Oct. 2025, 日本脳循環代謝学会賞　　　　　　　　　　　　　　　

Jan. 2023, 日本脳神経外傷学会賞（平川賞）　　　　　　　　　　　　　　　

Oct. 2021, 日本脳循環代謝学会賞　　　　　　　　　　　　　　　

Jun. 2019, アジア細胞治療学会優秀発表賞　　　　　　　　　　　　　　　

Aug. 2018, 北海道大学医学部エクセレントティーチャー（優秀賞）　　　　　　　　　　　　　　　

Apr. 2018, ヨーロッパ脳卒中学会, 優秀研究賞　　　　　　　　　　　　　　　
川堀真人

Oct. 2017, アジア細胞治療学会, 優秀ポスター賞　　　　　　　　　　　　　　　
川堀真人

Mar. 2016, Hokkaido University Graduate School of Medicine, Takakuwa Eimatsu Scholar Award　　　　　　　　　　　　　　　
Masahito Kawabori

Feb. 2016, Hokkaido University School of Medicine Alumni, Furate Research Award　　　　　　　　　　　　　　　
Masahito Kawabori

Jul. 2011, Hokkaido University Graduate School of Medicine, Otoha Scholar Award　　　　　　　　　　　　　　　
Masahito Kawabori

Reverse translational research of transient magnetic resonance imaging hyperintensity following intracranial stem cell therapy
Yi Qi, Masahito Kawabori, Yo Nakahara, Khin Khin Tha, Sumio Ohtsuki, Miki Fujimura
Stem Cell Research & Therapy, 16, 1, 646, 646, 18 Nov. 2025, [International Magazine]
English, Scientific journal, BACKGROUND: Neurological disorders, such as stroke and traumatic brain injury are the most significant global health challenges, leading to long-term physical and cognitive impairments. Cell transplantation therapy holds substantial promise for facilitating recovery, with numerous clinical trials currently underway. Intracerebral stem cell infusion offers the advantage of directly delivering a sufficient number of stem cells to the targeted area. Both our team and other researchers have observed a notable phenomenon following intracerebral stem cell therapy in clinical trials, wherein transient edema, as detected by Fluid Attenuated Inversion Recovery (FLAIR) magnetic resonance (MR) imaging, can be monitored between one and two weeks post-transplantation, with a subsequent resolution occurring approximately one month later. Notably, patient recovery appears to accelerate during the period of elevated FLAIR signals. However, the precise mechanisms underlying this distinctive phenomenon remain poorly understood. Therefore, this reverse translational research employs proteomics and histological analysis to investigate the mechanisms driving this phenomenon, thereby enhancing our understanding of stem cell therapy. METHODS: Bone marrow-derived mesenchymal stem cells (BMSCs) were isolated from Sprague-Dawley (SD) rats, with passage 3 cells utilized for subsequent experiments. A total of one million cells, suspended in 10 µL of phosphate-buffered saline, were intracerebrally transplanted into the striatum of SD rats. Serial magnetic resonance imaging (FLAIR) scans were performed up to three weeks post-transplantation. Brain tissues were collected from the pre-signal (1 week post-transplantation), signal (2 weeks post-transplantation), and post-signal (3 weeks post-transplantation) groups for proteomic analysis, network analysis, and immunofluorescence imaging. RESULTS: Consistent with clinical trials, transient FLAIR hyperintense signals were not detected until approximately two weeks post-intracranial stem cell therapy. These signals emerged around week two and diminished by week three. Proteomic analysis of brain specimens from the pre-signal and signal groups identified 231 differentially expressed proteins, which were primarily involved in vesicle-mediated transport, synaptic remodeling, and cellular communication. Glial fibrillary acidic protein (GFAP), Aquaporin-4 (AQP4), and Apolipoprotein E (APOE) were identified as key hub proteins. Immunofluorescence studies further confirmed that expression levels of GFAP, AQP4, and APOE increased around two weeks post-transplantation and significantly decreased by week three, coinciding with the resolution of the FLAIR signal. CONCLUSIONS: Our findings suggest that the transient FLAIR hyperintensity observed following intracerebral stem cell therapy is primarily attributed to transient glial cell activation, resulting in increased AQP4 expression and transient brain water influx. Additional mechanisms, including vesicle-mediated transport, secretion, synaptic activity, and lipid signaling, also contribute to the transient FLAIR hyperintensity signals and may play a role in the manifestation of clinical symptoms.

Intra-Arterial Administration of Stem Cells and Exosomes for Central Nervous System Disease
Taishi Honda, Masahito Kawabori, Miki Fujimura
International Journal of Molecular Sciences, 26, 15, Jul. 2025, [International Magazine]
English, Scientific journal, Central nervous system (CNS) disorders present significant therapeutic challenges due to the limited regenerative capacity of neural tissues, resulting in long-term disability for many patients. Consequently, the development of novel therapeutic strategies is urgently warranted. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Recent research has also identified exosomes-small vesicles enclosed by a lipid bilayer, secreted by stem cells-as a key mechanism underlying the therapeutic effects of stem cell therapies, and given their enhanced stability and superior blood-brain barrier permeability compared to the stem cells themselves, exosomes have emerged as a promising alternative treatment for CNS disorders. A key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration. Intracerebral injection can deliver a substantial quantity of stem cells directly to the brain, but it carries the potential risk of inducing additional brain injury. Conversely, intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain, which may compromise the therapeutic efficacy. With advancements in catheter technology, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages. In this comprehensive review, we aim to summarize both basic and clinical research exploring the intra-arterial administration of stem cells and exosomes for the treatment of CNS diseases. Additionally, we will elucidate the underlying therapeutic mechanisms and provide insights into the future potential of this approach.

