泉本 修一 (イズモト シュウイチ)

  • 近畿大学奈良病院 教授/部長
Last Updated :2024/04/26

コミュニケーション情報 byコメンテータガイド

  • コメント

    悪性脳腫瘍、間脳下垂体腫瘍、良性脳腫瘍、小児脳腫瘍
  • 報道関連出演・掲載一覧

    <報道関連出演・掲載一覧> ●2016/3/4  毎日放送「ちちんぷいぷい」  「もやもや病」について ●2016/3/3  毎日放送「ちちんぷいぷい」  「脳リンパ腫」について

研究者情報

学位

  • 博士(医学)(大阪大学)

ホームページURL

J-Global ID

研究キーワード

  • 脳腫瘍   Brain tumor   

現在の研究分野(キーワード)

    悪性脳腫瘍、間脳下垂体腫瘍、良性脳腫瘍、小児脳腫瘍

研究分野

  • ライフサイエンス / 脳神経外科学

学歴

  •         - 1983年   金沢大学   医学部   医学科
  •         - 1983年   金沢大学   Faculty of Medicine

所属学協会

  • 分子脳神経外科学会   日本脳腫瘍カンファレンス   日本癌学会   日本脳神経外学会   

研究活動情報

論文

  • Chisato Yokota; Naoki Kagawa; Koji Takano; Yasuyoshi Chiba; Manabu Kinoshita; Noriyuki Kijima; Yusuke Oji; Yoshihiro Oka; Haruo Sugiyama; Akihiro Tsuboi; Shuichi Izumoto; Haruhiko Kishima; Naoya Hashimoto
    Cancer immunology, immunotherapy : CII 71 1 189 - 201 2021年06月 
    We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.
  • Masayuki Kanamori; Hirokazu Takami; Shigeru Yamaguchi; Takashi Sasayama; Koji Yoshimoto; Teiji Tominaga; Akihiro Inoue; Naokado Ikeda; Atsushi Kambe; Toshihiro Kumabe; Masahide Matsuda; Shota Tanaka; Manabu Natsumeda; Ken-Ichiro Matsuda; Masahiro Nonaka; Jun Kurihara; Masayoshi Yamaoka; Naoki Kagawa; Naoki Shinojima; Tetsuya Negoto; Yukiko Nakahara; Yoshiki Arakawa; Seiji Hatazaki; Hiroaki Shimizu; Atsuo Yoshino; Hiroshi Abe; Jiro Akimoto; Yu Kawanishi; Tomonari Suzuki; Atsushi Natsume; Motoo Nagane; Yukinori Akiyama; Dai Keino; Tadateru Fukami; Takahiro Tomita; Kohei Kanaya; Tsutomu Tokuyama; Shuichi Izumoto; Mitsutoshi Nakada; Daisuke Kuga; Shohei Yamamoto; Ryogo Anei; Takeo Uzuka; Junya Fukai; Noriyuki Kijima; Keita Terashima; Koichi Ichimura; Ryo Nishikawa
    Neuro-oncology 23 2 295 - 303 2021年02月 
    BACKGROUND: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. METHODS: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. RESULTS: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. CONCLUSION: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.
  • Nobuhiro Nakagawa; Norihito Fukawa; Kiyoshi Tsuji; Kentaro Furukawa; Akira Watanabe; Shuichi Izumoto
    Journal of Neuroendovascular Therapy 2021年
  • 中尾 剛幸; 泉本 修一; 露口 尚弘; 加藤 天美; 横尾 英明; 榎木 英介
    BRAIN and NERVE: 神経研究の進歩 72 2 0159 - 0165 (株)医学書院 2020年02月 
    <文献概要>37歳女性,左下肢筋力低下を認め,頭部MRIで右大脳半球に多発性造影陽性腫瘤を認めた。他臓器に病変はなく,開頭腫瘍生検術を施行,脳原発リンパ腫様肉芽腫症(LYG)grade 1と診断した。ステロイド単独治療を行った結果,治療終了後24ヵ月間にわたり完全寛解を維持している。エプスタイン・バーウイルス陰性を含めた病理検査や全身画像検査を経て,脳原発LYG grade 1であれば,ステロイド単独治療が奏効する可能性があると考えられ,確実な診断が望まれる。
  • Takayuki Nakao; Shuichi Izumoto; Naohiro Tsuyuguchi; Amami Kato; Hideaki Yokoo; Eisuke Enoki
    Brain and nerve = Shinkei kenkyu no shinpo 72 2 159 - 165 2020年02月 [査読有り]
     
    Lymphomatoid granulomatosis (LYG) is an angiocentric, angiodestructive lymphoreticular proliferative disease that usually affects the lungs but it has been speculated to also effect the central nervous system (CNS). However, unique primary LYG of the CNS has rarely been reported in the literature. Herein, we describe a clinical case of a 37-year-old female patient with grade 1 primary CNS-LYG having a good prognosis owing to corticosteroid treatment. The aforesaid patient, presented with a headache and left leg weakness with no evidence of a systemic disease. MRI revealed multiple small enhancing nodules in the right hemisphere with diffuse high-intensity lesions on T2/ FLAIR image. A brain biopsy showed lymphohistiocytic cells with blood vessels infiltrated with CD3+ and CD20+. The Epstein-Barr virus encoded small RNA-ISH test was negative. Based on the above findings, grade 1 primary CNS-LYG was diagnosed. Following the administration of oral corticosteroids, a systemic high-dose corticosteroid therapy was administrated. Complete remission was achieved and maintained for 24 months following treatment. Grade 1 primary CNS-LYG is a rare disease that is not apparently associated with the Epstein-Barr virus (EBV) and possibly yields much better prognosis than the frequently EBV-positive systemic LYG with CNS localization. (Received November 5, 2019; Accepted November 20, 2019; Published February 1, 2020).
  • Ryohei Fukuma; Takufumi Yanagisawa; Manabu Kinoshita; Takashi Shinozaki; Hideyuki Arita; Atsushi Kawaguchi; Masamichi Takahashi; Yoshitaka Narita; Yuzo Terakawa; Naohiro Tsuyuguchi; Yoshiko Okita; Masahiro Nonaka; Shusuke Moriuchi; Masatoshi Takagaki; Yasunori Fujimoto; Junya Fukai; Shuichi Izumoto; Kenichi Ishibashi; Yoshikazu Nakajima; Tomoko Shofuda; Daisuke Kanematsu; Ema Yoshioka; Yoshinori Kodama; Masayuki Mano; Kanji Mori; Koichi Ichimura; Yonehiro Kanemura; Haruhiko Kishima
    Scientific reports 9 1 20311 - 20311 2019年12月 [査読有り]
     
    Identification of genotypes is crucial for treatment of glioma. Here, we developed a method to predict tumor genotypes using a pretrained convolutional neural network (CNN) from magnetic resonance (MR) images and compared the accuracy to that of a diagnosis based on conventional radiomic features and patient age. Multisite preoperative MR images of 164 patients with grade II/III glioma were grouped by IDH and TERT promoter (pTERT) mutations as follows: (1) IDH wild type, (2) IDH and pTERT co-mutations, (3) IDH mutant and pTERT wild type. We applied a CNN (AlexNet) to four types of MR sequence and obtained the CNN texture features to classify the groups with a linear support vector machine. The classification was also performed using conventional radiomic features and/or patient age. Using all features, we succeeded in classifying patients with an accuracy of 63.1%, which was significantly higher than the accuracy obtained from using either the radiomic features or patient age alone. In particular, prediction of the pTERT mutation was significantly improved by the CNN texture features. In conclusion, the pretrained CNN texture features capture the information of IDH and TERT genotypes in grade II/III gliomas better than the conventional radiomic features.
  • Shigeru Kawai; Takeshi Okuda; Ayano Fukui; Yasuhiro Sanada; Keisuke Yoshikawa; Miyuki Morikawa; Motoi Kuwahara; Osamu Maenishi; Yasuyoshi Morita; Shuichi Izumoto; Amami Kato; Itaru Matsumura; Susumu Kusunoki
    Internal medicine (Tokyo, Japan) 58 14 2085 - 2089 2019年07月 [査読有り]
     
    Intravascular lymphoma (IVL) is a malignant lymphoma that lacks the expression of cell surface adhesion molecules so that cells fluidly migrate within the blood vessels. The patient in the present study had restricted eye movement caused by IVL, mimicking a cavernous sinus tumor. Because the cavernous sinus lumen is divided into multiple compartments by trabeculae and venous channels, IVL tumor cells were trapped in these compartments, thus forming a mass, which subsequently extended into the contralateral cavernous sinus via the anterior and posterior intercavernous sinuses. This is a rare case of IVL forming a mass inside the cavernous sinus.
  • Nakao Takayuki; Izumoto Shuichi; Tuyuguchi Naohiro; Kato Amami; Yokoo Hiddeaki; Enoki Eisuke
    BRAIN PATHOLOGY 29 166  2019年02月 [査読有り]
  • Kohei Fukuoka; Yonehiro Kanemura; Tomoko Shofuda; Shintaro Fukushima; Satoshi Yamashita; Daichi Narushima; Mamoru Kato; Mai Honda-Kitahara; Hitoshi Ichikawa; Takashi Kohno; Atsushi Sasaki; Junko Hirato; Takanori Hirose; Takashi Komori; Kaishi Satomi; Akihiko Yoshida; Kai Yamasaki; Yoshiko Nakano; Ai Takada; Taishi Nakamura; Hirokazu Takami; Yuko Matsushita; Tomonari Suzuki; Hideo Nakamura; Keishi Makino; Yukihiko Sonoda; Ryuta Saito; Teiji Tominaga; Yasuhiro Matsusaka; Keiichi Kobayashi; Motoo Nagane; Takuya Furuta; Mitsutoshi Nakada; Yoshitaka Narita; Yuichi Hirose; Shigeo Ohba; Akira Wada; Katsuyoshi Shimizu; Kazuhiko Kurozumi; Isao Date; Junya Fukai; Yousuke Miyairi; Naoki Kagawa; Atsufumi Kawamura; Makiko Yoshida; Namiko Nishida; Takafumi Wataya; Masayoshi Yamaoka; Naohiro Tsuyuguchi; Takehiro Uda; Mayu Takahashi; Yoshiteru Nakano; Takuya Akai; Shuichi Izumoto; Masahiro Nonaka; Kazuhisa Yoshifuji; Yoshinori Kodama; Masayuki Mano; Tatsuya Ozawa; Vijay Ramaswamy; Michael D Taylor; Toshikazu Ushijima; Soichiro Shibui; Mami Yamasaki; Hajime Arai; Hiroaki Sakamoto; Ryo Nishikawa; Koichi Ichimura
    Acta neuropathologica communications 6 1 134 - 134 2018年12月 [査読有り]
     
    Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.
  • Takahiro Sasaki; Junya Fukai; Yoshinori Kodama; Takanori Hirose; Yoshiko Okita; Shusuke Moriuchi; Masahiro Nonaka; Naohiro Tsuyuguchi; Yuzo Terakawa; Takehiro Uda; Yusuke Tomogane; Manabu Kinoshita; Namiko Nishida; Shuichi Izumoto; Yoshikazu Nakajima; Hideyuki Arita; Kenichi Ishibashi; Tomoko Shofuda; Daisuke Kanematsu; Ema Yoshioka; Masayuki Mano; Koji Fujita; Yuji Uematsu; Naoyuki Nakao; Kanji Mori; Yonehiro Kanemura
    Journal of neuro-oncology 140 2 329 - 339 2018年11月 [査読有り]
     
