Faculty Profiles - HASHIZUME Atsushi

Papers - HASHIZUME Atsushi

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Impact of periodic neck ultrasonography on locoregional disease control in surveillance after total thyroidectomy for patients with low- and intermediate-risk papillary thyroid carcinoma: a propensity score-matched study

Inaishi Takahiro, Takeuchi Dai, Ichikawa Takahiro, Inaguma Gai, Hashizume Atsushi, Okazaki Masaki, Masuda Norikazu, Kikumori Toyone

Endocrine Journal Vol. 71 ( 12 ) page： 1135 - 1143 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Endocrine Society

This study aimed to evaluate the impact of periodic neck ultrasonography (US) on postoperative surveillance for locoregional disease control of patients with low- and intermediate-risk papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. This retrospective cohort study included patients with PTC who underwent total thyroidectomy and central neck dissection at our institution between January, 2000 and December, 2016. The patients were divided into two groups: the physical examination (PE) group (follow-up by PE without periodic US) and the US group (follow-up by PE with periodic US). Serum thyroglobulin levels were measured periodically in both groups. Propensity score matching was used to rigorously balance the significant variables and assess the 10-year postoperative outcomes between the groups. Of the 189 patients, 150 were included after matching (75 in each group). There were no significant differences between the two groups in terms of background characteristics. The median follow-up period was 127.9 months. There was no significant difference in locoregional relapse-free survival between the PE and US groups (97.0 vs. 98.7%, p = 0.541). The overall survival was 96.7% and 98.7% in the PE and US groups, respectively, with no significant difference (p = 0.364). This study demonstrated that the addition of periodic US to PE for postoperative surveillance of patients with low- and intermediate-risk PTC who underwent total thyroidectomy did not significantly affect locoregional control.

DOI： 10.1507/endocrj.ej24-0194

球脊髄性筋萎縮症に対するリュープロレリン酢酸塩の薬事承認とその後 Reviewed

橋詰淳

神経治療学 Vol. 41 ( 6 ) page： S225 - S225 2024

Efficacy of the latest new stimulation patterns of spinal cord stimulation for intractable neuropathic pain compared to conventional stimulation: study protocol for a clinical trial. Reviewed International journal Open Access

Takafumi Tanei, Satoshi Maesawa, Yusuke Nishimura, Yoshitaka Nagashima, Tomotaka Ishizaki, Masahiko Ando, Yachiyo Kuwatsuka, Atsushi Hashizume, Shimon Kurasawa, Ryuta Saito

Trials Vol. 24 ( 1 ) page： 604 - 604 2023.9

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

BACKGROUND: Spinal cord stimulation (SCS) is one of the neuromodulation therapies for chronic neuropathic pain. The conventional paresthesia-based SCS involves the application of tonic stimulation that induces a sense of paresthesia. Recently, new SCS stimulation patterns without paresthesia have been developed. Differential target multiplexed (DTM) stimulation and fast-acting subperception therapy (FAST) stimulation are the latest paresthesia-free SCS patterns. METHODS: A single-center, open-label, crossover, randomized clinical trial to investigate the superiority of SCS using the latest new stimulation patterns over conventional tonic stimulation for neuropathic pain is planned. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). In the SCS trial, participants will be randomly assigned to 4 groups receiving stimulation, including tonic, DTM, and FAST. Each stimulation will then be performed for 2 days, and a visual analog scale (VAS) for pain will be evaluated before and after each stimulation pattern. A stimulation-off period for 1 day is set between each stimulation pattern to wash out the residual previous stimulation effects. Pain improvement is defined as more than 33% reduction in the pain VAS. The primary analysis will compare pain improvement between the new stimulation patterns and the conventional tonic stimulation pattern in the SCS trial. The secondary outcomes will be evaluated as follows: (1) the relationships between causative disease and improvement rate by each stimulation pattern; (2) comparison of pain improvement between the DTM and FAST stimulation patterns in all cases and by causative disease; (3) changes in assessment items preoperatively to 24 months after the implantation; (4) preoperative factors associated with long-term effects defined as continuing for more than 12 months; and (5) adverse events related to this study 3 months after the implantation. DISCUSSION: This study aims to clarify the effectiveness of the latest new stimulation patterns compared to the conventional tonic stimulation. In addition, which stimulation pattern is most effective for which kind of causative disease will be clarified. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 1,042,220,094. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is an approved member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07637-x