Editorial: Novel therapeutic modalities for stroke: Stem cells and exosomes.
Masahito Kawabori
Experimental neurology, 392, 115344, 115344, 10 Jun. 2025, [International Magazine]
English

Human platelet lysate produced from leukoreduction filter contents enables sufficient MSC growth.
Shinobu Wakamoto, Tomoko Furukawa, Masahito Kawabori, Mitsuaki Akino, Shiho Kato, Hisae Fuse, Sumio Ohtsuki, Yoshihiro Torimoto, Miki Fujimura, Shuichi Kino
Stem cell research & therapy, 16, 1, 205, 205, 23 Apr. 2025, [International Magazine]
English, Scientific journal, BACKGROUND: Stem cell therapy holds significant potential for promoting recovery, with numerous products currently under development. Blood-derived supplements are often essential for successful stem cell expansion, with fetal bovine serum (FBS) being the most commonly used supplement. However, FBS has drawbacks, including the risk of immune responses, ethical concerns about animal welfare, and potential zoonotic infections. Human platelet lysate (hPL), derived from lysed platelets, contains various growth factors and has been proposed as an alternative to FBS. However, obtaining sufficient human platelets for clinical use remains challenging. Leukoreduction filters, used during blood transfusion manufacturing to remove leukocytes, also retain significant amounts of platelets and plasma. This study investigates the feasibility and efficacy of filter-derived hPL (f-hPL) for mesenchymal stem cell (MSC) expansion. METHODS: Leukoreduction filters were collected after their use in the manufacturing of whole blood transfusion products. Each filter was reverse-perfused with saline to extract residual blood contents. Platelets (f-platelet) and supernatant were separated by multiple centrifugation steps. f-Platelet were lysed with varying concentrations of fresh frozen plasma (FFP) to determine the optimal protein concentration for the lysate solution. Then, plasma left in the leukoreduction filters were used to generate lysate solution (f-plasma) at optimal protein concentration. f-Platelet (1.1 × 109/mL) and f-plasma (27 mg/mL protein) were combined in a freezing bag and subjected to three freeze-thaw cycles to produce f-hPL. Both small- and large-scale f-hPL were manufactured, and MSCs expansion and quality assessments were perfomed to evaluate the efficacy of f-hPL. RESULTS: A total of 3.5 ± 0.6 × 1010 f-platelets were obtained from a single leukoreduction filter, yielding a collection efficiency of 37.1 ± 5.3%. The optimal protein concentration of lysate solution for cell expansion was > 27 mg/mL. Subsequently, six leukoreduction filters used to produce enough f-platelet and p-plasma for 100 mL of f-hPL. MSCs cultured in medium supplemented with 10% f-hPL demonstrated superior expansion, with cell proliferation rates 20% higher than those observed with commercial hPL and 300% higher than those cultured with FBS. The expanded MSCs met the International Society for Cell & Gene Therapy criteria for cell surface markers and differentiation potential. MSCs expanded with f-hPL expressed similar to or higher amounts of hepatocyte growth factor compared with those cultured with FBS and human AB serum. Furthermore, f-hPL significantly enhanced cell proliferation up to P12 and effectively prevented cell senescence. CONCLUSION: f-hPL derived from leukoreduction filters demonstrated strong capacity for MSCs expansion. The use of discarded blood materials for regenerative medicine represents a sustainable and efficient approach, with significant therapeutic potential.

Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage.
Shuho Gotoh, Masahito Kawabori, Sho Yamaguchi, Yo Nakahara, Erika Yoshie, Kohtarou Konno, Yuki Mizuno, Yoichiro Fujioka, Yusuke Ohba, Yuji Kuge, Masahiko Watanabe, Miki Fujimura
Experimental neurology, 386, 115143, 115143, Apr. 2025, [International Magazine]
English, Scientific journal, INTRODUCTION: Brain damage caused by subarachnoid hemorrhage (SAH) currently lacks effective treatment, leading to stagnation in the improvement of functional outcomes for decades. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells (MSC), which effectively attenuate neuronal apoptosis and inflammation in neurological diseases. Due to the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a novel approach for targeting the brain. In this study, we investigate the effects of intranasally administered MSC-derived exosomes in a SAH animal model and elucidate their mode of action. METHODS: Exosomes were isolated from the cell supernatants of amnion-derived MSC. SAH was induced in 8-week-old Sprague-Dawley rats using an autologous blood prechiasmatic cistern injection model. A total of 1.2 × 1010 particles of exosomes in 200 μL of PBS or PBS alone were intranasally administered immediately and 24 h post-injury. Neurological function was assessed up to 7 days after injury, and histological analysis was performed to evaluate their anti-apoptotic and anti-inflammatory effects. The biodistribution of exosomes was assessed using PET/CT imaging of 64Cu labeled exosome. In vitro analyses were performed using primary glial cells and cell lines to evaluate the anti-inflammatory effects of the exosomes. RESULTS: Animals treated with exosomes exhibited significant improvement in cognitive function compared with PBS treated animal. Apoptotic cells and inflammation were reduced for the exosome group in the hippocampal CA1 area and in cortex, resulting in better neuronal cell survival. Blood brain barrier permeability was also preserved in the exosome group. Nuclear imaging revealed that exosomes were primarily transferred to the olfactory nerve and cerebrum; furthermore, exosomes were also observed in the trigeminal nerve and brainstem, where exosomes were co-localized with microglia and with endothelial cells. In vitro assessment showed that exosome administration ameliorated inflammation and prevented the death of glial cells. CONCLUSIONS: MSC-derived exosomes were successfully transferred into the brain through intranasal administration and alleviated brain damage following SAH.

Validity of E-PASS Score for Evaluating Perioperative Minor Complications Associated with Carotid Endarterectomy.
Yutaka Morishima, Masahito Kawabori, Yoichi M Ito, Masayuki Gekka, Koji Furukawa, Yoshimasa Niiya, Miki Fujimura
Neurologia medico-chirurgica, 65, 1, 9, 14, 15 Jan. 2025, [Domestic magazines]
English, Scientific journal, Carotid endarterectomy (CEA) is conducted to reduce the risk of cerebral infarction; therefore, a low complication rate is highly required. To predict long-term morbidity and mortality, various scoring systems have been considered; nonetheless, a model that can be utilized to estimate nonmajor temporary complications and minor complications is currently lacking. To evaluate the occurrence rate of perioperative complications in various surgical domains, the E-PASS (Estimation of Physiological Ability and Surgical Stress) score is employed. This study was carried out to investigate the utility of the E-PASS score as a predictive factor for the risk of minor complications in patients undergoing CEA. The retrospective analysis was performed for 104 consecutive series of CEA procedures carried out at Otaru Municipal Hospital. The correlation between E-PASS and the rate of minor complications was examined. Sensitivity and specificity were used to construct a receiver operating characteristic curve, and the area under the curve (AUC) was calculated for accuracy. Postoperative minor complications occurred in eight cases (7.7%), including six vagal nerve injuries and two pneumonia cases. Three categorical data-preoperative risk score, surgical stress scores, and comprehensive risk score (CRS) -showed a good relationship with the postoperative minor complication. Among them, CRS presented the highest sensitivity and specificity, as indicated by an AUC of 0.68. The CRS cutoff value was calculated as -0.068, with a 1.7% postoperative minor complication rate for those lower than -0.068 and 14.0% for those higher than -0.068. The E-PASS score was effective for evaluating and predicting postoperative minor complications in patients with CEA procedures.