    INTRODUCTION: This study investigates the current state of clinical practice and molecular analysis for elderly patients with diffuse gliomas and aims to elucidate treatment outcomes and prognostic factors of patients with glioblastomas. METHODS: We collected elderly cases (≥ 70 years) diagnosed with primary diffuse gliomas and enrolled in Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and pathological characteristics were analyzed retrospectively. Various factors were evaluated in univariate and multivariate models to examine their effects on overall survival. RESULTS: Included in the study were 140 elderly patients (WHO grade II: 7, III: 19, IV: 114), median age was 75 years. Sixty-seven patients (47.9%) had preoperative Karnofsky Performance Status score of ≥ 80. All patients underwent resection (gross-total: 20.0%, subtotal: 14.3%, partial: 39.3%, biopsy: 26.4%). Ninety-six of the patients (68.6%) received adjuvant treatment consisting of radiotherapy (RT) with temozolomide (TMZ). Seventy-eight of the patients (75.0%) received radiation dose of ≥ 50 Gy. MGMT promoter was methylated in 68 tumors (48.6%), IDH1/2 was wild-type in 129 tumors (92.1%), and TERT promoter was mutated in 78 of 128 tumors (60.9%). Median progression-free and overall survival of grade IV cases was 8.2 and 13.6 months, respectively. Higher age (≥ 80 years) and TERT promoter mutated were associated with shorter survival. Resection and adjuvant RT + TMZ were identified as independent factors for good prognosis. CONCLUSIONS: This community-based study reveals characteristics and outcomes of elderly glioma patients in a real-world setting. Elderly patients have several potential factors for poor prognosis, but resection followed by RT + TMZ could lengthen duration of survival.
  • ステロイド療法が奏功した脳原発リンパ腫様肉芽腫症の一例
    中尾 剛幸; 泉本 修一; 露口 尚弘; 加藤 天美; 横尾 英明; 榎木 英介
    Brain Tumor Pathology 35 Suppl. 178 - 178 日本脳腫瘍病理学会 2018年09月
  • Hideyuki Arita; Manabu Kinoshita; Atsushi Kawaguchi; Masamichi Takahashi; Yoshitaka Narita; Yuzo Terakawa; Naohiro Tsuyuguchi; Yoshiko Okita; Masahiro Nonaka; Shusuke Moriuchi; Masatoshi Takagaki; Yasunori Fujimoto; Junya Fukai; Shuichi Izumoto; Kenichi Ishibashi; Yoshikazu Nakajima; Tomoko Shofuda; Daisuke Kanematsu; Ema Yoshioka; Yoshinori Kodama; Masayuki Mano; Kanji Mori; Koichi Ichimura; Yonehiro Kanemura
    Scientific reports 8 1 11773 - 11773 2018年08月 [査読有り]
     
    Molecular biological characterization of tumors has become a pivotal procedure for glioma patient care. The aim of this study is to build conventional MRI-based radiomics model to predict genetic alterations within grade II/III gliomas attempting to implement lesion location information in the model to improve diagnostic accuracy. One-hundred and ninety-nine grade II/III gliomas patients were enrolled. Three molecular subtypes were identified: IDH1/2-mutant, IDH1/2-mutant with TERT promoter mutation, and IDH-wild type. A total of 109 radiomics features from 169 MRI datasets and location information from 199 datasets were extracted. Prediction modeling for genetic alteration was trained via LASSO regression for 111 datasets and validated by the remaining 58 datasets. IDH mutation was detected with an accuracy of 0.82 for the training set and 0.83 for the validation set without lesion location information. Diagnostic accuracy improved to 0.85 for the training set and 0.87 for the validation set when lesion location information was implemented. Diagnostic accuracy for predicting 3 molecular subtypes of grade II/III gliomas was 0.74 for the training set and 0.56 for the validation set with lesion location information implemented. Conventional MRI-based radiomics is one of the most promising strategies that may lead to a non-invasive diagnostic technique for molecular characterization of grade II/III gliomas.
  • Shuichi Izumoto; Masaharu Miyauchi; Takayuki Tasaki; Takeshi Okuda; Nobuhiro Nakagawa; Naoki Nakano; Amami Kato; Mitsugu Fujita
    Anticancer research 38 7 4361 - 4366 2018年07月 [査読有り]
     
    BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.
  • Takamasa Kayama; Shinya Sato; Kaori Sakurada; Junki Mizusawa; Ryo Nishikawa; Yoshitaka Narita; Minako Sumi; Yasuji Miyakita; Toshihiro Kumabe; Yukihiko Sonoda; Yoshiki Arakawa; Susumu Miyamoto; Takaaki Beppu; Kazuhiko Sugiyama; Hirohiko Nakamura; Motoo Nagane; Yoko Nakasu; Naoya Hashimoto; Mizuhiko Terasaki; Akira Matsumura; Eiichi Ishikawa; Toshihiko Wakabayashi; Yasuo Iwadate; Shiro Ohue; Hiroyuki Kobayashi; Manabu Kinoshita; Kenichiro Asano; Akitake Mukasa; Katsuyuki Tanaka; Akio Asai; Hideo Nakamura; Tatsuya Abe; Yoshihiro Muragaki; Koichi Iwasaki; Tomokazu Aoki; Takao Watanabe; Hikaru Sasaki; Shuichi Izumoto; Masahiro Mizoguchi; Takayuki Matsuo; Hideo Takeshima; Motohiro Hayashi; Hidefumi Jokura; Takashi Mizowaki; Eiji Shimizu; Hiroki Shirato; Masao Tago; Hiroshi Katayama; Haruhiko Fukuda; Soichiro Shibui
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2018786186  2018年06月 [査読有り]
     
    Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.
  • Manabu Kinoshita; Hideyuki Arita; Masamichi Takahashi; Yoshitaka Narita; Yuzo Terakawa; Naohiro Tsuyuguchi; Yoshiko Okita; Masahiro Nonaka; Shusuke Moriuchi; Junya Fukai; Shuichi Izumoto; Kenichi Ishibashi; Yoshinori Kodama; Kanji Mori; Kohichi Ichimura; Yonehiro Kanemura
    NEURO-ONCOLOGY 19 162 - 162 2017年11月 [査読有り]
  • Takeshi Okuda; Takayuki Tasaki; Susumu Nakata; Kimihiro Yamashita; Hiromasa Yoshioka; Shuichi Izumoto; Amami Kato; Mitsugu Fujita
    ANTICANCER RESEARCH 37 7 3871 - 3876 2017年07月 [査読有り]
     
    Background: Glioblastoma multiforme (GBM) is a malignant brain tumor with an extremely poor prognosis. GBM tissues frequently express mesenchymal-epithelial transition factor (MET), which induces cell division, growth and migration. In addition, angiogenesis is a significant feature of GBM, attributable to the overexpression of vascular endothelial growth factor (VEGF). Although the VEGF inhibitor bevacizumab was recently highlighted as the second-line drug for GBM treatment, GBMs often recur even with bevacizumab therapy. Based on these findings, we hypothesized that inhibition of both MET and VEGF would exhibit a synergistic effect on MET-overexpressing GBM. Materials and Methods: As we observed MET expression at high levels in some patients with GBM, we designed GL261 murine glioma-based experiments. GL261 cells were transfected with siRNAs specific for MET and VEGF in vitro, and the cell growth ratios were evaluated. Simultaneously, transfected GL261 cells were transplanted into the brain of C57BL/6 mice, and their survival was monitored. Results: GBM tissues frequently overexpressed MET protein at high levels compared with lower-grade gliomas. These GBMs at first responded to bevacizumab, but often eventually recurred. When GL261 cells were co-transfected with both MET-specific siRNA and VEGF-specific siRNA, the in vitro tumor cell growth significantly decelerated compared to single siRNA transfection. Consistently, when mice were transplanted with co-transfected GL261 cells, their survival was significantly prolonged compared to those given cells transfected with single siRNA. Conclusion: The current data indicate that the inhibition of both MET and VEGF exhibits efficient therapeutic effects of GBM-bearing hosts.
  • Manabu Kinoshita; Hideyuki Arita; Toshiki Yoshimine; Masamichi Takahashi; Yoshitaka Narita; Yuzo Terakawa; Naohiro Tsuyuguchi; Yoshiko Okita; Masahiro Nonaka; Shusuke Moriuchi; Junya Fukai; Shuichi Izumoto; Kenichi Ishibashi; Yoshikazu Nakajima; Masatoshi Takagaki; Tomoko Shofuda; Yoshinori Kodama; Kanji Mori; Koichi Ichimura; Yonehiro Kanemura
    NEURO-ONCOLOGY 18 128 - 128 2016年11月 [査読有り]
  • Izumoto S; Sanada Y; Tomogane Y
    Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 7 307 - 312 2016年09月 [査読有り]
  • Yusuke Oji; Naoya Hashimoto; Akihiro Tsuboi; Yui Murakami; Miki Iwai; Naoki Kagawa; Yasuyoshi Chiba; Shuichi Izumoto; Olga Elisseeva; Ryo Ichinohasama; Junichi Sakamoto; Satoshi Morita; Hiroko Nakajima; Satoshi Takashima; Yoshiki Nakae; Jun Nakata; Manabu Kawakami; Sumiyuki Nishida; Naoki Hosen; Fumihiro Fujiki; Soyoko Morimoto; Mayuko Adachi; Masahiro Iwamoto; Yoshihiro Oka; Toshiki Yoshimine; Haruo Sugiyama
    INTERNATIONAL JOURNAL OF CANCER 139 6 1391 - 1401 2016年09月 [査読有り]
     
    We previously evaluated Wilms' tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA-A* 24: 02 restricted, 9-mer WT1-235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1-235-specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1-235 peptide (WT1-235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1-235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1-235 IgG antibody subclass was Th1-type, IgG(1) and IgG(3). WT1-235 IgG antibody production was significantly and positively correlated with both progression-free survival (PFS) and overall survival (OS). Importantly, the combination of WT1-235 IgG antibody production and positive delayed type-hypersensitivity (DTH) to the WT1-235 peptide was a better prognostic marker for long-term OS than either parameter alone. These results suggested that WT1-235 peptide vaccination induces not only WT1-235-specific CTLs as previously described but also WT1-235-specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine-treated patients.
  • Takayuki Tasaki; Mitsugu Fujita; Takeshi Okuda; Azusa Yoneshige; Susumu Nakata; Kimihiro Yamashita; Hiromasa Yoshioka; Shuichi Izumoto; Amami Kato
    ANTICANCER RESEARCH 36 7 3571 - 3577 2016年07月 [査読有り]
     
