to reperfusion. Although the centralized 'mothership' method is considered preferable, the required transportation time increases the risk that a patient with a stroke may not receive intravenous or endovascular therapy. In contrast, 'drive and retrieve' describes a system wherein doctors from comprehensive stroke centers travel to primary stroke centers and provide endovascular treatment for acute ischemic stroke. OBJECTIVE: To describe the drive and retrieve system and verify the effects of this new collaboration on outcomes in patients with acute ischemic stroke among facilities. METHODS: This non-randomized, single-arm study retrospectively analyzed patients who met the inclusion criteria for endovascular treatment provided through a drive and retrieve system. Among the 122 patients treated by this system, we analyzed the time of onset to recanalization as the primary outcome. We also analyzed the efficacy of the drive and retrieve system using geographic information system analysis. RESULTS: The median time from onset to recanalization was 229 min (IQR 170-307 min, 95% CI 201 to 252 min). The upper limit of the 95% CI for the time from onset to recanalization was shorter than the median times reported in two previous trials. Geographic information system analysis revealed an upward trend in the population coverage rate in each secondary medical area after the drive and retrieve method was introduced. CONCLUSION: The drive and retrieve method may be an effective form of cooperation between facilities located within 1 hour of a comprehensive stroke center.

【脳卒中-診断・治療の最新動向-】基礎研究 脳卒中患者に対する細胞移植・再生医療の現状と将来
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博
日本臨床, 77, 6, 945, 953, (株)日本臨床社, 2019年06月
日本語

Mollaret Meningitis with a High Level of Cytokines in the Cerebrospinal Fluid Successfully Treated by Indomethacin.
Masahito Kawabori, Kota Kurisu, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
Internal medicine (Tokyo, Japan), 58, 8, 1163, 1166, 2019年04月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A rare case of Mollaret meningitis characterized by four recurrent episodes of aseptic meningitis during a three-year period is reported. The patient showed a high fever and severe headache accompanied by a high level of cerebrospinal fluid (CSF) cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The symptoms and high CSF cytokines were resolved immediately after introducing indomethacin treatment. Reactivation of the latent virus is considered to be the cause of this rare disease, and indomethacin is believed to inhibit the periodic abnormal generation of eicosanoid in the brain, resulting in a reduction in the fever and subsequent inflammation.

Postoperative Intracerebral Hemorrhage After Combined Revascularization Surgery in Moyamoya Disease: Profiles and Clinical Associations.
Kikutaro Tokairin, Ken Kazumata, Haruto Uchino, Masaki Ito, Kota Ono, Ryota Tatezawa, Takafumi Shindo, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin
World neurosurgery, 120, e593-e600, e600, 2018年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: In combined revascularization surgery for patients with moyamoya disease, intracerebral hemorrhage (ICH) during the postoperative acute phase is a rarely observed but severe complication. Its clinical features remain unclear because of its low incidence rate. The aim of this study was to clarify the clinical characteristics of immediate postoperative ICH. METHODS: The frequency, onset timing, and hematoma location of patients who demonstrated immediate postoperative ICH were investigated in 201 consecutive surgeries performed in 134 patients. Associations between immediate postoperative ICH and demographics, clinical presentation type, perioperative blood pressure (BP), and neuroimaging data were analyzed. RESULTS: Postoperative ICH was observed in 6 cases (2.99%; mean age, 46.0 ± 7.6 years). The onset timing of ICH was within 24 hours after surgery in most patients (83.3%). Hematomas were located at the subcortical lesion beneath the anastomosed cortex (n = 5) and caudate head (n = 1). Three cases (50.0%) required hematoma evacuation. A higher age at surgery was associated with postoperative ICH (P = 0.046). In adult cases (132 surgeries, 65.7%), hemorrhagic presentation at onset (P = 0.0027) and an increase in BP from pre- to postoperative stage (systolic BP increase: P = 0.0058, diastolic BP increase: P = 0.0274) were significantly associated with postoperative ICH. CONCLUSIONS: The results suggest that older patients, with hemorrhagic presentation and greater postoperative BP increase, should be carefully managed to avoid postoperative ICH. Immediate hematoma evacuation may be effective in preventing devastating outcomes after postoperative ICH.

The validity of the Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method for acute thrombectomy.
Daisuke Oura, Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shinpei Satoh, Takumi Yokohama, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 2018年11月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Recent clinical trials demonstrated the efficacy of thrombectomy for ischemic stroke against acute large vessel occlusion (LVO). To overcome the problem with excessive examination time for diagnosis of cerebral perfusion and/or the use of contrast agent to determine penumbra, we adopted a new magnetic resonance imaging technique named Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method. METHODS: The study included healthy volunteers and clinical patients. The signal to noise ratio (SNR) and acquisition time were compared with various numbers of signal average (NSA) of rapid pseudo-continuous arterial spin labeling (pCASL) using the 10-mm thick slice width and narrow scan range focusing the level of basal ganglia by healthy volunteers. After applying clinically acceptable protocol for ASAP-ASL, we then checked image qualities and an accuracy of the method by comparing with the angiographical imaging obtained from the clinical patients regarding the degree of consistency. RESULTS: NSA were compared between two and fourteen, and 10 NSA was decided to be introduced for clinical use (1 minutes and 17 second) for obtaining clinically acceptable image, which was shorter than the time required for ordinary whole brain pCASL (approximately 5 minutes). In the clinical study, the occlusion site estimated by ASAP-ASL showed high correlation with that of digital subtraction angiography (κ = 0.63-0.79). CONCLUSIONS: ASAP-ASL method requires approximately one minutes to obtain clinically relevant brain perfusion imaging which can successfully identify ischemic region in LVO patients.

Intraoperative real-time identification of abnormal vessels within the bright field by superselective arterial injection of saline and its slow-motion recording using a high frame rate digital camera during surgical treatment of spinal arteriovenous shunts: technical note.
Shuji Hamauchi, Toshiya Osanai, Toshitaka Seki, Masahito Kawabori, Michinari Okamoto, Kazutoshi Hida, Kiyohiro Houkin
Journal of neurosurgery. Spine, 29, 5, 576, 581, 2018年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The authors describe a novel method of observing blood flow in abnormal vessels with slow-motion video during surgical treatment of spinal arteriovenous shunts. The method is based on the use of superselective angiography with saline for visualizing abnormal vessels in bright field and commercially available high frame rate digital camera for recording slow-motion video.

Direct common carotid artery puncture for acute thrombectomy against ischemic stroke.
Masahito Kawabori, Toshiya Osanai, Shuho Goto, Motoyuki Iwasaki, Yoshimasa Niiya, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 62, 5, 612, 614, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Identification of plaque location using intraoperative indocyanine green during carotid endarterectomy for patient with near occlusion.
Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 65, 4, 397, 401, 2018年09月25日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Microscope-integrated near-infrared indocyanine green (ICG) videoangiography (VA) is an effective method of intraoperative blood flow assessment and identification of plaque location during carotid endarterectomy (CEA). However, the validity of ICG-VA during CEA for patient with near occlusion has not been elucidated. PATIENTS AND METHODS: Thirty-four CEA procedures were performed between June 2009 and December 2017 for patient with near occlusion, which are more than 95% stenosis. The lesions were classified into three groups according to the diameter of distal ICA compared with ipsilateral external carotid artery (ECA), as normal diameter (>100%), moderate diameter reduction (50-100%), severe diameter reduction (<50%). 5 mg of ICG was injected intravenously before arteriotomy, and ICG-VA was taken to identify the distal end of the plaque. Depiction of the distal end and its accuracy were retrospectively reviewed. RESULTS: There were 18 cases with normal diameter group, 14 cases with moderate diameter reduction group, and 2 cases with severe diameter reduction group. All but one case in the severe diameter reduction group showed apparent distal end signal which were confirmed by arteriotomy afterward. CONCLUSIONS: The present study clearly denotes that ICG-VA can visualize the carotid plaque distal end during the CEA, even with the patient with near occlusion. However, it should be noted that there may be a difficulty in visualization of the distal plaque end for patient with severely collapsed distal ICA.

[A Case of Onion-Skin Hemifacial Dysesthesia Caused by Ossification of the Cervical Posterior Longitudinal Ligament].
Gotoh S, Iwasaki M, Kawabori M, Niiya Y, Mabuchi S
No shinkei geka. Neurological surgery, 46, 9, 783, 787, 2018年09月, ［査読有り］

Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects.
Masayuki Gekka, Takeo Abumiya, Teruyuki Komatsu, Ryosuke Funaki, Kota Kurisu, Daisuke Shimbo, Masato Kawabori, Toshiya Osanai, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
Stroke, 49, 8, 1960, 1968, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.

Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Moyamoya Disease: Region-Symptom Mapping and Estimating a Critical Threshold.
Ken Kazumata, Haruto Uchino, Kikutaro Tokairin, Masaki Ito, Tohru Shiga, Toshiya Osanai, Masahito Kawabori
World neurosurgery, 114, e388-e395, e395, 2018年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Cerebral hyperperfusion complicates the postoperative course of patients with moyamoya disease after direct revascularization surgery. There is no clear distinction between cerebral hyperperfusion syndrome and benign postoperative increase in regional cerebral blood flow (rCBF). OBJECTIVE: The present study aimed to determine clinically relevant changes in rCBF, anatomical correlations, and factors associated with transient neurologic symptoms after revascularization surgery in moyamoya disease. METHODS: Whole-brain voxel-based perfusion mapping was used to identify regions involved in cerebral hyperperfusion and quantify the changes in 105 hemispheric surgeries with the use of single-photon computed tomography acquired on postoperative day 7. The changes in rCBF were quantitatively analyzed, and associations with cerebral hyperperfusion syndrome were determined. RESULTS: Transient neurologic symptoms appeared with rCBF increase in 37.9% of adults. Speech impairments were associated with an increase in rCBF in the operculo-insula region. Cheiro-oral syndrome was associated with the posterior insula as well as the prefrontal region. A receiver operating curve analysis yielded transient neurologic symptoms with maximum accuracy at >15.5% increase from baseline. Age and preoperative rCBF were independently associated with transient neurologic symptoms (P < 0.001). CONCLUSIONS: Areas showing rCBF increase during the experience of transient neurologic symptoms were spatially compatible with the known functional anatomy of the brain. An increase of approximately 15% from baseline was found to be critical, which is a far lower threshold than what has been reported previously. Increasing age was significantly associated with the occurrence of symptomatic hyperperfusion. Furthermore, patients with preserved rCBF also showed symptomatic hyperperfusion.

[18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia.
Chengbo Tan, Songji Zhao, Kei Higashikawa, Zifeng Wang, Masahito Kawabori, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Naoyuki Ukon, Hironobu Yasui, Nagara Tamaki, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin
EJNMMI research, 8, 1, 35, 35, 2018年05月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. RESULTS: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. CONCLUSIONS: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

Characteristics of Symptomatic Intracerebral Hemorrhage in Patient Receiving Direct Oral Anticoagulants: Comparison with Warfarin.
Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shoji Mabuchi, Hiroyuki Ozaki, Koji Matsubara, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 27, 5, 1338, 1342, 2018年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated. METHODS: We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015. RESULTS: Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time. CONCLUSIONS: Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak.

Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke.
Michiyuki Miyamoto, Kentaro Nakamura, Hideo Shichinohe, Tomohiro Yamauchi, Masaki Ito, Hisayasu Saito, Masahito Kawabori, Toshiya Osanai, Tasuku Sasaki, Kiyohiro Houkin, Satoshi Kuroda
Stem cells international, 2018, 4829534, 4829534, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

Serial Arterial Spin Labeling May Be Useful in Assessing the Therapeutic Course of Cerebral Venous Thrombosis: Case Reports.
Sho Furuya, Masahito Kawabori, Noriyuki Fujima, Kikutaro Tokairin, Shuho Goto, Motoyuki Iwasaki, Yoshimasa Niiya, Shoji Mabuchi
Neurologia medico-chirurgica, 57, 10, 557, 561, JAPAN NEUROSURGICAL SOC, 2017年10月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We report two cases of cerebral venous thrombosis (CVT) which serial arterial spin labeling (ASL) was useful in evaluating the clinical course of the disease. A 48-year-old female presented with acute seizure, and was diagnosed as transverse-sigmoid sinus thrombosis. ASL imaging revealed low signal intensity in the right temporal lobe, suggesting the decreased perfusion by elevated venous pressure. Soon after the treatment, while the development of venous collateral has not fully observed by magnetic resonance (MR) angiography, low ASL signal within the right temporal lobe have shown remarkable improvement. A 65-year-old female presented with vomiting and subsequent seizure was diagnosed as superior sagittal sinus thrombosis. The low ASL signal within the right frontal lobe seen in the acute stage improved to the normal level by the course of time, before the good collateral can be seen by MR angiography. This is the first report to assess the sequential change of the cerebral perfusion of CVT by ASL, and ASL may provide additional useful information in combination with conventional modalities.

Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke.
Hideo Shichinohe, Masahito Kawabori, Hiroaki Iijima, Tuyoshi Teramoto, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Shunsuke Terasaka, Teruyo Arato, Kiyohiro Houkin
BMC neurology, 17, 1, 179, 179, BIOMED CENTRAL LTD, 2017年09月08日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW). METHODS/DESIGN: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001-01 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F-fuorodeoxyglucose positron emission tomography, and 123I-Iomazenil single-photon emission computed tomography will be performed for 1 year after the administration. DISCUSSION: This is a first-in-human trial for HUNS001-01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms. TRIAL REGISTRATION: The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130 ). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Route, cell dose, and timing
Masahito Kawabori
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 73, 85, Springer Japan, 2017年01月01日, ［査読有り］
英語, 論文集(書籍)内論文, Cell transplantation therapy has been expected as one of the novel therapeutic strategies. However, there still exist several fundamental problems to be solved prior to clinical application of stem cell transplantation, such as optimal cell types, transplantation routes, cell dose, and transplantation timing. It is quite important to determine the most desirable and the maximal therapeutic effects of transplantation methods prior to clinical application of cell-based therapy, but there are not so many studies that scientifically determine the most favorable protocol even in animal experiments. Here, we will review and summarize the current experimental results focusing on the unsolved questions, optimal transplantation route, transplantation cell dose, and transplantation timings.

A case of midbrain infarction with acute bilateral cerebellar ataxia visualized by diffusion tensor imaging.
Yuka Maya, Masahito Kawabori, Daisuke Oura, Yoshimasa Niiya, Motoyuki Iwasaki, Shoji Mabuchi
Rinsho shinkeigaku = Clinical neurology, 56, 8, 565, 8, 2016年08月31日, ［査読有り］, ［国内誌］
日本語, An 85-year-old woman with hypertension was admitted with a sudden onset of gait disturbance and dysarthria. On admission, the patient showed severe bilateral cerebellar ataxia with moderate right medial longitudinal fasciculus (MLF) syndrome. Magnetic resonance (MR) imaging showed an acute infarction in the lower and medial part of midbrain. Diffusion tensor imaging (DTI) started from both cerebellar peduncles revealed that the lesion of the acute infarction matched the decussation of superior cerebellar peduncle where crossing of tract was seen and a part of its tract was interrupted at the site. Interruption of the cerebellum red nuclear path at the medial part of midbrain was considered to be the reason for bilateral cerebellar ataxia and visualization of cerebellum red nuclear path by DTI can give better understanding of the neurological symptom.

The role of the microglia in acute CNS injury.
Masahito Kawabori, Midori A Yenari
Metabolic brain disease, 30, 2, 381, 92, 2015年04月, ［査読有り］, ［国際誌］
英語, Microglia are considered the brain's resident immune cell involved in immune defense, immunocompetence, and phagocytosis. They maintain tissue homeostasis within the brain and spinal cord under normal condition and serves as its initial host defense system. However, when the central nervous system (CNS) faces injury, microglia respond through signaling molecules expressed or released by neighboring cells. Microglial responses are dual in nature. They induce a nonspecific immune response that may exacerbate CNS injury, especially in the acute stages, but are also essential to CNS recovery and repair. The full range of microglial mechanisms have yet to be clarified, but there is accumulating knowledge about microglial activation in acute CNS injury. Microglial responses require hours to days to fully develop, and may present a therapeutic target for intervention with a much longer window of opportunity compare to other neurological treatments. The challenge will be to find ways to selectively suppress the deleterious effects of microglial activation without compromising its beneficial functions. This review aims to provide an overview of the recent progress relating on the deleterious and beneficial effect of microglia in the setting of acute CNS injury and the potential therapeutic intervention against microglial activation to CNS injury.

Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke.
Masahito Kawabori, Rachid Kacimi, Tiina Kauppinen, Cyrus Calosing, Jong Youl Kim, Christine L Hsieh, Mary C Nakamura, Midori A Yenari
The Journal of neuroscience : the official journal of the Society for Neuroscience, 35, 8, 3384, 96, 2015年02月25日, ［査読有り］, ［国際誌］
英語, Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore TREM2 in both in vitro and in vivo stroke models and identify a potential endogenous TREM2 ligand. TREM2 knockdown in microglia reduced microglial activation to an amoeboid phenotype and decreased the phagocytosis of injured neurons. Phagocytosis and infarcted brain tissue resorption was reduced in TREM2 knock-out (KO) mice compared with wild-type (WT) mice. TREM2 KO mice also had worsened neurological recovery and decreased viable brain tissue in the ipsilateral hemisphere. The numbers of activated microglia and phagocytes in TREM2 KO mice were decreased compared with WT mice, and foamy macrophages were nearly absent in the TREM2 KO mice. Postischemia, TREM2 was highly expressed on microglia and TREM2-Fc fusion protein (used as a probe to identify potential TREM2 binding partners) bound to an unknown TREM2 ligand that colocalized to neurons. Oxygen glucose deprivation-exposed neuronal media, or cellular fractions containing nuclei or purified DNA, but not cytosolic fractions, stimulated signaling through TREM2. TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia.