Efficacy and Safety of Combined Revascularization Surgery for Moyamoya Disease: Standard Procedure and Perioperative Management.
Miki Fujimura, Masaki Ito, Haruto Uchino, Masahito Kawabori, Taku Sugiyama
Acta neurochirurgica. Supplement, 136, 99, 104, 2025, [International Magazine]
English, Scientific journal, OBJECTIVE: Revascularization surgery such as superficial temporal artery-middle cerebral artery (STA-MCA) bypass is a standard management choice for symptomatic moyamoya disease (MMD) patients, with either ischemic or hemorrhagic presentation. We sought to clarify the efficacy and safety of institutional standardized revascularization procedures for MMD. MATERIALS AND METHODS: The present study includes 37 consecutive patients with MMD (2-60 years old, 42.0 on average) undergoing revascularization surgery on 42 affected hemispheres. Direct-indirect combined revascularization surgery was performed on most hemispheres (41/42, 97.6%), including STA-MCA bypass (39 hemispheres) and occipital artery-posterior cerebral artery bypass (2 hemispheres). All patients underwent standardized perioperative management with strict blood pressure control (110-130 mmHg) based on routine single-photon emission computed tomography (SPECT) 1 and 7 days after surgery. Then we investigated the outcome of surgeries, focusing mainly on that of combined revascularization procedures. RESULTS: The outcome of 42 surgeries was favorable in all cases, except for one adult (2.3%) manifesting with cerebral hyperperfusion syndrome leading to neurological worsening. None of the patients developed perioperative cerebral infarction (0/42; 0%), and the patency of the direct bypass was confirmed via MRA in all patients undergoing combined procedure (41/41, 100%). Two patients suffered wound-healing delay, one of which required resuture. CONCLUSION: The combined revascularization surgery is a safe and effective treatment for MMD, while local cerebral hyperperfusion is a potential complication that should be avoided through intensive perioperative care.

Intraventricular continuous BDNF administration ameliorates neuroinflammation and enhances neurogenesis against rodent intracerebral hemorrhage model.
Ting-Chun Lin, Masahito Kawabori, Erika Yoshie, Yo Nakahara, Li-Kai Tsai, Miki Fujimura
Frontiers in neurology, 16, 1606606, 1606606, 2025, [International Magazine]
English, Scientific journal, OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a pivotal growth factor for neuronal survival; however, its precise role following intracerebral hemorrhage (ICH) remains poorly understood. This study sought to investigate whether intraventricular administration of BDNF could enhance neurogenesis and ameliorate neuroinflammation, resulting in improvement of neurological outcomes in a rat ICH model. METHODS: Male Sprague-Dawley rats were utilized to create an acute ICH model by collagenase infusion into the internal capsule. An intraventricular minipump was subcutaneously implanted, with the catheter tip inserted into the contralateral ventricle to deliver BDNF for 7 consecutive days. The rats were assigned to one of three experimental groups; the BDNF group, the anti-BDNF antibody group, and the sham group. Functional assessment was conducted up to 14 days post-ICH, and immunohistochemical analysis was performed to evaluate neurogenesis, apoptosis, and neuroinflammation in the perihematomal area and the subventricular zone (SVZ). RESULTS: Brain-derived neurotrophic factor treatment significantly increased the proliferation of neural stem cells in the perihematomal region. It also reduced the neuroinflammation 14 days post-ICH. Additionally, BDNF treatment demonstrated a favorable neurological function at 14 days post-ICH. CONCLUSION: Intraventricular administration of BDNF demonstrated favorable recovery after ICH by reducing inflammation and enhancing neurogenesis.

Relationship Between Location of Cell Transplantation and Recovery for Intracerebral Stem Cell Transplantation for Chronic Traumatic Brain Injury: Post-hoc Analysis of STEMTRA Trial.
Masahito Kawabori, Yasuaki Karasawa, Jun Suenaga, Hajime Nakamura, Hideaki Imai, Takao Yasuhara, Naoki Tani, Tatsuya Sasaki, Takashi Kawasaki, Kenta Totsuka, Dai Chida, Yoichi M Ito, Tetsuya Yamamoto, Isao Date, Shota Tanaka, Haruhiko Kishima, Miki Fujimura
Neurotrauma reports, 6, 1, 106, 114, 2025, [International Magazine]
English, Scientific journal, Traumatic brain injury is a world-leading cause of disability. Current treatments are not sufficient to promote neurological recovery. Intracerebral transplantation of allogeneic mesenchymal stem cells, specifically SB623, has shown promise in achieving better neurological recovery compared with a sham surgery group in the STEMTRA trial. However, the optimal location for cell transplantation remains unclear, as transplanted lesions vary between patients. This study aimed to explore the relationship between functional recovery and the location of transplanted lesions. This study included all Japanese subjects from the STEMTRA trial who were assigned to the cell transplantation group. Functional recovery was assessed by the difference in Fugl-Meyer Motor Scale (FMMS) scores between the screening period and 24 or 48 weeks post-transplantation. An FMMS score improvement of >8 was defined as an improved group. Lesions responsible for motor deficits were categorized into three groups: motor cortex (Cortex), deep white matter (DWM), or both (Cortex and DWM). Data on the 15 transplanted sites per patient were obtained from surgical navigation software, and the distance from the damaged area to the transplanted sites was calculated. Twelve patients were included in this post-hoc analysis. No patients in the 2.5 × 106 cells group showed improvement and were therefore excluded from further analysis. Five patients were categorized into the Cortex group and four into the DWM group. The distance between the transplanted site and the injury point ranged from 0 to 39 mm. A moderate to strong trend of correlations was observed, suggesting that a shorter distance is preferable for the motor cortex group, while a greater distance is preferable for the DWM group. The optimal site for stem cell transplantation may be different from the damaged site of the patient; however, a further large number cohort is necessary to elucidate this hypothesis.

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, 02 Dec. 2024, [International Magazine]
English, Scientific journal, 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, e209797, Ovid Technologies (Wolters Kluwer Health), 08 Oct. 2024, [International Magazine]
English, Scientific journal, BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Intranasal administration of stem cell-derived exosomes for central nervous system diseases.
Shuho Gotoh, Masahito Kawabori, Miki Fujimura
Neural regeneration research, 19, 6, 1249, 1255, 01 Jun. 2024, [International Magazine]
English, Scientific journal, Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosome-based treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury.
Takuma Ikeda, Masahito Kawabori, Yuyuan Zheng, Sho Yamaguchi, Shuho Gotoh, Yo Nakahara, Erika Yoshie, Miki Fujimura
Pharmaceutics, 16, 4, 23 Mar. 2024, [International Magazine]
English, Scientific journal, Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers.

