研究者詳細 - 石田　穣治

論文 - 石田　穣治

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Identification of factors related to functional prognoses in craniopharyngiomas. 国際誌

Tsuyoshi Umeda, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Shuichiro Hirano, Yasuki Suruga, Naoya Kemmotsu, Ryoji Imoto, Yasuhito Kegoya, Ryo Mizuta, Yohei Inoue, Madoka Hokama, Seiichiro Makihara, Kosei Hasegawa, Kenichi Inagaki, Fumio Otsuka, Takao Yasuhara, Shota Tanaka

Journal of neuro-oncology 2025年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Craniopharyngiomas are histologically benign tumors, but their proximity to vital neurovascular structures can significantly deteriorate functional prognoses and severely restrict patients' social interaction and activity. We retrospectively identified risk factors related to the functional prognoses in patients with craniopharyngioma treated at our center. METHODS: A retrospective analysis was conducted on 40 patients who underwent surgery for craniopharyngioma and follow-up at our institution between 2003 and 2022. Functional prognoses were evaluated in terms of obesity (body mass index [BMI] ≥ 25 for adults, BMI-Z ≥ 1.65 for children), visual function, endocrine function, and social participation. We investigated whether patient characteristics, tumor size, tumor location, hypothalamic involvement, surgical hypothalamic damage, extent of resection, and recurrence rate correlated with these functional prognostic factors. RESULTS: The median age at diagnosis was 28.0 years, with a median follow-up of 80.5 months. Postoperative obesity was present in 22 patients, and those with postoperative obesity had a significantly higher preoperative BMI or BMI-Z (preoperative BMI for adults: p = 0.074; preoperative BMI-Z for children: p = 0.020) and were significantly correlated with preoperative hypothalamic involvement grade 2 (p = 0.012) and surgical hypothalamic damage grade II (p = 0.0001). Deterioration in social participation was significantly associated with a larger tumor size (p = 0.023) and tumor recurrence (p = 0.0047). CONCLUSIONS: Patients with higher preoperative BMI or BMI-Z and hypothalamic involvement have a greater risk of postoperative obesity, and larger tumor size and recurrence can significantly deteriorate the rate of patients' social participation.

DOI： 10.1007/s11060-024-04925-7

Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy. 国際誌

Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi

Cancer research 2025年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.

DOI： 10.1158/0008-5472.CAN-24-2274

Comparative analysis of intraoperative MRI and early postoperative MRI findings in glioma surgery patients. 国際誌

Yoshihiro Otani, Fumiyo Higaki, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryoji Imoto, Ryo Mizuta, Yasuhito Kegoya, Yohei Inoue, Tsuyoshi Umeda, Madoka Hokama, Takao Yasuhara, Takao Hiraki, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Shota Tanaka, Isao Date

Journal of neurosurgery 1 - 9 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The extent of resection (EOR) is an important prognostic factor for both low- and high-grade gliomas. Intraoperative MRI (iMRI) has been used to increase the EOR in glioma surgery. While a recent study reported differences between iMRI and early postoperative MRI (epMRI), their specific relationship to postoperative clinical symptoms remains unclear. This study aims to compare the differences between iMRI and epMRI in glioma surgery. METHODS: A retrospective assessment was conducted on 43 patients with glioma who underwent surgery with iMRI and for whom no additional resection was performed after iMRI. The study evaluated the discrepancies in EOR, surgically induced contrast enhancement (SICE), and diffusion-weighted imaging (DWI) abnormality between iMRI and epMRI. EOR was defined as gross-total resection (GTR), near-total resection, subtotal resection (STR), or partial resection (PR) for enhancing lesions, and GTR, STR, or PR for nonenhancing lesions. In addition, the relationship between postoperative neurological findings and iMRI findings was evaluated. RESULTS: Discrepancies in EOR were observed in 2 (11.1%) of 18 cases with nonenhanced lesions and 1 (4.0%) of 25 cases with enhanced lesions. The positive rate of SICE was 25.0% on iMRI and 67.9% on epMRI. Enhancement at the resection cavity was the most frequent pattern in both iMRI and epMRI. The positive rate of enhancement of the resection cavity was strongly increased on epMRI compared with iMRI, potentially mimicking residual tumor. The positive rate of DWI abnormality was 73% on iMRI and 89.2% on epMRI. Among the 10 patients who showed no DWI abnormality on iMRI, 6 exhibited DWI abnormality on epMRI (the late-developing group). Two patients developed new neurological deficits postoperatively, and both showed DWI abnormality on both iMRI and epMRI. No patient in the late-developing group developed postoperative neurological deficits. CONCLUSIONS: Overall, iMRI demonstrated more accurate EOR and less SICE compared with epMRI. Although the positive rate of DWI abnormality was lower on iMRI than on epMRI, the late-developing group showed no postoperative neurological deficits. Therefore, iMRI is more useful in assessing accurate EOR and detecting postoperative neurological deficits than epMRI.

DOI： 10.3171/2024.7.JNS24784

EXTH-04. COMBINATION OF BEVACIZUMAB ENHANCES THE ANTI-TUMOR EFFICACY OF AD-SGE-REIC FOR GLIOMA

Yoshihiro Otani, Yasuhiko Hattori, Atsuhito Uneda, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Joji Ishida, Kentaro Fujii, Yusuke Tomita, Tetsuo Oka, Yuji Matsumoto, Yosuke Shimazu, Hiroyuki Michiue, Kazuhiko Kurozumi, Hiromu Kumon, Isao Date, Shota Tanaka

Neuro-Oncology 26 ( Supplement_8 ) viii236 - viii237 2024年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor gene and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we revealed the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC) and conducted the phase Ⅰ/Ⅱ a clinical trial for recurrent malignant glioma (jRCT2063190013). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic efficacy in patients with glioma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab in vitro and in vivo. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In glioma-bearing mouse models, survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab showed anti-glioma effects by suppressing the angiogenesis and invasion of tumor cells. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.

DOI： 10.1093/neuonc/noae165.0935

TMIC-31. MOLECULAR PROGNOSTIC FACTORS OF THE PROGRESSION OF VESTIBULAR SCHWANNOMA AFTER PRIMARY TUMOR RESECTION

Ryo Mizuta, Keigo Makino, Yoshihiro Otai, Kentaro Fujii, Joji Ishida, Atsuhito Uneda, Nobushige Tsuboi, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryoji Imoto, Yasuhito Kegoya, Madoka Hokama, Ryosuke Ikemachi, Yuji Matsumoto, Yusuke Tomita, Yosuke Shimazu, Hirofumi Inoue, Yuanqing Yan, Ziyi Wang, Mitsuaki Ono, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Takao Yasuhara, Shota Tanaka

Neuro-Oncology 26 ( Supplement_8 ) viii304 - viii305 2024年11月

掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

BACKGROUND

Although vestibular schwannoma is a benign tumor, 10% of the tumor regrow after primary tumor resection. The factors associated with tumor progression from several reports remain controversial, and the role of the tumor microenvironment in vestibular schwannoma is still unclear. In this study, we analyzed the prognostic factors associated with the tumor progression after primary resection.

METHODS

We retrospectively reviewed the medical records of patients who underwent surgical resection and were diagnosed with vestibular schwannoma between January 2005 and June 2020. We performed RNA sequencing to identify the prognostic factors and immunohistochemistry to assess the tumor microenvironment, including analysis of the CD80 and CD206 expression of macrophages. We compared the progressed group whose tumor size got larger than 2mm after primary resection or who underwent additional treatment because of regrowth with the stable group.

RESULTS

Fifty-five patients underwent surgical resection for newly diagnosed vestibular schwannoma, and 12 of them had tumor regrowth. RNA sequencing revealed that the significantly upregulated pathways in the stable group was related to immune systems, while that of the progressed group was related to cell cycle. In addition, there were more myeloid cells, especially M2 macrophage infiltration in the stable group. Immunohistochemistry also showed higher M2 macrophages in the stable group.

CONCLUSION

In this study, multiomic analysis revealed the upregulation of immune-related pathways in the stable group and the cell cycle pathway in the progressed group. Altering the tumor microenvironment may offer a therapeutic strategy in vestibular schwannoma after primary resection.

DOI： 10.1093/neuonc/noae165.1209

Tectal glioma: clinical, radiological, and pathological features, and the importance of molecular analysis.

Ryoji Imoto, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryo Mizuta, Yasuhito Kegoya, Yohei Inoue, Tsuyoshi Umeda, Madoka Hokama, Kana Washio, Hiroyuki Yanai, Shota Tanaka, Kaishi Satomi, Koichi Ichimura, Isao Date

Brain tumor pathology 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tectal glioma (TG) is a rare lower grade glioma (LrGG) that occurs in the tectum, mainly affecting children. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. We conducted a retrospective review of cases clinically diagnosed as TG and treated at our institute between January 2005 and March 2023. Six cases were identified and the median age was 30.5 years. Four patients underwent biopsy and two patients underwent tumor resection. Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. The integrated diagnosis, according to the fifth edition of the World Health Organization Classification of Tumours of the central nervous system, included two cases of PA and one case each of diffuse high-grade glioma; diffuse midline glioma H3 K27-altered; glioblastoma; and circumscribed astrocytic glioma. Among the three patients who underwent molecular evaluation, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation.