    Background: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the protooncogene mesenchymal-epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. Patients and Methods: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. Results: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. Conclusion: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.
  • Endoscopic Biopsy using High-Dose Fluorescein Sodium for Malignant Brain Tumors
    Okuda T; Fujita M; Yoshioka H; Tasaki T; Izumoto S; Kato A
    International Journal of Neurology and Neurotherapy 3 3 052  2016年06月 [査読有り]
  • Naoya Hashimoto; Akihiro Tsuboi; Naoki Kagawa; Yasuyoshi Chiba; Shuichi Izumoto; Manabu Kinoshita; Noriyuki Kijima; Yoshihiro Oka; Soyoko Morimoto; Hiroko Nakajima; Satoshi Morita; Junichi Sakamoto; Sumiyuki Nishida; Naoki Hosen; Yusuke Oji; Norio Arita; Toshiki Yoshimine; Haruo Sugiyama
    CANCER IMMUNOLOGY IMMUNOTHERAPY 64 6 707 - 716 2015年06月 [査読有り]
     
    To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks from the first administration of maintenance temozolomide. All patients showed good tolerability during the observation period. Skin disorders, such as grade 1/2 injection-site reactions, were observed in all seven patients. Although grade 3 lymphocytopenia potentially due to concurrent radio/temozolomide therapy was observed in five patients (71.4 %), no other grade 3/4 hematological or neurological toxicities were observed. No autoimmune reactions were observed. All patients are still alive, and six are on Wilms tumor 1 peptide vaccination without progression, yielding a progression-free survival from histological diagnosis of 5.2-49.1 months. Wilms tumor 1 peptide vaccination was stopped in one patient after 12 injections by the patient's request. The safety profile of the combined Wilms tumor 1 peptide vaccination and temozolomide therapy approach for treating glioblastoma was confirmed.
  • Tasaki T; Fujita M; Izumoto S; Nakagawa K; Kato A
    Jpn J Neurosurg 24 3 192 - 197 2015年01月 [査読有り]
  • Naoya Hashimoto; Akihiro Tsuboi; Yasuyoshi Chiba; Ryuichi Hirayama; Koji Takano; Noriyuki Kijima; Yoshihiro Oka; Naoki Kagawa; Shuichi Izumoto; Haruo Sugiyama; Toshiki Yoshimine
    NEURO-ONCOLOGY 16 2014年07月 [査読有り]
  • Oji Y; Tatsumi N; Fukuda M; Nakatsuka S; Aoyagi S; Hirata E; Nanchi I; Fujiki F; Nakajima H; Yamamoto Y; Shibata S; Nakamura M; Hasegawa K; Takagi S; Fukuda I; Hoshikawa T; Murakami Y; Mori M; Inoue M; Naka T; Tomonaga T; Shimizu Y; Nakagawa M; Hasegawa J; Nezu R; Inohara H; Izumoto S; Nonomura N; Yoshimine T; Okumura M; Morii E; Maeda H; Nishida S; Hosen N; Tsuboi A; Oka Y; Sugiyama H
    International journal of oncology 44 5 1461 - 1469 2014年05月 [査読有り]
     
    Recent studies have shown that cancer immunotherapy could be a promising therapeutic approach for the treatment of cancer. In the present study, to identify novel tumor-associated antigens (TAAs), the proteins expressed in a panel of cancer cells were serologically screened by immunoblot analysis and the eukaryotic elongation factor 2 (eEF2) was identified as an antigen that was recognized by IgG autoantibody in sera from a group of patients with head and neck squamous cell carcinoma (HNSCC) or colon cancer. Enzyme-linked immunosorbent assay showed that serum eEF2 IgG Ab levels were significantly higher in colorectal and gastric cancer patients compared to healthy individuals. Immunohistochemistry experiments showed that the eEF2 protein was overexpressed in the majority of lung, esophageal, pancreatic, breast and prostate cancers, HNSCC, glioblastoma multiforme and non-Hodgkin's lymphoma (NHL). Knockdown of eEF2 by short hairpin RNA (shRNA) significantly inhibited the growth in four eEF2-expressing cell lines, PC14 lung cancer, PCI6 pancreatic cancer, HT1080 fibrosarcoma and A172 glioblastoma cells, but not in eEF2-undetectable MCF7 cells. Furthermore, eEF2-derived 9-mer peptides, EF786 (eEF2 786-794 aa) and EF292 (eEF2 292-300 aa), elicited cytotoxic T lymphocyte (CTL) responses in peripheral blood mononuclear cells (PBMCs) from an HLA-A*24:02- and an HLA-A*02:01-positive healthy donor, respectively, in an HLA-A-restricted manner. These results indicated that the eEF2 gene is overexpressed in the majority of several types of cancers and plays an oncogenic role in cancer cell growth. Moreover, the eEF2 gene product is immunogenic and a promising target molecule of cancer immunotherapy for several types of cancers.
  • Shuichi Izumoto
    Neurological Surgery 42 6 507 - 521 2014年 [査読有り]
  • Kanji Mori; Reiichi Ishikura; Yusuke Tomogane; Kumiko Ando; Shuichi Izumoto
    NEURO-ONCOLOGY 15 200 - 200 2013年11月 [査読有り]
  • Yusuke Tomogane; Kanji Mori; Shuichi Izumoto; Keizo Kaba; Reiichi Ishikura; Kumiko Ando; Yuki Wakata; Shigekazu Fujita; Manabu Shirakawa; Norio Arita
    NEUROLOGIA MEDICO-CHIRURGICA 53 7 482 - 489 2013年07月 [査読有り]
     
    The principles of echo-shifting with a train of observations (PRESTO) magnetic resonance (MR) imaging technique employs an MR sequence that sensitively detects susceptibility changes in the brain. The effectiveness of PRESTO MR imaging was examined for distinguishing between cerebellopontine angle (CPA) schwannomas and meningiomas in 24 patients with CPA tumors, 12 with vestibular schwannomas, and 12 with meningiomas. Histopathological study of surgical specimens showed that 11 of the 12 schwannomas contained hemosiderin deposits and all had microhemorrhages. One meningioma contained hemosiderin deposits and two involved microhemorrhages. Abnormal vessel proliferation, and dilated and thrombosed vessels were observed in all schwannomas and in 4 meningiomas. In addition to MR imaging with all basic sequences, PRESTO MR imaging and computed tomography were performed. PRESTO imaging showed significantly more schwannomas (n = 12) than meningiomas (n = 2) exhibited intratumoral spotty signal voids which were isointense to air in the mastoid air cells (p < 0.001). These spotty signal voids were significantly associated with histopathologically demonstrated hemosiderin deposits (p < 0.001), microhemorrhages (p < 0.01), and abnormal vessels (p < 0.04). The visualization of spotty signal voids on PRESTO images is useful to distinguish schwannomas from meningiomas.
  • Soyoko Morimoto; Yoshihiro Oka; Akihiro Tsuboi; Yukie Tanaka; Fumihiro Fujiki; Hiroko Nakajima; Naoki Hosen; Sumiyuki Nishida; Jun Nakata; Yoshiki Nakae; Motohiko Maruno; Akira Myoui; Takayuki Enomoto; Shuichi Izumoto; Mitsugu Sekimoto; Naoki Kagawa; Naoya Hashimoto; Toshiki Yoshimine; Yusuke Oji; Atsushi Kumanogoh; Haruo Sugiyama
    Cancer Sci. 103 3 408 - 414 2012年03月 [査読有り]
     
    Wilms' tumor gene 1 (WT1) protein is a promising tumor-associated antigen. In patients with WT1-expressing malignancies, WT1-specific CTLs are spontaneously induced as a result of an immune response to the WT1 protein. In the present study, we performed single cell-level comparative analysis of T cell receptor β-chain variable region (TCR-BV) gene families of a total of 750 spontaneously induced WT1(126) peptide (amino acids 126-134, WT1(126))-specific CTLs in both HLA-A*0201(+) patients with solid tumors and healthy donors (HDs). This is the first report of direct usage analysis of 24 kinds of TCR-BV gene families of WT1(126)-specific CTLs at the single cell level. Usage analysis with single-cell RT-PCR of TCR-BV gene families of individual FACS-sorted WT1(126) tetramer(+) CD8(+) T cells showed, for the first time, that: (i) BVs 3, 6, 7, 20, 27, and 28 were commonly biased in patients and HDs; (ii) BVs 2, 11, and 15 were biased only in patients; and (iii) BVs 4, 5, 9, and 19 were biased only in HDs. However, statistical analysis of similarity of individual usage frequencies of 24 kinds of TCR-BV gene families between patients and HDs indicated that the usage frequencies of TCR-BV
  • Morimoto S; Oka Y; Tsuboi A; Tanaka Y; Fujiki F; Nakajima H; Hosen N; Nishida S; Nakata J; Nakae Y; Maruno M; Myoui A; Enomoto T; Izumoto S; Sekimoto M; Kagawa N; Hashimoto N; Yoshimine T; Oji Y; Kumanogoh A; Sugiyama H
    Cancer science 103 3 408 - 414 2012年03月 [査読有り]
     
    Wilms tumor gene 1 (WT1) protein is a promising tumor-associated antigen. In patients with WT1-expressing malignancies, WT1-specific CTLs are spontaneously induced as a result of an immune response to the WT1 protein. In the present study, we performed single cell-level comparative analysis of T cell receptor beta-chain variable region (TCR-BV) gene families of a total of 750 spontaneously induced WT1126 peptide (amino acids 126134, WT1126)-specific CTLs in both HLA-A*0201+ patients with solid tumors and healthy donors (HDs). This is the first report of direct usage analysis of 24 kinds of TCR-BV gene families of WT1126-specific CTLs at the single cell level. Usage analysis with single-cell RT-PCR of TCR-BV gene families of individual FACS-sorted WT1126 tetramer+ CD8+ T cells showed, for the first time, that: (i) BVs 3, 6, 7, 20, 27, and 28 were commonly biased in patients and HDs; (ii) BVs 2, 11, and 15 were biased only in patients; and (iii) BVs 4, 5, 9, and 19 were biased only in HDs. However, statistical analysis of similarity of individual usage frequencies of 24 kinds of TCR-BV gene families between patients and HDs indicated that the usage frequencies of TCR-BV gene families in patients reflected those in HDs. These results should provide us with a novel insight for a better understanding of WT1-specific immune responses. (Cancer Sci 2012; 103: 408414)
  • Shuichi Izumoto
    GLIOMA: IMMUNOTHERAPEUTIC APPROACHES 746 166 - 177 2012年 [査読有り]
     
    Current combinations of surgical therapy, radiotherapy and chemotherapy regimens do not significantly improve long-term survival of the patients with malignant glioma. Cancer immunotherapy against malignant glioma is a potentially new therapeutic strategy that primes a patient's immune system to attack glioma cells. Peptide-based vaccination appears promising as an approach to successfully induce an antineoplastic immune response, produce clinical response and prolong survival in patients with malignant glioma without major side effects. In this chapter, clinical progress is reviewed in developing peptide-based vaccinations for malignant glioma to date.
  • 転移性脳腫瘍の病理学的病型細分類の重要性 乳がん脳転移組織の免疫組織学的検討
    泉本 修一; 森 鑑二; 藤田 重一; 友金 佑介; 三好 康雄; 中正 恵二; 有田 憲生
    Brain Tumor Pathology 28 Suppl. 105 - 105 日本脳腫瘍病理学会 2011年05月
  • Hideyuki Arita; Shuichi Izumoto; Manabu Kinoshita; Yoshiko Okita; Naoya Hashimoto; Toshiaki Fujita; Naotsugu Ichimaru; Shiro Takahara; Toshiki Yoshimine
    NEUROLOGIA MEDICO-CHIRURGICA 50 12 1079 - 1083 2010年12月 [査読有り]
     
    Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.
  • Manabu Kinoshita; Naoya Hashimoto; Shuichi Izumoto; Yoshiko Okita; Naoki Kagawa; Motohiko Maruno; Takanori Ohnishi; Norio Arita; Toshiki Yoshimine
    JOURNAL OF NEURO-ONCOLOGY 99 1 95 - 101 2010年08月 [査読有り]
     
    Primary central nervous system lymphoma (PCNSL) remains a devastating disease with poor prognosis, despite the improvement offered by methotrexate (MTX)-based chemotherapy. Several studies have attempted to identify biomarkers predictive of prognosis, which are expected to be both clinically useful and biologically important for understanding PCNSL. The present study attempts to classify human immunodeficiency virus (HIV)-unrelated PCNSL patients treated with radiation combined with rapid high-dose MTX chemotherapy according to B-cell differentiation status, and retrospectively examines the prognostic impact. Initial response to MTX was a strong predictor of favorable prognosis in terms of both progression-free survival (PFS) and overall survival (OS). Thirteen out of 29 cases were CD10(-)/BCL-6(+)/MUM-1(+), being more frequent compared with systemic peripheral nodal lymphoma. Although post-germinal-center B-cell-originating PCNSLs (CD10(-)/BCL-6(-)/MUM-1(+)) showed a trend towards better response to MTX and progression-free survival than did germinal-center-related B-cell-originating PCNSLs (CD10(+) OR CD10(-)/BCL-6(+)/MUM-1(+)), the difference was only marginal (P = 0.04 Gehan-Breslow-Wilcoxon, P = 0.17 log-rank). Our results imply that different B-cell stages in PCNSL have significant relevance in terms of biological behavior. However, clinical use as a prognostic marker requires further investigation.
  • Fumihiro Fujiki; Yoshihiro Oka; Mai Kawakatsu; Akihiro Tsuboi; Yukie Tanaka-Harada; Naoki Hosen; Sumiyuki Nishida; Toshiaki Shirakata; Hiroko Nakajima; Naoya Tatsumi; Naoya Hashimoto; Tetsuya Taguchi; Satsuki Ueda; Norio Nonomura; Yutaka Takeda; Toshinori Ito; Akira Myoui; Shuichi Izumoto; Motohiko Maruno; Toshiki Yoshimine; Shinzaburo Noguchi; Akihiko Okuyama; Ichiro Kawase; Yusuke Oji; Haruo Sugiyama
    ANTICANCER RESEARCH 30 6 2247 - 2254 2010年06月 [査読有り]
     
    Clinical studies of WT1-targeted cancer vaccine are being performed. However, WT1-specific Th response in cancer patients remains unclear. Using quantitative real-time RT-PCR, we investigated IFN-gamma and IL-10 mRNA expression from Th cells by stimulation with helper peptide WT1(332). Seventeen patients, of whom 10 had achieved stable disease and the remaining 7 had progressive disease, were weekly vaccinated with WT1 CTL epitope (modified WT1(235)) and examined for WT1(332)-specific Th response. A clear correlation between WT1(332)-specific Th response and clinical response was observed at 4 weeks post-vaccination. In patients who responded, a clear inverse correlation between IL-10-type and IFN-gamma-type WT1(332)-specific Th response was detected at pre- and 4 weeks post-vaccination, and the shift of the Th response from IL-10-type dominancy at early phase to IFN-gamma-type dominancy at late phase was observed. From this study we concluded that occurrence of WT1(332)-specific Th response could predict good clinical response of WT1 CTL epitope vaccination.
  • 第3脳室、第4脳室内に同時発生した中枢神経系primitive neuroectodermal tumor(cPNET)の剖検例
    木嶋 教行; 香川 尚己; 千葉 泰良; 橋本 直哉; 木下 学; 沖田 典子; 山本 福子; 後藤 哲; 泉本 修一; 吉峰 俊樹
    Brain Tumor Pathology 27 Suppl. 120 - 120 日本脳腫瘍病理学会 2010年05月
  • Masahiro Ishihara; Shuichi Izumoto; Koichi Iwatsuki; Toshiki Yoshimine
    NEUROLOGIA MEDICO-CHIRURGICA 50 3 246 - 250 2010年03月 [査読有り]
     
    A 55-year-old man presented with a rare case of both intracranial and intraspinal inflammatory pseudotumors manifesting as progressive motor weakness in his lower extremities. Magnetic resonance imaging revealed a 24-mm diameter tumor-like lesion in the left parietal lobe and an intramedullary 24-mm diameter lesion at the C7 and T1 levels of the spinal cord. These lesions were resected by sequential operations. Histological examination of the resected lesions revealed the presence of excessive collagen fibers infiltrated with polyclonal lymphocytes and plasma cells, and the diagnosis was inflammatory pseudotumor. Immunohistochemical staining with anti-immunoglobulin G4 (IgG4) antibody found no accumulation of IgG4-positive cells. The serum IgG4 level was normal. Thus, this case did not meet the criteria for IgG4-related disease.
  • Shuichi Izumoto; Norio Arita
    Neurological Surgery 38 1 79 - 89 2010年01月 [査読有り]
  • 沖田 典子; 橋本 直哉; 泉本 修一; 吉峰 俊樹
    Neuro-Oncologyの進歩 18 1 18 - 18 近畿脳腫瘍病理検討会 2009年11月
  • Naoya Hashimoto; Akihiro Tsuboi; Yasuyoshi Chiba; Shuichi Izumoto; Yoshihiro Oka; Toshiki Yoshimine; Haruo Sugiyama
    Brain and Nerve 61 7 805 - 814 2009年07月 [査読有り]
     
    In this paper, we review the current status of immunotherapy targeting Wilms' tumor 1 (WT1) peptide in malignant brain tumors as well as in other hematological and solid malignancies. WT1 is expressed in various kinds of malignancies, and is involved in oncogenesis. The titers of antibodies against WT1 and the frequency of WT1-specific cytotoxic T lymphocytes (CTLs) were higher in cancer patients than in healthy donors, indicating that WT1 protein has immunogenic function. These findings provided us with a rationale for developing cancer immunotherapy that targets the WT1 peptide. Clinical trials of the WT1 peptide vaccination were initiated, and definite immunological and clinical responses were observed. The disease control rate of 57.1% was obtained especially in the case of recurrent glioblastomas, with a median progression-free survival period of 20.0 weeks and progression-free survival rate at 6 months of 33.3%. The trial showed that WT1 vaccination for malignant gliomas, which is generally believed to be an intractable disease, was safe and elicited a favorable clinical response. Further clinical studies of WT1 vaccination in patients with malignant gliomas as well as other cancers are warranted. An enhancement of the efficacy of WT1 vaccination can be expected with a combined treatment using the WT1-specific helper peptide or anti-cancer chemotherapeutic agents. Administration of WT1 vaccination along with other therapeutic modalities during initial treatment or in the case showing minimal residual disease may prolong the survival time of the cancer patients.
  • Tetsuo Hashiba; Naoya Hashimoto; Shuichi Izumoto; Tsuyoshi Suzuki; Naoki Kagawa; Motohiko Maruno; Amami Kato; Toshiki Yoshimine
    JOURNAL OF NEUROSURGERY 110 4 675 - 684 2009年04月 [査読有り]
     
    Object. Due to advances in neuroimaging and the increasing use of imaging to screen for brain disease ("brain checkups"), meningiomas are now often detected as an incidental finding. The natural history of these asymptomatic meningiomas remains unclear, however. In this study, the authors investigated the natural history and growth pattern of incidentally detected meningiomas using serial volumetric assessment and regression analysis. Methods. In 70 patients with incidentally discovered meningiomas who underwent follow-Lip for longer than 1 year, tumor volumes were calculated volumetrically at each follow-up visit, and tumor growth was determined. In patients with tumor growth, regression analysis was performed to determine the pattern of growth. Results. Forty-four tumors exhibited growth and 26 did not. In a regression analysis, 16 of the tumors that grew followed an exponential growth pattern and 15 exhibited linear growth patterns. The presence of calcification was the only imaging characteristic that significantly distinguished the group with tumor growth from that without, although no radiological characteristics significantly distinguished the exponential growth group from the linear growth group. Two patients with obvious tumor growth underwent surgical removal and the pathological specimens extracted showed a high proliferative potential. Conclusions. The authors found that incidentally discovered meningiomas did not always follow an exponential growth pattern but often exhibited more complex patterns of growth. Serial monitoring of tumor volumes and regression analysis may reveal the growth pattern of incidental meningiomas and provide information useful for determining treatment strategy. (DOI: 10.3171/2008.8.JNS08481)
  • Manabu Kinoshita; Shuichi Izumoto; Naoya Hashimoto; Haruhiko Kishima; Naoki Kagawa; Tetsuo Hashiba; Yasuyoshi Chiba; Toshiki Yoshimine
    BRAIN TUMOR PATHOLOGY 25 2 73 - 78 2008年11月 [査読有り]
     
    Two distinct forms of malignant lymphomas can invade the central nervous system (CNS). Although primary CNS malignant lymphomas (PCNSMLs) invade the brain parenchyma, intravascular lymphomas (IVLs) form tumor cell aggregates in the vasculature and produce stroke-like symptoms and cognitive impairment. Although the tumor cells are mostly of B-cell origin in both types of lymphoma, their biological behavior is different, and the detailed mechanism(s) underlying this difference are not well understood. We studied the expression level of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and integrin-beta 1 in tumor tissue samples from patients with primary CNS lymphoma (n = 8) and intravascular lymphoma (n = 2) using immunohistochemical analysis. We also assessed the expression of the matrix metalloproteinases (MMP)-2 and MMP-9. ICAM-1 was positive in six and integrin-beta 1 was positive in seven patients among eight PCNSML patients. MMP-2 and MMP-9 were expressed in all PCNSML. In contrast, none of them was positive in both IVL cases. Our findings suggest that adhesion molecules and MMPs are essential for malignant lymphoma cell invasion from the vasculature into the brain parenchyma and that they may be the key determinants for malignant lymphoma cells to behave as PCNSML or IVL cells.
  • Manabu Kinoshita; Naoya Hashimoto; Tetsu Goto; Naoki Kagawa; Haruhiko Kishima; Shuichi Izumoto; Hisashi Tanaka; Norihiko Fujita; Toshiki Yoshimine
    NEUROIMAGE 43 1 29 - 35 2008年10月 [査読有り]
     