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.), 5, 5, 432, 444, 18 Mar. 2024, [International Magazine]
English, Scientific journal, 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, 18 Feb. 2024, [International Magazine]
English, Scientific journal, 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, 81, 2, 154, 162, 16 Jan. 2024, [International Magazine]
English, Scientific journal, 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, 40, 5, 1603, 1607, 02 Jan. 2024, [International Magazine]
English, Scientific journal, 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.

Use of Botulinum Toxin for Limb Immobilization for Rehabilitation in Rats with Experimental Stroke.
Hongxia Zhang, Jialing Liu, Deborah Bingham, Adrienne Orr, Masahito Kawabori, Jong Youl Kim, Zhen Zheng, Tina I Lam, Stephen M Massa, Raymond A Swanson, Midori A Yenari
Biomolecules, 13, 3, 10 Mar. 2023, [International Magazine]
English, Scientific journal, Motor rehabilitation strategies after unilateral stroke suggest that the immobilization of the healthy, unimpaired limb can promote the functional recovery of a paretic limb. In rodents, this has been modeled using casts, harnesses, and other means of restricting the use of the non-paretic forelimb in models of experimental stroke. Here, we evaluated an alternative approach, using botulinum toxin injections to limit the function of the non-paretic forelimb. Adult male rats were subjected to permanent ligation of the left distal middle cerebral artery, resulting in right forelimb paresis. The rats were then subjected to: (1) no treatment; (2) botulinum toxin injections 1 day post stroke; or (3) cast placement 5 days post stroke. Casts were removed after 5 weeks, while the botulinum toxin injection effectively immobilized subjects for approximately the same duration. Rats with bilateral forelimb impairment due to the stroke plus casting or botulinum injections were still able to feed and groom normally. Both immobilization groups showed modest recovery following the stroke compared to those that did not receive immobilization, but the casting approach led to unacceptable levels of animal stress. The botulinum toxin approach to limb immobilization had both advantages and disadvantages over traditional physical limb immobilization. The major advantage was that it was far less stress-inducing to the subject animals and appeared to be well tolerated. A disadvantage was that the paresis took roughly 10 weeks to fully resolve, and any degree of residual paresis could confound the interpretation of the behavioral assessments.

Stem Cell Therapies for Intracerebral Hemorrhage: Review of Preclinical and Clinical Studies.
Soichiro Takamiya, Masahito Kawabori, Miki Fujimura
Cell transplantation, 32, 9636897231158153, 9636897231158153, 2023, [International Magazine]
English, Scientific journal, Despite recent developments in the treatments for ischemic stroke, such as tissue plasminogen activator (t-PA) and thrombectomy, effective therapies for intracerebral hemorrhage (ICH) remain scarce. Stem cell therapies have attracted considerable attention owing to their potential neuro-regenerative ability; preclinical and clinical studies have been conducted to explore strategies for achieving functional recovery following ICH. In this review, we summarize the findings of preclinical studies on stem cell therapies of ICH, with a focus on different animal models, stem cell sources, transplantation methods, and their potential mechanisms of action. We also provide an overview of data from clinical trials to discuss the current status and future perspectives. Understanding the effectiveness and limitations of stem cell therapy and the future prospects could expand the applications of this novel therapeutic approach for ICH.

Cell therapies for acute and chronic traumatic brain injury.
Masahito Kawabori, Dai Chida, Bijan Nejadnik, Anthony H Stonehouse, David O Okonkwo
Current medical research and opinion, 38, 12, 2183, 2189, Dec. 2022, [International Magazine]
English, Scientific journal, Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.

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, Oct. 2022
Japanese

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, Oct. 2022
Japanese

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, Oct. 2022
Japanese

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, Oct. 2022
Japanese

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, 05 Sep. 2022, [International Magazine]
English, Scientific journal, 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, Sep. 2022
Japanese

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, 31 Jul. 2022, [International Magazine]
English, Scientific journal, 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, 165, e446-e451, 21 Jun. 2022, [International Magazine]
English, Scientific journal, 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, May 2022
Japanese

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, May 2022
Japanese

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, 07 Feb. 2022, [International Magazine]
English, Scientific journal, 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, [International Magazine]
English, Scientific journal, 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, 04 Jan. 2021, [International Magazine]
English, Scientific journal, 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, [International Magazine]
English, [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, [International Magazine]
English, Scientific journal, 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, Dec. 2020, [International Magazine]
English, Scientific journal, 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, 06 Oct. 2020, [International Magazine]
English, Scientific journal, 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, 09 Jul. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 02 Jun. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jun. 2020, [Domestic magazines]
Japanese, Scientific journal, 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, 18 May 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 03 Apr. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Apr. 2020, [Peer-reviewed]
Japanese

【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), Mar. 2020, [Peer-reviewed]
Japanese

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, 27 Feb. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 04 Feb. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Feb. 2020, [Peer-reviewed], [International Magazine]
English, 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
Japanese, Scientific journal

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, [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Nov. 2019, [Peer-reviewed]
Japanese

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, 01 Nov. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 11 Oct. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Oct. 2019, [Peer-reviewed]
Japanese

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, 15 Sep. 2019, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, Sep. 2019, [Peer-reviewed]
Japanese, 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, Aug. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jun. 2019
Japanese

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, 15 Apr. 2019, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, Dec. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 21 Nov. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 01 Nov. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Oct. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 25 Sep. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Sep. 2018, [Peer-reviewed]

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, Aug. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jun. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 02 May 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, May 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, 15 Oct. 2017, [Peer-reviewed], [Domestic magazines]
English, Scientific journal

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, 08 Sep. 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal

Route, cell dose, and timing
Masahito Kawabori
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 73, 85, Springer Japan, 01 Jan. 2017, [Peer-reviewed]
English, In book

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, 31 Aug. 2016, [Peer-reviewed], [Domestic magazines]
Japanese, 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, Apr. 2015, [Peer-reviewed], [International Magazine]
English, 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, 25 Feb. 2015, [Peer-reviewed], [International Magazine]
English, 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, [Peer-reviewed], [International Magazine]
English, 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, Jun. 2014, [Peer-reviewed]
English, Scientific journal

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, Jan. 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, 01 Dec. 2013, [Peer-reviewed], [International Magazine]
English, 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, Nov. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Aug. 2013, [Peer-reviewed], [International Magazine]
English, 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, 26 Apr. 2013, [Peer-reviewed], [International Magazine]
English, 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, Apr. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Nov. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal

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, Oct. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Oct. 2012, [Peer-reviewed]
Japanese

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, Aug. 2012, [Peer-reviewed]
Japanese

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, Jun. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Mar. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Feb. 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Jan. 2012, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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
Japanese, Research society