DOI： 10.1007/s10014-024-00494-9

New Anti-Angiogenic Therapy for Glioblastoma With the Anti-Depressant Sertraline. 国際誌

Nobushige Tsuboi, Yoshihiro Otani, Atsuhito Uneda, Joji Ishida, Yasuki Suruga, Yuji Matsumoto, Atsushi Fujimura, Kentaro Fujii, Hideki Matsui, Kazuhiko Kurozumi, Isao Date, Hiroyuki Michiue

Cancer medicine 13 ( 20 ) e70288 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications. RESULTS: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. CONCLUSION: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability.

DOI： 10.1002/cam4.70288

中枢神経原発リンパ腫におけるplasmablastサブポピュレーションの分子学的特性について

小林宏紀, 千々松良太, 直井友亮, 大谷理浩, 水田亮, 藤井謙太郎, 石田穣治, 村上裕之, 氏家英貴, 池内一廣, 浦田知宏, 清家圭介, 藤原英晃, 淺田騰, 藤井伸治, 松岡賢市, 佐藤康晴, 前田嘉信, 遠西大輔

日本血液学会学術集会 86回 O3 - 2 2024年10月

脳腫瘍に対する全ゲノム解析(Whole-genome sequencing analysis of brain tumors)

鈴木啓道, 中島拓真, 舟越勇介, 金森政之, 柴原一陽, 鈴木智成, 木下学, 園田順彦, 荒川芳輝, 永根基雄, 田中將太, 石田穣治, 齋藤竜太, 花谷亮典, 吉本幸司, 成田善孝

日本癌学会総会記事 83回 S08 - 3 2024年9月

脳腫瘍の分子診断と治療2 NF1関連グリオーマにおける腫瘍微小環境の解析

駿河和城, 大谷理浩, 松本悠司, 平野秀一郎, 藤井謙太郎, 石田穣治, 柳井広之, 田中將太

Brain Tumor Pathology 41 ( Suppl. ) 100 - 100 2024年5月

【頭蓋頸椎移行部病変】Chiari奇形に対する治療

安原隆雄, 佐々田晋, 石田穣治, 金恭平

脊椎脊髄ジャーナル 37 ( 4 ) 267 - 273 2024年5月

記述言語：日本語出版者・発行元：(株)三輪書店

＜文献概要＞はじめに 2023年12月末日現在,'Chiari malformation'をPubMed検索すると,1938年のAringの報告を皮切りに,5,698件の論文がhitし,2010年以降が2,979件,2023年は314件と,いまだに議論が尽きない病態であることがわかる.Chiari奇形は4型に分類され,成人や小児期に発症することが多く脊髄空洞を半数以上で合併するI型が最も多い.次いで,乳幼児期に発症することが多く,水頭症や脊髄髄膜瘤を合併するII型がそれに続く.本稿では,臨床家が最も遭遇する可能性が高いChiari I型奇形をChiari奇形として以下表記し議論する.外科治療については,谷らが2008年に報告しているように,大孔部減圧術+C1椎弓切除が行われることが多いが,硬膜形成の方法や小脳扁桃切除に関しては,いまだ議論が分かれる部分もある.本稿では,最近の報告からChiari奇形の病態や治療について概説し,私たちの試みについて症例を交えて報告する.

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02317&link_issn=&doc_id=20240530070010&doc_link_id=10.11477%2Fmf.5002202300&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.5002202300&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

当院で経験したDiffuse midline glioma,H3K27-alteredの臨床的特徴

外間まどか, 大谷理浩, 石田穣治, 梅田剛志, 井上陽平, 水田亮, 井本良二, 駿河和城, 劒持直也, 家護谷泰仁, 平野秀一郎, 冨田祐介, 藤井謙太郎, 鷲尾佳奈, 田中將太

小児の脳神経 49 ( 2 ) 209 - 209 2024年4月

頭蓋咽頭腫の神経内分泌機能予後に関する因子の検討

梅田剛志, 大谷理浩, 井上陽平, 外間まどか, 水田亮, 井本良二, 駿河和城, 劒持直也, 家護谷泰仁, 平野秀一郎, 石田穣治, 藤井謙太郎, 安原隆雄, 長谷川高誠, 稲垣兼一, 伊達勲

日本内分泌学会雑誌 99 ( 5 ) 1422 - 1422 2024年4月

当院で経験したDiffuse midline glioma,H3K27-alteredの臨床的特徴

外間まどか, 大谷理浩, 石田穣治, 梅田剛志, 井上陽平, 水田亮, 井本良二, 駿河和城, 劒持直也, 家護谷泰仁, 平野秀一郎, 冨田祐介, 藤井謙太郎, 鷲尾佳奈, 田中將太

小児の脳神経 49 ( 2 ) 209 - 209 2024年4月

Combined simultaneous endoscopic endonasal and transcranial surgery using high-definition three-dimensional exoscope for malignant tumors of the anterior skull base. 査読国際誌

Seiichiro Makihara, Yoshihiro Otani, Kensuke Uraguchi, Aiko Shimizu, Aya Murai, Takaya Higaki, Naoki Akisada, Shohei Fujimoto, Takuma Makino, Joji Ishida, Kentaro Fujii, Takao Yasuhara, Tomoyuki Ota, Hiroshi Matsumoto, Mizuo Ando

Head & neck 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Advanced surgical interventions are required to treat malignancies in the anterior skull base (ASB). This study investigates the utility of endoscopic endonasal and transcranial surgery (EETS) using a high-definition three-dimensional exoscope as an alternative to traditional microscopy. METHODS: Six patients with carcinomas of varying histopathologies underwent surgery employing the EETS maneuver, which synchronized three distinct surgical modalities: harvesting of the anterolateral thigh flap, initiation of the transnasal technique, and initiation of the transcranial procedure. RESULTS: The innovative strategy enabled successful tumor resection and skull base reconstruction without postoperative local neoplastic recurrence, cerebrospinal fluid leakage, or neurological deficits. CONCLUSION: The integration of the exoscope and EETS is a novel therapeutic approach for ASB malignancies. This strategy demonstrates the potential of the exoscope in augmenting surgical visualization, enhancing ergonomics, and achieving seamless alignment of multiple surgical interventions. This technique represents a progressive shift in the management of these complex oncological challenges.

DOI： 10.1002/hed.27724

Midline invasion predicts poor prognosis in diffuse hemispheric glioma, H3 G34-mutant: an individual participant data review. 査読国際誌

Yasuhito Kegoya, Yoshihiro Otani, Yohei Inoue, Ryo Mizuta, Fumiyo Higaki, Kana Washio, Shinichiro Koizumi, Kazuhiko Kurozumi, Joji Ishida, Kentaro Fujii, Norio Yamamoto, Yoshihiro Tanaka, Isao Date

Journal of neuro-oncology 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Diffuse hemispheric glioma, H3 G34-mutant (DHGs), is a newly categorized tumor in pediatric-type diffuse high-grade gliomas, World Health Organization grade 4, with a poor prognosis. Although prognostic factors associated with genetic abnormalities have been reported, few reports have examined the clinical presentation of DHGs, especially from the viewpoint of imaging findings. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs. METHODS: We searched Medline through the PubMed database using two search terms: "G34" and "glioma", between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan-Meier curves and logistic regression. RESULTS: A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS was 14.4 months. Univariate logistic regression analysis revealed that OS was significantly worse in the MI-positive group compared with the MI-negative group. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs. CONCLUSIONS: In this study, MI-positive cases had a worse prognosis compared with MI-negative cases. PREVIOUS PRESENTATIONS: No portion of this study has been presented or published previously.

DOI： 10.1007/s11060-024-04587-5

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study. 査読国際誌

Kohei Fukuoka, Jun Kurihara, Tomoko Shofuda, Naoki Kagawa, Kai Yamasaki, Ryo Ando, Joji Ishida, Masayuki Kanamori, Atsufumi Kawamura, Young-Soo Park, Chikako Kiyotani, Takuya Akai, Dai Keino, Yosuke Miyairi, Atsushi Sasaki, Junko Hirato, Takeshi Inoue, Atsuko Nakazawa, Katsuyoshi Koh, Ryo Nishikawa, Isao Date, Motoo Nagane, Koichi Ichimura, Yonehiro Kanemura

Acta neuropathologica communications 11 ( 1 ) 153 - 153 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. RESULTS: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival). CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

DOI： 10.1186/s40478-023-01652-4

Utility of Comprehensive Genomic Profiling for Precise Diagnosis of Pediatric-Type Diffuse High-Grade Glioma.