Inflammatory responses in brain ischemia.
Masahito Kawabori, Midori A Yenari
Current medicinal chemistry, 22, 10, 1258, 77, 2015年, ［査読有り］, ［国際誌］
英語, Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke.

Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets
J. Y. Kim, M. Kawabori, M. A. Yenari
CURRENT MEDICINAL CHEMISTRY, 21, 18, 2076, 2097, BENTHAM SCIENCE PUBL LTD, 2014年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke.

Clinical significance of STA-MCA double anastomosis for hemodynamic compromise in post-JET/COSS era.
Satoshi Kuroda, Masahito Kawabori, Kenji Hirata, Tohru Shiga, Daina Kashiwazaki, Kiyohiro Houkin, Nagara Tamaki
Acta neurochirurgica, 156, 1, 77, 83, SPRINGER WIEN, 2014年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Even after the recent randomized clinical trials JET and COSS, it is still unclear that impaired cerebrovascular reactivity (CVR) to acetazolamide and oxygen extraction fraction (OEF) can identify the candidates for superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. This prospective study was aimed to evaluate the benefits of STA-MCA "double" anastomosis on long-term outcome in patients with reduced cerebral blood flow (CBF) and CVR (Type 3 ischemia) and elevated OEF attributable to occlusive carotid diseases. METHODS: This study included 49 patients with reduced CBF and CVR on SPECT in the ipsilateral MCA area. Using (15)O-gas PET, OEF was also measured in all patients. STA-MCA double anastomosis was recommended to the patients with Type 3 and elevated OEF. Those with Type 3 but normal OEF were medically treated. RESULTS: Of 36 patients with Type 3 and elevated OEF, 25 consented to surgery. No perioperative morbidity or mortality were noted. The other 11 patients with Type 3 and elevated OEF were medically treated. Annual incidence of ipsilateral stroke was 0.7% and 6.5% in surgically and medically treated patients with Type 3 and elevated OEF, respectively (P = 0.0188). None of patients with Type 3 but normal OEF developed ipsilateral stroke during follow-up periods. STA-MCA "double" anastomosis significantly decreased OEF. CONCLUSIONS: STA-MCA "double" anastomosis may still have the potential to reduce the risk of recurrent ipsilateral stroke in hemodynamically compromised patients. Further studies would be essential to advance diagnosis, surgical procedures, and perioperative managements to bring out maximal effects of bypass surgery.

Triggering Receptor Expressed on Myeloid Cells-2 Correlates to Hypothermic Neuroprotection in Ischemic Stroke.
Masahito Kawabori, Masaaki Hokari, Zhen Zheng, Jong Youl Kim, Cyrus Calosing, Christine L Hsieh, Mary C Nakamura, Midori A Yenari
Therapeutic hypothermia and temperature management, 3, 4, 189, 198, 2013年12月01日, ［査読有り］, ［国際誌］
英語, Hypothermia is neuroprotective against many acute neurological insults, including ischemic stroke. We and others have previously shown that protection by hypothermia is partially associated with an anti-inflammatory effect. Phagocytes are thought to play an important role in the clearance of necrotic debris, paving the way for endogenous repair mechanisms to commence, but the effect of cooling and phagocytosis has not been extensively studied. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified surface receptor shown to be involved in phagocytosis. In this study, we examined the effect of therapeutic hypothermia on TREM2 expression. Mice underwent permanent middle cerebral artery occlusion (MCAO) and were treated with one of the two cooling paradigms: one where cooling (30°C) began at the onset of MCAO (early hypothermia [eHT]) and another where cooling began 1 hour later (delayed hypothermia [dHT]). In both groups, cooling was maintained for 2 hours. A third group was maintained at normothermia (NT) as a control (37°C). Mice from the NT and dHT groups had similar ischemic lesion sizes and neurological performance, but the eHT group showed marked protection as evidenced by a smaller lesion size and less neurological deficits up to 30 days after the insult. Microglia and macrophages increased after MCAO as early as 3 days, peaked at 7 days, and decreased by 14 days. Both hypothermia paradigms were associated with decreased numbers of microglia and macrophages at 3 and 7 days, with greater decreases in the early paradigm. However, the proportion of the TREM2-positive microglia/macrophages was actually increased among the eHT group at day 7. eHT showed a long-term neurological benefit, but neuroprotection did not correlate to immune suppression. However, hypothermic neuroprotection was associated with a relative increase in TREM2 expression, and suggests that TREM2 may serve a beneficial role in brain ischemia.

Effective surgical revascularization improves cerebral hemodynamics and resolves headache in pediatric Moyamoya disease.
Masahito Kawabori, Satoshi Kuroda, Naoki Nakayama, Kenji Hirata, Toru Shiga, Kiyohiro Houkin, Nagara Tamaki
World neurosurgery, 80, 5, 612, 9, 2013年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Headache is one of the major clinical presentations in pediatric Moyamoya disease. However, the clinical features and underlying mechanisms are not fully understood. This study aimed to clarify the clinical feature of headache in pediatric Moyamoya disease and the effect of surgical revascularization. METHODS: This study included 29 pediatric patients who underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass for Moyamoya disease. Their medical records were precisely evaluated to identify the clinical features of their headache. The findings on magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography also were analyzed. RESULTS: Preoperative headache was documented in 11 (38%) of 29 patients. The majority of them complained of severe headache in the frontal or temporal region in the morning. Headache was significantly related to more advanced disease stage and to the decreases in cerebral blood flow and its reactivity to acetazolamide. Surgical revascularization completely resolved headache in all 11 patients. CONCLUSIONS: These findings strongly suggest that disturbed cerebral hemodynamics may play key roles in developing severe headache in pediatric Moyamoya disease. STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis may be effective procedures to rapidly resolve headache by widely supplying collateral blood flow to the operated hemispheres.

Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy.
Masaki Ito, Tetsuyuki Yoshimoto, Masahito Kawabori, Shin Fujimoto, Tohru Yamauchi, Hideshi Yamaguchi, Kouichi Tokuda, Sadao Kaneko
Clinical neurology and neurosurgery, 115, 8, 1464, 9, 2013年08月, ［査読有り］, ［国際誌］
英語, OBJECTIVE: To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). METHODS: We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. RESULTS: Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 (n=3) and 0.3±0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% (n=3) and 0.43±0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. CONCLUSION: These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy.

Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets.
Masahito Kawabori, Rachid Kacimi, Joel S Karliner, Midori A Yenari
World journal of cardiology, 5, 4, 75, 86, 2013年04月26日, ［査読有り］, ［国際誌］
英語, The sphingolipid metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) and its enzyme sphingosine kinase (SphK) play an important role in the regulation of cell proliferation, survival, inflammation, and cell death. Ceramide and sphingosine usually inhibit proliferation and promote apoptosis, while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate. The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic ceramide and sphingosine. Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease, and these observations have considerable relevance for future potential therapeutic targets.

Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct.
Masahito Kawabori, Satoshi Kuroda, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
Neuropathology : official journal of the Japanese Society of Neuropathology, 33, 2, 140, 8, 2013年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1 × 10(5) or 1 × 10(6) ) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.

Experience of (123)I-iomazenil SPECT study for crossed cerebellocerebral diaschisis: report of two cases.
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Naoki Nakayama, Satoshi Kuroda, Shoji Mabuchi, Kiyohiro Houkin
Clinical neurology and neurosurgery, 114, 9, 1274, 6, 2012年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats.
Masaki Ito, Satoshi Kuroda, Taku Sugiyama, Katsuhiko Maruichi, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin, Yoshinobu Iwasaki
Neuropathology : official journal of the Japanese Society of Neuropathology, 32, 5, 522, 33, 2012年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke.

Systematic review of complications for proper informed consent (4) cerebrospinal fluid shunts for hydrocephalus and related disorders
Masaki Ito, Kiyohiro Houkin, Hisayasu Saito, Daisuke Shimbo, Hiroaki Motegi, Masahito Kawabori, Michiyuki Miyamoto, Tomohiro Yamauchi
Neurological Surgery, 40, 10, 923, 945, 2012年10月, ［査読有り］
日本語, Cerebrospinal fluid (CSF) shunts are commonly employed to treat patients with hydrocephalus. A large number of papers have been published focusing on complications and failures of CSF shunts. However, there appears to be a paucity of knowledge comprehensively covering both common complications and rare ones. In this systematic review, we surveyed articles about surgical complications of CSF shunts as comprehensively as possible. Quantitative analysis was performed to determine the frequency of well-known complications, mortality and revision rates of CSF shunts. Furthermore, rare complications of CSF shunts have also been reviewed.

Systematic review of complications for proper informed consent (3) surgery for unruptured middle cerebral artery aneurysm
Masahito Kawabori, Ken Kazumata, Kosuke Ohnishi, Taku Sugiyama, Masaki Itoh, Naoki Nakayama, Kiyohiro Houkin
Neurological Surgery, 40, 8, 731, 740, 2012年08月, ［査読有り］
日本語, Although a large number of patients with unruptured middle cerebral artery (MCA) aneurysms (AN) have been treated by surgical clipping in Japan, there has yet been no comprehensive study investigating the surgical risks based on a quantitative evaluation of the extensive existing body of patient records. This systematic review was conducted to determine morbidity of the procedure by performing a meta-analysis of the literature. The authors used a PubMed and J-stage search from 2000 to 2011 for studies containing the surgical clipping of the unruptured MCA AN. There were 21 articles, containing a total 1.323 cases of unruptured AN with morbidity specifically located in the MCA. 54 cases indicated significant neurological deficits for a morbidity rate of 4.1% (95% CI
3.0-5.1). A limited number of studies disclosed an incremental increase in morbidity with the size of the aneurysm. Smaller MCA AN (7±3 mm) presented a lower morbidity of 1.48%. whereas giant MCA AN (>
25 mm) corresponded with a higher morbidity of 27.8%. Factors consistently associated with high morbidity included incorporated MCA branches, plaque at the neck of the AN, an unclippable configuration, and M1 superior wall AN. Complex aneurysms required a wide array of intracranial bypass procedures, yielding morbidity of 23.4% (95% CI
20.9-25.9). This is the first systematic review and quantitative meta-analysis of the surgical complications related to unruptured MCA AN.

Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: an optical imaging study.
Masahito Kawabori, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
Neuropathology : official journal of the Japanese Society of Neuropathology, 32, 3, 217, 26, 2012年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 × 10⁶ cells) or intravenously (3 × 10⁶ cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

Visualization of the Superparamagnetic Iron Oxide (SPIO)-Labeled Bone Marrow Stromal Cells Using a 3.0-T MRI-a Pilot Study for Clinical Testing of Neurotransplantation.
Hideo Shichinohe, Satoshi Kuroda, Kohsuke Kudo, Masaki Ito, Masahito Kawabori, Michiyuki Miyamoto, Mitsuhiro Nakanishi, Satoshi Terae, Kiyohiro Houkin
Translational stroke research, 3, 1, 99, 106, 2012年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have elucidated that transplantation of the bone marrow stromal cells (BMSC) has therapeutic potential for the central nervous system (CNS) disorders. However, no imaging modalities have been established to track the engrafted cells in the CNS in clinical situation. This study aimed to investigate the ability of magnetic resonance imaging (MRI) to visualize the BMSC labeled with superparamagnetic iron oxide (SPIO). The BMSC of mice were labeled with SPIO. Various numbers of the cells were injected into the agar phantom and were visualized using a 3.0-T MR apparatus. The SPIO-labeled cells were injected into the temperature-sensitive gelation polymer (TGP) hydrogel and were cultured for 7 days. They were also visualized just after the injection and at 7 days postinjection. After a 7-day culture, they were stained with Turnbull blue technique. T2-, T2*-, and susceptibility-weighted imaging could identify minimally 1,000 cells in the agar or TGP hydrogel, although it was difficult to quantify their number on MRI. All of these sequences could track the SPIO-labeled BMSC for at least 7 days when injected into the TGP. Turnbull blue staining revealed the survival and proliferation of the SPIO-labeled BMSC in the TGP for 7 days. The findings strongly suggest that the SPIO labeling may enable to track minimally 1,000 cells engrafted in the CNS on clinical MR apparatus. These data would be valuable to consider the application of imaging technique into cell transplantation therapy for CNS disorders.

Therapeutic effects of intra-arterial delivery of bone marrow stromal cells in traumatic brain injury of rats--in vivo cell tracking study by near-infrared fluorescence imaging.
Toshiya Osanai, Satoshi Kuroda, Taku Sugiyama, Masahito Kawabori, Masaki Ito, Hideo Shichinohe, Yuji Kuge, Kiyohiro Houkin, Nagara Tamaki, Yoshinobu Iwasaki
Neurosurgery, 70, 2, 435, 44, 2012年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders. OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats. METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry. RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation. CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization.

Neurohypophyseal germinoma with abundant fibrous tissue.
Shunsuke Terasaka, Masahito Kawabori, Hiroyuki Kobayashi, Junichi Murata, Hiromi Kanno, Shinya Tanaka, Kiyohiro Houkin
Brain tumor pathology, 29, 1, 58, 62, 2012年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We report an unusual case of neurohypophyseal germinoma with abundant fibrous tissue and clival invasion that was initially misdiagnosed as lymphocytic hypophysitis. A 40-year-old woman presented with diabetes insipidus and panhypopituitarism after delivering her second son and which lasted for 4 years. Magnetic resonance imaging showed the intrasellar mass extending to the suprasellar region with enlarged pituitary stalk. The mass was heterogeneously enhanced and invaded the clivus. Biopsy of the intrasellar mass was performed via the trans-sphenoidal route, and histological examination revealed marked fibrous tissue and infiltration of lymphocytes, with no evidence of tumor cells. Lymphocytic hypophysitis was the initial diagnosis, and corticosteroid therapy was begun. Despite intensive treatment, the lesion enlarged and clinical symptoms worsened 2 weeks after surgery. Subtotal removal of the mass was performed, and a second histological examination revealed typical findings of the germinoma. Subsequently, the patient underwent chemoradiotherapy, and complete remission was achieved. Histological diagnosis is sometimes incorrect in fibrous tumors at the sellar region, and biopsy from several points is strongly recommended for this entity.

Pituitary apoplexy manifesting as massive intracerebral hemorrhage. Case report.
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
Neurologia medico-chirurgica, 52, 8, 587, 90, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.

骨髄間質細胞移植は脳梗塞後の局所糖代謝を改善する―小動物用PET/CTによる検討　　　　　　　　　　　　　　　
宮本倫行, 黒田敏, 趙松吉, 孫田恵一, 伊東雅基, 川堀真人, 丸一勝彦, 七戸秀夫, 宝金清博, 久下裕司, 玉木長良
再生医療, 11, 191, 2012年
日本語, 研究論文（その他学術会議資料等）

脳梗塞をターゲットとした骨髄間質細胞移植―新たな培養・移植・イメージング技術による展開　　　　　　　　　　　　　　　
黒田敏, 宮本倫行, 山内朋裕, 斉藤久泰, 伊東雅基, 川堀真人, 杉山拓, 千葉泰弘, 七戸秀夫, 宝金清博, 久下裕司, 趙松吉, 玉木長良
再生医療, 11, 136, 2012年
日本語, 研究論文（その他学術会議資料等）

Bilateral chronic subdural hematomas of the posterior fossae.
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
Neurologia medico-chirurgica, 52, 11, 822, 5, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

Spontaneous echo contrast and thrombus formation at the carotid bifurcation after carotid endarterectomy.
Masahito Kawabori, Tetsuyuki Yoshimoto, Masaki Ito, Shin Fujimoto, Taisei Mikami, Mutsuko Muraki, Sadao Kaneko, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
Neurologia medico-chirurgica, 52, 12, 885, 91, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Spontaneous echo contrast (SEC) consists of numerous microechoes swirling in the cardiovascular lumen and is usually seen during blood stasis in dysfunctional left atrium. However, SEC and consecutive local thrombus formation at the carotid artery early after carotid endarterectomy (CEA) have not been reported. This study retrospectively investigated the clinical importance and therapeutic strategy of postoperative SEC and thrombus formation in 113 consecutive patients who underwent CEA between 2001 and 2009. Ultrasonography was routinely performed preoperatively, intraoperatively, and 1 day and 1 week after the operation. If SEC and/or thrombus was detected at any time after the operation, follow-up ultrasonography was performed at short intervals, once a week for inpatients and once every 1-2 months for outpatients. Eight of the 113 patients (7%) had SEC after the operation from Day 1 to 12 (mean 7.2 days), and 6 of these 8 patients developed local de novo thrombus formation at the site of SEC from Day 6 to 33 (mean 14.7 days). The maximum luminal narrowing by the thrombi were 26-62% (mean 37%). After administering anticoagulant therapy, all thrombi disappeared from Day 13 to 190 (mean 57 days) from CEA. SEC seen after CEA is highly associated with consecutive local thrombus formation. Postoperative geometric blood stasis with the absence of intima may be the causative factor for its development.