    A noninvasive technique for assessing tumor tissue characteristics is required to assist preoperative surgical planning for malignant brain tumors. Preoperative information on tumor cell density within a tumor would help better define the target for tumor biopsy, resulting in more accurate diagnosis and grading of malignant brain tumors. One possible source of this information is diffusion tensor imaging (DTI), although to date studies have focused on its ability to delineate white matter fiber tracks by fiber-tracking and to detect tumor infiltration around the tumor and normal white matter interface. However, the use of DTI for providing information on cell density has also been examined, although with the controversial results. In addition the exact relationships between cell density and the two key values that DTI provides, namely fractional anisotropy (FA) and mean diffusivity (MID), still need to be investigated. In the present study we performed a retrospective investigation of tumor cell density and FA and MD values in biopsy cases. We found that FA has a good positive correlation (R=0.75) and MD has a good negative correlation (R=0.70) with tumor cell density within the tumor core. Similar correlation was observed between the Ki-67 labeling index and FA (R=0.71) and MD (R=0.62). Thus, measurement of both FA and MD within the tumor core has a potential to provide detailed information on tumor cell density within the tumor. Although data obtained from DTI should be interpreted carefully and comprehensively with other imaging modalities such as positron emission tomography, DTI seems to be informative for planning the best biopsy target containing the highest cell density. (C) 2008 Elsevier Inc. All rights reserved.
  • Shuichi Izumoto; Akihiro Tsuboi; Yoshihiro Oka; Tsuyoshi Suzuki; Tetsuo Hashiba; Naoki Kagawa; Naoya Hashimoto; Motohiko Maruno; Olga A. Elisseeva; Toshiaki Shirakata; Manabu Kawakami; Yusuke Oji; Sumiyuki Nishida; Satoshi Ohno; Ichiro Kawase; Jun Hatazawa; Shin-icih Nakatsuka; Katsuyuki Aozasa; Satoshi Morita; Junichi Sakamoto; Haruo Sugiyama; Toshiki Yosihmine
    JOURNAL OF NEUROSURGERY 108 5 963 - 971 2008年05月 [査読有り]
     
    Object. The object of this study was to investigate the safety and clinical responses of immunotherapy targeting the WT1 (Wilms tumor 1) gene product in patients with recurrent glioblastoma multiforme (GBM). Methods. Twenty-one patients with WTI/HLA-A*2402-positive recurrent GBM were included in a Phase 11 clinical study of WT1 vaccine therapy. In all patients, the tumors were resistant to standard therapy. Patients received intradermal injections of an HLA-A*2402-restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was obtained by measuring the contrast-enhanced area on magnetic resonance images, was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST) 12 weeks after the initial vaccination. Patients who achieved ail effective response continued to be vaccinated until tumor progression occurred. Progression-free survival and overall survival after initial WT1 treatment were estimated. Results. The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: partial response in 2 patients, stable disease in 10 patients, and progressive disease in 9 patients. No patient had a complete response. The overall response rate (cases with complete or partial response) was 9.5%, and the disease control rate (cases with complete or partial response as well as those in which disease was stable) was 57.1%. The median progression-free survival (PFS) period was 20.0 weeks, and the 6-month (26-week) PFS rate was 33.3%. Conclusions. Although a small uncontrolled nonrandomized trial, this study showed that WT1 vaccine therapy for patients with WT1 /HLA-A*2402-positive recurrent GBM was safe and produced a clinical response. Based on these results, further clinical studies of WT1 vaccine therapy in patients with malignant glioma are warranted.
  • 髄芽腫治療における外科治療の影響と役割について
    香川 尚己; 千葉 泰良; 橋本 直哉; 泉本 修一; 太田 秀明; 橋井 佳子; 時政 定雄; 吉峰 俊樹
    小児がん 44 プログラム・総会号 250 - 250 (NPO)日本小児がん学会 2007年12月
  • 穿頭による定位的生検術の診断率と危険性についての検討
    有田 英之; 橋本 直哉; 木下 学; 香川 尚己; 貴島 晴彦; 泉本 修一; 馬淵 英一郎; 吉峰 俊樹
    日本脳神経外科学会総会CD-ROM抄録集 66回 3K - 7 (一社)日本脳神経外科学会 2007年10月
  • Shinya Morita; Michio Otsuki; Maki Izumi; Nobuyuki Asanuma; Shuichi Izumoto; Youichi Saitoh; Toshiki Yoshimine; Soji Kasayama
    EUROPEAN JOURNAL OF ENDOCRINOLOGY 157 3 265 - 270 2007年09月 [査読有り]
     
    Objective: Hypoglycemia induces rapid secretion of counterregulatory hormones such as catecholamine. glucagon, cortisol, and GH. Insulin-induced hypoglycemia is used for evaluating GH-IGF-I and ACTH-adrenal axes in patients with pituitary disorders. The aim of this study was to determine whether the response of catecholamine secretion to hypoglycemia is disrupted in patients with pituitary adenoma. Methods: The study population comprised 23 patients with pituitary adenoma (non-functioning adenoma or prolactinoma). An insulin tolerance test was performed and serum catecholamines as well as plasma GH and serum cortisol were measured. Results: The study patients showed diminished response of plasma epinephrine to insulin-induced hypoglycemia. With the cutoff level of peak epinephrine for defining severe impairment set at 400 pg/ml, more patients with secondary adrenal insufficiency showed severe impairment of the epinephrine response than did those without it. Peak epinephrine levels to insulin-induced hypoglycemia were significantly correlated with peak cortisol levels. In patients with secondary hypothyroidism, secondary hypogonadism, GH deficiency, or diabetes insipidus, the prevalence of severe impairment of the epinephrine response was similar to that in patients without these deficiencies. Conclusions: Impaired epinephrine secretion in response to insulin-induced hypoglycemia was frequently observed in patients with pituitary adenoma. This disorder was especially severe in patients with secondary adrenal insufficiency.
  • 胎生マウス脳・脊髄におけるWilms' tumor(WT1)蛋白の発現
    香川 尚己; 小山 佳久; 丸野 元彦; 泉本 修一; 橋本 直哉; 鈴木 強; 羽柴 哲夫; 遠山 正彌; 吉峰 俊樹
    Brain Tumor Pathology 23 Suppl. 101 - 101 日本脳腫瘍病理学会 2006年06月
  • S Morita; Y Oka; A Tsuboi; M Kawakami; M Maruno; S Izumoto; T Osaki; T Taguchi; T Ueda; A Myoui; S Nishida; T Shirakata; S Ohno; Y Oji; K Aozasa; J Hatazawa; K Udaka; H Yoshikawa; T Yoshimine; S Noguchi; Kawase, I; SI Nakatsuka; H Sugiyama; J Sakamoto
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 36 4 231 - 236 2006年04月 [査読有り]
     
    Objective: We conducted a phase I study to investigate the safety of a weekly WT1 tumor vaccine therapy in patients with solid tumors that had been refractory to all other anti-cancer therapies. Methods: Skin-test-negative patients were intradermally injected weekly for 12 weeks with 3.0 mg of an HLA-A(*)2402-restricted modified 9-mer WT1 peptide emulsified in Montanide ISA51 adjuvant. We estimated the Bayesian posterior probability of the occurrence of grade 3 or 4 toxicity when receiving the weekly WT1 vaccination. This analysis provided the basis for making a decision to terminate the phase I study and switch to phase II. Moreover, we performed an exploratory assessment of the anti-tumor effects of WT1 treatment. Results: Ten patients received 114 vaccinations with WT1 on a weekly schedule. No grade 3 or 4 toxicities were observed. Based on the Bayesian approach, it was highly likely that the probability of grade 3 or 4 toxicity was below 20% (the posterior probability = 0.914). Fifteen grade 2 and two grade 1 toxicities were observed; all of these incidents, however, were determined by the Independent Data and Safety Monitoring Committee to be unrelated to the WT1 treatment. One patient exhibited a partial response; five additional patients had stable disease while receiving weekly WT1 treatment. Conclusion: This paper confirms that the potential toxicities of the treatment schedule of weekly WT1 vaccination are acceptable and suggested a potential anti-tumor effect. Consequently, we validated the decision to continue to the phase II trial.
  • S Oshino; Y Saitoh; S Kasayama; N Arita; T Ohnishi; H Kohara; S Izumoto; T Yoshimine
    ENDOCRINE JOURNAL 53 1 125 - 132 2006年02月 [査読有り]
     
    We reviewed the cases of 32 patients with growth hormone (GH)-secreting rnacroadenoma who underwent short-term octreotide treatment before transsphenoidal surgery to determine which types of adenoma the preoperative treatment were sensitive and whether predictors of tumor shrinkage could be identified. The effects of preoperative octreotide treatment, endocrinologic effect and effect on tumor volume in 32 patients were evaluated retrospectively in relation to tumor features on magnetic resonance images and responses to endocrinologic challenge tests. At a daily dose of 300 mu g for 2-3 weeks, octreotide reduced serum GH and insulin-like growth factor-1 (IGF-1) levels to 31.9% and 51.6% of pretreatment values, respectively, and led to a mean tumor volume of 68% of pretreatment volume in 52% of the patients. The endocrinologic effect and the effect on tumor volume were larger in Knosp grades 0-2 than in Knosp grades 3-4. Tumor shrinkage occurred significantly more often among patients that had a good response to both octreotide and bromocriptine challenge tests. For surgical removal of the tumor, the effect of reducing tumor to 68% of pretreatment volume will be beneficial for the macroadenomas of Knosp grades 1-2. Preoperative short-term octreotide treatment is effective for GH-secreting macroadeomas of Knosp grades 1-2 and a good response to both octreotide and bromocriptine challenge tests is a predictor of subsequent tumor shrinkage. These results will lead to more effective selection of patients for preoperative octreotide treatment.
  • Naoki Kagawa; Motohiko Maruno; Tsuyoshi Suzuki; Tetsuo Hashiba; Naoya Hashimoto; Shuichi Izumoto; Toshiki Yoshimine
    BRAIN TUMOR PATHOLOGY 23 1 41 - 47 2006年 [査読有り]
     
    Medulloblastoma (MB) is the most frequent infratentorial malignant brain tumor in children. In contrast, primitive neuroectodermal tumor (PNET) is defined as a supratentorial malignant tumor generated from the cerebral hemisphere. These tumors have considerable histological overlap but have different clinical outcomes including overall survival period, recurrence rate, and chemosensitivity. We investigated the amplification and/or deletion of genes and the chromosomal gain and/or loss in 10MBs and 3 PNETs with a genomic DNA microarray system. Genes that are frequently amplified in these both these tumors include MSH2, N-myc, AKT3, and EGFR. Amplifications of SNRPN, MYB, and PTEN are observed only in MB. The genes associated with Wnt/APC and Shh/PTCH pathways also have some aberrations. Common chromosomal aberrations include gains at 17q and 7q and losses at 17p. Minor chromosomal losses were also detected at 1p, 8p + q, 11p, 10p + q, 13q, 16q, and Xp + q in MB. SPNETs tend to contain fewer chromosomal and genetic abnormalities than MBs. In conclusion, there are gene expression and chromosomal differences between MBs and SPNETs. These differences may correlate with the prognosis.
  • Tetsuo Hashiba; Naoya Hashimoto; Motohiko Maruno; Shuichi Izumoto; Tsuyoshi Suzuki; Naoki Kagawa; Toshiki Yoshimine
    BRAIN TUMOR PATHOLOGY 23 1 49 - 54 2006年 [査読有り]
     