Keigo Makino, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Shuichiro Hirano, Yasuki Suruga, Kana Washio, Kenji Nishida, Hiroyuki Yanai, Shuta Tomida, Daisuke Ennishi, Isao Date

Acta medica Okayama 77 ( 3 ) 323 - 330 2023年6月

記述言語：英語

In the current World Health Organization classification of central nervous system tumors, comprehensive genetic and epigenetic analyses are considered essential for precise diagnosis. A 14-year-old male patient who presented with a cerebellar tumor was initially diagnosed with glioblastoma and treated with radiation and concomitant temozolomide chemotherapy after resection. During maintenance temozolomide therapy, a new contrast-enhanced lesion developed in the bottom of the cavity formed by the resection. A second surgery was performed, but the histological findings in specimens from the second surgery were different from those of the first surgery. Although genome-wide DNA methylation profiling was conducted using frozen tissue for a precise diagnosis, the proportion of tumor cells was insufficient and only normal cerebellum was observed. We then performed comprehensive genetic analysis using formalin-fixed paraffin-embedded sections, which revealed MYCN amplification without alteration of IDH1, IDH2, or Histone H3. Finally, the patient was diagnosed with pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype. In conclusion, comprehensive genetic and epigenetic analysis should be considered in pediatric brain tumor cases.

DOI： 10.18926/AMO/65502

脳腫瘍のメチル化診断診断困難症例に対するゲノムワイドメチル化解析の検討

大谷理浩, 藤井謙太郎, 石田穣治, 駿河和城, 鷲尾佳奈, 柳井広之, 里見介史, 市村幸一, 伊達勲

Brain Tumor Pathology 40 ( Suppl. ) 062 - 062 2023年5月

Utility of genome-wide DNA methylation profiling for pediatric-type diffuse gliomas.

Yoshihiro Otani, Kaishi Satomi, Yasuki Suruga, Joji Ishida, Kentaro Fujii, Koichi Ichimura, Isao Date

Brain tumor pathology 40 ( 2 ) 56 - 65 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite the current progress of treatment, pediatric-type diffuse glioma is one of the most lethal primary malignant tumors in the central nervous system (CNS). Since pediatric-type CNS tumors are rare disease entities and highly heterogeneous, the diagnosis is challenging. An accurate diagnosis is essential for the choice of optimal treatment, which leads to precision oncology and improvement of the patient's outcome. Genome-wide DNA methylation profiling recently emerged as one of the most important tools for the diagnosis of CNS tumors, and the utility of this novel assay has been reported in both pediatric and adult patients. In the current World Health Organization classification published in 2021, several new entities are recognized in pediatric-type diffuse gliomas, some of which require methylation profiling. In this review, we investigated the utility of genome-wide DNA methylation profiling in pediatric-type diffuse glioma, as well as issues in the clinical application of this assay. Furthermore, the combination of genome-wide DNA methylation profiling and other comprehensive genomic assays, which may improve diagnostic accuracy and detection of the actionable target, will be discussed.

DOI： 10.1007/s10014-023-00457-6

がんゲノム医療がもたらす小児脳腫瘍の展開当院における小児グリオーマ診療についてがんゲノム医療時代における変遷

石田穣治, 大谷理浩, 藤井謙太郎, 佐々木達也, 鷲尾佳奈, 柳井広之, 遠西大輔, 山本英喜, 伊達勲

小児の脳神経 48 ( 2 ) 153 - 153 2023年4月

IDH-mutant Astrocytoma Arising in the Brainstem with Symptom Improvement by Foramen Magnum Decompression: A Case Report.

Takayuki Nagase, Joji Ishida, Susumu Sasada, Tatsuya Sasaki, Yoshihiro Otani, Satoru Yabuno, Kentaro Fujii, Atsuhito Uneda, Takao Yasuhara, Isao Date

NMC case report journal 10 75 - 80 2023年

記述言語：英語

Diffusely infiltrative midline gliomas are known to have a poor prognosis. The standard treatment for typical diffuse midline glioma in the pons is local radiotherapy as surgical resection is inappropriate. This case reports a brainstem glioma in which stereotactic biopsy and foramen magnum decompression were concomitantly performed to confirm the diagnosis and improve symptoms. A 23-year-old woman was referred to our department with a chief complaint of headache for six months. Magnetic resonance imaging (MRI) showed diffuse T2 hyperintense swelling of the brainstem with the pons as the main locus. Enlargement of the lateral ventricles was observed because of cerebrospinal fluid obstruction out of the posterior fossa. This was atypical for a diffuse midline glioma in terms of the longstanding slow progression of symptoms and patient age. Stereotactic biopsy was performed for diagnosis, and foramen magnum decompression (FMD) was concomitantly performed to treat the obstructive hydrocephalus. The histological diagnosis was astrocytoma, IDH-mutant. Post-surgery, the patient's symptoms were relieved, and she was discharged on the fifth day after surgery. The hydrocephalus was resolved, and the patient returned to normal life without any symptoms. The tumor size follow-up with MRI demonstrated no marked change for 12 months. Even though diffuse midline glioma is considered to have a poor prognosis, clinicians should contemplate if it is atypical. In atypical cases like the one described herein, surgical treatment may contribute to pathological diagnosis and symptom improvement.

DOI： 10.2176/jns-nmc.2022-0159

[Surgical Tips and Precautions for Supratentorial Tumors in Children].

Joji Ishida, Isao Date

No shinkei geka. Neurological surgery 50 ( 6 ) 1314 - 1322 2022年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Pediatric brain tumors account for approximately 15% of all pediatric cancers. Approximately half of the cases are malignant, and entail postoperative radiation therapy and chemotherapy. Herein, we describe perioperative tips and precautions for pediatric supratentorial tumors other than suprasellar tumors from our institution. Postoperative cerebrospinal fluid issues are especially prevalent in children, and three representative cases have been presented for discussion. Further, skull closure deems close attention, being crucial for children's future growth, in terms of a cosmetic aspect.

DOI： 10.11477/mf.1436204697

The utility of DNA methylation analysis in elderly patients with pilocytic astrocytoma morphology. 国際誌

Yasuki Suruga, Kaishi Satomi, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Atsuhito Uneda, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Naoya Kemmotsu, Ryoji Imoto, Ryo Mizuta, Yusuke Tomita, Takao Yasuhara, Kana Washio, Hiroyuki Yanai, Yuko Matsushita, Yuko Hibiya, Akihiko Yoshida, David Capper, Koichi Ichimura, Isao Date

Journal of neuro-oncology 160 ( 1 ) 179 - 189 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, a subset of PA patients shows unfavorable outcomes. In this study, we retrospectively reviewed PA patients and performed further molecular analysis, such as DNA methylation profiling, to identify prognostic factors. METHODS: We analyzed 29 histologically-confirmed PA patients from a single center from 2002 to 2021 and conducted integrated molecular analyses among elderly PA patients since age was an independent prognostic factor for poor outcomes. RESULTS: The median age at diagnosis was 14 years (range 3-82 years) and 4 patients (14%) were elderly (patients ≥ 60 years old). Age over 60 was associated with poor progression-free survival and overall survival. We performed DNA methylation analysis on 2 of the 4 elderly patients. Both cases were histologically diagnosed as PA, but DNA methylation profiling revealed one as high-grade astrocytoma with piloid features (all methylation class scores were below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score was over 0.5 in both v11b4 and v12.5), using the German Cancer Research Center methylation profiling classifiers and t-SNE analysis. CONCLUSIONS: Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, further molecular analysis and DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.

DOI： 10.1007/s11060-022-04131-3

Age is a major determinant for poor prognosis in patients with pilocytic astrocytoma: a SEER population study. 国際誌

Yusuke Tomita, Elizabeth A Hibler, Yasuki Suruga, Joji Ishida, Kentaro Fujii, Kaishi Satomi, Koichi Ichimura, Nobuyuki Hirotsune, Isao Date, Yoshihiro Tanaka, Yoshihiro Otani

Clinical and experimental medicine 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background Pilocytic astrocytomas (PAs) are central nervous system tumors with variable prognosis and poorly understood risk factors. Little evidence exists regarding the effect of age on mortality in PA. Therefore, we conducted a thorough characterization of PA in the US. Methods We queried the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018 to extract age-adjusted incidence rate (AAIR), age-adjusted mortality rate (AAMR), and survival data on PA. The age group comparisons for each measure varied depending on available SEER data. We compared trends in AAIR and AAMR by two age groups (children, 0-19 years; adults, 20 + years) and by sex. The cumulative incidence function and the Fine-Gray competing risk model were applied by 0-19, 20-39, 40-59, and 60 + years of age groups. Results This study included 5211 incident PA and 462 PA-specific deaths between 2000 and 2018. Trends in AAIRs and AAMRs were almost constant between 2000 and 2018. Average AAIRs had a sharp peak in 1-4 years of age groups, whereas AAMRs had a gradual peak in 80-84 years of age groups. Age groups, tumor location, and race/ethnicity were significantly associated with PA-specific death, whereas only age was associated with other cause of deaths. Conclusions Trends in AAIRs and AAMRs were constant regardless of age. PAs in older populations, especially over 60 years old, have higher incidence of death than those in younger populations.