A possible mechanism of isolated oculomotor nerve palsy by apoplexy of pituitary adenoma without cavernous sinus invasion: a report of two cases.
Hiroyuki Kobayashi, Masahito Kawabori, Shunsuke Terasaka, Junichi Murata, Kiyohiro Houkin
Acta neurochirurgica, 153, 12, 2453, 6, 2011年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Isolated oculomotor nerve palsy occasionally occurs in patients with cavernous sinus invasion with or without pituitary apoplexy. We describe two cases of pituitary apoplexy without cavernous sinus invasion presenting with isolated oculomotor palsy. In both cases, computed tomography (CT) showed erosion of the right posterior clinoid process. Magnetic resonance imaging (MRI) depicted pituitary adenoma with apoplexy protruding latero-posteriorly to the right cavernous sinus. The medio-posterior wall of the cavernous sinus was markedly displaced latero-posteriorly by the tumor, and there was no evidence of cavernous sinus invasion. Oculomotor palsy may be caused first by unilateral erosion of the posterior clinoid process, resulting in latero-posterior protrusion of the adenoma. Hemorrhage may result in sudden kinking of the oculomotor nerve at the entrance of the oculomotor trigone.

Biological Features of Human Bone Marrow Stromal Cells (hBMSC) Cultured with Animal Protein-Free Medium-Safety and Efficacy of Clinical Use for Neurotransplantation.
Hideo Shichinohe, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Masahito Kawabori, Mitsufumi Nishio, Yukari Takeda, Takao Koike, Kiyohiro Houkin
Translational stroke research, 2, 3, 307, 15, 2011年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The donor cell culture in animal serum-free medium is quite important for the clinical application of cell transplantation therapy. This study was aimed to test the hypothesis that the human bone marrow stromal cells (hBMSC) expanded with fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium retain their biological features favoring central nervous system regeneration. The hBMSC were cultured with 5% PL or 10% FCS. Their phenotypes were analyzed with flow cytometry, and their production of growth factors was quantified with enzyme-linked immunosorbent assay. Their capacity of neural differentiation was verified by immunocytochemistry. There was no significant difference in morphology and cell surface marker between the hBMSC-FCS and hBMSC-PL. Both of them were positive for CD44, CD90, CD105, and CD166 and were negative for CD34, CD45, and CD271. The production of human brain-derived neurotrophic factor, human hepatocyte growth factor, human β-nerve growth factor, and human platelet-derived growth factor-BB did not differ between the two groups, although the hBMSC-PL produced significantly more amount of TGF-β1 than the hBMSC-FCS. There was no significant difference in their in vitro differentiation into the neurons and astrocytes between the two groups. The hBMSC expanded with PL-containing medium retain their biological capacity of neural differentiation and neuroprotection. The PL may be a clinically valuable and safe substitute for FCS in expanding the hBMSC for cell therapy.

[A rare case of diffuse astrocytoma complicated with giant pigmented hairy nevi, suspected neurocutaneous melanosis].
Yuuta Kamoshima, Yutaka Sawamura, Nobuharu Saitoh, Masahito Kawabori, Kiyohiro Houkin, Kanako Kubota
No shinkei geka. Neurological surgery, 39, 5, 479, 83, 2011年05月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, A 1-year-old female infant presented with congenital giant, hairy and pigmented nevi. MRI scan as screening test revealed a cerebellar tumor. A diagnosis of provisional neurocutaneous melanosis was made on the basis of the patient's MRI and physical findings. At her 6 years of age, MRI revealed the tumor grown up to 3 cm diameter in 5 years. The cerebellar tumor was removed partially using the occipital transtentorial approach for tissue diagnosis. The color of the cerebellar tumor was whitish and contained neither benign nor malignant melanocyte. Pathological examination revealed diffuse astrocytoma. Finally residual cerebellar tumor was totally removed at a second surgical resection. To our knowledge, this is the first patient to be reported with astrocytoma complicated giant skin nevus except neurocutaneous syndrome cases.

Near-infrared fluorescence labeling allows noninvasive tracking of bone marrow stromal cells transplanted into rat infarct brain.
Taku Sugiyama, Satoshi Kuroda, Toshiya Osanai, Hideo Shichinohe, Yuji Kuge, Masaki Ito, Masahito Kawabori, Yoshinobu Iwasaki
Neurosurgery, 68, 4, 1036, 47, 2011年04月, ［査読有り］, ［国際誌］
英語, BACKGROUND: Noninvasive imaging techniques would be needed to validate the therapeutic benefits of cell transplantation therapy for central nervous system disorders. OBJECTIVE: To evaluate whether near-infrared (NIR)-emitting fluorescence tracer, quantum dots, would be useful to noninvasively visualize the bone marrow stromal cells (BMSC) transplanted into the infarct brain in living animals. METHODS: Rat BMSCs were labeled with QD800. In vitro and in vivo conditions to visualize NIR fluorescence were precisely optimized. The QD800-labeled BMSCs were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Using the NIR fluorescence imaging technique, the behaviors of BMSCs were serially visualized during the 8 weeks after transplantation. RESULTS: NIR fluorescence imaging could noninvasively detect the NIR fluorescence emitted from the transplanted BMSCs engrafted in the peri-infarct neocortex through the scalp up to 8 weeks after transplantation. The intensity gradually increased and reached the peak at 4 weeks. The results were supported by the findings on ex vivo NIR fluorescence imaging and histological analysis. CONCLUSION: NIR fluorescence imaging is valuable in monitoring the behaviors of donor cells in the rodent brain. The results would allow new opportunities to develop noninvasive NIR fluorescence imaging as a modality to track the BMSCs transplanted into the brain.

Revascularization surgery for asymptomatic adult moyamoya disease presenting silent disease progression: Report of two cases
Kagari Kawai, Satoshi Kuroda, Masahito Kawabori, Naoki Nakayama, Shunsuke Terasaka, Yoshinobu Iwasaki
Neurological Surgery, 38, 9, 825, 830, 2010年09月10日, ［査読有り］
英語, 研究論文（学術雑誌）, The authors describe two cases with asymptomatic moyamoya disease. Both of them demonstrated the progression of disease stage on follow-up MRA and DSA, although they were still asymptomatic. The intervals between initial diagnosis and disease progression were 10 and 36 months, respectively. Their SPECT or PET study also revealed a deterioration of cerebral hemodynamics in the involved hemispheres. They underwent superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and indirect bypass on the involved hemispheres in order to reduce the risk of subsequent occurrence of ischemic stroke. Postoperative courses were uneventful. Follow-up radiological examinations showed well-developed surgical collaterals and improved cerebral hemodynamics on the operated hemispheres. In conclusion, the patients with asymptomatic moyamoya disease should be carefully followed up in order to avoid overlooking latent progression of disease stage. Surgical revascularization should be considered when disease stage progresses even if the patients are still asymptomatic, although further investigations are needed to establish the indication for surgical revascularization for asymptomatic moyamoya disease.

病期が進行した無症候性成人もやもや病に対する脳血行再建術 2例報告
川合 かがり, 黒田 敏, 川堀 真人, 中山 若樹, 寺坂 俊介, 岩崎 喜信
Neurological Surgery, 38, 9, 825, 830, (株)医学書院, 2010年09月
日本語, 症例1:50歳女。頭部打撲で受診し、脳血管撮影上右2期、左3期のもやもや病と診断した。左MCA領域でACZ反応性の低下を認めたが、酸素摂取率(OEF)が正常範囲であったため保存的に経過観察した。10ヵ月後の脳血管撮影で左4期へ進行、PETで左前頭葉の安静時脳血流(CBF)とacetazolamide(ACZ)反応性の顕著な低下を認めた。初診後15ヵ月に脳血行再建術として左STA-MCA anastomosisおよび間接バイパス術を施行した。術後3ヵ月に側副血行路の形成および左前頭葉を中心とした脳循環動態の改善を認めた。症例2:50歳女。交通事故を契機に脳血管撮影にて右2期、左3期のもやもや病と診断した。CBFやACZ反応性がほぼ正常のため保存的に経過観察とした。3年後の脳血管撮影で左4期へ進行、SPECTで左前頭葉のACZ反応性の低下を認めた。症例1同様の脳血行再建術を初診後3年2ヵ月に施行し、術後4ヵ月の脳血管撮影およびPETで症例1同様の改善を認めた。

Therapeutic strategies for patients with internal carotid or middle cerebral artery occlusion complicated by severe coronary artery disease.
Masahito Kawabori, Satoshi Kuroda, Shunsuke Terasaka, Naoki Nakayama, Yoshiro Matsui, Suguru Kubota, Masanori Nakamura, Katsuhiko Nakanishi, Fumiyuki Okamoto, Yoshinobu Iwasaki
World neurosurgery, 73, 4, 345, 50, 2010年04月, ［査読有り］, ［国際誌］
英語, BACKGROUND/OBJECTIVES: Ischemic stroke is one of major complications of cardiac surgery. Although a current American Heart Association (AHA) guideline states that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) for the carotid stenosis, there is no report that analyzed optimal strategies in cardiac surgery for patients with total occlusion of the internal carotid artery (ICA) or the middle cerebral artery (MCA). Therefore, this preliminary study was aimed to clarify whether preoperative blood flow measurements and prophylactic superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis could reduce the incidence of perioperative ischemic stroke during cardiac surgery in patients with total occlusion of the ICA or MCA. METHODS: This prospective study included eight patients who were admitted to undergo cardiac surgery including CABG. All of them had total ICA or MCA occlusion on preoperative magnetic resonance (MR) examinations. Preoperative cerebral blood flow and its reactivity to acetazolamide were quantitatively determined in all eight patients using single photon emission computed tomography or positron emission tomography. RESULTS: Preoperative blood flow measurements revealed that two (25%) of eight patients had normal cerebral hemodynamics because of well-developed collaterals. They safely underwent cardiac surgery. However, a marked impairment of cerebral perfusion reserve was identified in six (75%) of eight patients in the ipsilateral hemispheres. Of these, four patients underwent prophylactic STA-MCA anastomosis prior to CABG. Subsequently, they safely underwent CABG without perioperative ischemic stroke. CONCLUSION: This is the first report suggesting that preoperative identification of hemodynamic compromise and prophylactic STA-MCA anastomosis may reduce perioperative ischemic stroke during cardiac surgery in patients with ICA or MCA occlusion, although further studies are needed to assess the validity.

Bone marrow stromal cell transplantation attenuates cognitive dysfunction due to chronic cerebral ischemia in rats.
Hideo Shichinohe, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Masahito Kawabori
Dementia and geriatric cognitive disorders, 30, 4, 293, 301, 2010年, ［査読有り］, ［国際誌］
英語, AIMS: This study was aimed to elucidate if bone marrow stromal cells (BMSC) could ameliorate cognitive dysfunction due to chronic cerebral ischemia when transplanted into the brain. METHODS: The BMSC were harvested from green fluorescence protein (GFP)-expressing mice. Wistar rats were subjected to bilateral common carotid artery (CCA) ligation. The BMSC (4 × 10⁵ cells) or vehicle were stereotactically injected into the right striatum 24 h after the insult. Cognitive function was evaluated with the Morris water maze task after 3 and 5 weeks. Histological analysis was performed after 6 weeks. RESULTS: Cognitive function was significantly impaired in the vehicle-transplanted animals, when compared with the non-CCA-ligation animals. BMSC transplantation significantly improved it. The BMSC were widely distributed in the ischemic brain, including the neocortex, white matter and hippocampus, and some of them expressed the phenotypes of neurons, astrocytes and endothelium. They also significantly ameliorated white matter damage. CONCLUSIONS: These findings strongly suggest that the BMSC may have the potential to attenuate white matter injury and improve cognitive dysfunction due to chronic cerebral ischemia. The present results would shed light on the potential of a novel strategy, cell therapy against ischemia-related cognitive dysfunction.

Intracerebral hemorrhage from a ruptured aneurysm at the site of anastomosis 27 years after superficial temporal artery-middle cerebral artery bypass.
Masaaki Hokari, Hiroshi Yasuda, Motoyuki Iwasaki, Masahito Kawabori, Satoshi Kuroda, Satoru Abe, Hisatoshi Saitoh
Neurologia medico-chirurgica, 50, 11, 1012, 4, 2010年, ［査読有り］, ［国内誌］
英語, A 77-year-old female presented with a very rare case of intracerebral hemorrhage (ICH) from a ruptured aneurysm at the site of the anastomosis 27 years after superficial temporal artery-middle cerebral artery (STA-MCA) bypass manifesting as sudden onset of unconsciousness and right hemiparesis. Computed tomography (CT) on admission demonstrated massive ICH in the left frontoparietal region. Magnetic resonance angiography showed good patency of the anastomosis and no obvious aneurysm, but three-dimensional CT (3D-CT) angiography revealed a small aneurysm at the site of the left STA-MCA anastomosis. Emergency evacuation of the hematoma was performed, and the aneurysm was trapped and resected after ligation. After the operation, she continued to exhibit deep consciousness disturbance. Unfortunately, her general condition grew steadily worse and she died 3 months later. Patients who undergo STA-MCA anastomosis should be carefully followed up by periodical imaging examinations. 3D-CT angiography is very useful to detect aneurysm formation at the anastomosis site.

A Case of Brainstem Variant of Reversible Posterior Leukoencephalopathy Syndrome
Masahito Kawabori, Junichi Murata, Satoru Abe, Hisatoshi Saito
NEUROLOGICAL SURGERY, 37, 11, 1105, 1109, IGAKU-SHOIN LTD, 2009年11月, ［査読有り］
日本語, 研究論文（学術雑誌）, A rare case of a brainstem variant of reversible posterior leukoencephalopathy syndrome (RPLS) is reported. A 34-year-old man with a past history of untreated chronic renal failure and hypertension was admitted to our hospital complaining of severe nuchal headache lasting for about four days. His neurological examination was normal, however physical examination revealed his blood pressure was 216/120 mmHg. Computed tomography imaging (CT) showed his brain stem with a low attenuation. Magnetic resonance imaging (MRI) revealed extensive hyperintensity and enlargement of the midbrain and pons on T2 weighted and fluid attenuated inversion-recovery (FLAIR) image. However, there was no abnormal lesion seen in either bilateral occipital lobe. Diffusion-weighted image (DWI) was normal at the brainstem, but apparent diffusion coefficient (ADO values were slightly elevated at the left midbrain. There was no contrast enhancement. His symptom and radiological finding improved soon after his blood pressure was controlled. A repeated MRI taken two weeks later showed complete resolution of the lesion.
RPLS associated with predominant involvement of the brainstem and sparing of the supratentorial region is rare, but it should be differentiated from brain stem infarction, pontine glioma, central pontine myelinolysis and infective encephalitis. since the neulological consequences are potentially fully reversible after adequate and prompt treatment.

Malpositioned spinal instrument as a possible cause of superficial siderosis
T. Aoyama, K. Hida, S. Yano, M. Kawabori, M. Iwasaki, Y. Iwasaki
SPINAL CORD, 47, 11, 826, 828, NATURE PUBLISHING GROUP, 2009年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Study design: Case report.
Objective: To report a patient with superficial siderosis as a complication after posterior fixation surgery for odontoid fracture.
Setting: Department of Neurosurgery, Hokkaido University, Japan.
Methods: A 36-year-old man had undergone C1-C2 posterior fixation using lamina hooks for an odontoid fracture in 1997. In 2003, he presented with hearing loss and ataxia; and in 2006, a diagnosis of superficial siderosis was made and spinal instrument malpositioning was detected.
Results: The malpositioned instrument, suspected as the cause of superficial siderosis, was removed.
Conclusions: Superficial siderosis of the central nervous system is rare; it results in progressive hearing loss, cerebellar ataxia and pyramidal sign. Chronic hemorrhage in the subarachnoid space precipitates hemosiderin around the cerebellum and brainstem resulting in neurological symptoms. Recurrent hemorrhage and cervical root pathology, for example, root avulsion, are factors; the symptoms worsen gradually and result in hemostasis. Superficial siderosis because of complications from spinal instrumentation surgery is extremely rare. If the instrument is malpositioned in the subarachnoid space, we suggest its removal. Spinal Cord (2009) 47, 826-828; doi:10.1038/sc.2009.35; published online 31 March 2009

脳幹部にのみ画像所見を呈したRPLS(reversible posterior leukoencephalopathy syndrome)脳幹型variantの1例　　　　　　　　　　　　　　　
川堀 真人, 村田 純一, 阿部 悟, 斉藤 久寿
Neurological Surgery, 37, 11, 1105, 1109, (株)医学書院, 2009年11月
日本語, 34歳男。既往歴として肥満傾向、未治療の高血圧があった。今回、後頭部から後頸部に強い痛みが出現し、脳CTで中脳〜橋に低信号を認め、血圧は216/120mmHgと著明高値であった。MRIでは中脳左側および橋全体に、T2強調像・FLAIR画像の異常高信号と腫大を認め、後頭葉には異常高信号は認めず、ガドリニウムによる造影効果もなかった。拡散強調画像では信号変化は認めず、左中脳においてapparent diffusion coefficient値が軽度上昇していた。脳MRAでは著明な血管の屈曲・蛇行を認めたが、明らかな狭窄はなかった。Reversible posterior leukoencephalopathy syndrome(RPLS)の脳幹型variantの可能性を考え、塩酸ジルチアゼムの持続点滴を開始し、血圧を160〜170mmHgにコントロールしたところ、頸部痛は劇的に改善した。また、翌日のMRIでは脳幹部の高信号と腫脹は改善傾向となっていた。以上よりRPLSの脳幹型variantによる病態と診断し、降圧剤投与で2週間後には脳幹部の画像所見は消失し、独歩退院した。

Carotid Endarterectomy for Internal Carotid Artery Stenosis Associated with Persistent Primitive Hypoglossal Artery: Efficacy of Intraoperative Multi-modality Monitoring
M. Kawabori, S. Kuroda, H. Yasuda, M. Hokari, N. Nakayama, H. Saito, Y. Iwasaki
MINIMALLY INVASIVE NEUROSURGERY, 52, 5-6, 263, 266, GEORG THIEME VERLAG KG, 2009年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: A persistent primitive hypoglossal artery (PPHA) is a rare vascular anomaly and is usually asymptomatic. However, the PPHA may cause multi-territorial infarction when complicated by internal carotid artery (ICA) stenosis.
Case Report: We describe a 73-year-old male who simultaneously developed cerebral infarction in both carotid and vertebrobasilar territories due to ICA stenosis associated with an ipsilateral PPHA. The PPHA mainly provided blood flow to the vertebrobasilar territory in this case, because the bilateral vertebral arteries were markedly hypoplastic. He underwent carotid endarterectomy under internal shunting. Intraoperative multi-modality monitoring including angiography, motor evoked potential, and near infrared spectroscopy was very useful to avoid ischemic complications during surgery. The postoperative course was uneventful.
Conclusion: It should be reminded that a persistent carotid-basilar anastomosis can cause multi-territorial cerebral infarction mimicking cardiogenic embolism and may be a candidate for aggressive prophylactic intervention, when occlusive lesions develop in the carotid artery. It is very important to monitor hemodynamic and/or electrophysiological status in both carotid and verebrobasilar territories in order to perform carotid endarterectomy safely in such cases.

