研究者詳細 - 關　守信

關　守信（セキ　モリノブ）

Seki, Morinobu

写真a

所属（所属キャンパス）: 医学部内科学教室（神経）（信濃町）

職名: 准教授

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Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors

Matsubara S., Seki M., Suzuki S., Komori T., Takamori M.

Journal for ImmunoTherapy of Cancer （Journal for ImmunoTherapy of Cancer） 7 （ 1 ） 256 2019年09月

　概要を見る

© 2019 The Author(s). Background: Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. Methods: Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. Results: Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. Conclusions: In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.
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Diagnostic Potential of Multimodal MRI Markers in Atypical Parkinsonian Disorders.

Seki M, Seppi K, Mueller C, Potrusil T, Goebel G, Reiter E, Nocker M, Kremser C, Wildauer M, Schocke M, Gizewski ER, Wenning GK, Poewe W, Scherfler C

Journal of Parkinson's disease （Journal of Parkinson's disease） 9 （ 4 ） 681 - 691 2019年08月

ISSN 1877-7171

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BACKGROUND: The diagnostic potential of multimodal MRI approaches to discriminate among progressive supranuclear palsy (PSP), Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD) has not been well investigated. OBJECTIVE: To identify disease-specific neurodegenerative patterns and evaluate the diagnostic accuracy of dedicated MRI, iron concentration (R2*), microstructural integrity (mean diffusivity; MD and fractional anisotropy; FA) as well as volumes were analyzed in patients with PSP, MSA-P and PD. METHODS: 3T MRI of 18 PSP and 16 MSA-P patients were compared with 16 PD patients matched for age and disease duration as well as 21 healthy controls. Statistical parametric mapping (SPM) was applied to objectively identify focal MRI changes throughout the whole-brain. Following dimensionality reduction of significant and multiple comparison-corrected SPM clusters through principal component analysis (PCA), stepwise receiver-operating characteristic curve analysis (ROC) was applied to determine the diagnostic potential of multimodal MRI parameters. RESULTS: PCA revealed two components involving multiple regions identified from SPM analysis. The first component was primarily composed of the mean MD value of the thalamus and the mean MD and FA values of the dentatorubrothalamic tract and the corpus callosum. The second component mainly consisted of mean MD and FA values of the middle cerebellar peduncle. ROC analysis showed 92% of PSP patients were differentiated correctly from MSA-P and PD and 80% of MSA-P patients could be distinguished from PD. CONCLUSION: Multimodal MRI improved the detection of disease-specific neurodegenerative patterns in PSP and MSA-P and highlights its potential to improve the diagnostic accuracy of atypical parkinsonian disorders.
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Inflammatory myopathy associated with PD-1 inhibitors

Seki M., Uruha A., Ohnuki Y., Kamada S., Noda T., Onda A., Ohira M., Isami A., Hiramatsu S., Hibino M., Nakane S., Noda S., Yutani S., Hanazono A., Yaguchi H., Takao M., Shiina T., Katsuno M., Nakahara J., Matsubara S., Nishino I., Suzuki S.

Journal of Autoimmunity （Journal of Autoimmunity） 100 105 - 113 2019年06月

ISSN 08968411

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© 2019 Elsevier Ltd Objective: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). Methods: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. Results: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%)patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. Conclusions: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.
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Myelopathy due to human T-cell leukemia virus type-1 from the donor after ABO-incompatible liver transplantation

Wakabayashi T., Obara H., Seki M., Shinoda M., Kitago M., Yagi H., Abe Y., Matsubara K., Yamada Y., Oshima G., Oki K., Nagoshi N., Watanabe K., Hibi T., Itano O., Hoshino K., Suzuki N., Kuroda T., Kitagawa Y.

Annals of Hepatology （Annals of Hepatology） 18 （ 2 ） 397 - 401 2019年03月

ISSN 16652681

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© 2019 Fundación Clínica Médica Sur, A.C. We report the case of a 53-year-old-man who developed human T-cell leukemia virus type-1-associated myelopathy (HAM) after ABO-incompatible liver transplantation for alcoholic liver cirrhosis. The living donor was seropositive for human T-cell leukemia virus type-1 (HTLV-1) and the recipient was seronegative for HTLV-1 before transplantation. After transplantation, the recipient developed steroid-resistant acute cellular rejection, which was successfully treated using anti-thymocyte globulin, and he was eventually discharged. He underwent spinal surgery twice after the transplantation for the treatment of cervical spondylosis that had been present for a period of 9 months before the transplantation. The surgery improved his gait impairment temporarily. However, his gait impairment progressed, and magnetic resonance imaging revealed multiple sites of myelopathy. He was diagnosed with HAM 16 months after the transplantation. Pulse steroid therapy (1000 mg) was administered over a period of 3 days, and his limb paresis improved. Presently, steroid therapy is being continued, with a plan to eventually taper the dose, and he is being carefully followed up at our institution. Our case suggests that liver transplantation involving an HTLV-1-positive living donor carries the risk of virus transmission and short-term development of HAM after transplantation.
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The reorganization of functional architecture in the early-stages of Parkinson's disease