DOI： 10.1007/s10238-022-00882-5

Genomic Profiling of a Case of Glioneuronal Tumor with Neuropil-like Islands.

Nobushige Tsuboi, Joji Ishida, Yosuke Shimazu, Hisanori Edaki, Atsuhito Uneda, Yoshihiro Otani, Kentaro Fujii, Kazuhiko Kurozumi, Daisuke Ennishi, Hiroyuki Yanai, Isao Date

Acta medica Okayama 76 ( 4 ) 473 - 477 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioneuronal tumor with neuropil-like islands (GNTNI) is a very rare subtype of glioneuronal tumor. We present a case of a 62-year-old man with GNTNI. Two adjacent lesions in the left parietal lobe were removed by left parietal craniotomy. The histological findings were glial cell proliferation and scattered rosettes consisting of synaptophysin-positive and NeuN-positive cells, leading to the diagnosis of GNTNI. Target sequencing revealed a genetic alteration similar to glioblastoma, IDH-wild type, which suggested adjuvant therapies. There are few previous reports on the treatment of this disease, and the patient should be followed carefully.

DOI： 10.18926/AMO/63907

当院における毛様細胞性星細胞腫の予後因子に関する検討

駿河和城, 里見介史, 大谷理浩, 石田穣治, 藤井謙太郎, 安原隆雄, 鷲尾佳奈, 柳井広之, 市村幸一, 伊達勲

Brain Tumor Pathology 39 ( Suppl. ) 103 - 103 2022年5月

AYA世代の脳腫瘍病理小児、AYA世代の脳腫瘍に対する網羅的メチル化解析を用いた診断の有用性と限界

大谷理浩, 藤井謙太郎, 石田穣治, 坪井伸成, 鷲尾佳奈, 柳井広之, 里見介史, 市村幸一, 伊達勲

Brain Tumor Pathology 39 ( Suppl. ) 076 - 076 2022年5月

A Case of Relapsed Primary Central Nervous System Lymphoma Treated with CD19-directed Chimeric Antigen Receptor T Cell Therapy.

Ryo Mizuta, Yoshihiro Otani, Kentaro Fujii, Atsuhito Uneda, Joji Ishida, Takehiro Tanaka, Shuntaro Ikegawa, Nobuharu Fujii, Yoshinobu Maeda, Isao Date

NMC case report journal 9 275 - 280 2022年

記述言語：英語

Although high-dose methotrexate (HD-MTX) is the standard therapy for primary central nervous system lymphoma (PCNSL), the prognosis remains poor. Because 90% of PCNSL is diffuse large B-cell lymphoma (DLBCL), chimeric antigen receptor (CAR)-T cell therapy is expected to be beneficial. However, there are limited reports on CAR-T cell therapy for PCNSL because of the concern of neurotoxicity. Here, we report a case of relapsed PCNSL treated with anti-CD19 CAR-T cell therapy. A 40-year-old woman presenting with visual disturbance in her left eye was initially diagnosed with bilateral uveitis. Her histological diagnosis was DLBCL, and she was positive for CD19. Although she received chemotherapy including HD-MTX, the tumor relapsed in her right occipital lobe. She underwent remission induction therapy and then anti-CD19 CAR-T cell therapy. Cytokine release syndrome (CRS) grade 2 occurred, but there were no complications of CAR-T cell-related encephalopathy syndrome (CRES). She has achieved complete response for more than 1 year. Anti-CD19 CAR-T cell therapy is a revolutionary immunotherapy for treating relapsed or refractory (R/R) B lineage malignancies. Although there are concerns regarding CRS and CRES in central nervous system lymphoma, the use of anti-CD19 CAR-T cells to treat R/R PCNSL is safe and feasible.

DOI： 10.2176/jns-nmc.2022-0134

Response to entrectinib in a malignant glioneuronal tumor with ARHGEF2-NTRK fusion. 国際誌

Kazuhiko Kurozumi, Kentaro Fujii, Kana Washio, Joji Ishida, Yoshihiro Otani, Tamotsu Sudo, Makoto Tahara, Koichi Ichimura, Daisuke Ennishi, Isao Date

Neuro-oncology advances 4 ( 1 ) vdac094 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioneuronal tumor (GNT) is a rare tumor. We previously reported a case of high-grade GNT with Rho/Rac guanine nucleotide factor 2 (ARHGEF2)-neurotrophic tropomyosin receptor kinase (NTRK)1 fusion and emphasized the importance of complementary molecular analysis.1 MRI at follow-up showed tumor progression. A cancer gene panel test was performed, and the presence of the ARHGEF2-NTRK1 fusion gene was confirmed. Treatment with entrectinib, an inhibitor of NTRK, was started. MRI follow-ups revealed dramatic responses. However, the patient reported severe general fatigue, and the dose was decreased following the reduced drug protocol. This case highlights the necessity of determining an optimal dose and further profiling the side effects of NTRK inhibitors.

DOI： 10.1093/noajnl/vdac094

Histopathology and prognosis of germ cell tumors metastatic to brain: cohort study. 国際誌

Hirokazu Takami, Christopher S Graffeo, Avital Perry, Makoto Ohno, Joji Ishida, Caterina Giannini, Yoshitaka Narita, Yoichi Nakazato, Nobuhito Saito, Ryo Nishikawa, Masao Matsutani, Koichi Ichimura, David J Daniels

Journal of neuro-oncology 154 ( 1 ) 121 - 130 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Germ cell tumors (GCTs) are uncommon neoplasms predominantly arising in midline tissues. The prognostic significance of histopathology in predicting metastatic GCT behavior is poorly understood. METHODS: Multicenter international cohort study including 29 patients with GCTs metastatic to brain were retrospectively investigated (18 patients from Mayo Clinic and 11 patients from the intracranial germ cell tumor genome analysis consortium in Japan). Clinical characteristics were analyzed using the Chi-square test (two-tailed) for categorical variables and using the log-rank test for survival data. RESULTS: Median age at treatment was 31 years (range 14-58). Primary disease sites were testis (71%), mediastinum (18%), and female reproductive organs (11%). Median metastatic interval was 223 days (range, 6-6124). Median follow-up was 346 days (range, 1-5356), with 16 deaths (57%) occurring after the median overall survival of 455 days. Actuarial one-year survival was 51%; 12-of-16 deaths (75%) were attributed to intracranial disease. Appearance of the same GCT subtype at the metastatic site as the primary was high for non-seminomatous GCT (NSGCT, 64-100%), but low for seminoma/dysgerminoma and mature teratoma (MT, 14, 17%, respectively). Gain of a new component was seen in 4 (20%)-3 of which included embryonal carcinoma (EC) at the primary site (75%). Incidence of cases without seminoma/dysgerminoma increased significantly after metastasis (p = 0.02). Metastatic interval was shorter in cases with histological change (199 vs 454 days, p = 0.009). Overall survival was associated with MT primary histopathology (p = 0.02). CONCLUSION: Histological differentiation at the primary GCT site influences metastatic prognosis. Aggressive behavior is associated with NSGCT, while EC frequently demonstrates multi-directional histological differentiation after brain metastasis, and such histological dynamism is associated with shorter metastatic interval. Most metastases occurred within one year of diagnosis, emphasizing the need for close surveillance in newly diagnosed extra-cranial GCT.

DOI： 10.1007/s11060-021-03810-x

Large-vessel vasculitis induced by granulocyte colony-stimulating factor administration after chemotherapy. 国際誌

Koichiro Yamamoto, Nayu Tamura, Kosuke Oka, Kou Hasegawa, Hideharu Hagiya, Madoka Hokama, Joji Ishida, Fumio Otsuka

Modern rheumatology case reports 5 ( 2 ) 322 - 326 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Granulocyte colony-stimulating factor (G-CSF) is a relatively new drug that is used for recovery of chemotherapy-associated neutropenia. It is known to cause bone pain, headache and fatigue as side-effects; however, large-vessel vasculitis is extremely rare and its relation with G-CSF remains unknown. We describe a 49-year-old woman in whom arteritis developed after chemotherapy and subsequent G-CSF administration. She had experienced pinealoma 3 months ago and received surgery and chemotherapy, leading to neutropenia. After administration of lenograstim at 100 μg/day for 1 week, high fever and neck pain appeared. White blood cell count and serum levels of C-reactive protein and interleukin-6 were increased to 37,930/μL, 23.71 mg/dL, and 241 pg/mL, respectively. Contrast-enhanced computed tomography revealed thickened walls of large vessels including the bilateral common carotid artery (CCA), right brachiocephalic artery, and ascending aorta. Ultrasonography showed wall thickening of the CCA (maximum of intima media thickness: right, 2.9 mm; left, 3.2 mm). As differential diagnoses, infection, chemotherapy, autoimmune diseases, and cancer were considered other than G-CSF. Blood culture tests, lumbar puncture, β-D-glucan tests, and tests for viral antibodies indicated no active infection, and autoantibodies were negative. Empirical antibiotic therapy was ineffective. The score of Naranjo's algorithm to lenograstim was 6, indicating "probable" causality. Considering the clinical course and test results, we made a diagnosis of G-CSF-associated arteritis and commenced glucocorticoid therapy, which drastically improved the symptoms and inflammation. Clinicians should be aware of this uncommon but significant complication of GCS-F administration, for which glucocorticoid treatment can be a useful therapeutic option.