球脊髄性筋萎縮症に対する自記式評価指標SBMAPROの開発 Reviewed

橋詰淳, 山田晋一郎, 伊藤大輔, 岸本祥之, 小森祥太, 森田光哉, 山本知孝, 勝野雅央

臨床神経学 Vol. 63 ( Suppl. ) page： S297 - S297 2023.9

筋萎縮性側索硬化症における発症前症状の検討 Reviewed

小森祥太, 橋詰淳, 山田晋一郎, 伊藤大輔, 岸本祥之, 勝野雅央

臨床神経学 Vol. 63 ( Suppl. ) page： S247 - S247 2023.9

球脊髄性筋萎縮症患者における遺伝リテラシーの調査 Reviewed

山田晋一郎, 橋詰淳, 伊藤大輔, 岸本祥之, 小森祥太, 勝野雅央

臨床神経学 Vol. 63 ( Suppl. ) page： S297 - S297 2023.9

Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan Reviewed International journal Open Access

Madoka Mori-Yoshimura, Naoki Suzuki, Masahisa Katsuno, Masanori P. Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

Orphanet Journal of Rare Diseases Vol. 18 ( 1 ) page： 241 - 241 2023.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media {LLC}

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>A rare muscle disease, GNE myopathy is caused by mutations in the <jats:italic>GNE</jats:italic> gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy.</jats:p>
<jats:p><jats:italic>Trial registration number</jats:italic>: ClinicalTrials.gov (NCT04671472).</jats:p>
</jats:sec>

DOI： 10.1186/s13023-023-02850-y

Differential target multiplexed spinal cord stimulation using a paddle-type lead placed at the appropriate site for neuropathic pain after spinal cord injury in patients with past spinal surgical histories: study protocol for an exploratory clinical trial. Reviewed International journal Open Access

Takafumi Tanei, Satoshi Maesawa, Yusuke Nishimura, Yoshitaka Nagashima, Tomotaka Ishizaki, Masahiko Ando, Yachiyo Kuwatsuka, Atsushi Hashizume, Shimon Kurasawa, Ryuta Saito

Trials Vol. 24 ( 1 ) page： 395 - 395 2023.6

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

BACKGROUND: Neuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation. METHODS: A single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: (1) effectiveness of DTM and tonic stimulations during the SCS trial; (2) changes of assessment items from 1 to 24 months; (3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; (4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and (5) whether gait function improves from 1 to 24 months. DISCUSSION: A paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07433-7

Phase II/III Study of Aceneuramic Acid Administration for GNE Myopathy in Japan. Reviewed International journal Open Access

Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

Journal of neuromuscular diseases Vol. 10 ( 4 ) page： 555 - 566 2023.4

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

BACKGROUND: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. OBJECTIVE: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. METHODS: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. RESULTS: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. CONCLUSIONS: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

DOI： 10.3233/JND-230029

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome. Reviewed International journal Open Access

Ikuko Aiba, Yuichi Hayashi, Takayoshi Shimohata, Mari Yoshida, Yuko Saito, Koichi Wakabayashi, Takashi Komori, Masato Hasegawa, Takeshi Ikeuchi, Aya M Tokumaru, Keita Sakurai, Shigeo Murayama, Kazuko Hasegawa, Toshiki Uchihara, Yasuko Toyoshima, Yufuko Saito, Ichiro Yabe, Satoshi Tanikawa, Keizo Sugaya, Kentaro Hayashi, Terunori Sano, Masaki Takao, Motoko Sakai, Harutoshi Fujimura, Hiroshi Takigawa, Tadashi Adachi, Ritsuko Hanajima, Osamu Yokota, Tomoko Miki, Yasushi Iwasaki, Michio Kobayashi, Nobutaka Arai, Takuya Ohkubo, Takanori Yokota, Keiko Mori, Masumi Ito, Chiho Ishida, Masaharu Tanaka, Jiro Idezuka, Masato Kanazawa, Kenju Aoki, Masashi Aoki, Takafumi Hasegawa, Hirohisa Watanabe, Atsushi Hashizume, Hisayoshi Niwa, Keizo Yasui, Keita Ito, Yukihiko Washimi, Eiichiro Mukai, Akatsuki Kubota, Tatsushi Toda, Kenji Nakashima