Tuovinen N., Seppi K., de Pasquale F., Müller C., Nocker M., Schocke M., Gizewski E., Kremser C., Wenning G., Poewe W., Djamshidian A., Scherfler C., Seki M.

Parkinsonism and Related Disorders （Parkinsonism and Related Disorders） 50 61 - 68 2018年05月

ISSN 13538020

　概要を見る

© 2018 Elsevier Ltd Introduction: The study aim was to identify longitudinal abnormalities of functional connectivity and its relation with motor disability in early to moderately advanced stages of Parkinson's disease patients. Methods: 3.0T structural and resting-state functional MRI was performed in healthy subjects (n = 16) and Parkinson's disease patients (n = 16) with mean disease duration of 2.2 ± 1.2 years at baseline with a clinical follow-up of 1.5 ± 0.3 years. Resting-state fMRI analysis included region-to-region connectivity in correlation with UPDRS-III scores and computation of Global Efficiency and Degree Centrality. Results: At baseline, patients' connectivity increased between the cerebellum and somatomotor network, and decreased between motor regions (Rolandic operculum, precentral gyrus, supplementary motor area, postcentral gyrus) and cingulate connectivity. At 1.5 years follow-up, connectivity remained altered in the same regions identified at baseline. The cerebellum showed additional hyperconnectivity within itself and to the caudate nucleus, thalamus and amygdala compared to controls. These differences correlated with UPDRS-III scores. Seed-based connectivity revealed increased involvement of the default mode network with precentral gyrus in patients at follow-up investigation. Conclusion: Resting-state fMRI identified marked disturbances of the overall architecture of connectivity in Parkinson's disease. The noted alterations in cortical motor areas were associated with cerebellar hyperconnectivity in early to moderately advanced stages of Parkinson's disease suggesting ongoing attempts of recovery and compensatory mechanism for affected functions. The potential to identify connectivity alterations in regions related to both motor and attentional functions requires further evaluation as an objective marker to monitor disease progression, and medical, as well as surgical interventions.
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Novel tau tracer, PI 2620, for Alzheimer's disease(AD) and non-AD tauopathies(和訳中)

手塚俊樹, 高畑圭輔, 関守信, 田渕肇, 上田亮, 馬島恭子, 大山宗徳, 岡田健祐, 船木桂, 山縣文, 吉崎崇仁, 中原理紀, 百田友紀, 白岩美花, 柴田護, 三浦瑛祐, 陣崎雅弘, 中原仁, 三村將, 伊東大介

Dementia Japan （(一社)日本認知症学会） 33 （ 4 ） 513 - 513 2019年10月

ISSN 1342-646X
磁化率強調画像におけるswallow tail signのパーキンソン病及び関連疾患診断における有用性

関守信, 上田亮, 手塚俊樹, 岡田健佑, 馬島恭子, 吉崎崇仁, 中原仁

神経治療学（(一社)日本神経治療学会） 36 （ 6 ） S262 - S262 2019年10月

ISSN 0916-8443
抗programmed cell death-1(PD-1)抗体による炎症性ミオパチーの治療と予後

関守信, 中原仁, 鈴木重明

神経治療学（(一社)日本神経治療学会） 36 （ 6 ） S263 - S263 2019年10月

ISSN 0916-8443
免疫関連有害事象(irAE)に対するステロイド中止により筋炎の再燃を繰り返した1例

大山宗徳, 関守信, 松原四郎, 宮本和人, 中原仁, 鈴木重明

神経治療学（(一社)日本神経治療学会） 36 （ 6 ） S277 - S277 2019年10月

ISSN 0916-8443
パーキンソン病ナース　その役割と海外の現状

関守信

神経治療学（(一社)日本神経治療学会） 36 （ 6 ） S206 - S206 2019年10月

ISSN 0916-8443