Cervical myelopathy by C1 posterior tubercle impingement in a patient with DISH.
Masahito Kawabori, Kazutoshi Hida, Minoru Akino, Shunsuke Yano, Hisatoshi Saito, Yoshinobu Iwasaki
Spine, 34, 19, E709-11, 11, 2009年09月01日, ［査読有り］, ［国際誌］
英語, STUDY DESIGN: A unique case of a patient with diffuse idiopathic skeletal hyperostosis (DISH) associated with C1 posterior tubercle impingement resulting in spinal canal stenosis and cervical myelopathy. OBJECTIVE: To describe an uncommon mechanism of spinal cord compression in patient with DISH. SUMMARY OF BACKGROUND DATA: The neurologic deficits due to cervical DISH are relatively rare and a few cases of cervical spinal cord compression due to atlantoaxial subluxation, odontoid fracture, pseudotumor, ligamentous hypertrophy, and basilar impression have been reported. To the best of our knowledge, there has been no other report of a patient with DISH causing C1 posterior tubercle impingement and cervical myelopathy. METHODS: A 75-year-old Japanese man, first diagnosed as hyperostosis of anterior and posterior longitudinal ligament 25 years ago, presented with gradual progression of numbness in both lower extremities, disturbed precise hand motion and urinary function. DISH, OPLL, and C1 posterior tubercle impingement was diagnosed by radiograph, CT, and MRI. Hyperintense signal in the C1 spinal cord on T2 weighted sequence was observed. RESULT: Laminectomy from C1-C3 was performed. Myelocompression and myelopathy improved after the surgical intervention. Multilevel fusion of the subaxial cervical spine and increase of the mechanical stress on the craniocervical segment may leads to partial damage of the ligaments and resulted in C1 posterior arch impingement. CONCLUSION: This is the first report of unique C1 posterior tubercle impingement and myelopathy caused by DISH. We should keep it in mind that DISH can cause serious problems in the upper cervical spine even after 25 years of interval.

【もやもや病】 側頭葉から後頭葉にかけて高度の虚血を有するもやもや病に対する脳血行再建術
黒田 敏, 川堀 真人, 宮本 倫行, 笹森 徹, 遠藤 将吾, 中山 若樹, 石川 達哉, 宝金 清博, 岩崎 喜信
脳卒中の外科, 37, 5, 345, 349, (一社)日本脳卒中の外科学会, 2009年09月
日本語, 1998年4月〜2008年7月にもやもや病と診断され、脳血行再建術を施行された71例117側中同側後大脳動脈に高度の狭窄を有し、側頭葉から後頭葉にかけての神経症状と著しい脳虚血を有していた4症例(全例女性、8〜38歳)に対する術式の実際を呈示した。その結果、術前MRIでは2例には脳梗塞を認めず、他の2例では後頭葉から側頭葉下面にかけて脳梗塞を認め、PETでは前頭葉の虚血に加え側頭葉から後頭葉の著しい脳虚血を認めた。術後3〜4ヵ月の外頸動脈撮影ではSTA-MCA吻合部と間接バイパス術を介して前頭部のみならず側頭部から後頭部にかけて側副血行路が広範に形成されていた。以上より、後大脳動脈狭窄病変のため前頭葉、側頭葉や後頭葉に高度の脳虚血を有し、その領域に起因する脳虚血発作を呈する症例では、一期的に実施する後方に拡大した複合的血行再建術が周術期の脳虚血合併症を予防し、脳虚血発作を消失させる上で有用と考えられた。

[Improvement of peduncular hallucinosis by surgical resection and carbamazepin administration in a young patient with pineocytoma].
Masahito Kawabori, Yutaka Sawamura, Yoshinobu Iwasaki
No shinkei geka. Neurological surgery, 37, 7, 687, 91, 2009年07月, ［査読有り］, ［国内誌］
日本語, Peduncular hallucinosis is a rare phenomenon characterized by visual hallucination consisting of vivid, colored image of people, animals, scenes or geometric patterns. In most of the cases the hallucination is accompanied by sleeping disorder, and is by the patient recognized as not being real. It can be observed mainly in patients with thalamic/midbrain vascular disease, and is less frequently seen in brain stem tumor. The damage of the ascending reticular activating system by brain stem compression causing dream activity releasing what is normally suppressed during wakefulness is thought to be the mechanism of peduncular hallucinosis. The authors report a 13-year-old female presenting peduncular hallucinosis due to brainstem compression by a pineocytoma. The patient had a 3-month history of complex visual hallucination and slight somnolence. The hallucination mainly consisted of TV game characters, animals, and vegetables which were colorful and vivid. She was well oriented and realized that the hallucination was not real. MRI showed a pineal mass compressing the quadrigeminal plate inferiorly. There was mild obstructive hydrocephalus due to aqueduct stenosis. The tumor was totally removed and was pathologically diagnosed as pineocytoma. After the surgery, the hallucination ameliorated remarkably. Although the administration of benzodiazepine exacerbated the hallucination and sleep disorder, oral carbamazepine was clearly effective and produced nearly complete disappearance of hallucination. To the best of our knowledge, this is the first report of peduncular hallucinosis caused by quadrigeminal plate compression by a pineal tumor.

手術およびカルバマゼピン内服療法が著効した松果体細胞腫による脳脚幻覚症(peduncular hallucinosis)の1例　　　　　　　　　　　　　　　
川堀 真人, 澤村 豊, 岩崎 喜信
Neurological Surgery, 37, 7, 687, 691, (株)医学書院, 2009年07月
日本語, 13歳女児。内向的な性格であったが、ボーっとして一点を見つめて動かなくなり集中できなくなるなどの症状があり幻視が出現した。本人はこれが現実でないことを認識していたが、友人の名前や卑劣な言葉がテロップで流れるという症状も出現した。頭部MRIで異常所見を認めた。意識レベルはほぼ清明で、受け答えも可能であったが完全に覚醒している状態ではなかった。食欲は低下気味で朝の起床後数時間、夕方遅いとき傾眠傾向が出現した。頭部MRIで松果体部から第三脳室に突出する長径30mmの楕円形腫瘤が存在し、中脳視蓋を圧迫し、そのため中脳視蓋の上丘は扁平化し、中脳水道の狭窄により軽度の閉塞性水頭症を合併していた。松果体嚢胞又は嚢胞性松果体細胞腫を疑い手術した。病理所見は松果体細胞腫WHOグレードIIで腫瘍の摘出による脳幹圧迫解除が認められ残存腫瘍は認めなかった。

Susceptibility-weighted magnetic resonance imaging detects impaired cerebral hemodynamics in the superior sagittal sinus thrombosis--case report.
Masahito Kawabori, Satoshi Kuroda, Kohsuke Kudo, Satoshi Terae, Makoto Kaneda, Naoki Nakayama, Yoshinobu Iwasaki
Neurologia medico-chirurgica, 49, 6, 248, 51, 2009年06月, ［査読有り］, ［国内誌］
英語, An 11-year-old female receiving treatment for acute lymphoblastic leukemia presented with superior sagittal sinus (SSS) thrombosis. T(1)-weighted, T(2)-weighted, and fluid-attenuated inversion recovery magnetic resonance (MR) imaging, and MR venography showed that the SSS was totally occluded by thrombus. Susceptibility-weighted MR imaging showed hypointense thrombus in the SSS and markedly dilated cortical veins over the bilateral cerebral hemispheres. Two days later, her symptoms had slightly resolved. Iodine-123 N-isopropyl-p-iodoamphetamine single photon emission computed tomography showed marked decrease of cerebral blood flow in the bilateral frontal lobes, indicating that venous congestion had disturbed the cerebral hemodynamics. MR venography showed that the SSS was still mostly occluded, but susceptibility-weighted imaging showed that the dilation of the cortical veins was less marked, suggesting that collateral venous routes had gradually developed. The finding of dilated cortical veins had almost disappeared at 28 days after the onset. Susceptibility-weighted imaging can be used as a non-invasive method to monitor the severity of venous congestion caused by cerebral venous sinus thrombosis.

[Cervicogenic headache caused by lower cervical spondylosis].
Masahito Kawabori, Kazutoshi Hida, Shunsuke Yano, Yoshinobu Iwasaki
No shinkei geka. Neurological surgery, 37, 5, 491, 5, 2009年05月, ［査読有り］, ［国内誌］
日本語, We report a rare case of severe facial pain and headache due to cervical spondylosis successfully treated by surgical intervention. A 48-year-old woman had been suffering from severe left side facial pain and headache since she was 44 years old. Analgesics were not effective. At 48 years of age, a magnetic resonance imaging of the cervical spine revealed a degenerated disk at the C5/6 level with encroachment on the foramina and the cord. Anesthetic blockade to the C5/6 facet joint was effective, but was temporary. After the anterior decompression and stabilization using a titanium cage, the pain disappeared completely and has not recurred through 1 year of follow up. This report indicates that lower cervical root compression may cause cervicogenic headache, which can be treated effectively by surgical intervention.

Spontaneous giant aneurysm of the superficial temporal artery: case report.
Masahito Kawabori, Satoshi Kuroda, Naoki Nakayama, Yasuko Kenmotsu, Hiroshi Shimizu, Michie Tanino, Yoshinobu Iwasaki
Neurologia medico-chirurgica, 49, 5, 198, 201, 2009年05月, ［査読有り］, ［国内誌］
英語, A 78-year-old woman presented with preauricular superficial temporal artery (STA) aneurysm and scalp porocarcinoma, which had both increased in size over 2 years. She had no previous history of head trauma. Three-dimensional (3D) computed tomography (CT) angiography revealed a 4-cm diameter STA aneurysm arising from the main trunk of the left STA and located just lateral to the zygomatic arch. The scalp porocarcinoma was excised by dermatologists. The STA aneurysm was carefully dissected from the surrounding tissues, and was resected after ligation of the proximal STA. Histological examination showed the aneurysm consisted of intima, media, and adventitia, and the diagnosis was atherosclerotic fusiform aneurysm. 3D CT angiography is quite useful to plan surgical strategy for such an unusually large STA aneurysm.

前方固定術が著効した頸椎症による難治性顔面痛・頭痛(cervicogenic headache)の1例
川堀 真人, 飛騨 一利, 矢野 俊介, 岩崎 喜信
Neurological Surgery, 37, 5, 491, 495, (株)医学書院, 2009年05月
日本語, 研究論文（学術雑誌）, 48歳女。44歳時より左の鼻の中に痛みを自覚し、その後痛みの拡大・増悪を生じ左顔面から頭頂部・頸部にかけての耐え難い痛みとなった。薬物治療は無効であり、最終的にMRI検査で頸椎C5/6のcervical spondylosisを指摘され、頸椎症による顔面痛の可能性からcervical facet blockを施行したところ、痛みは著明に改善した。しかし、その後痛みが再燃し、手術適応の検討となった。左顔面全域から一部頸部にかけてtrigger pointのない強い痛みと、頭頂部にしびれ感が存在し、同部位で痛覚過敏と触覚低下を認めた。また、軽度の左上肢脱力と左側C5-8に痛覚低下があった。頸椎CTでC6上縁の椎体後面右側に骨棘形成を認め、頸椎MRIで同部位の骨棘および肥厚した黄色靱帯による頸髄圧迫を認めた。C5/6レベルでの頸部脊椎症と診断し、ケージ挿入による前方固定術を施行して脊髄根の除圧を行った。術直後より疼痛・痛覚低下は消失し、1年経過して再発はない。

Cervical epidural arteriovenous fistula with radiculopathy mimicking cervical spondylosis.
Masahito Kawabori, Kazutoshi Hida, Shunsuke Yano, Takeshi Asano, Yoshinobu Iwasaki
Neurologia medico-chirurgica, 49, 3, 108, 13, 2009年03月, ［査読有り］, ［国内誌］
英語, A 65-year-old woman presented with a rare case of cervical epidural arteriovenous fistula (AVF) manifesting as radiculopathy of the right upper extremity that mimicked cervical spondylosis. She had a 2-month history of gradually progressive right-hand motor weakness and sensory disturbance. The initial diagnosis was cervical disk herniation. However, computed tomography with contrast medium showed abnormal enhancement at the right C5-6 and C6-7 intervertebral foramina. Magnetic resonance (MR) imaging with gadolinium disclosed an enhanced abnormal epidural mass at the dorsal surface of the dural tube between the C5 and C6 vertebrae. T(2)-weighted MR imaging showed a slight flow void on the dorsal and ventral surfaces of the spinal cord between C3 and T4. Digital subtraction angiography disclosed cervical epidural and dural AVFs fed by the C5 and C6 radicular arteries. The diagnosis was concomitant epidural and dural AVFs. The dilated internal vertebral venous plexus attributable to epidural AVF was considered to be responsible for the radiculopathy. Transarterial embolization using n-butylcyanoacrylate achieved complete occlusion of the lesions. Her symptoms improved immediately and MR imaging and angiography performed 10 days postembolization showed reduction of both the epidural and dural AVFs.

遺残舌下動脈を伴う内頸動脈起始部狭窄病変により頭蓋内多発梗塞をきたした1例
川堀 真人, 黒田 敏, 安田 宏, 穂刈 正昭, 岩崎 素之, 斉藤 久寿, 中山 若樹, 岩崎 喜信
脳卒中, 31, 2, 96, 99, (一社)日本脳卒中学会, 2009年03月
日本語, 73歳男。2年前に頭痛の精査で右内頸動脈分岐部の狭窄と、その末梢から分岐する遺残舌下動脈(PHA)を指摘されていた。今回、自宅で倒れているところを発見され緊急搬送された。意識障害、眼球運動障害、左不全片麻痺があり、脳MRI拡散強調像で右前頭葉皮質、右視床、両側頭頂後頭葉、脳幹、両側小脳に急性期の多発性梗塞巣を認めた。第9病日の3D-CTAでは、PHAが舌下神経を通過し脳底動脈に合流しており、右後大脳動脈が再開しているのを確認した。アルガトロバン・エダラボンの点滴治療、および急性期リハビリを行った。ホルター心電図、心エコー、大動脈弓3D-CTAで心原性脳塞栓症は否定され、内頸動脈狭窄症に起因するartery-to-artery embolismが内頸動脈を介して右前頭葉に、PHAを介して脳幹・小脳・頭頂後頭葉に多発性塞栓症を生じたと考えた。神経症状は徐々に改善し、皮質盲、認知機能障害を後遺したが、1ヵ月後には杖歩行可能なまでに改善した。

周産期に発症したreversible posterior leukoencephalopathy syndrome(RPLS)の1例
川堀 真人, 加藤 功, 竹田 誠, 山村 満恵, 片岡 宙門
周産期医学, 39, 1, 128, 130, (株)東京医学社, 2009年01月
日本語, 33歳女0経妊0経産。妊娠36週、定期検査で重症妊娠高血圧症候群と診断され緊急入院し、症状増悪のため帝王切開で出産した。手術中・出産後も高血圧が持続し、子癇発作と思われる全身性硬直間代性痙攣を認めた。CTで明らかな異常は認めず、硫酸マグネシウム水和物・ブドウ糖持続点滴・抗痙攣薬で経過観察とした。翌日も意識障害が遷延し、頭痛も訴えたためMRIを施行し、後頭葉に異常所見を認めた。両側後頭葉皮質・皮質下白質にT1強調像で低信号、T2強調像・FLAIR画像で高信号、拡散強調像で淡い高信号を呈する病変を認めた。MRAでは明らかな血管閉塞・狭窄は認められず、脳SPECT画像定性値では両側頭頂後頭葉で血流低下を認めた。reversible posterior leukoencephalopathy syndrome(RPLS)と診断しニカルジピン持続静注を用いた積極的降圧治療で頭痛・意識障害は軽快し血圧コントロール可能となった。