DOI： 10.1080/24725625.2020.1857022

Modeling human brain tumors in flies, worms, and zebrafish: From proof of principle to novel therapeutic targets. 国際誌

Uswa Shahzad, Michael S Taccone, Sachin A Kumar, Hidehiro Okura, Stacey Krumholtz, Joji Ishida, Coco Mine, Kyle Gouveia, Julia Edgar, Christian Smith, Madeline Hayes, Xi Huang, W Brent Derry, Michael D Taylor, James T Rutka

Neuro-oncology 23 ( 5 ) 718 - 731 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.

DOI： 10.1093/neuonc/noaa306

Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration. 国際誌

Atsuhito Uneda, Kazuhiko Kurozumi, Atsushi Fujimura, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Yoshihiro Otani, Yusuke Tomita, Yasuhiko Hattori, Yuji Matsumoto, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Atsunori Kamiya, Isao Date

Acta neuropathologica communications 9 ( 1 ) 29 - 29 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

DOI： 10.1186/s40478-021-01124-7

MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma. 国際誌

Joji Ishida, Saira Alli, Andrew Bondoc, Brian Golbourn, Nesrin Sabha, Kristina Mikloska, Stacey Krumholtz, Dilakshan Srikanthan, Naohide Fujita, Amanda Luck, Colin Maslink, Christian Smith, Kullervo Hynynen, James Rutka

Journal of controlled release : official journal of the Controlled Release Society 330 1034 - 1045 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive method for treating CNS tumours. Moreover, MRgFUS allows for the temporary and repeated disruption of the BBB. Our group previously reported the feasibility of temporary BBB opening within the normal murine brainstem using MRgFUS following intravenous (IV) administration of microbubbles. In the current study, we set out to test the effectiveness of targeted chemotherapy when paired with MRgFUS in murine models of DIPG. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested on patient-derived cell lines. We studied the RCAS/Tv-a model where RCAS-Cre, RCAS-PDGFB, and RCAS-H3.3K27M were used to drive tumourigenesis upon injection in the pons. We also used orthotopically injected SU-DIPG-6 and SU-DIPG-17 xenografts which demonstrated a diffusely infiltrative tumour growth pattern similar to human DIPG. In our study, SU-DIPG-17 xenografts were more representative of human DIPG with an intact BBB. Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression. Herein, we provide evidence for the ability of MRgFUS to enhance drug delivery in a mouse model of DIPG. These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.

DOI： 10.1016/j.jconrel.2020.11.010

Diffuse intrinsic pontine glioma: current insights and future directions. 国際誌

Dilakshan Srikanthan, Michael S Taccone, Randy Van Ommeren, Joji Ishida, Stacey L Krumholtz, James T Rutka

Chinese neurosurgical journal 7 ( 1 ) 6 - 6 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor-related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

DOI： 10.1186/s41016-020-00218-w

Spinal Cord Diffuse Midline Glioma, H3K27M- mutant Effectively Treated with Bevacizumab: A Report of Two Cases.

Satoru Yabuno, Satoshi Kawauchi, Michiari Umakoshi, Atsuhito Uneda, Kentaro Fujii, Joji Ishida, Yoshihiro Otani, Yasuhiko Hattori, Nobushige Tsuboi, Shohei Kohno, Mai Noujima, Tomohiro Toji, Hiroyuki Yanai, Takao Yasuhara, Isao Date

NMC case report journal 8 ( 1 ) 505 - 511 2021年

記述言語：英語

"Diffuse midline glioma (DMG), H3K27M-mutant" was newly classified in the revised World Health Organization (WHO) 2016 classification of central nervous system tumors. Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols. In this study, we report two cases of spinal cord DMG, H3K27M-mutant treated with bevacizumab. The two patients were women in their 40s who initially presented with sensory impairment. MRI showed spinal intramedullary tumors, and each patient underwent laminectomy/laminoplasty and biopsy of the tumors. Histological examination initially suggested low-grade astrocytoma in case 1 and glioblastoma in case 2. Upon further immunohistochemical examination in case 1 and molecular examination in case 2, however, both cases were diagnosed as DMG, H3K27M-mutant. Case 1 was treated with radiation therapy and temozolomide (TMZ) chemotherapy, which induced a transient improvement of symptoms; 3 months after surgery, however, the patient's symptoms rapidly deteriorated. MRI showed tumor enlargement with edema to the medulla. Triweekly administration of bevacizumab improved her symptoms for the following 12 months. Case 2 was treated with bevacizumab from the beginning because of acute deterioration of breathing. After bevacizumab administration, both cases showed tumor regression on MRI and drastic improvement of symptoms within a few days. Although spinal cord DMG, H3K27M-mutant has an aggressive clinical course and poor prognosis, bevacizumab administration may offer the significant clinical benefit of alleviating edema, which improves patient's capacity for activities of daily life.

DOI： 10.2176/nmccrj.cr.2021-0033

Carotid-anterior cerebral artery (ACA) anastomosis associated with azygos ACA and ophthalmic artery arising from the middle meningeal artery: a case report. 国際誌

Koichiro Matsuura, Akira Uchino, Naoko Saito, Joji Ishida, Tomonari Suzuki

Surgical and radiologic anatomy : SRA 42 ( 2 ) 211 - 214 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Among variations of the anterior cerebral artery (ACA), anastomosis of its A1-A2 junction with the ophthalmic segment of the internal carotid artery is rare and described as carotid-ACA anastomosis or infraoptic course of the ACA. One common variant, an azygos ACA, demonstrates no pairing of the A2 segment. To our knowledge, association of a carotid-ACA anastomosis with an azygos ACA is not reported in the English-language literature. We report a case diagnosed by magnetic resonance angiography in which right carotid-ACA anastomosis was associated with an azygos ACA and the right ophthalmic artery originated from the middle meningeal artery.

DOI： 10.1007/s00276-019-02353-1

High-grade glioneuronal tumor with an ARHGEF2-NTRK1 fusion gene.

Kazuhiko Kurozumi, Yoshiko Nakano, Joji Ishida, Takehiro Tanaka, Masatomo Doi, Junko Hirato, Akihiko Yoshida, Kana Washio, Akira Shimada, Takashi Kohno, Koichi Ichimura, Hiroyuki Yanai, Isao Date

Brain tumor pathology 36 ( 3 ) 121 - 128 2019年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Here, we report a highly unusual case of high-grade glioneuronal tumor with a neurotrophic tropomyosin receptor kinase (NTRK) fusion gene. A 13-year-old girl presented with headache and vomiting and MRI detected two cystic lesions bilaterally in the frontal areas with surrounding edema. The left larger tumor was removed by left frontal craniotomy. The tumor was diagnosed as a high-grade glioneuronal tumor, unclassified. Methylation profiling classified it as a diffuse leptomeningeal glioneuronal tumor (DLGNT) with low confidence. This tumor showed genotypes frequently found in DLGNT such as 1p/19q codeletion without IDH mutation and, however, did not have the typical DLGNT clinical and histological features. RNA sequencing identified an ARHGEF2 (encoding Rho/Rac guanine nucleotide exchange factor 2)-NTRK1 fusion gene. The presence of recurrent NTRK fusion in glioneuronal tumors has an important implication in the clinical decision making and opens up a possibility of novel targeted therapy.

DOI： 10.1007/s10014-019-00345-y

δ-Catenin Promotes Bevacizumab-Induced Glioma Invasion. 国際誌

Toshihiko Shimizu, Joji Ishida, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Yoshihiro Otani, Tetsuo Oka, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Isao Date

Molecular cancer therapeutics 18 ( 4 ) 812 - 822 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed patients with glioblastoma, and this emphasizes the potential of bevacizumab as a glioma treatment. However, although bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. We made a human glioma U87ΔEGFR cell xenograft model by stereotactically injecting these cells into the brain of animals. We administered bevacizumab intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology and mRNA was extracted. In vivo, bevacizumab treatment increased glioma cell invasion. qRT-PCR array analysis revealed upregulation of δ-catenin (CTNND2) and several other factors. In vitro, bevacizumab treatment upregulated δ-catenin expression. A low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased in scratch wound assays and two-chamber assays. Overexpression of δ-catenin increased the tumor invasion in vitro and in vivo However, δ-catenin knockdown decreased glioma cell invasiveness. The depth of tumor invasion in the U87ΔEGFR cells expressing δ-catenin was significantly increased compared with empty vector-transfected cells. The increase in invasive capacity induced by bevacizumab therapy was associated with upregulation of δ-catenin expression in invasive tumor cells. This finding suggests that δ-catenin is related to tumor invasion and migration.