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
Japanese, Research society

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, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, [Peer-reviewed], [Domestic magazines]
English, Scientific journal, 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, Dec. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, Sep. 2011, [Peer-reviewed], [International Magazine]
English, Scientific journal, 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, May 2011, [Peer-reviewed], [Domestic magazines]
Japanese, Scientific journal, 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, Apr. 2011, [Peer-reviewed], [International Magazine]
English, 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, 10 Sep. 2010, [Peer-reviewed]
English, Scientific journal

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, Sep. 2010
Japanese, 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, Apr. 2010, [Peer-reviewed], [International Magazine]
English, 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, [Peer-reviewed], [International Magazine]
English, 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, [Peer-reviewed], [Domestic magazines]
English, 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, Nov. 2009, [Peer-reviewed]
Japanese, Scientific journal

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, Nov. 2009, [Peer-reviewed]
English, Scientific journal

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, Nov. 2009
Japanese, 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, Oct. 2009, [Peer-reviewed]
English, Scientific journal

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, 01 Sep. 2009, [Peer-reviewed], [International Magazine]
English, 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, Sep. 2009
Japanese, 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, Jul. 2009, [Peer-reviewed], [Domestic magazines]
Japanese, 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, Jul. 2009
Japanese, 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, Jun. 2009, [Peer-reviewed], [Domestic magazines]
English, 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, May 2009, [Peer-reviewed], [Domestic magazines]
Japanese, 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, May 2009, [Peer-reviewed], [Domestic magazines]
English, 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.

Cervicogenic Headache Caused by Lower Cervical Spondylosis
Masahito Kawabori, Kazutoshi Hida, Shunsuke Yano, Yoshinobu Iwasaki
NEUROLOGICAL SURGERY, 37, 5, 491, 495, May 2009
Japanese, Scientific journal

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, Mar. 2009, [Peer-reviewed], [Domestic magazines]
English, 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, Mar. 2009
Japanese, 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, Jan. 2009
Japanese, 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, Mar. 2008
Japanese, 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, Jun. 2006
Japanese, 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

Comprehensive validation of circulating microRNA signatures for Moyamoya disease
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

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

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, Nov. 2021
(一社)日本脳循環代謝学会, Japanese

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, Nov. 2021
(一社)日本脳循環代謝学会, Japanese

【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, Nov. 2020
(一社)日本脳神経外科コングレス, Japanese

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, Nov. 2020
(一社)日本脳循環代謝学会, Japanese

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, Nov. 2020
(一社)日本脳循環代謝学会, Japanese

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, Nov. 2020
(一社)日本脳循環代謝学会, Japanese

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, Nov. 2020
(一社)日本脳循環代謝学会, Japanese

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, Nov. 2020
(NPO)日本脳神経血管内治療学会, Japanese

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, Jun. 2020, [International Magazine]
English

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, May 2020
(一財)バイオインダストリー協会, Japanese

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, May 2020
(一社)日本神経治療学会, Japanese

Cell therapy against central nervous disorders - Current and future perspectives -
川堀真人, 七戸秀夫, 黒田敏, 寳金清博, 神経治療学(Web), 37, 3, 2020

Successful Total Resection with Preceding Arterial Coil Embolization of Intradural Extramedullary Tumor at Craniovertebral Junction Encasing Dominant-side Vertebral Artery
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, [Domestic magazines]
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., (株)医学書院, Japanese

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, Nov. 2019
(NPO)日本脳神経血管内治療学会, Japanese

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, Sep. 2019
(株)先端医学社, Japanese

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, 20 Apr. 2019
Japanese

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
Japanese

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
Japanese

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, Oct. 2018
日本脳循環代謝学会, Japanese

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, Oct. 2018
日本脳循環代謝学会, Japanese

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, Oct. 2018
日本脳循環代謝学会, Japanese

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, Oct. 2018
日本脳循環代謝学会, Japanese

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, Sep. 2018
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, Japanese

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, Aug. 2018
English, Summary international conference

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, Jun. 2018
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, Japanese

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, May 2018
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, Japanese

【(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, May 2018
(一社)レギュラトリーサイエンス学会, Japanese

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, May 2018
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, Japanese

【(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, May 2018
(一社)レギュラトリーサイエンス学会, Japanese

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, Apr. 2018
(一社)日本病理学会, Japanese

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
Japanese

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
Japanese

【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, Jan. 2018
バイエル薬品(株), Japanese

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, Nov. 2017
日本脳循環代謝学会, Japanese

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, Nov. 2017
日本血液代替物学会, Japanese

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, Nov. 2017
日本血液代替物学会, Japanese

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, Nov. 2017
日本脳循環代謝学会, Japanese

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, Nov. 2017
日本脳循環代謝学会, Japanese

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, Nov. 2017
(NPO)日本脳神経血管内治療学会, Japanese

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, Nov. 2017
(NPO)日本脳神経血管内治療学会, Japanese

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, Aug. 2017
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, Japanese

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, 01 Feb. 2017
Japanese

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, Feb. 2017
(NPO)日本脳神経外科救急学会, Japanese

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, Dec. 2016
産業開発機構(株), Japanese

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, Dec. 2016
小樽市病院局, Japanese

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, Dec. 2016
小樽市病院局, Japanese

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, Nov. 2016
(NPO)日本脳神経血管内治療学会, Japanese

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, Nov. 2016
(NPO)日本脳神経血管内治療学会, Japanese

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, Nov. 2016
(NPO)日本脳神経血管内治療学会, Japanese

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, Sep. 2016
(一社)日本てんかん学会, Japanese

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, Aug. 2016
(一社)日本神経学会, Japanese

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, Jun. 2016
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, Japanese

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, Feb. 2016
小樽市病院局, Japanese

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, Feb. 2016
小樽市病院局, Japanese

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, Dec. 2015
(一社)日本神経学会, Japanese

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, Nov. 2015
(NPO)日本脳神経血管内治療学会, Japanese

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, Sep. 2015
(公社)日本放射線技術学会, Japanese

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, Apr. 2015
English, Summary international conference

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, Feb. 2013
English, Summary international conference

Bone marrow stromal cell transplantation enhances recovery of local glucose metabolism after cerebral infarct in rats : A serial [18]F-FDG PET study
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, 01 Nov. 2012
Japanese

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, Oct. 2012
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, Japanese

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, 01 Aug. 2012
Japanese

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, Aug. 2012
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, Japanese

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, Aug. 2012
(一社)日本核医学会, Japanese

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, Jun. 2012
(一財)博慈会老人病研究所, Japanese

【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, Mar. 2012
(一社)日本脳卒中の外科学会, Japanese