    We investigated the feasibility of using radiologic characteristics to predict the proliferative potential in meningiomas. Our statistical analysis revealed that the presence of peritumoral edema, an ambiguous brain-tumor border, and irregular tumor shape were significantly correlated with a higher MIB-1 staining index (SI) value. We developed the following scoring system for specific features in each tumor: peritumoral edema (tumor with edema = 1, tumor without edema = 0); brain-tumor border (tumor with any ambiguous border = 1, tumor circumscribed by a distinct rim = 0); and tumor shape (tumor with irregular shape = 1, tumor with smooth shape = 0). Using Spearman's correlation coefficient analysis, we found a significant correlation (P < 0.005) between total score calculated for each patient and SI value. Our findings suggest that the proliferative potential of meningiomas can be predicted using a less invasive preoperative examination focusing on the presence of peritumoral edema, ambiguous brain-tumor border, and irregular tumor shape.
  • K Wada; M Maruno; T Suzuki; N Kagawa; T Hashiba; Y Fujimoto; N Hashimoto; S Izumoto; T Yoshimine
    NEUROLOGICAL RESEARCH 27 7 747 - 754 2005年10月 [査読有り]
     
    Background: Meningioma is the commonest brain tumor and many genetic abnormalities, such as the loss of chromosome 22q and the mutation of NF2, have been reported. Methods: These classical abnormalities were detected using Southern blot, PCR, fluorescence in situ hybridization and comparative genomic hybridization, but these methods examine only very, we used DNA limited regions or limited mapping resolution of the tumor genome. In this stud microarray assay, which detects numerous genetic abnormalities simultaneously and analyses a global assessment of molecular events in meningioma cells. We studied 31 meningiomas by GenoSensorArray 300 in order to detect the chromosomal aberrations and genetic abnormalities in the whole genome. Results: This study demonstrated not only classical chromosomal aberration, such as loss of chromosome 22q in 19 meningiomas (61.3%), but also new genetic characteristics of meningiomas, such as amplification of MSH2 in 16 meningiomas (57.69%), deletion of GSCL in 13 meningiomas (41.9%) and deletion of HIRA in seven meningiomas (22.6%). Conclusions: These results suggest that DNA microarray assay is useful in research for the genetic characters of meningiomas and understanding tumorigenesis.
  • T Suzuki; S Izumoto; K Wada; Y Fujimoto; M Maruno; M Yamasaki; Y Kanemura; T Shimazaki; H Okano; T Yoshimine
    JOURNAL OF NEURO-ONCOLOGY 74 3 233 - 239 2005年09月 [査読有り]
     
    Neural stem cells (NSC) have unique differentiation-, proliferation-, and motility properties. To investigate whether they secrete factors that interfere with the proliferation of glioma cells, we grew glioma cells in conditioned medium (CM) obtained from cultures of neurospheres including neural stem / progenitor cells (NSPC) isolated from embryonic (E14)- or adult mouse brain or fetal human brain. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and BrdU-labeling assays showed that CM from NSPC (NSPC/CM) contained factor(s) that inhibited the proliferation of glioma cells by 28-87%. Filter-fractionation of NSPC/CM revealed that the 50,000-100,000 nominal molecular weight limit (NMWL) fraction contained the inhibitory activity. On the basis of these observations we transplanted 203G glioma cells and/or NSPC into the intrathecal space of the cisterna magna of mice to investigate whether NSPC interfere with the proliferation of glioma cells in vivo. Mice transplanted with both 203G and NSPC survived significantly longer than did mice transplanted only with 203G. We concluded that NSPC secrete factor(s) that may control glioma cell proliferation.
  • Izumoto S; Yoshimine T
    Nihon rinsho. Japanese journal of clinical medicine 63 Suppl 9 74 - 78 2005年09月 [査読有り]
  • S Izumoto; T Suzuki; M Kinoshita; T Hashiba; N Kagawa; K Wada; Y Fujimoto; N Hashimoto; Y Saitoh; M Maruno; T Yoshimine
    SURGICAL NEUROLOGY 63 6 520 - 525 2005年06月 [査読有り]
     
    Background: Although craniopharyngiomas have a histologically benign nature, their treatment can be difficult. The correlation among clinical, proliferative, and immumohistologic features of female sex hormone receptors was determined in craniopharyngiomas to analyze whether they influence the growth of the tumor. Methods: The study subjects were 43 patients with previously untreated craniopharyngioma who underwent surgery at our department over the past 15 years. Serial tissue sections were immunostained with the antibodies against estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Results: The Ki-67 labeling index was significantly higher in patients with regrowth (7.8%) than without regrowth (3.9%). ER and PR were detected in 9 of 30 (30%) craniopharyngiomas, and the incidence of postoperative tumor regrowth was significantly higher in patients negative for ER and PR (29%) than in those positive for both receptors (11%). Conclusions: A high Ki-67 labeling index suggests a high possibility of tumor regrowth, and the presence of ER and PR is suggestive of a high tissue differentiating potential. ER and PR assay may be useful for determining the indication for additional radiation therapy in cramopharyngioma patients treated by incomplete resection. (c) 2005 Elsevier Inc. All rights reserved.
  • S Moriuchi; JC Glorioso; M Maruno; S Izumoto; D Wolfe; SH Huang; JB Cohen; T Yoshimine
    CANCER GENE THERAPY 12 5 487 - 496 2005年05月 [査読有り]
     
    To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOI kappa B expressing both HSV-TK and a mutant form of the NF-kappa B inhibitor I kappa B alpha (I kappa B alpha M) was developed. TO kappa kB was constructed by recombining the I kappa B alpha M gene into the U(L)41 locus of a replication-defective lacZ expression vector, TOZ.1. Expression of I kappa B alpha M was confirmed by Western blotting, and the ability of the mutant protein to inhibit NF-kappa B nuclear translocation was examined by electrophoretic mobility shift assay. In human glioblastoma U-87MG cells, the p50/p50 dimer of NF-kappa B was already translocated to the nucleus without receptor-dependent signaling by TNF-alpha. Following infection with TOI kappa B, nuclear translocation of NF-kappa B in U-87MG cells was significantly inhibited and caspase-3 activity increased compared with TOZ.1-infected cells. The cytotoxicity of TOI kappa B for U-87MG cells was investigated by colorimetric MTT assay. At an MOI of 3, TOI kappa B infection killed 85% of the cells compared to 20% killed by TOZ.1 infection. In the presence of GCV, these numbers increased to 95-100% for TOI kappa B and 80-85% for TOZ.1. TOI kappa B neurotoxicity measured on cultured murine neurons was relatively low and similar to that of TOZ.1. The survival of nude mice implanted into the brain with U-87MG tumor cells was markedly prolonged by intratumoral TOI kappa B injection and GCV administration. Survival of TOI kappa B+GCV group was significantly longer (P<.02, Wilcoxon test) than for the control groups (TOZ.1 or TOI kappa B only, PBS or PBS+GCV). These results suggest that I kappa B alpha M expression may be a safe enhancement of replication-defective HSV-based suicide gene therapy in vitro and in vivo.
  • T Yoshimine; N Hashimoto; M Maruno; S Izumoto; A Kato
    Proceedings of the 13th World Congress of Neurological Surgery, Vols 1 and 2 619 - 622 2005年 [査読有り]
     
    We tried to remove gliomas involving the primary motor cortex applying recent techniques of presurgical functional mapping, intraoperative navigation, direct cortical stimulation and awake anesthesia. Eight lesions were operated in 7 patients. The lesions were removed gross totally in 3 cases and subtotally/partially in 2 cases. Although removal may be associated withsome weakness immediately after surgery, it is only transient. Lesions were, however, not removed in 2 cases because preceding biopsy caused apparent, but temporary weakness and histologic examination demonstrated the involvement of neural tissue.
  • M Kinoshita; S Izumoto; N Kagawa; N Hashimoto; M Maruno; T Yoshimine
    NEUROLOGIA MEDICO-CHIRURGICA 44 12 669 - 673 2004年12月 [査読有り]
     
    An 11-year-old Japanese girl presented with a right frontal lobe anaplastic ependymoma. The tumor was removed surgically. However, she developed a secondary lesion and extracranial metastasis in the cervical lymph node. In total, she underwent eight intracranial tumor removal procedures, five stereotactic radiosurgeries with six targets, and five cervical lymph node removal surgeries during the course of 7 years. She is currently alive with a good quality of life, and has no major neurological deficits except right facial nerve palsy. The combination of surgery and radiosurgery can achieve local control of anaplastic ependymoma. Multiple surgery or radiosurgery procedures can result in good outcome, if the tumor does not involve crucial structures, even if extracranial metastasis occurs.
  • S Izumoto; T Ohnishi; S Hirano; S Hiraga; N Arita
    RESTORATIVE NEUROLOGY AND NEUROSCIENCE 12 4 247 - 254 1998年09月 [査読有り]
     
    Neural cell adhesion molecule L1 is a member of the immunoglobulin superfamily; it plays an important role in neurite outgrowth in vitro. We present evidence that the transected optic nerve in adult rats was promoted to regenerate by transplanted L1-expressing cells that were embedded in the Matrigel matrix. To obtain the maximum effects, a very careful operative procedure by which both stumps remained attached and the blood supply was preserved was essential. Visual evoked potential was partially recovered and traced fibers were seen to pass through the lesion site 7 weeks after optic nerve transection. Immunohistochemical analysis demonstrated that neurofilament-positive fibers were present around the site of experimental lesion. Our in vivo study demonstrated that L1 promoted the regeneration of the lesioned optic nerve in rats under strictly controlled environmental conditions.
  • S Izumoto; N Arita; T Ohnishi; S Hiraga; T Taki; N Tomita; M Ohue; T Hayakawa
    CANCER LETTERS 112 2 251 - 256 1997年01月 [査読有り]
     