DOI： 10.1158/1535-7163.MCT-18-0138

Delayed postoperative hyponatremia after endoscopic transsphenoidal surgery for pituitary adenoma. 国際誌

Yusuke Tomita, Kazuhiko Kurozumi, Kenichi Inagaki, Masahiro Kameda, Joji Ishida, Takao Yasuhara, Tomotsugu Ichikawa, Tomoko Sonoda, Fumio Otsuka, Isao Date

Acta neurochirurgica 161 ( 4 ) 707 - 715 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Hyponatremia generally occurs after transsphenoidal surgery (TSS) in a delayed fashion. Most patients with delayed postoperative hyponatremia (DPH) are asymptomatic or only express non-specific symptoms; consequently, DPH is associated with prolonged hospitalization. No consensus has been reached on which patients are at greatest risk of developing DPH. We reviewed patients with DPH and evaluated predictive factors for DPH. METHODS: We retrospectively analyzed 107 consecutive patients who underwent endoscopic TSS for pituitary adenoma (January 2010-December 2016). Patients with DPH (hyponatremia group) and without DPH (normonatremia group) were compared according to their nadir sodium levels on postoperative days 3 to 10. We documented the patients' demographics, clinical features, and postoperative physiological characteristics. RESULTS: Twenty-five (23.4%) patients developed DPH after endoscopic TSS. The patients' mean age was 54 ± 17 years, and 63.6% of the patients were female. The overall prevalence of DPH was 23.4%. The non-parametric χ2 test and the Mann-Whitney U test revealed statistically significant differences in age, use of antihypertensive drugs, nonfunctioning pituitary adenoma, and higher yet normal preoperative thyroid-stimulating hormone level between the hyponatremia and normonatremia groups (P < 0.05). Logistic regression analysis revealed that only older age was a useful independent predictive factor for DPH (odds ratio, 1.05; 95% confidence interval, 1.01-1.08; P = 0.01). The serum sodium levels on postoperative day 2 were significantly lower in the hyponatremia than normonatremia group (P < 0.01) and were negatively correlated with age (r = - 0.25, P < 0.05). The cut-off age for predicting DPH was 55 years. The hospital stay was significantly longer in the hyponatremia than normonatremia group (P < 0.01). CONCLUSIONS: Age of more than 55 years was an independent predictive factor for DPH even after adjusting for potential confounders. Older age was negatively correlated with the serum sodium level on postoperative day 2. Preventing early decreases in the sodium level could reduce the risk of DPH. TRIAL REGISTRATION: 1707-027.

DOI： 10.1007/s00701-019-03818-3

Comparative Histologic and Molecular Analysis of 2 Recurrent Lesions Showing Different Magnetic Resonance Imaging Responses After Bevacizumab Treatment: Report of a Case of Anaplastic Astrocytoma. 国際誌

Yoshihiro Otani, Tomotsugu Ichikawa, Atsuhito Uneda, Kazuhiko Kurozumi, Joji Ishida, Isao Date

World neurosurgery 116 464 - 471 2018年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: We report the case of a patient with anaplastic astrocytoma whose 2 recurrent lesions showed different imaging responses from one another after bevacizumab treatment. Histologic and genetic features of this patient are also described. CASE DESCRIPTION: A 31-year-old patient with left temporal anaplastic astrocytoma had surgery, local radiotherapy, and chemotherapy. Recurrent lesions appeared in the cerebellar vermis and left cerebellar hemisphere, and the patient was started on biweekly bevacizumab. Subsequently, the 2 enhanced lesions showed different response patterns on magnetic resonance imaging. Although the lesion in the cerebellar vermis showed an enlargement of enhancing mass, the lesion in the left cerebellar hemisphere showed disappearance of enhancement. We resected the cerebellar vermis lesion and performed biopsy on the cerebellar hemisphere lesion. The specimens were investigated. Both recurrent lesions showed higher Ki-67 labeling indices and pericyte proliferation, and less angiogenesis compared with the initial specimen. Transmission electron microscopy showed a reduction in the distance between the endothelial cells and tumor cells in both recurrent lesions, compared with the initial lesion. However, the tight junctions in the vermian lesion were still disrupted compared with the initial lesion and the cerebellar hemispheric lesion. Genetic analysis of the initial specimen showed proneural signature; however, the recurrent vermian lesion exhibited decreased expression of proneural markers. CONCLUSIONS: We report a case of anaplastic astrocytoma with 2 different imaging responses to bevacizumab. Our analysis suggests that differences in tight junctions possibly contributed to the changes on magnetic resonance imaging observed after bevacizumab treatment.

DOI： 10.1016/j.wneu.2018.05.036

Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion. 査読国際誌

Y Otani, T Ichikawa, K Kurozumi, S Inoue, J Ishida, T Oka, T Shimizu, Y Tomita, Y Hattori, A Uneda, Y Matsumoto, H Michiue, I Date

Oncogene 37 ( 6 ) 777 - 786 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.

DOI： 10.1038/onc.2017.373

Combination of the tubular retractor and brain spatulas provides an adequate operative field in surgery for deep-seated lesions: Case series and technical note. 国際誌

Yoshihiro Otani, Kazuhiko Kurozumi, Joji Ishida, Masafumi Hiramatsu, Masahiro Kameda, Tomotsugu Ichikawa, Isao Date

Surgical neurology international 9 ( 1 ) 220 - 220 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Surgeries for deep-seated lesions are challenging because making a corridor and observing the interface between lesions and normal brain tissue are difficult. The ViewSite Brain Access System, which is a clear plastic tubular retractor system, is used for resection of deep-seated lesions. However, the tapered shape of this system may result in limitation of the surgical field and cause brain injury to observe the interface between lesions and normal tissue. In this study, we evaluated the usefulness of the combination of ViewSite and brain spatulas. Methods: Nine patients were retrospectively identified who underwent resection of deep-seated lesions with the combination of Viewsite and brain spatulas. We assessed the extent of resection, prognosis, and quantitative brain injury from postoperative diffusion-weighed imaging (DWI). Results: There were four total radiographically confirmed resections. Subtotal resection in four patients and partial resection in one with central neurocytoma were achieved because these tumors were strongly adherent to the choroid plexus and ependymal veins. Only one case of metastatic tumor relapsed 6 months after surgery. The mean postoperative high signal on DWI was 3.68 ± 0.80 cm3. Conclusions: The combination of ViewSite and brain spatulas provides wide and adequate operative fields to observe the interface between lesions and normal tissue, and to prevent brain injury from excessive retraction pressure on the brain derived from repositioning of the ViewSite. Postoperative 3D volumetric analysis shows minimal damage to normal brain tissue. This report may provide new insight into the use of the ViewSite tubular retractor.

DOI： 10.4103/sni.sni_62_18

FIBROBLAST GROWTH FACTOR 13 REGULATES GLIOMA CELL INVASION 査読

Yoshihiro Otani, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Satoshi Inoue, Joji Ishida, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Isao Date

NEURO-ONCOLOGY 19 21 - 21 2017年11月

PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma. 国際誌

Yoshihiro Otani, Joji Ishida, Kazuhiko Kurozumi, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Shuta Tomida, Takehiro Matsubara, Tomotsugu Ichikawa, Isao Date

Scientific reports 7 ( 1 ) 7391 - 7391 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.

DOI： 10.1038/s41598-017-07745-0

Simultaneous combination of electromagnetic navigation with visual evoked potential in endoscopic transsphenoidal surgery: clinical experience and technical considerations. 国際誌

Kazuhiko Kurozumi, Masahiro Kameda, Joji Ishida, Isao Date

Acta neurochirurgica 159 ( 6 ) 1043 - 1048 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The combination of electromagnetic navigation with continuous monitoring techniques allows for the best available anatomic and real-time functional intraoperative monitoring. Methodological aspects and technical adaptations for this combination of methods and the results from 19 patients with tumors in the pituitary region are reported. METHODS: We retrospectively identified 19 patients who were treated with transsphenoidal surgery using high-resolution endoscopy (eTSS) at our hospital between June 2015 and June 2016. All patients underwent surgery under electromagnetic navigation with visual evoked potential (VEP) monitoring. The cases were reviewed for information on disease, and the distance between the patient tracker and emitter was measured. RESULTS: In 19 patients, 17 had pituitary adenomas, 1 had a Rathke cleft cyst, and 1 had an arachnoid cyst. The optimal distance between the patient tracker and emitter was 20-25 cm. VEP monitoring could be performed with unaffected recording quality under electromagnetic navigation. Also we were able to perform the registration and eTSS at this distance using both navigation and VEP monitoring. CONCLUSIONS: We performed eTSS for pituitary tumor by simultaneously using electromagnetic navigation and VEP. The optimal distance between the emitter and tracker minimizes VEP monitoring noise and allows accurate electromagnetic navigation.