脳神経外科手術におけるモノポーラー・メスの使用経験
川堀 真人, 黒田 敏, 成田 拓人, 中山 若樹, 太田 穣, 岩崎 喜信
脳神経外科速報, 18, 3, 357, 360, (株)メディカ出版, 2008年03月
日本語, 脳動脈瘤、もやもや病、頸部内頸動脈狭窄症などの手術時にモノポーラー・メス(コロラド・マイクロ・ダイセクション・ニードル)を使用し、その有用性について検討を行った。本モノポーラー・メスは、未破裂脳動脈瘤、脳動静脈奇形、もやもや病では頭皮及び側頭筋の切開時に使用し、頸部内頸動脈狭窄症例には頸動脈内膜剥離術で皮膚や広頸筋の切開時に使用した。いずれの手術でも出血が著明に軽減し、バイポーラー凝固子による止血操作も省略ができた。また、創部は通常のメスと同様の治癒を得られた。以上のことから、モノポーラー・メスは有用性があると考えられた。

鞍隔膜上部腫瘍に対するExtended transsphenoidal approachの一方法 Transsphenoidal-transtuberculum sellae approach　　　　　　　　　　　　　　　
加藤 功, 竹田 誠, 川堀 真人
日本内分泌学会雑誌, 82, Suppl., 135, 137, (一社)日本内分泌学会, 2006年06月
日本語, Transsphenoidal-transtuberculum sellae approachにより腫瘍摘出術を行った23例(男14例・女9例,平均51歳)の成績を報告した.内訳は下垂体腺腫10例,ラトケ嚢胞7例,頭蓋咽頭腫2例,髄膜腫2例,奇形腫,下垂体柄への転移性腫瘍各1例であった.全摘出できたのは頭蓋咽頭腫,ラトケ嚢胞各2例,下垂体腺腫,髄膜腫,転移性腫瘍各1例で,他の症例は亜全摘出または部分摘出,奇形腫は生検のみであった.術中所見では下垂体腺腫の7例で視交叉,1例で下垂体柄,2例で前大脳動脈を確認できた.また,下垂体腺腫以外の13例中11例で視交叉および下垂体柄,2例で前大脳動脈が確認でき,7例はアプローチに際して下垂体前葉の切開を要した.術後合併症は3例で一過性尿崩症が出現し,1例で髄液漏に対する再手術を行った.また,鞍結節部髄膜腫の1例では,腫瘍摘出中に癒着した前大脳動脈に小さな穴が開き,圧迫止血を行った.視野障害や下垂体機能障害の悪化を来たした症例はなかった

もやもや病のエピゲノム病態修飾因子探索
伊東雅基, 内野晴登, 東海林菊太郎, 杉山拓, 川堀真人, 岩田育子, 矢部一郎, 寶金清博, 藤村幹, 月刊メディカル・サイエンス・ダイジェスト, 50, 6, 2024年

パーキンソン病脳深部刺激療法術後5年目における治療有効性の評価　　　　　　　　　　　　　　　
白井 慎一, 江口 克紀, 山崎 和義, 松島 理明, 川堀 真人, 平田 健司, 藤村 幹, 矢部 一郎, パーキンソン病・運動障害疾患コングレスプログラム・抄録集, 17回, 86, 86, 2023年07月
Movement Disorder Society of Japan (MDSJ), 日本語

成人もやもや病のMRA末梢動脈信号強度と間接血行発達度の関連
内野晴登, 伊東雅基, 杉山拓, 川堀真人, 長内俊也, 藤村幹, 日本脳神経CI学会総会プログラム・抄録集, 46th, 2023年

成人もやもや病複合血行再建術後バイパス路発達におけるRNF213創始者変異の意義
伊東雅基, 川堀真人, 杉山拓, 東海林菊太郎, 舘澤諒大, 内野晴登, 数又研, 寳金清博, 藤村幹, Mt. Fuji Workshop on CVD, 39th, 2022年

成人もやもや病に対する直接・間接複合血行再建術後のバイパス路発達の術前要因
伊東雅基, 内野晴登, 川堀真人, 杉山拓, 数又研, 宝金清博, 藤村幹, 日本分子脳神経外科学会プログラム・抄録集, 22nd, 2022年

脳血管障害の病態評価における脳画像の有用性 もやもや病の周術期画像マーカーとRNF213遺伝子多型の関連　　　　　　　　　　　　　　　
内野 晴登, 伊東 雅樹, 東海林 菊太郎, 舘澤 諒大, 川堀 真人, 数又 研, 宝金 清博, 藤村 幹, 脳循環代謝, 33, 1, 70, 70, 2021年11月
(一社)日本脳循環代謝学会, 日本語

RNF213創始者変異は成人もやもや病複合血行再建術後の間接バイパス路発達に寄与する　　　　　　　　　　　　　　　
伊東 雅基, 川堀 真人, 杉山 拓, 東海林 菊太郎, 舘澤 諒大, 内野 晴登, 数又 研, 寳金 清博, 藤村 幹, 脳循環代謝, 33, 1, 94, 94, 2021年11月
(一社)日本脳循環代謝学会, 日本語

慢性期頭部外傷患者に対する間葉系幹細胞(SB623)脳内投与の治験成績(STEMTRA研究)　　　　　　　　　　　　　　　
川堀 真人, 今井 英明, 安原 隆雄, 末永 潤, 中村 元, 唐沢 康暉, 宝金 清博, 日本脳神経外傷学会プログラム・抄録集, 44回, 59, 59, 2021年01月
(一社)日本脳神経外傷学会, 日本語

ラット脊髄損傷モデルにおけるFTY720の神経障害性疼痛に対する治療効果の検証　　　　　　　　　　　　　　　
山崎 和義, 川堀 真人, 関 俊隆, 高宮 宗一朗, 今野 幸太郎, 渡邉 雅彦, 日本脳神経外傷学会プログラム・抄録集, 44回, 117, 117, 2021年01月
(一社)日本脳神経外傷学会, 日本語

【脳神経外科学の可能性】中枢神経疾患に対する再生医療・細胞治療の現状と今後の展望
川堀 真人, 七戸 秀夫, 黒田 敏, 寳金 清博, 脳神経外科ジャーナル, 29, 11, 777, 783, 2020年11月
脳梗塞・頭部外傷・脊髄損傷・パーキンソン病など中枢神経疾患に対する細胞治療・再生医療が、「基礎研究」の段階から、臨床応用に向けた「治験」さらには「保険診療」の段階に入ってきている。これらの成績は既存治療では成し得なかった中枢神経を再生ないし回復させる治療法として、十分期待できるものである。自家骨髄幹細胞の「ステミラック注」が脊髄損傷の亜急性期患者に対して期限つき条件つき承認で保険適応となり、中枢神経疾患に対する初めての「再生医療等製品」となった。また、脳梗塞においても複数の治験が進行中でその結果が待たれる。より効果の高い細胞の開発、投与方法、投与時期、医療費削減、効果が高い患者群の決定など残された課題も多いが、基礎研究および臨床経験の蓄積など今後の発展に期待したい。(著者抄録), (一社)日本脳神経外科コングレス, 日本語

脳梗塞に対する新規治療の開発-血栓回収療法時代のアンメットメディカルニーズと医薬品開発戦略- 主幹動脈閉塞脳梗塞患者に対する幹細胞脳内移植治験(RAINBOW研究)　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博, 脳循環代謝, 32, 1, 52, 52, 2020年11月
(一社)日本脳循環代謝学会, 日本語

脳梗塞急性期患者への自家BMSC脳内投与による再生治療(Phase 1)とPhase 2に向けた取り組み　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博, 脳循環代謝, 32, 1, 60, 60, 2020年11月
(一社)日本脳循環代謝学会, 日本語

脳神経細胞治療・遺伝子治療の実践 脳出血慢性期モデルに対する骨髄幹細胞+足場材製剤(CellSaic)の有効性　　　　　　　　　　　　　　　
高宮 宗一朗, 川堀 真人, 七戸 秀夫, 中村 健太郎, 北橋 宗, 岩澤 玲子, 古川 友子, 宝金 清博, 脳循環代謝, 32, 1, 68, 68, 2020年11月
(一社)日本脳循環代謝学会, 日本語

ラット亜急性期脊髄損傷モデルに対する骨髄間葉系幹細胞シート移植の治療効果検証　　　　　　　　　　　　　　　
山崎 和義, 川堀 真人, 関 俊隆, 高宮 宗一朗, 今野 幸太郎, 渡辺 雅彦, 宝金 清博, 脳循環代謝, 32, 1, 82, 82, 2020年11月
(一社)日本脳循環代謝学会, 日本語

急性期脳梗塞MRIで最善を尽くす Do Our Best MRI for Acute Ischemic Stroke　　　　　　　　　　　　　　　
大浦 大輔, 横浜 拓実, 伊原 陸, 新谷 好正, 川堀 真人, 脳血管内治療, 5, Suppl., 9, 9, 2020年11月
(NPO)日本脳神経血管内治療学会, 日本語

Clinical Trials of Stem Cell Treatment for Spinal Cord Injury
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Kiyohiro Houkin, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21, 11, 2020年06月, ［国際誌］
There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted., MDPI, 英語

脳や脊髄などの中枢神経疾患に対する再生医療・細胞治療の現状と課題　　　　　　　　　　　　　　　
川堀 真人, バイオサイエンスとインダストリー, 78, 3, 202, 208, 2020年05月
いったん障害を受けると回復することがないと言われてきた脳・脊髄の病気に対する再生医療の期待は大きい。脳梗塞・頭部外傷・脊髄損傷・パーキンソン病などに対する細胞治療が、「基礎研究」の段階から臨床応用に向けた「治験」、さらに一部は「保険診療」の段階に入ってきている。2019年には、自家骨髄由来幹細胞の「ステミラック注」が脊髄損傷の亜急性期患者に対して期限付き・条件付き承認下で保険適応となり、中枢神経疾患に対する初めての「再生医療等製品」となった。脳梗塞に対しても複数の治験が進行中で、その結果が待たれる。本稿では、幹細胞の作用機序、基礎・臨床研究の進捗状況、残された科学的・産業的課題について概説する。(著者抄録), (一財)バイオインダストリー協会, 日本語

神経難病におけるトランスレーショナル・リサーチ 中枢神経疾患に対する再生医療 現状と展望
川堀 真人, 七戸 秀夫, 黒田 敏, 寳金 清博, 神経治療学, 37, 3, 386, 390, 2020年05月
(一社)日本神経治療学会, 日本語

ラット脊髄損傷モデルにおける骨髄間葉系幹細胞シートによる治療効果の検証　　　　　　　　　　　　　　　
山崎 和義, 川堀 真人, 関 俊隆, 高宮 宗一朗, 寳金 清博, 日本脳神経外傷学会プログラム・抄録集, 43回, 128, 128, 2020年02月
(一社)日本脳神経外傷学会, 日本語

中枢神経疾患に対する再生医療 現状と展望
川堀真人, 七戸秀夫, 黒田敏, 寳金清博, 神経治療学(Web), 37, 3, 2020年

優位側椎骨動脈浸潤を伴った頭蓋頚椎移行部硬膜内髄外腫瘍に対し,椎骨動脈塞栓術を行い全摘出し得た1例
舘澤諒大, 舘澤諒大, 岩崎素之, 飛騨一利, 長内俊也, 川堀真人, 守田玲菜, 山内朋裕, 新谷好正, 古川浩司, 鐙谷武雄, 馬渕正二, Neurological Surgery, 48, 6, 509, 514, 2020年, ［国内誌］
46歳女。主訴は後頸部痛、一過性左片麻痺で、頭頸部MRIではCVJ部の右側を基部とした硬膜内髄外に腫瘤性病変を認め、延髄尾側〜上位頸髄を圧排し椎骨動脈(VA)が内包されていた。脳血管造影検査では右VAの筋枝2本が腫瘍のfeederとなり、右posterior inferior cerebellar arteryは描出されず、右小脳はanterior inferior cerebellar arteryにより灌流されていた。前脊髄動脈は左VAからの描出が強かった。髄膜腫を疑い、右VA閉塞試験で20分以上神経陽性所見が出現しないことを確認後、VAのコイル塞栓を施行した。塞栓4日後の腹臥位にてfar lateral approach、C1 laminectomyによる腫瘍摘出術を施行した。露出したVAはコイル毎に離断して以後の作業を容易にし、腫瘍を安全に摘出した。術後、右延髄に点状梗塞を認め左半身の温痛覚障害が出現したが、短期で改善し社会復帰した。, (株)医学書院, 日本語

ASLと胸部MRAを含めた超短時間・急性期脳梗塞用MRIプロトコールの運用成績　　　　　　　　　　　　　　　
大浦 大輔, 伊原 陸, 新谷 好正, 川堀 真人, 脳血管内治療, 4, Suppl., S402, S402, 2019年11月
(NPO)日本脳神経血管内治療学会, 日本語

脳梗塞に対する再生医療の現状と展望は?　　　　　　　　　　　　　　　
川堀 真人, 寳金 清博, 脳血管病Trend Review, 1, 1, 28, 31, 2019年09月
(株)先端医学社, 日本語

中枢神経疾患に対する細胞治療の現状と今後の展望 幹細胞で脳は治るのか?
川堀真人, 七戸秀夫, 山崎和義, 黒田敏, 寳金清博, 脳神経外科ジャーナル, 28, Supplement, 101, 2019年04月20日
日本語

脳梗塞亜急性期に対する自家骨髄幹細胞の直接投与(第一相治験:RAINBOW研究)
川堀真人, 七戸秀夫, 七戸秀夫, 黒田敏, 寳金清博, 寳金清博, 神経治療学(Web), 36, 6, S128(J‐STAGE), 2019年
日本語

脳梗塞に対する自家骨髄間質細胞直接投与第一相治験:RAINBOW研究
川堀真人, 七戸秀夫, 黒田敏, 寳金清博, 日本再生医療学会総会(Web), 18th, ROMBUNNO.O‐20‐6 (WEB ONLY), 2019年
日本語

脳梗塞急性期に対する自家骨髄間質細胞(BMSC)移植治療 医師主導治験RAINBOW研究　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 山崎 和義, 黒田 敏, 寳金 清博, 脳循環代謝, 30, 1, 66, 66, 2018年10月
日本脳循環代謝学会, 日本語

Brain Japanがめざす脳卒中治療への取り組み 脳梗塞に対する細胞療法　　　　　　　　　　　　　　　
寳金 清博, 川堀 真人, 七戸 秀夫, 脳循環代謝, 30, 1, 71, 71, 2018年10月
日本脳循環代謝学会, 日本語

Brain Japanがめざす脳卒中治療への取り組み 脳梗塞に対する細胞療法　　　　　　　　　　　　　　　
寳金 清博, 川堀 真人, 七戸 秀夫, 脳循環代謝, 30, 1, 71, 71, 2018年10月
日本脳循環代謝学会, 日本語

脳梗塞急性期に対する自家骨髄間質細胞(BMSC)移植治療:医師主導治験RAINBOW研究
川堀真人, 七戸秀夫, 山崎和義, 黒田敏, 寳金清博, 脳循環代謝(Web), 30, 1, 66, 66, 2018年10月
日本脳循環代謝学会, 日本語

Onion-skin patternの異常感覚を呈した後縦靱帯骨化症の1例　　　　　　　　　　　　　　　
後藤 秀輔, 岩崎 素之, 川堀 真人, 新谷 好正, 馬渕 正二, Neurological Surgery, 46, 9, 783, 787, 2018年09月
73歳男。右耳珠周囲から右顎にかけての異常感覚を主訴に近医を受診した。頭部MRIを含む精査が行われたが診断確定には至らず、対症療法として鎮痛薬やビタミンB12製剤、抗痙縮薬、抗うつ薬などを処方されたが効果は認められず、薬剤抵抗性の顔面片側異常感覚として当科に紹介された。頸椎CTでC2/3椎間レベルからC3上縁レベルに後縦靱帯骨化症(OPLL)を認め、またC3上縁レベルに頸髄圧迫を認めた。これらの所見から、異常感覚の原因はOPLLによるC3上縁レベルの脊髄障害と考えてC2-3レベルの脊柱管拡大術を施行し、異常感覚は消失した。, (株)医学書院, 日本語

THE DEVELOPMENT AND EVALUATION OF A NEW SIMPLE MODIFIED ANEURYSM CLIP FOR SMALL ANIMAL SCI MODELS
Kazuyoshi Yamazaki, Toshitaka Seki, Masahito Kawabori, Syuji Hamauchi, Izumi Koyanagi, Kiyohiro Houkin, JOURNAL OF NEUROTRAUMA, 35, 16, A168, A168, 2018年08月
MARY ANN LIEBERT, INC, 英語, 研究発表ペーパー・要旨（国際会議）