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, Nov. 2011
日本脳循環代謝学会, Japanese

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, Nov. 2011
日本脳循環代謝学会, Japanese

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, May 2011
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, Japanese

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, Mar. 2011
English, Summary international conference

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, Mar. 2011
English, Summary international conference

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, 01 Feb. 2011
Japanese

Progress and perspective of bone marrow stromal cell transplantation for ischemic stroke
KURODA Satoshi, SHICHINOHE Hideo, SUGIYAMA Taku, ITO Masaki, KAWABORI Masato, CHIBA Yasuhiro, OSANAI Toshiya, MARUICHI Katsuhiko, HOUKIN Kiyohiro, IWASAKI Yoshinobu, Nosotchu, 32, 6, 532, 537, 25 Nov. 2010
数多くの基礎研究によって、骨髄間質細胞(BMSC)移植は脳梗塞や脊髄損傷後の神経症状の回復を有意に促進することが証明されている。基礎研究の成果を基に、中枢神経疾患に対するBMSC移植が国内外で小規模な臨床試験として開始されつつある。脳梗塞に対してBMSC移植を臨床応用するに当って解決すべき以下の問題点と解決策について述べた。1)ヒトBMSCの培養法、2)ヒトBMSC移植のプロトコール、3)ヒトにおける細胞イメージング。, The Japan Stroke Society, Japanese

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, Nov. 2010
(株)メディカルレビュー社, Japanese

【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, Nov. 2010
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, Japanese

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, Nov. 2010
(NPO)日本脳神経血管内治療学会, Japanese

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, Nov. 2010
日本脳循環代謝学会, Japanese

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, Nov. 2010
日本脳循環代謝学会, Japanese

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, Nov. 2010
日本脳循環代謝学会, Japanese

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, Jun. 2010
(一社)日本脳神経超音波学会, Japanese

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, Apr. 2010
(一社)日本小児神経外科学会, Japanese

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, Apr. 2010
(一社)日本小児神経外科学会, Japanese

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

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, Jul. 2008
(株)にゅーろん社, Japanese

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, Jun. 2006
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, Japanese

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, Oct. 2005
(一社)日本循環器学会, Japanese

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, Sep. 2004
(一財)日本消化器病学会, Japanese

脳梗塞血栓回収治療後の間葉系幹細胞由来エクソソーム局所動注による神経保護効果
科学研究費助成事業
01 Apr. 2024 - 31 Mar. 2027
栗栖 宏多, 川堀 真人
日本学術振興会, 基盤研究(C), 北海道大学, 24K12212

くも膜下出血後の神経炎症に対する間葉系幹細胞由来エクソソームの制御効果
科学研究費助成事業
01 Apr. 2024 - 31 Mar. 2027
下田 祐介, 川堀 真人
日本学術振興会, 基盤研究(C), 北海道大学, 24K12278

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
01 Apr. 2023 - 31 Mar. 2027
藤村 幹, 伊東 雅基, 川堀 真人, 久下 裕司
ラット慢性脳虚血モデル（4 vessel occlusion model、両側椎骨動脈遮断の翌日に両側の内頚動脈遮断を追加する）の習得を行い、低い死亡率（約10%)にて全脳虚血が誘発される状態を作成する事が可能となった。全脳虚血の確認には心臓から墨汁液を灌流する事で全身の血管に墨汁が充填されるが、脳に関しては細い側副血行を介する事から墨汁が入っていかない事によって確認した。このモデルに対して、ヒト羊膜由来間葉系幹細胞（Amnion derived mesenchymal stem cell)からなる幹細胞シートをCellSaic社のアップセルを使用して作成し、脳表に貼り付けることによる血流回復の検討を行った。貼り付けは当初硬膜越しに行っていたが、通常のモヤモヤ病患者の手術に類似する形態を目指して、より血管を呼び込む効果が高いと考えられる硬膜下に貼り付ける方法に変更した。これらのシートを貼り付けた後に、骨を戻さず側頭筋を脳表に貼り付け、モヤモヤ病患者と同じように血管新生を誘発できるかについて検討する事にした。
しかし予想に反し、ヒト幹細胞シートを貼り付けた群においては、脳表の神経細胞の脱落が顕著に認められており、運動機能的にも回復は認められなかった。これはヒト由来のシート張付けによって強力な炎症反応とそれに引き続く形での脳の損傷が生じている事が原因と考えられた。これまでの我々の報告とも違った結果となり、異種に対する免疫反応が生じている事が原因と考えられた。これに対してラット由来の卵膜シートを検討する事としてその製造方法の改良に着手し、製法が確立された
日本学術振興会, 基盤研究(B), 北海道大学, 23K27706

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
Apr. 2023 - Mar. 2027
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

脳梗塞急性期に対する間葉系幹細胞由来細胞外小胞の経鼻的投与
科学研究費助成事業
01 Apr. 2023 - 31 Mar. 2026
川堀 真人
準備：エクソソームの抽出（10万Gの超遠心法）・ラベリング（ExosparklerとPKH26）・モデル動物（Threadモデル・全脳虚血モデル・distal MCAOモデル）の作成・組織学的評価などの予備的な検討を大学院生が行い、手技の習熟を行った。その後In-vitro・In-vivoの研究を開始した。
In-vitro研究：セルライン（神経芽細胞種株SY5Y・マイクログリア株BV2)に対してLPS負荷もしくは酸素栄養剥離（Oxygen glucose deprivation: OGD)を加え、エクソソームの投与を行い、生存率（CCK）および炎症性サイトカイン（IL6/TNF-a)の定量を行った。エクソソームの投与によって生存率の改善および炎症性サイトカインの低下が認められた。エクソソーム内に含まれる成分の分析を行いmiR125a-3pにTargetを絞ってmiR125a-3pのmimicもしくはinhibitorを使用し追加の検討し、炎症の制御に関係している事を確認した。
In-vivo研究：ラット全脳虚血モデルに対してエクソソーム（1x10^8個）を経鼻的に梗塞後3日間連続投与を行い、高次脳機能障害・脳内アポトーシス・脳内炎症に対する評価をおこなった。結果、エクソソーム投与群において8方向アームテストで高次脳機能障害が軽減している事を確認し、記憶に投与している海馬のアポトーシス（Apoptag染色、Caspase染色）および炎症細胞浸潤（CD68染色）が軽減している事を確認した。また経鼻的に投与したエクソソームが投与1時間では嗅球周囲に多く存在するが、その後24時間までの間に脳内に経時的に増加している事も確認した。
日本学術振興会, 基盤研究(C), 北海道大学, 23K08535