Brain communications Vol. 5 ( 6 ) page： fcad296 2023

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

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

DOI： 10.1093/braincomms/fcad296

PMDAでの経験とその後　アカデミアでの倫理指針下研究支援 Reviewed

橋詰淳

神経治療学 Vol. 40 ( 6 ) page： S149 - S149 2023

Prevention therapy for neurodegenerative disease Reviewed

Katsuno Masahisa, Hashizume Atsushi

Neurological Therapeutics Vol. 40 ( 2 ) page： 74 - 78 2023

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Neurological Therapeutics

Recent advancement in studies on pathogenesis led to development of disease–modifying therapies such as nucleic acid therapies for neuromuscular disorders. Such therapies target disease causing genes and proteins, but therapeutic benefits in clinic is limited at a symptomatic stage of disease. To overcome this, strategies for prevention have been actively developed for neurodegenerative disease. Before manifestation of core motor/cognitive symptoms, preclinical and then prodromal stages exist during the progression of neurodegeneration. At preclinical stage, molecular changes occurs but symptoms are hardly detectable. At prodromal stage, heralding symptoms appear prior to manifestation of core symptoms. In cohort studies on at–risk subjects, mild motor/cognitive symptoms emerge ∼20 years prior to the onset of subjective symptoms in various diseases. For instance, non–motor symptoms including REM sleep behavior disorder occurs approximately 15 years before clinical diagnosis of Parkinson disease, which is made on the basis of subjective motor symptoms. The effects of disease–modifying therapy for preventing neurodegeneration is clearly shown in a clinical trial of nusinersen, a nucleic acid therapy of spinal muscular atrophy, for pre–symptomatic subjects, in which initiation of disease–modifying therapy before manifestation achieved potent therapeutic effects particularly in mild patients. Currently, cohort studies, biomarker research, and novel therapies are being developed to further prevent various neurodegenerative diseases.