    Microsatellite instability has been reported in familial cancer syndrome and in various kinds of human sporadic tumors. We investigated the replication error (RER) and mutation rate of the transforming growth factor-beta type II receptor (TGF-beta RII) gene to determine the frequency of the RER+ phenotype and elucidate the relation between the mutation of the TGF-beta RII gene and RER in the tumorigenesis of glioma. We screened genomic DNA from 40 gliomas, comprised from 24 glioblastomas (GB), 11 anaplastic astrocytomas (AA) and five astrocytomas (AS) and compared the results with DNA from corresponding leukocytes. Seven of the 40 (18%) gliomas had the RER+ phenotype: five (21%) of 24 GB and two (18%) of 11 AA. In six gliomas we detected mutation of the TGF-beta RII gene. Five (71%) of seven RER+ and one (3%) of 33 RER- tumors had one A deletion in the (A)(10) repeat of the TGF-beta RII gene. No mutations were detected in the (GT)(3) repeat area of the TGF-beta RII gene. As the normal cells of these glioma patients had no mutations, we concluded that the mutations were somatic. We posit that the observed mutations inactivate the receptor through a frameshift mutation resulting in protein truncation. Our data suggest that the TGF-beta RII (A)(10) repeat may be one area of genomic instability in the early stages of malignant glioma tumorigenesis. (C) 1997 Elsevier Science Ireland Ltd.
  • S Izumoto; N Arita; T Ohnishi; S Hiraga; T Taki; T Hayakawa
    BRAIN TUMOR 103 - 107 1996年 [査読有り]
  • S Izumoto; N Arita; T Ohnishi; S Hiraga; T Taki; T Hayakawa
    BRAIN TUMOR 263 - 268 1996年 [査読有り]
  • T Ohnishi; S Izumoto; N Arita; S Hiraga; T Taki; T Hayakawa
    BRAIN TUMOR 109 - 118 1996年 [査読有り]
  • H. Yamamoto; N. Arita; T. Ohnishi; S. Hiraga; S. Izumoto; T. Taki; M. Higuchi; T. Hayakawa; H. Shinkai
    Japanese Journal of Cancer and Chemotherapy 20 9 1227 - 1230 1993年 [査読有り]
  • H. Nakagawa; S. Kimura; Y. Nakajima; S. Izumoto; T. Hayakawa
    Neurological Surgery 20 2 115 - 121 1992年 [査読有り]
  • H. Nakagawa; A. Murasawa; S. Nakajima; Y. Nakajima; S. Izumoto; S. Kubo; T. Hayakawa
    Neurological Surgery 20 1 31 - 37 1992年 [査読有り]
  • H. Nakagawa; S. Kubo; A. Murasawa; S. Nakajima; Y. Nakajima; S. Izumoto; T. Hayakawa
    Neurological Surgery 19 12 1135 - 1141 1991年 [査読有り]
  • S. Izumoto; N. Arita; T. Hayakawa; T. Ohnishi; S. Hiraga; T. Taki; H. Yamamoto
    Japanese Journal of Cancer and Chemotherapy 18 3 371 - 375 1991年 [査読有り]
  • T. Taki; N. Arita; T. Hayakawa; H. Yamamoto; S. Izumoto; T. Oonisi; H. Mogami
    Brain and Nerve 41 11 1065 - 1070 1989年 [査読有り]
  • 奥 謙; 呉 淳東; 村沢 明; 斉藤 洋一; 泉本 修一
    脳卒中の外科 16 2 103 - 106 一般社団法人 日本脳卒中の外科学会 1988年 
    Materials hitherto used for wrapping intracranial aneurysms failed to prevent early and late recurrent hemorrhage. This is probably because the mechanical strength of these materials is insufficient to reinforce the aneurysmal wall. To obtain early as well as long term prevention of bleeding, we have been using a Dacron fabric to wrap the aneurysms.
    So far five aneurysms at various locations (three at the IC, two blister-like, non-ruptured and one fusiform, non-ruptured, one at the MCA bifurcation, non-ruptured, and one at the vertebral artery fusiform, ruptured) have been wrapped. Although the follow-up periods are short,-the longest one being two and a half years -the patients are all doing well with no hemorrhage. The Dacron fabric which has been commonly used in cardiovascular surgery is rather inelastic and the cut end does not come loose. So it was thought that this material would have sufficient toughness to reinforce the aneurysmal wall as long as it made contact with the wall or pressed against it after the wrapping was completed. But since the Dacron fabric is slightly hard and thick (0.5mm thick), there were some difficulties in manipulating it during the operative procedure. At the end of wrapping, the free ends of the Dacron fabric were approximated and closed with Sugita's clips. For this purpose "L" shaped clips with blades which open parallel to each other were used because other types of clips did not close at the tips due to the thickness of the Dacron fabric.
    Occasionally sutures or Weck's clips were required to close the Dacron fabric.
  • S. Izumoto; N. Arita; Y. Ushio; T. Hayakawa; T. Yoshimine; H. Tzuu-Yuan; R. Kuroda; H. Mogami
    Brain and Nerve 40 2 127 - 131 1988年 [査読有り]
     
    We have developed an experimental model of leptomeningeal tumor by inoculating Walker 256 carcinosarcoma cells into the cisterna magna of rats. This model was considered to be useful in studying pathophysiology and treatment of malignant brain tumors. In this study, the growth kinetics of this experimental tumor was investigated by using the immunohistochemical technique with an anti-BrdU monoclonal antibody. Walker 256 carcinosarcoma was subcutaneously passaged in female Wistar rats. Seven days after subcutaneous inoculation, the tumor was aseptically removed and minced in Hank's medium by scissors to make single cell suspension of the tumor. The cell suspension was adjusted to 1 x 105 cells/ml. And 0.1 ml was inoculated percutaneously into the cisterna magna of female Wistar rats weighing 150 gr. Every day after tumor inoculation, the animal (5 on each day) was sacrificed 30 minutes after intravenous BrdU (200 mg/kg) and perfused by saline. Then, the brain was removed, fixed in ethanol and embedded in paraffin. Coronal sections of the brain 6 μ in thickness were cut and stained by the indirect immunoperoxidase (ABC) method. The anti-BrdU monoclonal antibody (Becton-Dickinson) was diluted in 1 : 100. The sections were counterstained by hematoxylin. Labelling index (L.I.) of the tumor was obtained by counting immunoreactive cells under the microscope. L.I. of the subcutaneous tumor 7 days after inoculation was 52.4%. In the tumor 1 to 3 days after inoculation, L.I. was still low and between 11.9 and 15.1%. Four or 5 days after inoculation, the tumor cells grew in several layers in the subarachnoid space. L.I. at this stage of the tumor growth was 26.6 to 34.8%. Six to 9 days after tumor inoculation, the massive tumor was growing in the subarachnoid space, and L.I. reached 37.9 to 47.7%. Ten days after inoculation, the tumor became necrotic in part and had a lower L.I. of 31.7%. Thus, in this experimental tumor, L.I. began to increase 4 to 5 days after tumor inoculation. Therefore, it is considered that the tumor entered the exponential stage of the growth at the relatively early time after inoculation in this experimental tumor. Between 6 and 9 days after inoculation, L.I. reached a plateau and was almost the same as that of the subcutaneous tumor. It is possible that the immunohistochemical method using the anti-BrdU monoclonal antibody in our experimental model of the leptomeningeal tumor can be used as a topographical drug sensitivity test of various antineoplastic agents.
  • N. Arita; Y. Ushio; T. Hayakawa; S. Izumoto; T. Y. Huang; H. Yamamoto; S. Bitoh; H. Mogami
    Brain and Nerve 40 6 575 - 579 1988年 [査読有り]
     
    A monoclonal antibody (Amersham) to epidermal growth factor receptor (EGFR) was used for immunohistochemical study to confirm the presence of EGFR in the glioma tissue. Fresh surgical material was stored at -80°C, and frozen sections were stained. Positive staining was demonstrated in 8 of 9 gliomas. In 2 of 8, more than 50% of tumor cells were positively stained. In 4 of 8, positive cells were seen scattered in the tissue. In the remaining 2 gliomas, few tumor cells were positively stained. The most representative staining was seen on the cytoplasmic membrane. But there were also nuclear and cytoplasmic stainings. The distribution of EGFR in the glioma cells suggests possible role of the epidermal growth factor in the proliferation of gliomas.
  • S. Izumoto; N. Arita; Y. Ushio; T. Hayakawa; T. Yoshimine; H. Tzuu-Yuan; M. Nagatani; Y. Oku; H. Mogami
    Brain and Nerve 40 11 1095 - 1099 1988年 [査読有り]
  • Y. Saitoh; T. Ikeda; S. Izumoto; Y. Ushio; M. Miyamoto; H. Mogami
    Brain and Nerve 38 10 987 - 991 1986年 [査読有り]

MISC

受賞

  • 2006年 第65回社団法人日本脳神経外科学会総会優秀ポスター賞
  • 1997年 第5回「星野賞」
  • 1997年 第6回日本脳腫瘍カンファレス「星野賞」
     JPN

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 泉本 修一; 加藤 天美; 奥田 武司; 藤田 貢
     
    マウス脳腫瘍モデルおよびヒト神経膠腫において、グレード2/3神経膠腫に対するWT1ワクチン治療の開発を検討した。担脳腫瘍マウス脳では、限局性にCD4およびCD8陽性の免疫担当細胞を評価した。ヒトグレード2/3神経膠腫組織において、腫瘍組織のWT1の発現およびCD4、CD8陽性細胞を同定し、その免疫担当細胞の集族を明らかにした。全ての腫瘍細胞でWT1は発現されていたがグレード2神経膠腫に弱い傾向があった。WT1ペプチド投与下での局所獲得免疫細胞の同定は、投与皮下組織で可能であり長時間の免疫維持が確認された。グレード2/3神経膠腫でもWT1ワクチン治療の有用性が示唆された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 泉本 修一; 友金 祐介; 奥田 武司; 藤田 貢; 加藤 天美
     
    転移性脳腫瘍に対してWT1免疫療法を行う妥当性を、動物モデル研究、ヒト免疫反応の研究を通して、治療前後の細胞性免疫反応を中心に解析した。担脳腫瘍マウスモデルでは、脳腫瘍細胞のWT1発現を確認し、限局性であったが免疫担当細胞の集族を明らかにした。しかしながらWT1ペプチドに治療よる効果発現は軽度であった。ヒトにおいて、乳癌の転移性脳腫瘍に対し分子標的治療時の免疫担当細胞の動態解析を行った。腫瘍細胞表面抗原WT1の発現は軽度でありWT1特異的キラーT細胞の変化も軽度であった。しかしながらWT1ペプチドの投与局所皮下組織においてCD4およびCD8免疫担当細胞が集族していることを確認した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2011年 -2013年 
    代表者 : 泉本 修一; 森 鑑二; 友金 祐介; 有田 憲生
     
    膠芽腫に対してWT1ワクチン療法を行い、WT1免疫獲得効果が高いこと、約6割の有効群と4割の効果の乏しい群に分かれることを明らかにした。テモゾロミド化学療法下でのワクチン治療で血中リンパ球の総量は減少するが、WT1キラーT細胞の頻度はやや上昇しており、化学療法下でも免疫反応は確保されていた。組織でのT細胞は脳腫瘍組織内での集積と、血管周囲での集積に分かれ、WT1が腫瘍細胞だけでなく腫瘍新生血管内皮細胞に発現し、WT1ワクチン治療の攻撃対象となると考えられた。マウスモデル研究では、CD4陽性細胞、CD8陽性細胞の出現がみられたが、Treg細胞出現やinterferonγの発現に差は認めなかった。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2008年 -2010年 
    代表者 : 泉本 修一; 坪井 昭博; 橋本 直哉; 木下 学; 森 鑑二; 友金 祐介
     
    初期化学療法に同期した集学的治療のひとつとしてWT1免疫療法を行う妥当性、安全性および相乗効果を、詳細な免疫担当細胞の機能解析を行い検討した。(1)悪性神経膠腫患者におけるWT1特異的T細胞の割合と数は、テモゾロミド・放射線(TMZ/RT併用療法)の治療前0.196%からTMZ/RT併用療法6週終了後に0.256%と上昇傾向を示した。Treg細胞の割合はWT1療法前が4.83%からTMZ/RT併用療法6週終了後には7.50%と増加したが、絶対数は有意な変化を示さなかった。(2)「悪性神経膠腫に対するテモゾロミド併用WT1ペプチドワクチン療法の第I相臨床多施設共同研究」を平成22年5月から実施した結果、安全性は確保され、併用による有意なリンパ球総数の減少は見られなかった。(3)WT1ペプチド投与よって反応したWT1特異的CD4陽性ヘルパーT細胞からのIFN-γ、IL-10の発現量をRT-PCRにより評価した結果、WT1ペプチドワクチン療法有効群はワクチン投与4週間後から投与終了後にかけてIL-10typeのヘルパーT細胞の反応からIFN-γtypeのヘルパーT細胞の反応にシフトしていた。(4)総括すると、TMZ維持療法中にWT1免疫療法を行っても効果的に抗腫瘍効果が誘導されると考えられた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2007年 -2008年 
    代表者 : 泉本 修一; 橋本 直哉; 貴島 晴彦; 坪井 昭博
     