DOI： 10.1007/s00701-017-3111-6

診断に苦慮している左前頭葉嚢胞性腫瘍の一例

黒住和彦, 石田穣治, 市川智継, 大谷理浩, 清水俊彦, 冨田祐介, 服部靖彦, 田中健大, 柳井広之, 伊達勲

Brain Tumor Pathology 34 ( Suppl. ) 090 - 090 2017年5月

診断と治療方針に苦慮した左前頭葉嚢胞性腫瘍の1例

石田穣治, 黒住和彦, 市川智継, 大谷理浩, 服部靖彦, 清水俊彦, 冨田祐介, 鷲尾佳奈, 嶋田明, 田中健大, 柳井広之, 伊達勲

小児の脳神経 42 ( 2 ) 201 - 201 2017年4月

Perioperative Management Center (PERIO) for Neurosurgical Patients.

Takao Yasuhara, Tomohito Hishikawa, Takashi Agari, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Masahiro Kameda, Aiko Shinko, Joji Ishida, Masafumi Hiramatsu, Motomu Kobayashi, Yoshikazu Matsuoka, Toshihiro Sasaki, Yoshihiko Soga, Reiko Yamanaka, Takako Ashiwa, Akemi Arioka, Yasuko Hashimoto, Ayasa Misaki, Yuriko Ishihara, Machiko Sato, Hiroshi Morimatsu, Isao Date

Neurologia medico-chirurgica 56 ( 9 ) 574 - 9 2016年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Perioperative management is critical for positive neurosurgical outcomes. In order to maintain safe and authentic perioperative management, a perioperative management center (PERIO) was introduced to patients of our Neurosurgery Department beginning in June 2014. PERIO involves a multidisciplinary team consisting of anesthesiologists, dentists/dental hygienists/technicians, nurses, physical therapists, pharmacists, and nutritionists. After neurosurgeons decide on the course of surgery, a preoperative evaluation consisting of blood sampling, electrocardiogram, chest X-ray, and lung function test was performed. The patients then visited the PERIO clinic 7-14 days before surgery. One or two days before surgery, the patients without particular issues enter the hospital and receive a mouth cleaning one day before surgery. After surgery, postoperative support involving eating/swallowing evaluation, rehabilitation, and pain control is provided. The differences in duration from admission to surgery, cancellation of surgery, and postoperative complications between PERIO and non-PERIO groups were examined. Eighty-five patients were enrolled in the PERIO group and 131 patients in the non-PERIO group. The duration from admission to surgery was significantly decreased in the PERIO group (3.6 ± 0.3 days), compared to that in the non-PERIO group (4.7 ± 0.2 days). There was one cancelled surgery in the PERIO group and six in the non-PERIO group. Postoperative complications and the overall hospital stay did not differ between the two groups. The PERIO system decreased the duration from admission to surgery, and it is useful in providing high-quality medical service, although the system should be improved so as not to increase the burden on medical staff.

DOI： 10.2176/nmc.oa.2016-0085

A super gene expression system enhances the anti-glioma effects of adenovirus-mediated REIC/Dkk-3 gene therapy. 国際誌

Tetsuo Oka, Kazuhiko Kurozumi, Yosuke Shimazu, Tomotsugu Ichikawa, Joji Ishida, Yoshihiro Otani, Toshihiko Shimizu, Yusuke Tomita, Masakiyo Sakaguchi, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Isao Date

Scientific reports 6 33319 - 33319 2016年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87ΔEGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.

DOI： 10.1038/srep33319

[Cilengitide].

Kazuhiko Kurozumi, Joji Ishida, Tomotsugu Ichikawa, Isao Date

Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 7 672 - 676 2016年9月

[Molecular targeted drugs in gliomas].

Kazuhiko Kurozumi, Joji Ishida, Tomotsugu Ichikawa, Isao Date

Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 7 665 - 671 2016年9月

Adhesion molecules and the extracellular matrix as drug targets for glioma.

Toshihiko Shimizu, Kazuhiko Kurozumi, Joji Ishida, Tomotsugu Ichikawa, Isao Date

Brain tumor pathology 33 ( 2 ) 97 - 106 2016年4月

記述言語：英語

The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.

DOI： 10.1007/s10014-016-0261-9

Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion. 国際誌

Hiroyuki Mori, Yao Yao, Brian S Learman, Kazuhiko Kurozumi, Joji Ishida, Sadeesh K Ramakrishnan, Katherine A Overmyer, Xiang Xue, William P Cawthorn, Michael A Reid, Matthew Taylor, Xiaomin Ning, Yatrik M Shah, Ormond A MacDougald

Scientific reports 6 21520 - 21520 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Changes in cellular oxygen tension play important roles in physiological processes including development and pathological processes such as tumor promotion. The cellular adaptations to sustained hypoxia are mediated by hypoxia-inducible factors (HIFs) to regulate downstream target gene expression. With hypoxia, the stabilized HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-β) heterodimer bind to hypoxia response elements (HREs) and regulate expression of target genes. Here, we report that WNT11 is induced by hypoxia in many cell types, and that transcription of WNT11 is regulated primarily by HIF-1α. We observed induced WNT11 expression in the hypoxic area of allograft tumors. In addition, in mice bearing orthotopic malignant gliomas, inhibition with bevacizumab of vascular endothelial growth factor, which is an important stimulus for angiogenesis, increased nuclear HIF-1α and HIF-2α, and expression of WNT11. Gain- and loss-of-function approaches revealed that WNT11 stimulates proliferation, migration and invasion of cancer-derived cells, and increases activity of matrix metalloproteinase (MMP)-2 and 9. Since tumor hypoxia has been proposed to increase tumor aggressiveness, these data suggest WNT11 as a possible target for cancer therapies, especially for tumors treated with antiangiogenic therapy.

DOI： 10.1038/srep21520

Hybrid Microscopic-Endoscopic Surgery for Craniopharyngioma in Neurosurgical Suite: Technical Notes. 国際誌

Tomotsugu Ichikawa, Yoshihiro Otani, Joji Ishida, Kentaro Fujii, Kazuhiko Kurozumi, Shigeki Ono, Isao Date

World neurosurgery 85 340 - 8 2016年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The best chance of curing craniopharyngioma is achieved by microsurgical total resection; however, its location adjacent to critical structures hinders complete resection without neurologic deterioration. Unrecognized residual tumor within microscopic blind spots might result in tumor recurrences. To improve outcomes, new techniques are necessary to visualize tissue within these blind spots. We examined the success of hybrid microscopic-endoscopic neurosurgery for craniopharyngioma in a neurosurgical suite. METHODS: Four children with craniopharyngiomas underwent microscopic resection. When the neurosurgeon was confident that most of the visible tumor was removed but was suspicious of residual tumor within the blind spot, he or she used an integrated endoscope-holder system to inspect and remove any residual tumor. Two ceiling monitors were mounted side by side in front of the surgeon to display both microscopic and endoscopic views and to view both monitors simultaneously. RESULTS: Surgery was performed in all patients via the frontobasal interhemispheric approach. Residual tumors were observed in the sella (2 patients), on the ventral surface of the chiasm and optic nerve (1 patient), and in the third ventricle (1 patient) and were resected to achieve total resection. Postoperatively, visual function was improved in 2 patients and none exhibited deterioration related to the surgery. CONCLUSIONS: Simultaneous microscopic and endoscopic observation with the use of dual monitors in a neurosurgical suite was ergonomically optimal for the surgeon to perform microsurgical procedures and to avoid traumatizing surrounding vessels or neural tissues. Hybrid microscopic-endoscopic neurosurgery may contribute to safe, less-invasive, and maximal resection to achieve better prognosis in children with craniopharyngioma.

DOI： 10.1016/j.wneu.2015.08.058

Evaluation of extracellular matrix protein CCN1 as a prognostic factor for glioblastoma.

Joji Ishida, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Yoshihiro Otani, Manabu Onishi, Kentaro Fujii, Yosuke Shimazu, Tetsuo Oka, Toshihiko Shimizu, Isao Date

Brain tumor pathology 32 ( 4 ) 245 - 52 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recently, research efforts in identifying prognostic molecular biomarkers for malignant glioma have intensified. Cysteine-rich protein 61 (CCN1) is one of the CCN family of matricellular proteins that promotes cell growth and angiogenesis in cancers through its interaction with several integrins. In this study, we investigated the relationships among CCN1, O(6)-methylguanine-DNA methyltransferase expression, the tumor removal rate, and prognosis in 46 glioblastoma patients treated at the Okayama University Hospital. CCN1 expression was high in 31 (67 %) of these patients. The median progression-free survival (PFS) and overall survival (OS) times of patients with high CCN1 expression was significantly shorter than those of patients with low CCN1 expression (p < 0.005). In a multivariate Cox analysis, CCN1 proved to be an independent prognostic factor for patient survival [PFS, hazard ratio (HR) = 3.53 (1.55-8.01), p = 0.003 and OS, HR = 3.05 (1.35-6.87), p = 0.007]. Moreover, in the 31 patients who underwent gross total resection, the PFS and OS times of those with high CCN1 expression were significantly shorter than those with low CCN1 expression. It was concluded that CCN1 might emerge as a significant prognostic factor regarding the prognosis of glioblastoma patients.

DOI： 10.1007/s10014-015-0227-3

Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma.