DOI： 10.15082/jsnt.40.2_74

CiNii Research

未来を創るデータの作り方　司会の言葉 Reviewed

橋詰淳, 三澤園子

神経治療学 Vol. 40 ( 4 ) page： 441 - 441 2023

オーバービュー　（臨床研究教育学の立場から） Reviewed

橋詰淳

日本臨床薬理学会学術総会抄録集 Vol. 44 ( 0 ) page： 3-C-S35-1 2023

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：一般社団法人日本臨床薬理学会

新薬研究開発の国際競争力の低下などに対応して、本邦でも、創薬シーズを製薬企業のみならずアカデミアにも求める気運が高まってきた。「有効な医薬品を創り、患者さんに届ける」ことは医療人共通の願いでもあり、その気運にのり、アカデミアでの創薬は推進されてきたといえる。しかし、2014年度には20件あった医師主導治験の初回治験届け出数は、2019年度～2021年度には平均で9件を割り込んでおり、アカデミア発の創薬が活性化しているとは推定しにくい。一般に、創薬研究プロセスは、生体分子の新しい機能や病態における役割などの情報から創薬標的を同定する基礎研究と、同定した創薬標的に適切に作用する物質を開発化合物にまで最適化する応用研究に分類されるが、「アカデミア創薬」では、この基礎研究から応用研究まで、また可能であればその後の臨床開発も加え、一貫してアカデミア研究者が実施することになる。アカデミア基礎研究者の中には、自身の画期的な基礎的発見が、ただちに有望な創薬シーズとなるものと考えたが、その時に、創薬のためには不足する情報がたくさんあることを初めて知り、そのことこそ「死の谷（The Valley of Death）」というのだと思ってしまった研究者も多いものと想像される。医薬品開発は、新規薬剤の発見と合成、新規物質の有効性と安全性の研究に始まり、各種非臨床・臨床試験の計画・実施・解析、製造販売承認申請準備・申請、と多種多様で長い道のりである。本邦のアカデミア発医薬品開発を活性化するためには、これらの道程を一人で完全走破するアントレプレナーを育てることも重要ではあるが、医学研究者個々の研究リテラシー向上なく、スーパーアントレプレナーを育てるだけでは、全体としての医薬品開発力向上を見込むことは難しい。少なくとも、創薬研究に関わるすべての医学研究者が、医薬品開発の全景やその困難さを理解したうえで、自らの研究の、「医薬品開発の上での位置付け」を十分に理解し、その開発を遂行するために不足するmissing pieceを埋めるパートナーとうまく協業を進めていく術を知ることが、今後長い目で見た際に、アカデミア発の創薬を育てるために重要ではないかと考えられる。

DOI： 10.50993/jsptsuppl.44.0_3-c-s35-1

CiNii Research

The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA): Protocol for a Longitudinal Observational Study. Reviewed International journal Open Access

Kentaro Sahashi, Atsushi Hashizume, Yachiyo Kuwatsuka, Madoka Chinen, Ai Saotome-Nakamura, Masahiko Ando, Masahisa Katsuno

JMIR research protocols Vol. 11 ( 12 ) page： e38878 2022.12

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

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder with progressive muscle weakness and atrophy, mainly caused by lower motor neuron degeneration resulting from decreased levels of the survival motor neuron protein. Recently, 3 disease-modifying therapies for SMA (nusinersen, onasemnogene abeparvovec, and risdiplam) were approved in Japan that are expected to improve the prognosis of patients with SMA. Long-term clinical follow-up of adult patients treated with disease-modifying therapies and the natural history of SMA are essential to assess the real-world effectiveness of available treatments. Until recently, nusinersen was the only treatment option for patients with SMA in Japan; however, because Japanese approval of nusinersen was based on global clinical trials in infants and children aged 0-15 years with SMA, the effectiveness of nusinersen in adult patients has not been fully assessed in Japan. In addition, longitudinal clinical data of adult patients have not been systematically collected in Japan. OBJECTIVE: This longitudinal observational study of adult patients with SMA who have been diagnosed with 5q-SMA in Japan aims to gain a better understanding of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies. Here, we describe the protocol for the study. METHODS: The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA) study is a longitudinal (prospective and retrospective) observational study with a 60-month prospective follow-up being conducted at 19 investigational sites using the newly established jREACT-SMA registry. Patients aged ≥18 years with genetically confirmed 5q-SMA were planned to be enrolled in the registry from December 2020 to May 2022. The planned enrollment was 100 patients. The protocol was approved on September 28, 2020 (approval 2020-0289) by the ethical review committee of Nagoya University. Registration, demographics, genetic diagnosis, motor functions, patient-reported outcomes/quality-of-life outcomes, and other clinical data have been or will be collected. RESULTS: As of May 2022, 113 patients had been enrolled, and the completion of patient registration has been extended from May 2022 to December 2022. Data at registration and during the follow-up period were and will be prospectively collected at least once a year until November 2025 (maximum 60 months). Data analyses will be conducted when all data have been collected. Results are expected to be available in 2026 and the study is expected to be completed by March 2027. CONCLUSIONS: This jREACT-SMA study will provide longitudinal prospective follow-up data in adult patients with SMA in Japan, including data on the natural history of the disease and data on the long-term effectiveness of disease-modifying therapies. TRIAL REGISTRATION: University Hospital Medical Information Network Center Clinical Trials Registry UMIN000042015; https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000042015. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38878.