羊膜間葉系幹細胞由来エクソソームの脊髄損傷急性期における作用機序解明
科学研究費助成事業
01 Apr. 2023 - 31 Mar. 2026
関 俊隆, 川堀 真人
MSC由来のエクソソームの静脈内投与の効果と、特にNET形成に焦点を当てた関連する分子機構を調査することを目的とした。
エクソソームは、超遠心法を用いて羊膜由来の間葉系幹細胞の細胞培養液から分離し、スプレーグ・ドーリー・ラット（9週齢）にクリップ損傷モデルを用いて脊髄損傷を誘発し、損傷後24時間に1 mLのPBS中に100 μgのエクソソームまたは単独のPBSを静脈内投与した。運動機能は、損傷後28日間連続的に評価した。3日目と28日目に、脊髄検体を解析して損傷の程度とNETの形成を評価しました。循環性好中球NETの形成を調べるために、フローサイトメトリーを用いました。炎症性NET形成の効果を評価するために、外部のmiRNAを好中球にエレクトロポレーションをおこなった。最後に、動物PETで64Cu標識されたエクソソームの生体分布を評価しました。エクソソームを投与されたラットは、運動機能の回復に著しい改善を示し、損傷のサイズが減少しました。特筆すべきことに、脊髄内の好中球浸潤とNET形成が著しく減少し、循環中のNETを形成する好中球も減少しました。in vitroの調査では、エクソソームが活性化された好中球の核の近くに蓄積され、miR-125a-3pミミックを導入した好中球はNET形成が著しく減少し、一方、miR-125a-3p阻害剤はその効果を逆転させた。PETの研究では、移植されたエクソソームの大部分が肝臓と脾臓に隔離されていたが、損傷した脊髄内で正常なラットと比較して顕著に多量のエクソソームが検出された。
日本学術振興会, 基盤研究(C), 北海道大学, 23K08557

Innovative Research of Neuroprotection for Delayed Cerebral Ischemia Associated with Cerebral Vasospasm after Subarachnoid Hemorrhage using Novel Hemoglobin-based Oxygen Carrier
Grants-in-Aid for Scientific Research
01 Apr. 2022 - 31 Mar. 2025
月花 正幸, 伊東 雅基, 川堀 真人, 鐙谷 武雄, 小松 晃之, 藤村 幹
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 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
01 Apr. 2022 - 31 Mar. 2025
穂刈 正昭, 藤村 幹, 川堀 真人
本研究では、動物モデルで鼻内に投与されたエクソソームの効果を検討した。エクソソームは、超遠心法（10万G）を用いて羊膜由来間葉系幹細胞上清から分離した。得られたエクソソームはExosparklerを用いて蛍光Labelingを行った。スプレーグ・ドーリー・ラットに一過性の四血管閉塞モデル（両側椎骨動脈遮断翌日に20分間の両側内頚動脈遮断を行う）を用いて脳損傷を誘発し、エクソソーム鼻内投与は、1日あたり20μLのPBS中に3×10^8個のエクソソーム粒子または単独のPBSを経鼻的に投与して、損傷後7日間毎日投与を行った。長期の認知行動評価（8方向アーム試験）、エクソソームの生体分布（免疫学的染色）、およびアポトーシス（Apoptag染色）と神経炎症（CD68・Iba1）の組織学的評価を行った。エクソソームは、鼻内投与後1時間で主に嗅球に検出され、その後、24時間で中脳まで分布していた。エクソソームを投与されたラットは、刺激後28日後の認知機能の有意な改善を示した。エクソソーム投与によって海馬におけるアポトーシスの細胞が有意に減少し、同部位における神経細胞の死亡率も低下していた。エクソソームは主にミクログリアに取り込まれており、細胞毒性の炎症マーカーの発現が減少し、これが作用機序であると推測される結果が得られた。エクソソームの内容物に対する検討についてはmicroarrayによってmir125a-3pが候補である事が分かり、これのmimicとinhibitorを用いたin-vitro検証を行ったところ、効果が確認された
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
01 Apr. 2022 - 31 Mar. 2025
鐙谷 武雄, 藤村 幹, 伊東 雅基, 小松 晃之, 川堀 真人
当該研究では抗酸化作用を付与したヘモグロビン人工酸素運搬体（HBOC）に一酸化炭素（CO）を結合しmulti-targetの脳保護効果を検討することを目的としている。前年度の報告書にある通り、当初の申請書には記載のないヘモグロビンナノ粒子（HbNP）が新たに開発され、使用薬剤の候補となった。HbNPはカタラーゼを内在して抗酸化作用を有するが、このHbNPを他の抗酸化能付与後のHBOCと比較した予備実験の結果、HbNPが最も脳保護効果を持っていたため、その後の研究ではHbNPに絞って実験を進める方針とした。HbNPが新規開発された製剤であることより、まずCO結合前のHbNP自体の脳保護効果を検討した。ラット脳虚血再灌流モデルを使用し、2時間虚血後の再灌流開始時に治療薬として、HbNPと比較対象としてHb-HSA3（以前より我々の研究室において用いていたHb-Albuminクラスター型のHBOCの一種）を静脈内に投与し、24時間後での梗塞体積、等を評価した。その結果、HbNPはHb-HSA3と比較して梗塞体積をより縮小させていた。次いで、脳組織内での炎症反応（ミエロペルオキシダーゼ）、酸化ストレス（４HNP）、微小血管障害（IgG血管外漏出）の状態を免疫染色、Western blottingにより検討した。いずれの検討項目においても、HbNPがより抑制する傾向を認めた。さらに、再灌流6時間以内の脳血流(CBF）、組織酸素分圧（PtO2）の評価を行った。その結果、CBFはHbNPとHb-HSA3で差を認めなかったが、PtO2はHbNPで数値が高く維持されていた。これらの実験結果からHbNPは再灌流早期に酸素運搬能を高く保つことで神経保護効果を示すものと考えられた。これらの結果を国内、国際学会で発表し、さらに英文雑誌Brain Researchにおいて掲載発表した。
日本学術振興会, 基盤研究(C), 北海道大学, 22K09224

Comprehensive Bench-to-Bedside Research on Regenerative Medicine for Ischemic stroke with Bone Marrow Stromal Cell-derived Extracellular Vesicles (EVs)
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
KURODA Satoshi
Pluripotent stem cells (Muse cells) isolated from bone marrow stromal cells were transplanted into three animal models of brain diseases via multiple routes, and their therapeutic effects were examined from various angles. (1) Cerebral infarction model: Muse cells were transplanted transvenously or intranasally, and the recovery of motor function was significantly enhanced. (2) Cerebral contusion model: Muse cells were transplanted intravenously, and the recovery of motor function was significantly enhanced. (3) Alzheimer's disease model: Transplantation of Muse cells intranasally significantly suppressed the deterioration of cognitive function. Based on these findings, we plan to expand the study to experiments using EVs derived from Muse cells.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), University of Toyama, 21H03043