血栓回収療法の時間短縮に向けたStrokeチームの取り組み 発見・搬送・検査・治療:すべての短縮を目指して　　　　　　　　　　　　　　　
三上 沙季, 木下 ひかり, 金子 慧, 林 誠一, 竹内 郁子, 金子 朱美, 川口 万友美, 新谷 好正, 岩崎 素之, 後藤 秀輔, 馬渕 正二, 川堀 真人, Brain Nursing, 34, 6, 561, 568, 2018年06月
2015年4月から2017年3月迄に血栓回収療法(rt-PA療法)が行われた64症例を対象に、血栓回収療法の時間短縮に向けて行ったStrokeチームの取り組みによって、どのような効果があったかを前期(システム構築時期26例)、後期(システム構築終了後38例)で分けて検討した。前期・後期で対象となった搬送患者のベースライン(年齢、性別、重症度、病型、搬送地区)に大きな違いはなかった。市民に対する広報活動を行ったが、前期および後期で発見から通報までの時間に短縮は得られなかった。院内システムの整備、迅速な治療については、前期での中央値は64分、後期では46分と短縮されており、時間のばらつきも著明に減少していた。治療記録シートから抽出した各看護師の血栓回収療法の介助に携わった回収を分析したところ、特定の看護師が介助に入っている傾向が認められた。取り組みによって来院から穿刺までの時間は短縮したが、看護師の教育や、一般市民や救急隊への啓発などの必要性が示唆された。, (株)メディカ出版, 日本語

中国における中枢神経疾患に対する細胞治療の最新動向　　　　　　　　　　　　　　　
王 子ほう, 譚 成博, 川堀 真人, 七戸 秀夫, 寶金 清博, 北海道医学雑誌, 93, 1, 13, 20, 2018年05月
オンライン上で、中枢神経再生の臨床試験に関する中国発の学術論文を検索した。網羅的に中枢神経系再生に関する臨床試験の論文は、英語379報、中国語3795報であった。中国発の幹細胞研究に関する臨床試験数は2012年初頭まで98であったが、2015年には244まで増加し、18試験が中枢神経系疾患に関する試験であった。中国において2015年末までに承認された幹細胞製品は10製品認め、5製品は中国の政府機関が申請しており、残りの5製品は中国企業によるものであった。最近(2015年7月20日)、中国国家食品薬品監督管理局(CFDA)が「幹細胞臨床研究管理方法(試行)」を発布したが、この法律が中国における幹細胞の管理方法に関する最初の規範となった。さらに2015年7月31日には、CFDAが「幹細胞製剤の品質管理及び臨床前指導原則」を発布している。, 北海道医学会, 日本語

【(間葉系幹細胞の再生医療)】 脳梗塞に対する細胞治療 RAINBOW研究の取り組み　　　　　　　　　　　　　　　
七戸 秀夫, 川堀 真人, 寳金 清博, レギュラトリーサイエンス学会誌, 8, 2, 115, 121, 2018年05月
脳梗塞に対する細胞治療が国内外で臨床試験として開始されつつある。2012年度に、われわれは「脳梗塞の再生医療」に関して厚生労働省から革新的医薬品・医療機器・再生医療製品実用化促進事業実施機関に選定された。本事業のもとで、われわれは自家骨髄間質細胞(bone marrow stromal cells:BMSC)移植による脳梗塞再生治療の医師主導治験(第I相:RAINBOW研究)を準備し、2017年6月に最初の被験者が登録された。本治験は、(1)ウシ胎仔血清(FBS)などの代替として、他家ヒト血小板溶解物(platelet lysate:PL)を添加し、自家BMSCを培養する、(2)脳梗塞周辺部へ脳定位的手術により細胞を直接移植する、(3)MRIによる移植細胞の挙動把握を目的とし、超常磁性酸化鉄(SPIO)製剤によりBMSCをラベルする、(4)FDG-PETやIomazenil-SPECTを用いて、細胞移植がホスト脳に及ぼす影響を評価するなど、過去の臨床試験と異なる新規性のあるプロトコルを採用し、われわれは第2世代の臨床試験と自負している。本稿ではBMSC移植治療の作用機序と治療戦略、非臨床試験、治験プロトコルの観点から、われわれの経験を報告する。(著者抄録), (一社)レギュラトリーサイエンス学会, 日本語

中国における中枢神経疾患に対する細胞治療の最新動向　　　　　　　　　　　　　　　
王 子ほう, 譚 成博, 川堀 真人, 七戸 秀夫, 寶金 清博, 北海道医学雑誌, 93, 1, 13, 20, 2018年05月
オンライン上で、中枢神経再生の臨床試験に関する中国発の学術論文を検索した。網羅的に中枢神経系再生に関する臨床試験の論文は、英語379報、中国語3795報であった。中国発の幹細胞研究に関する臨床試験数は2012年初頭まで98であったが、2015年には244まで増加し、18試験が中枢神経系疾患に関する試験であった。中国において2015年末までに承認された幹細胞製品は10製品認め、5製品は中国の政府機関が申請しており、残りの5製品は中国企業によるものであった。最近(2015年7月20日)、中国国家食品薬品監督管理局(CFDA)が「幹細胞臨床研究管理方法(試行)」を発布したが、この法律が中国における幹細胞の管理方法に関する最初の規範となった。さらに2015年7月31日には、CFDAが「幹細胞製剤の品質管理及び臨床前指導原則」を発布している。, 北海道医学会, 日本語

【(間葉系幹細胞の再生医療)】 脳梗塞に対する細胞治療 RAINBOW研究の取り組み　　　　　　　　　　　　　　　
七戸 秀夫, 川堀 真人, 寳金 清博, レギュラトリーサイエンス学会誌, 8, 2, 115, 121, 2018年05月
脳梗塞に対する細胞治療が国内外で臨床試験として開始されつつある。2012年度に、われわれは「脳梗塞の再生医療」に関して厚生労働省から革新的医薬品・医療機器・再生医療製品実用化促進事業実施機関に選定された。本事業のもとで、われわれは自家骨髄間質細胞(bone marrow stromal cells:BMSC)移植による脳梗塞再生治療の医師主導治験(第I相:RAINBOW研究)を準備し、2017年6月に最初の被験者が登録された。本治験は、(1)ウシ胎仔血清(FBS)などの代替として、他家ヒト血小板溶解物(platelet lysate:PL)を添加し、自家BMSCを培養する、(2)脳梗塞周辺部へ脳定位的手術により細胞を直接移植する、(3)MRIによる移植細胞の挙動把握を目的とし、超常磁性酸化鉄(SPIO)製剤によりBMSCをラベルする、(4)FDG-PETやIomazenil-SPECTを用いて、細胞移植がホスト脳に及ぼす影響を評価するなど、過去の臨床試験と異なる新規性のあるプロトコルを採用し、われわれは第2世代の臨床試験と自負している。本稿ではBMSC移植治療の作用機序と治療戦略、非臨床試験、治験プロトコルの観点から、われわれの経験を報告する。(著者抄録), (一社)レギュラトリーサイエンス学会, 日本語

再生医療と病理 脳梗塞急性期に対する自家骨髄間質細胞(BMSC)移植治療 医師主導治験RAINBOW研究　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 山崎 和義, 黒田 敏, 寺坂 俊介, 寶金 清博, 日本病理学会会誌, 107, 1, 230, 230, 2018年04月
(一社)日本病理学会, 日本語

急性期脳梗塞における短時間-基底核pCASLの臨床的有用性　　　　　　　　　　　　　　　
大浦 大輔, 新谷 好正, 川堀 真人, 佐藤 晋平, 横浜 拓実, 日本放射線技術学会総会学術大会予稿集, 74回, 230, 231, 2018年03月
(公社)日本放射線技術学会, 日本語

脳梗塞に対する細胞療法
寳金清博, 川堀真人, 七戸秀夫, 脳循環代謝(Web), 30, 1, 71, 2018年
日本語

脳梗塞に対する自家骨髄間葉系幹細胞治療の医療経済学的検討
七戸秀夫, 七戸秀夫, 川堀真人, 寳金清博, 日本再生医療学会総会(Web), 17th, ROMBUNNO.O‐51‐6 (WEB ONLY), 2018年
日本語

脊髄動静脈シャント手術時における血流のスローモーション撮影法
浜内祝嗣, 長内俊也, 関俊隆, 川堀真人, 岡本迪成, 飛騨一利, 寺坂俊介, 寳金清博, 日本脊髄外科学会プログラム・抄録集, 33rd, 310, 2018年
日本語

【脳梗塞超急性期診療】 脳血管障害患者に対する再生医療の現状と将来
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博, 日独医報, 62, 2, 161, 167, 2018年01月
バイエル薬品(株), 日本語

ラット一過性脳虚血モデルに対する細胞治療:【18F】DPA‐714PETイメージングを用いた神経免疫反応の評価
七戸秀夫, 七戸秀夫, 譚成博, 譚成博, 趙松吉, 趙松吉, 東川桂, 王子豊, 川堀真人, 鐙谷武雄, 右近直之, 安井博宣, 玉木長良, 久下裕司, 寳金清博, 脳循環代謝(Web), 29, 1, 155, 155, 2017年11月
日本脳循環代謝学会, 日本語

機能性蛋白質製剤の最前線 脳梗塞治療薬としてのヘモアクトの効果　　　　　　　　　　　　　　　
鐙谷 武雄, 月花 正幸, 小松 晃之, 船木 亮佑, 川堀 真人, 長内 俊也, 中山 若樹, 数又 研, 寳金 清博, 人工血液, 25, 1, 26, 26, 2017年11月
日本血液代替物学会, 日本語

機能性蛋白質製剤の最前線 脳梗塞治療薬としてのヘモアクトの効果　　　　　　　　　　　　　　　
鐙谷 武雄, 月花 正幸, 小松 晃之, 船木 亮佑, 川堀 真人, 長内 俊也, 中山 若樹, 数又 研, 寳金 清博, 人工血液, 25, 1, 26, 26, 2017年11月
日本血液代替物学会, 日本語

ラット一過性脳虚血モデルに対する細胞治療 [18F]DPA-714 PETイメージングを用いた神経免疫反応の評価　　　　　　　　　　　　　　　
七戸 秀夫, 譚 成博, 趙 松吉, 東川 桂, 王 子豊, 川堀 真人, 鐙谷 武雄, 右近 直之, 安井 博宣, 玉木 長良, 久下 裕司, 寳金 清博, 脳循環代謝, 29, 1, 155, 155, 2017年11月
日本脳循環代謝学会, 日本語

脳梗塞に対する自家骨髄間質細胞移植 RAINBOW研究　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 寺坂 俊介, 黒田 敏, 宝金 清博, 脳循環代謝, 29, 1, 158, 158, 2017年11月
日本脳循環代謝学会, 日本語

病院到着前の情報からtPA静注療法もしくは血栓回収療法を必要とする症例の予測因子に関する検討　　　　　　　　　　　　　　　
東海林 菊太郎, 長内 俊也, 川堀 真人, 新谷 好正, 寳金 清博, 脳血管内治療, 2, Suppl., S89, S89, 2017年11月
(NPO)日本脳神経血管内治療学会, 日本語

頸動脈直接穿刺を行った血栓回収療法の3例　　　　　　　　　　　　　　　
川堀 真人, 長内 俊也, 新谷 好正, 岩崎 素之, 馬渕 正二, 宝金 清博, 脳血管内治療, 2, Suppl., S305, S305, 2017年11月
(NPO)日本脳神経血管内治療学会, 日本語

脳神経外科患者における尿道カテーテル留置期間短縮や抜去後の発熱減少に向けた取り組み
齋藤 友香理, 石黒 智香子, 田中 美帆, 金子 朱美, 新谷 好正, 岩崎 素之, 後藤 秀輔, 馬渕 正二, 川堀 真人, Brain Nursing, 33, 8, 822, 828, 2017年08月
病棟における尿道カテーテル留置の実態調査、発熱との関連性を後方視的に検討し、結果から尿道カテーテル抜去アセスメントシート、抜去後の管理プロトコールを作り、それを実際に運用し有用性、課題について検討した。2015年5月〜7月に入院し尿道カテーテルを留置した患者41例(脳梗塞23例・脳出血18例、男性25例、女性16例)を対象にした。対象患者を尿道カテーテル抜去後に発熱した発熱群、発熱しない非発熱群に分け、患者背景、尿道カテーテル抜去後の発熱日、尿道カテーテル留置トータル日数、尿道カテーテル抜去可能とされた日以降に留置された日数、尿意の有無、臥床時失禁の有無、間欠導尿の有無について検討した。発熱群は7例(17.1%)、非発熱群は34例(82.9%)であった。患者背景は疾患別発熱率について検討したが、脳梗塞患者・脳出血患者、性別、年齢に違いはないが発熱群は有意に意識障害患者が多かった。尿道カテーテル抜去後の発熱は平均2.9±1.6日に起こり、発熱群(7例)の多く(71%)は抜去当日(2例)、翌日(3例)に発熱した。尿道カテーテルトータル留置期間は発熱群15.0±4.8日、非発熱群9.0±1.8日で有意差はないが発熱群で長かった。尿道カテーテル抜去可能と評価された日以降に留置され続けた日数は発熱群5.6±2.2日、非発熱群3.2±0.6日で有意差はないが発熱群で長かった。尿意は、尿意なしが発熱群43%、非発熱群41%で有意差はないが発熱群で高かった。間欠導尿施行の有無は発熱群63%、非発熱群89%で、発熱群で施行されていない確率が高かった。基礎データをもとにアセスメントシートを作成した結果、尿道カテーテル留置理由、抜去の指針が明確化され尿道カテーテル留置期間、抜去可能とされた後の留置期間が有意に短くなった。, (株)メディカ出版, 日本語

脳梗塞に対する自家骨髄間質細胞移植:RAINBOW研究
川堀真人, 七戸秀夫, 譚成博, 王子ほう, 鐙谷武雄, 中山若樹, 数又研, 宝金清博, 再生医療, 16, 273, 2017年02月01日
日本語

脳神経外科救急診療におけるArterial Spin Labelingの役割　　　　　　　　　　　　　　　
新谷 好正, 大浦 大輔, 後藤 秀補, 川堀 真人, 岩崎 素之, 井原 達夫, 馬渕 正二, 寶金 清博, Neurosurgical Emergency, 21, 3, 321, 321, 2017年02月
(NPO)日本脳神経外科救急学会, 日本語

脳梗塞に対する自家骨髄間質細胞移植:RAINBOW研究
七戸秀夫, 川堀真人, 寳金清博, 日本ニューロリハビリテーション学会学術集会プログラム・抄録集, 8th, 44, 2017年
日本語

クリッピング困難な脳動脈瘤におけるバイパス複合手術の治療計画と術中判断
中山若樹, 月花正幸, 伊藤康裕, 東海林菊太郎, 川堀真人, 長内俊也, 数又研, 鐙谷武雄, 寳金清博, 日本臨床脳神経外科学会プログラム・抄録集, 20th, 116, 2017年
日本語

ASL techniqueの臨床応用 脳神経外科救急診療を中心に　　　　　　　　　　　　　　　
大浦 大輔, 新谷 好正, 岩崎 素之, 川堀 真人, 後藤 秀輔, 馬淵 正二, 井原 達夫, 奥秋 知幸, 中村 理宣, 映像情報Medical, 48, 14, 129, 138, 2016年12月
産業開発機構(株), 日本語

急性進行性脊髄・末梢神経障害の早期治療　　　　　　　　　　　　　　　
井原 達夫, 岩崎 素之, 川堀 真人, 新谷 好正, 小樽市立病院誌, 5, 1, 39, 42, 2016年12月
近年、静注ステロイド治療に関する知見の集積や、グロブリン治療の適応拡大により早期に治療を開始すべき神経疾患に遭遇する機会が増えているが急性進行性の場合は必ずしも予後がよくない。当科診療開始後発症早期の進行性悪化を示す脊髄・末梢神経障害8例につき初期診療ならびに長期予後につき検討するため入院時か診断時に直ちに治療を開始し治療前後から慢性期理学治療に至るまでの改善度をBarthel indexで追跡した。末梢神経障害5例中4例で改善傾向がみられたが脊髄障害3例はいずれも予後不良であった。急性増悪例では早期の診断治療に加え新たな治療方法の開発が望まれる。(著者抄録), 小樽市病院局, 日本語

看護師主導による挿管実習および介助シミュレーションの効果について　　　　　　　　　　　　　　　
山尾 美南海, 林 誠一, 佐々木 悠人, 後藤 秀輔, 岩崎 素之, 新谷 好正, 馬渕 正二, 川堀 真人, 小樽市立病院誌, 5, 1, 75, 78, 2016年12月
脳神経外科病棟では、脳内出血など全身状態が悪い重症患者の看護が必要であり、これらの重症患者の看護では時に、心肺停止などの急変対応が必要となる場面がある。しかし実際の蘇生行為に対する系統だった教育は行われておらず、急変対応が不安であるという看護師は少なくない。そこで今回病棟看護師全員を対象とし、ICLSなどの参加経験がある看護師が指導の中心となってシミュレーターを使用した挿管手技および介助のトレーニングを行い、その効果について検討したので報告する。シミュレーション後の受講生の反応は、おおむね肯定的であったが、より介助にフォーカスしたトレーニングの必要性も指摘された。指導側の反応も肯定的な意見が主流を占めたが、より効率的なシミュレーション実施のための打ち合わせの必要性などの改善点も指摘された。(著者抄録), 小樽市病院局, 日本語

急性期脳梗塞における脳血栓回収療法後のASL高信号部位は最終脳梗塞部位を予想しうる　　　　　　　　　　　　　　　
後藤 秀輔, 川堀 真人, 岩崎 素之, 新谷 好正, 馬渕 正二, 長内 俊也, 宝金 清博, 脳血管内治療, 1, Suppl., S66, S66, 2016年11月
(NPO)日本脳神経血管内治療学会, 日本語