DOI： 10.2196/38878

【遺伝性神経・筋疾患-診療と研究の最前線】その他の神経・筋疾患の病態・診断・治療法開発球脊髄性筋萎縮症 Reviewed

橋詰淳, 佐橋健太郎, 勝野雅央

医学のあゆみ Vol. 283 ( 10 ) page： 1032 - 1037 2022.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：医歯薬出版(株)

球脊髄性筋萎縮症(SBMA)は,X染色体に存在するアンドロゲン受容体遺伝子上のCAG繰返し配列数の異常伸長を原因とするポリグルタミン病である.緩徐進行性の筋萎縮,筋力低下を特徴とする神経筋疾患であり,成人男性に発症する.下位運動ニューロン徴候を主体とするが,体毛の減少,皮膚の女性化,睾丸萎縮などのアンドロゲン不全症状,深部覚異常なども合併することが特徴的である.筋力低下発現の前に,手指振戦や筋クランプを高頻度に認めるが,血液検査においても血清クレアチニン値の低下や血清CK値の上昇を認め,診断の契機となる.通常,無症状と考えられる女性保因者においても極軽度の臨床所見と神経原性変化の存在を疑う検査所見が認められており,SBMAの早期病態の解明に寄与する可能性がある.わが国では2017年に抗アンドロゲン療法(リュープロレリン酢酸塩)が承認を取得しており,現在,実臨床下での有効性・安全性を検討する臨床研究が継続中である.(著者抄録)

DOI： 10.32118/ayu283101032

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20221206010019&doc_link_id=issn%3D0039-2359%26volume%3D283%26issue%3D10%26spage%3D1032&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D283%26issue%3D10%26spage%3D1032&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial. Reviewed International journal Open Access

Shinichiro Yamada, Atsushi Hashizume, Yasuhiro Hijikata, Tomonori Inagaki, Daisuke Ito, Yoshiyuki Kishimoto, Fumie Kinoshita, Akihiro Hirakawa, Shinobu Shimizu, Tomohiko Nakamura, Masahisa Katsuno

Annals of clinical and translational neurology Vol. 9 ( 11 ) page： 1702 - 1714 2022.11

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

OBJECTIVE: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. METHODS: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). RESULTS: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. INTERPRETATION: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.

DOI： 10.1002/acn3.51667

脳神経内科領域における医学教育の展望 Post/withコロナ時代を見据えて(Vol.15) 大学間連携によるオンライン臨床実習の試み Reviewed

吉倉延亮, 原一洋, 橋詰淳, 坪井崇, 下畑享良, 勝野雅央

BRAIN and NERVE: 神経研究の進歩 Vol. 74 ( 11 ) page： 1309 - 1312 2022.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(株)医学書院

＜文献概要＞COVID-19パンデミックは人類と社会に大きなインパクトを与えたが,パンデミック前と比べた最も大きな変化の1つが,オンライン会議システムの普及と活用である。その影響を受けているのは医学も例外ではなく,オンライン診療と並んでオンライン教育の試みも進んでいる。本稿では,東海国立大学機構(名古屋大学と岐阜大学)における脳神経内科領域の合同オンライン臨床実習の試みを紹介する。

Development of a functional composite for the evaluation of spinal and bulbar muscular atrophy. Reviewed International journal Open Access

Tomonori Inagaki, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Daisuke Ito, Yoshiyuki Kishimoto, Ryota Torii, Hiroyuki Sato, Akihiro Hirakawa, Masahisa Katsuno

Scientific reports Vol. 12 ( 1 ) page： 17443 - 17443 2022.10

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

This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

DOI： 10.1038/s41598-022-22322-w

球脊髄性筋萎縮症に対する定量的複合指標SBMAFCの開発 Reviewed

橋詰淳, 山田晋一郎, 伊藤大輔, 岸本祥之, 鳥居良太, 山本知孝, 森田光哉, 勝野雅央

臨床神経学 Vol. 62 ( Suppl. ) page： S308 - S308 2022.10

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