    WT1ワクチン療法を展開するうえでCD8陽性CTLのみならずWT1腫瘍抗原特異的CD4陽性T細胞(ヘルパーT細胞(Th))の役割を明らかにした。すなわち (1) MHC classⅡ拘束性にマウスWT1特異的CD4陽性T細胞を誘導できるマウスWT1エピトープを同定し、in vivoで、classⅡ拘束性WT1特異CD4陽性T細胞によるWT1特異的CTLの誘導活性化に対する影響、およびそのメカニズム解析を行った。(2)ヒトWT1_<332>ペプチドにより、HLA-DRB1*0405のタイプのみならずHLADRB1*1501、HLA-DRB1*1502、HLA-DRB1*0901のタイプに対しても特異的CD4陽性T細胞の反応が誘導された。WT1_<332>2ペプチドが“promiscuous”に反応するWT1 特異的ヘルパーエピトープであり、今後HLA-class Ⅰ拘束性のWT1ペプチドと組み合わせて、さまざまなHLA-class ⅡタイプでWT1特異的ヘルパーペプチドとしてのがんワクチン療法の相乗効果が考えられた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2007年 -2008年 
    代表者 : 有田 憲生; 泉本 修一; 森 鑑二; 金村 米博; 正札 智子
     
    ヒト成人脳組織、胎児由来性神経幹細胞および各種分化誘導因子による神経系細胞、星細胞系細胞におけるTLR2、TLR4分子の発現は確認されず、中枢神経系正常発生における上記2分子の果たしている役割は明らかにされなかった。ヒト脳腫瘍摘出組織を用いたTLR 分子の発現解析では神経膠腫、脳原発性悪性リンパ腫ともにTLR分子の有意な発現を明らかには同定できず、これら疾患における関与も明らかにされなかった。マウス正常脳、脳stab wound損傷マウスを用いた研究でも損傷に対する組織反応、治癒機転どの時期においてもreactive astrocyteとTLR分子発現の相関を明瞭に示す知見は得られなかった。悪性脳腫瘍に対する免疫療法と自然免疫の関係を調べるため、まずWT1腫瘍抗原特異的CD4陽性T 細胞(ヘルパーT 細胞(Th))の役割を以下のように明らかにした。(1)MHC class II拘束性にマウスWT1特異的CD4陽性T細胞を誘導できるマウスWT1エピトープを同定し、in vivoで class II拘束性WT1 特異的CD4陽性T細胞によるWT1特異的CTLの誘導活性化に対する影響およいそのメカニズム解析を行い、複数のHLAタイプに対して特異的CD4陽性T細胞の反応が誘導されることを確かめた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2005年 -2006年 
    代表者 : 泉本 修一; 橋本 直哉; 丸野 元彦
     
    TAT-PTDとヒト型インターフェロンβ(HuIFN-β)の融合タンパクを作成し、それが血液脳関門を貫通し脳実質内腫瘍細胞に直接到達することにより新規悪性グリオーマの治療法として成立するかどうかを検討した。まず、TAT-PTDならびにHis-tagがHuIFN-βのC末端に付加されるようにRT-PCRを行い、遺伝子配列が一致していることをシークエンスにより確認、それを大腸菌に形質転換させ遺伝子発現、大腸菌の大量培養により発現タンパク質を取得し、それを精製した。13種類の界面活性剤で比べるとSB3-14を持いた可溶化が効率よく、最終的にSB3-14を用いたカラム内リフォールディング、イミダゾールによる溶出を経てSDS-PAGEの結果より可溶化が確認された。すなわちSB3-14を用いたカラム法でのみTAT-PTDとHuIFN-βの融合タンパク(TAT-HuIFN-β)の可溶化が可能であった。コントロールとして、TAT-PTDをHAに融合させたものをラット腹腔内投与した後、その脳組織を免疫染色することにより高濃度でTAT-PTD-HA融合タンパクが脳組織内に移行することを検討し、TAT-PTDは融合タンパクの脳組織内移行手段として確実に有効であることを検証した。つぎにTAT-HuIFN-βの溶解物をラット腹腔内に注射し脳組織内に移行するか否かを検討した。しかしながら、脳組織内には免疫組織学的にあるいは免疫細胞学的に無投与脳とくらべ有意な差をもったHuIFN-βの移行が確認できず、濃度を変えても同様であった。よってTAT-HuIFN-βについては血液脳関門を貫通し脳実質内あるいは脳内腫瘍細胞に直接到達することは困難であり、脳腫瘍治療に応用することは難しいと考えられた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2003年 -2004年 
    代表者 : 泉本 修一; 貴島 晴彦; 丸野 元彦
     
    神経幹細胞は、その分化能のみならず増殖や運動能の面でも特異な性格を有している。我々はこのような性格の解明がグリオーマの治療に新しい展開が開ける可能性を求めた。結果、マウス培養神経幹細胞のconditioned medium(NSC/CM)を用いてグリオーマ細胞を培養すると、その増殖がNSC/CM濃度に依存して抑制されることをMTT assayにより明らかにした。また、NSC/CMの存在下ではグリオーマ細胞の運動能が抑制されることをBoyden Chamber法で明らかにした。その運動抑制作用は、実際の脳環境に近いbrain slice cultureモデルでも証明され、NSC/CM存在下でグリオーマ細胞の拡散や脳切片内深部への細胞浸潤が抑制されることを共焦点レーザーで証明した。以上より、神経幹細胞はグリオーマの増殖や運動に干渉するなんらかの生理活性物質をNSC/CM中に産生することを明らかにした。フィルターを通したところ、NSC/CMの5万から10万MWLの分画にその因子が存在することを明らかにした。高圧クロマトグラフィーでのタンパク抽出精製を行ったが単離するに至らなかった。 次に、培養マウス神経幹細胞をグリオーマ細胞と同時にマウス大槽内に投与すると、神経幹細胞を投与しないコントロール群に比べて投与した群での生存期間は有意に延長し、in vivoでも神経幹細胞からグリオーマの増殖を抑制するなんらかの活性物質が産生されることを明らかにした。以上より、神経幹細胞自体が細胞療法として有用である可能性が示された。 さらにその細胞が細胞増殖抑制因子の運搬担体となることを期待し、IL12発現ベクターを入手しIL12cDNAをGFP発現ベクターに組み込み、神経幹細胞にtransfectさせ、その発現が確認された。これは将来的にはex vivo遺伝子療法としての成果が期待できると考える。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2001年 -2002年 
    代表者 : 泉本 修一; 中辻 裕司; 森内 秀祐
     
    酸性糖シアル酸を持つ糖脂質、ガングリオシドが細胞周期に影響を与えることに注目し、そのなかでGM3がグリオーマ細胞の増殖抑制に有効ではないかと考え検討を行った。その結果、20から200μMの濃度でのGM3投与群はコントロール群に比べ有意にグリオーマ細胞株の増殖を抑制し、抑制度はGM3の濃度に依存した。その結果をもとにC6グリオーマ細胞をラット大槽内に移植し脳腫瘍モデルを作成し、in vivoの検討を行った。GM3投与群では800μMのGM3を移植10日目に大槽内に投与し、グリオーマ細胞移植後のラット生存日数を比較検討した。その結果、コントロール群の平均生存日数は19.5日であったがGM3の大槽内投与群の生存日数は22.0日に延長した(P<0.05)。さらに、その腫瘍細胞増殖抑制作用がGM3投与によるアポトーシス誘導によるものであることがTUNEL法により解明した。脳槽内単回投与では3日目を境にアポトーシス細胞は消退していき、GM3の脳あるいは脳腫瘍内への浸潤効果は限られることが示された。 一方ではグリオーマ細胞の接着浸潤に対する作用の解明を行った。GM3による細胞運動能への作用をBoyden Chamber Assayより求めたところ、GM3の濃度依存性に細胞運動が抑制された。さらに三次元構築脳組織培養モデル(slice culture)に共焦点レーザーを組み合わせ、腫瘍塊から脳組織に浸潤するグリオーマ細胞を経時的に生細胞として捉え、脳内浸潤への影響を明らかにした。その結果GM3が腫瘍増殖抑制のみならず、浸潤能の抑制に働いていることが明らかになった。以上のことより、高濃度のGM3局所投与が、悪性グリオーマに対して増殖、浸潤ともに抑制することがわかり、グリオーマ治療におけるGM3の局所投与は比較的安全でかつ有効な新しい治療方法となる可能性が示唆された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2001年 -2002年 
    代表者 : 吉峰 俊樹; 泉本 修一; 丸野 元彦; 池中 一裕; 森内 秀祐
     
    MAGE-E1a cDNAの塩基配列から予想される蛋白のアミノ酸配列のうち、MAGE-conserved domainを含まないようにしてN末端側、C末端側に14merのペプチドを作成した。これをウサギに免疫してペプチド抗体を作成した。これらの抗体はともに58kDaの単一のバンドを認識した。RT-PCRでMAGE-E1遺伝子が発現していないことが確認できた正常肺組織ではこのバンドは認められなかった。以上の結果より、この58kDaのバンドがMAGE-E1蛋白であると判断した。U87MG細胞より抽出した蛋白分画を用いたウェスタンブロット解析や同細胞を用いた免疫染色の結果、MAGE-E1蛋白は細胞質、特に核の周辺に局在していることが明らかとなった。MAGE-E1とGFPの癒合蛋白をHIH3T3,HEK293細胞に強制発現させて機能解析を試みた。MAGE-E1遺伝子を強制発現させると細胞が死滅したため、MAGE-E1の過剰な発現は細胞障害性があると考えられた。MAGE-E1が悪性グリオーマの増殖に関わっていることを示すために以下の実験を行った。T98G細胞を無血清培地で72時間培養することによって細胞をG0期に入るようにすると、通常の10%FBSで培養したもとと比較してMAGE-E1蛋白の発現は減少した。これらの細胞の免疫染色の結果、蛋白レベルの減少は特定の細胞に起因するものではなく、すべての細胞で一様に減少していた。グリオーマの摘出標本を用いたウェスタンブロット解析の結果、膠芽腫では星細胞腫に比べて蛋白レベルが高かった。また、免疫染色の結果も膠芽種では蛋白発現が高い細胞がびまん性に存在していたが、星細胞腫では発現が比較的高い細胞が散在していた。以上の結果より、MAGE-E1蛋白は悪性グリオーマで発現が上昇しており、グリオーマ細胞の増殖に関与していることが示唆された。
  • 悪性グリオーマの病態解明と治療
  • Molecular Pathological Evaluation of Malignant Brain Tumor

委員歴

  • 2004年   分子脳神経外科学会   世話人   分子脳神経外科学会

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