血栓回収療法におけるアプローチルート評価目的の心電図同期大動脈弓MRAの有効性の検討　　　　　　　　　　　　　　　
川堀 真人, 長内 俊也, 後藤 秀輔, 新谷 好正, 岩崎 素之, 馬渕 正二, 宝金 清博, 脳血管内治療, 1, Suppl., S190, S190, 2016年11月
(NPO)日本脳神経血管内治療学会, 日本語

血栓回収療法の時間短縮に向けた看護師の取り組み　　　　　　　　　　　　　　　
三上 沙季, 木下 ひかり, 川口 万友美, 林 誠一, 竹内 郁子, 金子 朱美, 新谷 好正, 岩崎 素之, 後藤 秀輔, 馬渕 正二, 川堀 真人, 脳血管内治療, 1, Suppl., S316, S316, 2016年11月
(NPO)日本脳神経血管内治療学会, 日本語

高齢者てんかん重責症例の臨床診断 診断におけるASL imagingを含めた機能画像の有用性　　　　　　　　　　　　　　　
井原 達夫, 新谷 好正, 岩崎 素之, 川堀 真人, てんかん研究, 34, 2, 514, 514, 2016年09月
(一社)日本てんかん学会, 日本語

拡散テンソル画像が病態理解に有用であった両側性小脳性運動性失調で発症した中脳正中部梗塞の1例
真屋 由佳, 川堀 真人, 大浦 大輔, 新谷 好正, 岩崎 素之, 馬渕 正二, 臨床神経学, 56, 8, 565, 568, 2016年08月
症例は85歳女性。歩行時のふらつきとろれつがまわらないことを主訴に来院した。来院時、比較的重度の両側性の小脳性運動失調と運動失調性構音障害、軽度の右medial longitudinal fasciculus(MLF)症候群を認め、画像検査にて中脳正中部に限局した急性期梗塞巣を認めた。両側小脳半球には異常を認めなかった。中脳正中部に限局した梗塞巣で両側小脳失調の原因として、小脳赤核路の交叉部位である上小脳脚交叉での障害による症状が考えられた。拡散テンソル画像(diffusion tensor imaging;DTI)において、左右の小脳核から投射される線維が交叉する上小脳脚交叉部位と今回の病巣が一致する画像が得られ、神経症状の病態理解に有効であったと考えられた。(著者抄録), (一社)日本神経学会, 日本語

急性期脳神経外科病棟における自宅退院患者に対する服薬自己管理能力判定基準標準化に向けた評価方法 Functional Independence Measure(FIM)の有用性について
吉川 貴之, 田村 広恵, 前田 麻美, 中村 昌恵, 木藤 貴弘, 新谷 好正, 伊東 雅基, 岩崎 素之, 馬渕 正二, 川堀 真人, Brain Nursing, 32, 6, 616, 623, 2016年06月
急性期脳神経外科病棟において、自宅退院可能な患者の服薬管理能力判定基準統一に向け、日常生活動作能力判定法の(FIM)がその判定に有用か検討した。2014年7月1日から8月31日迄に入院し、自宅退院が可能で服薬自己管理ができる可能性があると担当看護師が判断し、入院中に服薬自己管理を開始した35症例(男性26例、女性9例)を対象とした。自己管理期間に内服可能と判断された症例は25例(A群)、不可能と判断された症例は10例(B群)であった。服薬自己管理の可否とFIMスコアとの相関については、運動項目スコアでは有意差はなかったが、服薬自己管理ができなかったB群では、認知項目スコア合計が有意に低値であることが判明した。FIMの認知機能項目が、内服自己管理可否の判断に有用である可能性が示唆された。カットオフ値を測定するため、ROC曲線を作成したところ、35点となった。FIM認知項目が34点以下は自己管理が難しい可能性があると判断し、服薬自己管理アセスメントシートを作成した。, (株)メディカ出版, 日本語

頸動脈病変と脳梗塞　　　　　　　　　　　　　　　
新谷 好正, 川堀 真人, 岩崎 素之, 馬渕 正二, 小樽市立病院誌, 4, 1, 33, 38, 2016年02月
脳梗塞の原因は様々なものがあるが、その中の一つである頸動脈の動脈硬化について概説する。適切な対処によって動脈硬化の進行を予防することが可能である。また、不幸にして既に動脈硬化が進行してしまった場合でも、適切に対応することで大半は未然に脳梗塞を防ぐことが可能である。典型例を紹介し、頸動脈病変に関わる治療の実際を概説する。(著者抄録), 小樽市病院局, 日本語

頸動脈病変手術症例における全身性合併症 症候性と無症候性における比較検討　　　　　　　　　　　　　　　
井原 達夫, 牧田 圭弘, 新谷 好正, 川堀 真人, 岩崎 素之, 井戸坂 弘之, 馬渕 正二, 小樽市立病院誌, 4, 1, 39, 41, 2016年02月
頸部頸動脈病変手術症例を症候性と無症候性に分けその合併症を比較検討した。術前合併症(動脈硬化危険因子)については有意差はなかったが術後の全身性合併症は症候性群で有意に多かった。頸動脈病変の手術症例では予想される血管病変以外の合併症をきたす危険性があるため予後をよくするためには全身管理はもとより他疾患の可能性に留意する必要がある。また周術期では抗凝固療法の中断に伴う心原性塞栓の発症にも注意を要する。(著者抄録), 小樽市病院局, 日本語

アテローム血栓性脳梗塞を発症した頸動脈病変を有する患者における全身合併症管理　　　　　　　　　　　　　　　
井原 達夫, 牧田 圭弘, 新谷 好正, 川堀 真人, 岩崎 素之, 井戸坂 弘之, 馬渕 正二, 臨床神経学, 55, Suppl., S363, S363, 2015年12月
(一社)日本神経学会, 日本語

頸動脈分岐部に生じた可動性プラークに対するCASとCEAの治療戦略　　　　　　　　　　　　　　　
川堀 真人, 長内 俊也, 新谷 好正, 岩崎 素之, 馬渕 正二, 寶金 清博, JNET: Journal of Neuroendovascular Therapy, 9, 6, S403, S403, 2015年11月
(NPO)日本脳神経血管内治療学会, 日本語

pCASLによる一過性脳虚血発作(TIA)後の再灌流評価　　　　　　　　　　　　　　　
大浦 大輔, 富田 伸生, 宮地 隆文, 新谷 好正, 岩崎 素之, 川堀 真人, 南部 敏和, 工藤 京平, 日本放射線技術学会雑誌, 71, 9, 858, 858, 2015年09月
(公社)日本放射線技術学会, 日本語

Efficacy of adenosine-induced transient cardiac arrest for cerebral aneurysm surgery
Y. Niiya, H. Itosaka, M. Kawabori, M. Iwasaki, S. Mabuchi, K. Houkin, INTERNATIONAL JOURNAL OF STROKE, 10, 384, 384, 2015年04月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

Alteration in Gene Expression Profiles in Aging Cerebral Cortex Prior to the Occurrence of Stroke in Stroke-Prone Spontaneously Hypertensive Rats
Masaki Ito, Satoshi Kuroda, Koji Takahashi, Masahito Kawabori, Michiyuki Miyamoto, Tomohiro Yamauchi, Hisayasu Saito, Hideo Shichinohe, Kiyohiro Houkin, STROKE, 44, 2, 2013年02月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

骨髄間質細胞移植は脳梗塞後の局所糖代謝を改善する : 小動物用PET/CTによる検討
宮本 倫行, 黒田 敏, 趙 松吉, 孫田 恵一, 伊東 雅基, 川堀 真人, 七戸 秀夫, 宝金 清博, 久下 裕司, 玉木 長良, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 6, 269, 269, 2012年11月01日
日本語

合併症のシステマティック・レビュー 適切なInformed Consentのために 髄液シャント手術　　　　　　　　　　　　　　　
伊東 雅基, 寳金 清博, 斎藤 久泰, 新保 大輔, 茂木 洋晃, 川堀 真人, 宮本 倫行, 山内 朋裕, Neurological Surgery, 40, 10, 923, 945, 2012年10月
髄液シャント手術の合併症について、英文論文はPubMedで検索して127論文、日本語論文は雑誌「脳神経外科」から12編の計139編を対象として解析した。術式別では、脳室-腹腔(VP)シャント:109編、脳室-心房(VA)シャント:11編、腰椎クモ膜下腔-腹腔(LP)シャント:14編であった。術式別のmorbidity/mortality/revision rate(%)は、VP:31.7/5.0/49.9、VA:17.5-48.0/0.8-9.0/36.5-66、LP:25.2/0.4/23.1であった。合併症発生率(%)は、shunt related infectionがVP:10、VA:6.1、LP:1-10、obstructionがVPのoverall:9.3-38、VAの脳室カテーテル:20.5-30.1、バルブ:7.9、LPの腰椎クモ膜下腔カテーテル:1.3-5、バルブ:4.1、腹腔カテーテル:6.8-15であった。これらの他にも髄液シャント手術に特有の合併症から共通する合併症がみられ、稀な合併症では多岐にわたる事象の報告もあり、幅広い知識をもって周術期管理に当たる必要があると考えられた。, (株)医学書院, 日本語

ラット脳梗塞亜急性期モデルに対する骨髄間質細胞の直接投与と経静脈投与 : 光イメージングによる検討
川堀 真人, 黒田 敏, 杉山 拓, 七戸 秀夫, 宝金 清博, 久下 裕司, 玉木 長良, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 4, 205, 205, 2012年08月01日
日本語

合併症のシステマティック・レビュー 適切なInformed Consentのために 未破裂中大脳動脈瘤の外科治療
川堀 真人, 数又 研, 大西 浩介, 杉山 拓, 伊東 雅基, 中山 若樹, 寳金 清博, Neurological Surgery, 40, 8, 731, 740, 2012年08月
2000〜2011年の未破裂中大脳動脈瘤の手術成績が報告されている論文をPubMed(英文)、J-stage(和文)により検索し、開頭clipping術に関する21件1323例を抽出し解析した。21件のcase seriesにおけるmorbidityは0.0〜26.1%に分布していた。開頭術により合併症を呈した例は54例集積され、平均4.1%と算出された。瘤サイズ別では7mm以下が1.48%、15mm前後が5.93%、25mm以上が27.8%で、死亡は1例のみであった。中大脳動脈領域の虚血性合併症の出現率は2.1%、穿通枝領域では1.3%、術後1週間以降に生じたvasospasmは0.7%、静脈性梗塞は0.7%であった。巨大動脈瘤、血栓化動脈瘤、serpentine aneurysm、コイル塞栓術後の再処理などのcomplex aneurysmsは64例報告され、合併症は15例(23.4%)にみられた。稀な合併症としてはclipに関連するslip out、voaospasm、動脈瘤再増大・血栓化、ビオボンドによる遅発性動脈閉塞などが報告されていた。, (株)医学書院, 日本語

骨髄間質細胞移植は脳梗塞後の局所糖代謝を改善する 小動物用PET/CTによる検討
宮本 倫行, 黒田 敏, 趙 松吉, 孫田 恵一, 伊東 雅基, 川堀 真人, 七戸 秀夫, 宝金 清博, 久下 裕司, 玉木 長良, 核医学, 49, 3, S194, S194, 2012年08月
(一社)日本核医学会, 日本語

初発脳ラクナ梗塞患者における未治療高血圧の関与 未病と一次予防の重要性
川堀 真人, 新谷 好正, 栗栖 宏多, 太田 穣, 馬渕 正二, 宝金 清博, 未病と抗老化, 21, 130, 133, 2012年06月
脳ラクナ梗塞は穿通動脈の閉塞によって運動障害等をもたらす重大な疾患であり、その発症機序に関して高血圧の関与が一番大きいことが知られているが、実際ラクナ梗塞患者に占める未治療高血圧の頻度は不明である。そこで今回我々は北海道後志地区の唯一の脳疾患拠点病院である当院において初発脳梗塞患者における未治療高血圧と他のリスクファクターの頻度をretrospectiveに検討し、その一次予防の重要性について考察した。症例は2010年1月から10月までの10ヵ月間に当院脳神経外科に入院した615人のうち、初発脳ラクナ梗塞患者50人を対象とした。その内訳は男性26人・女性24人で平均年齢70.0±12.3歳であった。初発症状は軽度麻痺が62%、構音障害が20%、その他眼球運動障害、しびれなどであった。退院時のmodified Rankin Scale(mRS)はgood(mRS≦3)が86%であったが、poor(mRS≧4)が14%存在した。リスクファクターの頻度は高血圧85%、糖尿病34%、高脂血症32%、喫煙42%であり、特に高血圧を有する患者の55%が未治療(健康診断未受診、自己判断での通院中断等)であった。高血圧未治療患者群と治療患者群で退院時mRSに有意差はなかった。脳ラクナ梗塞は高血圧がその発症に強く関与していることがしられているが、半数以上の初発脳ラクナ梗塞患者において高血圧が未治療であることが示された。高齢社会を迎えている現在、このような脳梗塞高リスク患者をどのようにしてスクリーニングし、継続受診させていくかは今後の課題である。(著者抄録), (一財)博慈会老人病研究所, 日本語

【もやもや病】もやもや病の病態、診断と治療 最近の知見と今後の課題
黒田 敏, 杉山 拓, 川堀 真人, 笹森 徹, 栗栖 宏多, 内野 晴登, 七戸 秀夫, 中山 若樹, 宝金 清博, 脳卒中の外科, 40, 2, 77, 82, 2012年03月
(一社)日本脳卒中の外科学会, 日本語

骨髄間質細胞移植は脳梗塞後の局所糖代謝を改善する 小動物用PET/CTによる検討　　　　　　　　　　　　　　　
宮本 倫行, 黒田 敏, 七戸 秀夫, 伊東 雅基, 川堀 真人, 趙 松吉, 孫田 恵一, 久下 裕司, 玉木 長良, 宝金 清博, 脳循環代謝, 23, 1, 142, 142, 2011年11月
日本脳循環代謝学会, 日本語

慢性血行力学的脳虚血病変に対するEC-IC bypassの長期成績 PETを用いた治療選択における10年間の検討　　　　　　　　　　　　　　　
川堀 真人, 黒田 敏, 中山 若樹, 石川 達哉, 宝金 清博, 脳循環代謝, 23, 1, 155, 155, 2011年11月
日本脳循環代謝学会, 日本語

神経皮膚黒色症と鑑別を要した巨大色素性有毛性母斑と星細胞腫が合併した稀な1例　　　　　　　　　　　　　　　
鴨嶋 雄大, 澤村 豊, 斉藤 伸治, 川堀 真人, 寳金 清博, 久保田 佳奈子, Neurological Surgery, 39, 5, 479, 483, 2011年05月
症例は6歳女児で、生下時より前額部・背部・左腕・両下肢に多発有毛性母斑を認め、神経皮膚黒色症疑いで母斑切除術を受けた。1歳時に当院小児科で行ったMRIで左テント下小脳半球に腫瘍性病変を認め、毎年MRIにてスクリーニングを行い、今回腫瘍の増大を認め当科紹介となった。神経症状はないが組織診断目的で腫瘍摘出術を行った。腫瘍は正常小脳実質との境界は明瞭で、白色の弾性軟で血管成分が乏しく低悪性度神経膠腫が疑われた。術野にメラニン色素増殖部位は認めず、小脳歯状核機能温存のため近傍の腫瘍を残して終了した。病理診断はび漫性星細胞腫であった。術後に新たな神経症状出現は認めず、創部治癒後に退院した。3ヵ月後、左側歯状核近傍に残存する腫瘍の再摘出術を行った。術後に体幹失調・左側失測定症状の出現を認めたが、リハビリテーション後に独歩可能状態で退院した。, (株)医学書院, 日本語

Transplanted Bone Marrow Stromal Cells Protect Neurovascular Units and Ameliorate Brain Damage in Stroke-Prone Spontaneously Hypertensive Rats
Masaki Ito, Satoshi Kuroda, Taku Sugiyama, Katsuhiko Maruichi, Masahito Kawabori, Hideo Shichinohe, Kiyohiro Houkin, STROKE, 42, 3, E94, E95, 2011年03月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

Bone Marrow Stromal Cell Transplantation Attenuates Cognitive Dysfunction Due to Chronic Cerebral Ischemia in Rats
Hideo Shichinohe, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Masahito Kawabori, STROKE, 42, 3, E68, E68, 2011年03月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

臨床用MRIをもちいた,鉄製剤で標識された骨髄間質細胞のファントム内検出
七戸秀夫, 黒田敏, 工藤與亮, 伊東雅基, 川堀真人, 宮本倫行, 宝金清博, 寺江聡, 再生医療, 10, 257, 2011年02月01日
日本語

脳卒中に対する骨髄間質細胞移植研究の現状と課題
黒田 敏, 七戸 秀夫, 杉山 拓, 伊東 雅基, 川堀 真人, 千葉 泰弘, 長内 俊也, 丸一 勝彦, 宝金 清博, 岩崎 喜信, 脳卒中, 32, 6, 532, 537, 2010年11月25日
第35回日本脳卒中学会 シンポジウム1 総説, 日本脳卒中学会, 日本語