Manabu Onishi, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Satoshi Inoue, Tomoko Maruo, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Koichi Yoshida, Hiroyuki Michiue, E Antonio Chiocca, Isao Date

Brain tumor pathology 32 ( 3 ) 184 - 94 2015年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

We have established a pair of animal models (J3T-1 and J3T-2) with different invasive and angiogenic phenotypes, and demonstrated that annexin A2 is expressed at higher levels in J3T-1 than J3T-2 cells. The function of annexin A2 in relation to angiogenesis and invasion was investigated using these models. Stable silencing or overexpression of annexin A2 in J3T-1 and J3T-2 cells (J3T-1shA and J3T-2A cells) was established and used. Thirty human glioblastoma samples were evaluated for expression of annexin A2, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Immunohistochemical and quantitative reverse-transcription polymerase chain reaction analyses revealed higher expression of annexin A2, VEGF and PDGF in J3T-1 and J3T-2A cells. Cultured J3T-1 and J3T-2A cells exhibited higher adhesive ability to endothelial cells. Histopathological analysis of animal brain tumors revealed that J3T-1 and J3T-2A tumors displayed marked angiogenesis and invasion along the neovasculature, whereas J3T-2 and J3T-1shA tumors exhibited diffuse, infiltrative invasion without angiogenesis. Positive expression of annexin A2 was observed in tumor cells surrounding dilated vessels in 25/30 human glioblastoma specimens. Our results reveal that the phenotype of glioma invasion is closely related to angiogenesis. We identify annexin A2 as a factor regulating angiogenesis and invasion of malignant gliomas.

DOI： 10.1007/s10014-015-0216-6

Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma 査読

Y. Shimazu, K. Kurozumi, T. Ichikawa, K. Fujii, M. Onishi, J. Ishida, T. Oka, M. Watanabe, Y. Nasu, H. Kumon, I. Date

GENE THERAPY 22 ( 2 ) 146 - 154 2015年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma.

DOI： 10.1038/gt.2014.100

Reduced neurotoxicity with combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) and deferred radiotherapy for primary central nervous system lymphoma. 国際誌

Tomotsugu Ichikawa, Kazuhiko Kurozumi, Hiroyuki Michiue, Joji Ishida, Yoshinobu Maeda, Eisei Kondo, Akihiro Kawasaki, Isao Date

Clinical neurology and neurosurgery 127 106 - 11 2014年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Although high-dose methotrexate and whole-brain radiation therapy (WBRT) is the current standard for primary central nervous system lymphoma (PCNSL), it has a limited response rate and produces radiation-induced neurotoxicity. We report the effect of a combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) for immunocompetent patients with PCNSL. METHODS: We analyzed 24 patients who had received M-CHOP administered in 28-day cycles with or without WBRT. The response rate to M-CHOP, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS: Nine patients were treated with M-CHOP plus WBRT and 15 patients were treated with M-CHOP alone. Twenty-one patients achieved a complete response and three patients achieved a partial response to M-CHOP, for a 100% response rate. With a median follow-up of 70 months, the median OS and RFS were 33 and 13 months, respectively. The median OS for patients treated with M-CHOP plus WBRT and M-CHOP alone was 33 and 32 months, respectively. Of the 13 patients whose age was above 65 years, the median OS for the M-CHOP plus WBRT group (two patients) and the M-CHOP alone group (11 patients) was 14 and 32 months, respectively. Toxicities related to M-CHOP were mostly hematologic and generally mild to moderate. Two patients whose age was above 65 years in the M-CHOP plus WBRT group developed neurotoxicity. CONCLUSION: Combined treatment with M-CHOP was well tolerated and produced a high response rate. Deferring WBRT was associated with reduced neurotoxicity without worsening the prognosis, especially in elderly patients.

DOI： 10.1016/j.clineuro.2014.10.011

Integrin inhibitor suppresses bevacizumab-induced glioma invasion. 国際誌

Joji Ishida, Manabu Onishi, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Kentaro Fujii, Yosuke Shimazu, Tetsuo Oka, Isao Date

Translational oncology 7 ( 2 ) 292 - 302 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.

DOI： 10.1016/j.tranon.2014.02.016

Gene expression profiling of the anti-glioma effect of Cilengitide. 国際誌

Manabu Onishi, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Hiroyuki Michiue, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, E Antonio Chiocca, Balveen Kaur, Isao Date

SpringerPlus 2 ( 1 ) 160 - 160 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cilengitide (EMD121974), an inhibitor of the adhesive function of integrins, demonstrated preclinical efficacy against malignant glioma. It is speculated that cilengitide can inhibit tumor growth, invasion, and angiogenesis. However, the effects of cilengitide on these processes have not been sufficiently examined. In this study, we investigated the anti-glioma effect of cilengitide using DNA microarray analysis. U87ΔEGFR cells (human malignant glioma cell line) were used for this experiment. The cells were harvested after 16 h of cilengitide treatment, and mRNA was extracted. Gene expression and pathway analyses were performed using a DNA microarray (CodeLink™Human Whole Genome Bioarray). The expression of 265 genes was changed with cilengitide treatment. The expression of 214 genes was up-regulated by more than 4-fold and the expression of 51 genes was down-regulated by more than 4-fold compared to the controls. In pathway analysis, "apoptotic cleavage of cellular proteins" and "TNF receptor signaling pathway" were over-represented. Apoptotic-associated genes such as caspase 8 were up-regulated. Gene expression profiling revealed more detailed mechanism of the anti-glioma effect of cilengitide. Genes associated with apoptosis were over-represented following cilengitide treatment.

DOI： 10.1186/2193-1801-2-160

ANALYSIS OF COMBINATION THERAPY OF THE ADENOVIRUS VECTOR CARRYING REIC/Dkk-3 (Ad-REIC) AND THE INTEGRIN ANTAGONIST CILENGITIDE

Yosuke Shimazu, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Kentaro Fujii, Manabu Onishi, Joji Ishida, Tetsuo Oka, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Isao Date

NEURO-ONCOLOGY 15 58 - 58 2013年11月

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. 国際誌

K Fujii, K Kurozumi, T Ichikawa, M Onishi, Y Shimazu, J Ishida, E A Chiocca, B Kaur, I Date

Cancer gene therapy 20 ( 8 ) 437 - 44 2013年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87ΔEGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.

DOI： 10.1038/cgt.2013.38

内視鏡下経鼻的経蝶形骨洞手術後の遅発性鼻出血に対し塞栓術が有効であった1例

岡哲生, 杉生憲志, 石田穣治, 菱川朋人, 小野成紀, 徳永浩司, 伊達勲

Neurological Surgery 40 ( 1 ) 55 - 60 2012年1月

記述言語：日本語出版者・発行元：(株)医学書院

66歳男。頭部MRIで下垂体腺腫を指摘された。半年後のMRIで増大傾向を示し、手術目的で入院した。手術は右鼻腔から神経内視鏡を使用してアプローチした、腫瘍を肉眼的にほぼ全摘出した。動脈性の出血を含めmassiveな出血は術中に認めなかった。術後経過は良好で、術後10日目に自宅に退院した。退院14日後、自宅で突然鼻出血を来し、止血困難であった。耳鼻咽喉科医によりボスミンガーゼを挿入され、いったん止血した。自宅で経過をみていたが、再度鼻出血を来し緊急入院した。左外頸動脈造影にて左顎動脈末梢のsphenopalatine arteryより鼻咽頭への血液の流出を確認し、出血点と診断した。塞栓術を施行した。sphenopalatine arteryを血管損傷部とともに完全に閉塞した。再度外頸動脈撮影で完全止血を確認し、手技を終了とした。術後経過は良好で再出血もなく、塞栓術後2週間で退院となった。

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01228&link_issn=&doc_id=20120124070013&doc_link_id=10.11477%2Fmf.1436101628&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436101628&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

[Usefulness of endovascular treatment for delayed massive epistaxis following endoscopic endonasal transsphenoidal surgery: a case report].

Tetsuo Oka, Kenji Sugiu, Joji Ishida, Tomohito Hishikawa, Shigeki Ono, Koji Tokunaga, Isao Date

No shinkei geka. Neurological surgery 40 ( 1 ) 55 - 60 2012年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report here a case of massive nasal bleeding from the sphenopalatine artery three weeks after endonasal transsphenoidal surgery. This 66-year-old male suffered from massive nasal bleeding with the status of hypovolemic shock. Under general anesthesia, an emergent angiography revealed an extravasation from the sphenopalatine artery. Trans-arterial embolization using coil and n-butyl-cyanoacrylate (NBCA) was performed following the diagnostic angiography. Complete occlusion of the injured artery was achieved. The patient showed good recovery from general anesthesia. Delayed nasal bleeding after endonasal transsphenoidal surgery is a rare but important complication. The sphenopalatine artery and its branch are located in the hidden inferior lateral corner of the sphenoid sinus and may be injured during enlargement of the sphenoid opening. When massive delayed nasal bleeding follows transsphenoidal surgery and damage of the internal carotid artery has been ruled out, endovascular treatment of the external carotid artery should be considered.

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