Stem cell combined with scaffold for treating chronic cerebral hemorrhage
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
Kawabori Masahito
We were able to prove that stem cell attached with scafold showed better neurological recovery in chronic intracerebral hemorrhagic model animal.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 20K09382

Spine-gut relationship in the treatment of spinal cord injury with stem cell
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
Seki Toshitaka
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.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 20K09361

Development of neruoprotectice therapy by artificial oxygen carriier with antioxidant function
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2022
Abumiya Takeo
Different forms of artificial oxygen carriers with antioxidant function, (1) complex of platinum nanoparticle (Pt-NP) and HemoAct: PtNP-HemoAct, (2) mixture of complex cluster of catalase and albumin (C-Act) and HemoAct: C-Act＋HemoAct, (3) mixture of antioxidant drug Edravone and HemoAct: Edaravone＋HemoAct, and (4) spherically polymerized hemoglobin particles covered with albumin, Hemoglobin nanoparticle, were used to compare neuroprotecitive effects. We administrated these drugs in rat ischemia/reperfusion model and compared infarction volumes. Treatment groups had a tendency of showing smaller infarction volumes and HbNP group showed the smallest volume.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 19K09472

Relationship between Chronic inflammation and progression of Moyamoya disease
Grants-in-Aid for Scientific Research
01 Apr. 2018 - 31 Mar. 2021
Hokari Masaaki
In this study period, we examined three different types of experiment. First, the relationship between moyamoya disease and pylori infection, which did not prove to be involved in the pathogenesis. Second, the pathological changes of superficial temporal artery of Moyamoya patient and normal volunteer, which resulted that elastic membrane and collagen were decreased and damaged in the Moyamoya patients. Third, angiogensis after bypass surgery were examined with different genetic background, which RNF213 is strongly correlated with in-direct bypass. Taken together, we were able to elucidate the novel pathological mechanisms of Moyamoya disease.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 18K08931

Protective role of sphingo-lipid against brain ischemic re-perfusion injury
Grants-in-Aid for Scientific Research
01 Apr. 2016 - 31 Mar. 2019
Kawabori Masahito, Wang Zifeng
Treatment against acute ischemic stroke has shown great advancement with thrombectomy. However, severe brain edema and subsequent brain damage may occur even after the rapid recanalization. Ischemic/reperfusion (I/R) injury is considered one of the major causes of the damage and recently draws increasing attention for novel therapeutic target. FTY720 (fingolimod), a widely known sphingosine-1-phosphate (S1P) receptor agonist approved as a treatment for multiple sclerosis due to its strong anti-inflammatory effect plays a variety of roles in neuroprotection including reduction of neuroinflammation. However, the role of FTY720 against I/R injury has not been fully elucidated. FTY720 significantly reduced infarction size and numbers of cell with apoptosis, and improved neurological score after I/R injury compared with the vehicle group. FTY720 significantly inhibits worsening of inflammation 9 days after insult. The present results suggest that FTY720 can ameliorates I/R injury
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, 16K19992

優秀研究論文助成
Apr. 2011 - Mar. 2012
川堀真人
博慈会, Principal investigator, Competitive research funding

運動機能の状態を評価するための方法、プログラム及び装置
Patent right, 川堀 真人, タ キンキン, 株式会社RAINBOW
特願2025-145016, 02 Sep. 2025
特開2025-172133, 20 Nov. 2025
202503016672047068

幹細胞を非凍結で保存または輸送するための方法
Patent right, 川堀 真人, 株式会社RAINBOW
特願2022-573781, 01 Aug. 2022
特開2023-133621, 22 Sep. 2023
特許第7737156号, 02 Sep. 2025
202503012467640923

自動培養装置における細胞増殖制御方法
Patent right, 川堀 真人, 株式会社RAINBOW
JP2024002529, 26 Jan. 2024
特許第7725119号, 08 Aug. 2025
202503008541893092

投与キット
Patent right, 若林 彰, 原 玲子, 中村 健太郎, 北橋 宗, 川堀 真人, 富士フイルム株式会社, 国立大学法人北海道大学
特願2020-167930, 02 Oct. 2020
特開2022-059981, 14 Apr. 2022
特許第7619555号, 14 Jan. 2025
202503007835256930

脊髄損傷治療剤
Patent right, 小林 明, 中石 智之, 山口 翔, 川堀 真人, 株式会社カネカ, 国立大学法人北海道大学
特願2022-055677, 30 Mar. 2022
特開2023-147910, 13 Oct. 2023
202303010145071438

幹細胞を非凍結で保存または輸送するための方法
Patent right, 川堀 真人, 株式会社RAINBOW
JP2022029522, 01 Aug. 2022
特許第7333121号, 16 Aug. 2023
202303005561824107

自家血小板由来の血小板溶解物
Patent right, 川堀 真人, 株式会社RAINBOW
JP2021028298, 30 Jul. 2021
特許第7137883号, 07 Sep. 2022
202203016796902622

頭蓋内に安全に細胞を投与するための総合システム
Patent right, 川堀 真人, 株式会社RAINBOW
JP2020048838, 25 Dec. 2020
特許第7015605号, 26 Jan. 2022
202203013645604469

運動機能の状態を評価するための方法、プログラム及び装置
Patent right, 川堀 真人, タ キンキン, 株式会社RAINBOW
特願2021-506591, 29 Sep. 2020
特許第6966828号, 26 Oct. 2021
202103020909024295

穿刺針、穿刺針キット及び定位脳手術装置
Patent right, 川堀 真人, 株式会社RAINBOW
特願2020-558649, 29 May 2020
特許第6938064号, 03 Sep. 2021
202103015358975648

頭蓋内に安全に細胞を投与するための総合システム
Patent right, 川堀 真人, 株式会社RAINBOW
JP2020048838, 25 Dec. 2020
WO2021-132600, 01 Jul. 2021
202103009331825237

運動機能の状態を評価するための方法、プログラム及び装置
Patent right, 川堀 真人, タ キンキン, 株式会社RAINBOW
JP2020036854, 29 Sep. 2020
WO2021-065894, 08 Apr. 2021
202103005649864325

穿刺針、穿刺針キット及び定位脳手術装置
Patent right, 川堀 真人, 国立大学法人北海道大学
JP2020021373, 29 May 2020
WO2020-241833, 03 Dec. 2020
202103000539159438