脳梗塞をターゲットとした再生医療における最適な細胞移植法
川堀 真人, 黒田 敏, 七戸 秀夫, 宝金 清博, 再生医療, 9, 4, 477, 486, 2010年11月
近年の膨大な研究成果をもとに、さまざまな細胞ソースを用いた中枢神経の再生医療が臨床応用の段階を迎えようとしている。その主なターゲットは脳梗塞、脳挫傷、脊髄損傷、神経変性疾患などである。しかし、その移植細胞投与方法に関しては現時点においても定位的移植、経静脈的移植などさまざまな移植方法が個々に検討されていることがほとんどで、最適な移植ルートに関して科学的に比較検証されていないのが実情である。近い将来に展開されると考えられる臨床応用を考慮した場合、中枢神経への安全かつ効率的な移植ルートを科学的データに基づいて確立しておくことが急務である。本稿では、現在までに動物あるいはヒトで実施されてきた幹細胞の中枢神経への細胞移植の成果を、脳梗塞を中心に概説し、安全かつ効率的な移植ルートについて検証する。(著者抄録), (株)メディカルレビュー社, 日本語

【手術手技の工夫】 もやもや病における血行再建術手技の工夫と血流改善効果
吉本 哲之, 伊東 雅基, 川堀 真人, 小林 理奈, 藤本 真, 善積 威, 山内 亨, 徳田 耕一, 金子 貞男, 脳卒中の外科, 38, 6, 375, 379, 2010年11月
Surgical treatment for moyamoya disease is basically a combination of direct and indirect revascularization because of the characteristic pathogenesis. Surgical goals are to increase the collateral channels as much as possible and to widely cover the territory of the poor cerebral blood flow. We preoperatively evaluate cerebral perfusion by angiography and single photon emission CT, and plan the direct bypass between STAs and each cortical branch of ACA and MCA. We then add the indirect revascularization over them on the 2 cranial windows. Recently, the middle meningeal artery also has been utilized as a donor of the direct revascularization.
We estimated the postoperative perfusional change of the total revascularizations by SPECT, which showed improved cerebral blood flow and vascular reserve.
, (一社)日本脳卒中の外科学会, 日本語

脳血流SPECTによる脳循環評価および血栓溶解療法適応決定　　　　　　　　　　　　　　　
伊東 雅基, 吉本 哲之, 藤本 真, 川堀 真人, 宮本 倫行, 山口 日出志, 善積 威, 山内 亨, 徳田 耕一, 金子 貞男, JNET: Journal of Neuroendovascular Therapy, 4, 4, 371, 371, 2010年11月
(NPO)日本脳神経血管内治療学会, 日本語

脳虚血・臨床・モヤモヤ病 小児モヤモヤ病における頭痛と脳血行動態の関係について　　　　　　　　　　　　　　　
川堀 真人, 黒田 敏, 中山 若樹, 宝金 清博, 脳循環代謝, 22, 1, 80, 80, 2010年11月
日本脳循環代謝学会, 日本語

tPA療法前SPECTによる脳循環評価および治療適応決定　　　　　　　　　　　　　　　
伊東 雅基, 吉本 哲之, 川堀 真人, 藤本 真, 山口 日出志, 善積 威, 山内 亨, 徳田 耕一, 柏葉 武, 金子 貞男, 脳循環代謝, 22, 1, 100, 100, 2010年11月
日本脳循環代謝学会, 日本語

Platelet lysateを用いたヒト骨髄間質細胞培養 安全な中枢神経再生の臨床応用を目指して　　　　　　　　　　　　　　　
七戸 秀夫, 黒田 敏, 杉山 拓, 伊東 雅基, 川堀 真人, 西尾 充史, 武田 紫, 小池 隆夫, 寳金 清博, 脳循環代謝, 22, 1, 128, 128, 2010年11月
日本脳循環代謝学会, 日本語

頸動脈内膜剥離術後早期に剥離部においてモヤモヤエコーと血栓形成を認めた6症例の検討　　　　　　　　　　　　　　　
川堀 真人, 吉本 哲之, 村木 睦子, 伊東 雅基, 藤本 真, 金子 貞男, Neurosonology, 23, 増刊, 57, 57, 2010年06月
(一社)日本脳神経超音波学会, 日本語

小児もやもや病の治療戦略 小児もやもや病の外科治療 今後の課題
黒田 敏, 笹森 徹, 川堀 真人, 中山 若樹, 宝金 清博, 石川 達哉, 小児の脳神経, 35, 2, 183, 183, 2010年04月
(一社)日本小児神経外科学会, 日本語

小児モヤモヤ病における頭痛と脳血行動態の関係について　　　　　　　　　　　　　　　
川堀 真人, 黒田 敏, 中山 若樹, 小児の脳神経, 35, 2, 251, 251, 2010年04月
(一社)日本小児神経外科学会, 日本語

ヒト骨髄間質細胞(hBMSC)のラット脳梗塞における治療効果の検討
杉山拓, 黒田敏, 七戸秀夫, 伊東雅基, 川堀真人, 武田紫, 西尾充史, 再生医療, 9, 2010年

もやもや病の血行再建術手技の工夫と血流改善効果
吉本哲之, 伊東雅基, 川堀真人, 小林理奈, 藤本真, 善積威, 山内亨, 徳田耕一, 金子貞男, 日本脳神経外科学会総会抄録集(CD-ROM), 68th, ROMBUNNO.3N-DP104-03, 2009年
日本語

急性期内頸動脈閉塞に対するtPA療法の効果―tPA療法100症例の治療成績より―
伊東雅基, 吉本哲之, 川堀真人, 小林理奈, 藤本真, 善積威, 山内亨, 徳田耕一, 金子貞夫, 日本脳神経外科学会総会抄録集(CD-ROM), 68th, ROMBUNNO.3K-DP090-04, 2009年
日本語

重症冠動脈疾患を合併した内頸動脈 中大脳動脈閉塞症に対する周術期管理　　　　　　　　　　　　　　　
川堀 真人, 黒田 敏, 中山 若樹, 寺坂 俊介, 岩崎 喜信, 数又 研, 牛越 聡, The Mt. Fuji Workshop on CVD, 26, 89, 89, 2008年07月
(株)にゅーろん社, 日本語

海綿静脈洞浸潤腫瘍に対する誘発電位測定装置を用いた簡便な眼球運動モニター法　　　　　　　　　　　　　　　
石井 伸明, 川堀 真人, 村田 純一, 藤本 真, 白坂 智英, 善積 威, 吉本 哲之, 金子 貞男, 岩崎 喜信, 日本内分泌学会雑誌, 82, Suppl., 128, 131, 2006年06月
海綿静脈洞浸潤性腺腫手術でのelectro-oculography(EOG)による眼球運動モニター法を紹介し,本法を施行し陽性を示した2例(症例1:65歳女,症例2:65歳女)を提示した.症例1は鞍内から鞍上部,左海綿静脈洞に進展する腫瘍に対し,経蝶形骨洞手術を行った.腫瘍の内減圧が進み,左海綿静脈洞近傍に手術操作が及んだ際,左眼球の動きが感知された.これは核出操作や止血操作で再現され,これ以上の摘出操作は危険と判断し行わなかった.術翌日に複視の訴えがあり,左眼の外転障害を認めた.遅発性の微小腫瘍出血あるいは腫瘍の浮腫性変化による外転神経麻痺と判断し,止血剤およびステロイドパルス療法で保存的に経過観察した.1週間後には外転障害が改善し,複視も1ヵ月後に消失した.症例2は下垂体腫瘍摘出術における左海綿静脈洞内の操作中,EOGモニターで左側に波形が検出された.しかし,その後の腫瘍剥離操作でも両側性の速度波が陽性となった.術後経過は良好で,眼球運動障害もなかった, (一社)日本内分泌学会, 日本語

可動性巨大疣贅を認め緊急大動脈弁置換を施行した感染性心内膜炎の一例　　　　　　　　　　　　　　　
川堀 真人, 岡崎 修, 大野 邦彦, 田守 唯一, 木内 信太郎, 手塚 尚紀, 渡邊 剛毅, 田中 由利子, 竹下 聡, 樫田 光夫, 赤塚 宣治, 廣江 道昭, 杉山 佳代, 秋田 サム, 尾本 正, 久米 誠人, 賀嶋 俊隆, 保坂 茂, 木村 壮介, 吉川 和寛, 斉藤 澄, Circulation Journal, 69, Suppl.III, 890, 890, 2005年10月
(一社)日本循環器学会, 日本語

胃癌骨転移による骨髄癌症および播種性血管内凝固症候群に対して,新規抗癌剤併用療法により予後改善が得られた1例　　　　　　　　　　　　　　　
平野 直樹, 秋山 純一, 平賀 裕子, 大和 滋, 伊藤 公輝, 井上 雅人, 川堀 真人, 馬場 聡史, 小林 剛, 高畠 康策, 酒匂 赤人, 八坂 秀暁, 芹澤 浩子, 小飯塚 仁彦, 小早川 雅男, 今村 雅俊, 為我井 芳郎, 正木 尚彦, 上村 直実, 斉藤 澄, 日本消化器病学会雑誌, 101, 臨増大会, A694, A694, 2004年09月
(一財)日本消化器病学会, 日本語

間葉系幹細胞シートを用いたもやもや病の間接血行再建術における包括的研究
科学研究費助成事業
2023年04月 - 2027年03月
藤村 幹, 川堀 真人, 伊東 雅基, 久下 裕司
日本学術振興会, 基盤研究(B), 北海道大学, 23H03015

くも膜下出血後の脳血管攣縮に対する人工酸素運搬体を用いた新規治療法の開発
科学研究費助成事業
2022年04月01日 - 2025年03月31日
月花 正幸, 伊東 雅基, 川堀 真人, 鐙谷 武雄, 小松 晃之, 藤村 幹
日本学術振興会, 基盤研究(C), 北海道大学, 22K09275

広範性脳損傷に対する間葉系幹細胞培養液由来エクソソームの経鼻的投与の検討
科学研究費助成事業
2022年04月01日 - 2025年03月31日
穂刈 正昭, 藤村 幹, 川堀 真人
日本学術振興会, 基盤研究(C), 北海道大学, 22K09274

人工酸素運搬体を用いたmulti-targetの脳保護療法の開発
科学研究費助成事業
2022年04月01日 - 2025年03月31日
鐙谷 武雄, 藤村 幹, 伊東 雅基, 小松 晃之, 川堀 真人
日本学術振興会, 基盤研究(C), 北海道大学, 22K09224

骨髄間質細胞由来細胞外小胞を用いた脳梗塞の包括的再生治療研究
科学研究費助成事業
2021年04月01日 - 2024年03月31日
黒田 敏, 柏崎 大奈, 川堀 真人, 堀 恵美子
2021年度は、研究遂行のため、3つの動物モデルの確立を目指した。
1）マウス中大脳動脈閉塞モデル：脳梗塞による片側運動機能障害、高次脳機能障害を定量的に評価した結果、幹細胞およびextracellular vesicle (EV)の治療効果を検証するモデルとして適切であることを確認した。
2）マウス凍結損傷モデル：液体窒素を用いて経頭蓋的に大脳皮質に凍結損傷を作成して、脳挫傷による片側運動機能障害、高次脳機能障害を定量的に評価した結果、幹細胞およびextracellular vesicle (EV)の治療効果を検証するモデルとして適切であることを確認した。
3）マウス・アルツハイマー病モデル：アルツハイマー病による高次脳機能障害をシミュレートする遺伝子改変マウスを特定して、現在、高次脳機能障害、組織学的所見を評価している。
日本学術振興会, 基盤研究(B), 富山大学, 21H03043

脳出血慢性期モデルに対する幹細胞とScaffold合剤の有効性評価
科学研究費助成事業
2020年04月01日 - 2023年03月31日
川堀 真人, 七戸 秀夫
昨年度製法が確立したラット脳出血モデル（SDラットおよび免疫抑制ラット）に対して出血が吸収された2週後に出血腔内へのセルザイク投与（ラット由来およびヒト由来）を行い、その後1か月間の運動機能改善を評価した。またIn-vitroにおいてセルザイクとBMSCの栄養因子の分泌について評価した。In-vivoでセルザイク投与群の方がBMSC/生理食塩水より神経機能改善効果が有意に高く、脳萎縮率もCellSaic群で低い傾向であった。また、セルザイク投与群での血腫腔周囲の脳由来神経栄養因子（BDNF）量は生理食塩水群よりも有意に多く、BDNF抑制セルザイクは通常のセルザイクよりも神経機能改善の程度が小さかった。OGD環境では、CellSaicの方がBMSCより栄養因子分泌能および細胞増殖能が有意に高かった。
日本学術振興会, 基盤研究(C), 北海道大学, 20K09382

脊髄損傷急性期に対する間葉系幹細胞静脈投与に対する脊髄腸相関に関する研究
科学研究費助成事業
2020年04月01日 - 2023年03月31日
関 俊隆, 大西 俊介, 川堀 真人
【背景】脊髄損傷に対する再生治療・細胞治療は多くの基礎研究において有効性が報告され始めているが, その作用機序は全身の炎症制御や損傷部位への幹細胞生着によるネットワークの回復など多岐にわたると考えられている. 近年, 全身の免疫センターとしての機能を有する腸管と他臓器の関連が注目されており, 脊髄損傷においても腸管との関連（脊髄-腸相関）が報告されているが, 幹細胞投与がこの相関にどのように関与しているかは未だ明らかになっていない. 本研究では, 急性期脊髄損傷に対する羊膜由来間葉系幹細胞（AMSC）静脈投与が, “脊髄-腸相関”に与える影響を検討した.
【方法】SDラットを用い, Th6/7高位で, クリップ圧挫脊髄損傷モデルを作成した. 脊髄損傷の翌日, 一定以上の麻痺を認めたラットに対し, 無作為にヒトAMSC（1x107個, A群）または生理食塩水（C群）を尾静脈投与した. AMSCの分布は, XenoLight DiRで標識し, Fusionでin-vivo imagingを行った. 腸管評価は3日後と2週間後に, 運動機能評価は4週間後まで行い, その後に病理学的検討を加えた.
【結果】AMSCは1週間後まで主に肺と肝臓に集積していたが, 急性期には脊髄内にも確認された. A群はC群に比較し, 脊髄損傷3日後以降で回腸の絨毛構造の改善を認めた. 運動機能は2週以降, A群で有意に改善し, 病理学的評価においても, 損傷部位の縮小および炎症細胞浸潤が減少していた.
【考察・結語】本研究の結果から, 脊髄損傷により回腸絨毛構造が悪化するが, 羊膜細胞投与により, 運動機能回復に先立って回腸絨毛構造が改善することが明らかとなった. 今後、bacterial translocationの関与を検討する
日本学術振興会, 基盤研究(C), 北海道大学, 20K09361

抗酸化作用を付与した人工酸素運搬体による脳梗塞治療法の開発
科学研究費助成事業
2019年04月01日 - 2022年03月31日
鐙谷 武雄, 小松 晃之, 中山 若樹, 川堀 真人, 数又 研, 寳金 清博, 長内 俊也, 杉山 拓, 伊東 雅基
異なる形態の抗酸化付加人工酸素運搬体、(1)白金ナノ粒子(PtNP)とHemoActの結合体：PtNP-HemoAct、(2)Catalaseとアルブミンを結合したCluster（C-Act）とHemoActの混合物：C-Act＋HemoAct、(3)抗酸化剤EdaravoneとHemoActの混合物：Edaravone＋HemoAct、(4)ヘモグロビンを球状に重合させた表面にアルブミンを結合したHemoglobin nanoparticle：HbNPを用い、脳保護効果を比較した。ラット虚血再灌流モデルで各薬剤を投与し、脳梗塞体積は治療群で縮小傾向を認め、HbNPで最も縮小していた。
日本学術振興会, 基盤研究(C), 北海道大学, 19K09472

iPSを用いた難病Moyamoya病に対する慢性炎症の関与に関する基礎研究
科学研究費助成事業
2018年04月01日 - 2021年03月31日
穂刈 正昭, 川堀 真人, 数又 研, 寳金 清博
本研究期間内にモヤモヤ病に対する慢性炎症関与に関して大きく分けて3つの検討を行った。①モヤモヤ病におけるピロリ菌感染の有無について、②浅側頭動脈の分子生物学的特性評価、③バイパス手術後の間接血行再建の発達具合に対する評価。①は残念ながらモヤモヤ病患者においてはピロリ菌および分泌炎症物質CagAは有意に多く分泌されているという事は無かったが、浅側頭動脈においては弾性版と膠原繊維がモヤモヤ病患者において障害されいてることが分かった。また遺伝子変異の有無によってバイパス血管の発達が違うという新規的な発見も得られた。総合的にモヤモヤ病に対するより深い病態解明を進めることが出来た。
日本学術振興会, 基盤研究(C), 北海道大学, 18K08931

脳虚血再灌流障害に対するスフィンゴリン脂質の保護効果
科学研究費助成事業
2016年04月01日 - 2019年03月31日
川堀 真人, 王 シホウ
スフィンゴリン脂質を使用し脳梗塞の再開通後の障害である虚血再灌流に対する保護効果を検証した。スフィンゴリン脂質の一種であるS1Pと同様の効果を持つ薬剤FTY720を一過性脳虚血モデルに投与することでその効果を確認した。そうすることでラットの梗塞巣の縮小や運動機能改善等の保護効果が確認され、その理由として炎症反応の強力な抑制および脳血液関門の構成タンパク質の細胞内移行を抑えていることが新たに証明された。脳梗塞に対して再開通療法が行われているが、FTY720はその際の障害を軽減できる可能性があると考えられた。
日本学術振興会, 若手研究(B), 北海道大学, 16K19992

優秀研究論文助成
2011年04月 - 2012年03月
川堀真人
博慈会, 研究代表者, 競争的資金