2025/06/19 更新

お知らせ

 

写真a

オツジ　リヨウスケ
尾辻 亮介
OTSUJI RYOSUKE
所属
九州大学病院 脳神経外科 助教
医学部 医学科（併任）
職名
助教

研究分野

  • ライフサイエンス / 脳神経外科学

学位

  • 博士（医学） （ 2024年3月 九州大学 ）

経歴

  • 九州大学 九州大学病院 脳神経外科  助教 

    2024年4月 - 現在

受賞

  • がん研究助成金　優秀賞

    2023年12月   公益財団法人ふくおか公衆衛生推進機構  

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    受賞区分：出版社・新聞社・財団等の賞 

論文

  • Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma 査読 国際誌

    Otsuji, R; Hata, N; Yamamoto, H; Kuga, D; Hatae, R; Sangatsuda, Y; Fujioka, Y; Noguchi, N; Sako, A; Togao, O; Yoshitake, T; Nakamizo, A; Mizoguchi, M; Yoshimoto, K

    NEURO-ONCOLOGY ADVANCES   6 ( 1 )   vdae069   2024年7月   （ eISSN:2632-2498 ）

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    担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuro-Oncology Advances  

    Background. Homozygous deletion of the tumor suppression genes cyclin‑dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH‑mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH‑ mutant and 1p/19q‑codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH‑mutant gliomas. Methods. We enrolled 101 adults with IDH‑mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation‑dependent probe amplification (MLPA). Immunohistochemical anal‑ ysis of p16/MTAP and promoter methylation analysis with methylation‑specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan − Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression‑free survival. Results. Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16‑negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16‑negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozy‑ gous deletion, hemizygous deletion, and copy‑neutral groups (median OS: 38.5, 59.5, and 93.1 months, respec‑ tively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively. Conclusions. CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combina‑ tion with conventional molecular diagnosis.

    DOI： 10.1093/noajnl/vdae069

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  • Supramaximal Resection Can Prolong the Survival of Patients with Cortical Glioblastoma: A Volumetric Study 査読 国際誌

    Otsuji, R; Hata, N; Funakoshi, Y; Kuga, D; Togao, O; Hatae, R; Sangatsuda, Y; Fujioka, Y; Takigawa, K; Sako, A; Kikuchi, K; Yoshitake, T; Yamamoto, H; Mizoguchi, M; Yoshimoto, K

    NEUROLOGIA MEDICO-CHIRURGICA   63 ( 8 )   364 - 374   2023年8月   （ ISSN:04708105 eISSN:13498029 ）

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    担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本脳神経外科学会  

    We aimed to retrospectively determine the resection rate of fluid-attenuated inversion recovery (FLAIR) lesions to evaluate the clinical effects of supramaximal resection (SMR) on the survival of patients with glioblastoma (GBM). Thirty-three adults with newly diagnosed GBM who underwent gross total tumor resection were enrolled. The tumors were classified into cortical and deep-seated groups according to their contact with the cortical gray matter. Pre-and postoperative FLAIR and gadolinium-enhanced T1-weighted imaging tumor volumes were measured using a three-dimensional imaging volume analyzer, and the resection rate was calculated. To evaluate the association between SMR rate and outcome, we subdivided patients whose tumors were totally resected into the SMR and non-SMR groups by moving the threshold value of SMR in 10% increments from 0% and compared their overall survival (OS) change. An improvement in OS was observed when the threshold value of SMR was 30% or more. In the cortical group (n = 23), SMR (n = 8) tended to prolong OS compared with gross total resection (GTR) (n = 15), with the median OS of 69.6 and 22.1 months, respectively (p = 0.0945). Contrastingly, in the deep-seated group (n = 10), SMR (n = 4) significantly shortened OS compared with GTR (n = 6), with median OS of 10.2 and 27.9 months, respectively (p = 0.0221). SMR could help prolong OS in patients with cortical GBM when 30% or more volume reduction is achieved in FLAIR lesions, although the impact of SMR for deep-seated GBM must be validated in larger co-horts.

    DOI： 10.2176/jns-nmc.2022-0351

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    CiNii Research

  • Liquid biopsy with multiplex ligation-dependent probe amplification targeting cell-free tumor DNA in cerebrospinal fluid from patients with adult diffuse glioma 査読 国際誌

    Otsuji, R; Fujioka, Y; Hata, N; Kuga, D; Sangatsuda, Y; Takigawa, K; Funakoshi, Y; Sako, A; Yamamoto, H; Nakamizo, A; Mizoguchi, M; Yoshimoto, K

    NEURO-ONCOLOGY ADVANCES   5 ( 1 )   vdac178   2023年1月   （ eISSN:2632-2498 ）

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    担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuro-Oncology Advances  

    Background: Copy number alterations (CNAs) are common in diffuse gliomas and have been shown to have diagnostic significance. While liquid biopsy for diffuse glioma has been widely investigated, techniques for detecting CNAs are currently limited to methods such as next-generation sequencing. Multiplex ligation-dependent probe amplification (MLPA) is an established method for copy number analysis in pre-specified loci. In this study, we investigated whether CNAs could be detected by MLPA using patients' cerebrospinal fluid (CSF). Methods: Twenty-five cases of adult diffuse glioma with CNAs were selected. Cell-free DNA (cfDNA) was extracted from the CSF, and DNA sizes and concentrations were recorded. Twelve samples, which had appropriate DNA sizes and concentrations, were subsequently used for analysis. Results: MLPA could be successfully performed in all 12 cases, and the detected CNAs were concordant with those detected using tumor tissues. Cases with epidermal growth factor receptor (EGFR) amplification, combination of gain of chromosome 7 and loss of chromosome 10, platelet-derived growth factor receptor alpha amplification, cyclin-dependent kinase 4 amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion were clearly distinguished from those with normal copy numbers. Moreover, EGFR variant III was accurately detected based on CNA. Conclusions: Thus, our results demonstrate that copy number analysis can be successfully performed by MLPA of cfDNA extracted from the CSF of patients with diffuse glioma.

    DOI： 10.1093/noajnl/vdac178

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  • Analysis of clinical, histological, and genomic information of molecular glioblastoma in a Japanese glioma cohort

    Makino, R; Bajagain, M; Higa, N; Akahane, T; Yonezawa, H; Uchida, H; Takajo, T; Kirishima, M; Yokoyama, S; Otsuji, R; Fujioka, Y; Kuga, D; Yamahata, H; Kurosaki, M; Yamamoto, J; Yoshimoto, K; Tanimoto, A; Hanaya, R

    BRAIN TUMOR PATHOLOGY   2025年4月   （ ISSN:1433-7398 eISSN:1861-387X ）

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    記述言語：英語   出版者・発行元：Brain Tumor Pathology  

    In the 2021 WHO Central Nervous System tumor classification, the “Glioblastoma, IDH-wildtype” diagnosis changed markedly. In a Japanese cohort, we compared the clinical backgrounds and prognoses of molecular glioblastoma (mGBM) and conventional glioblastoma (histological glioblastoma, hGBM). We included 270 patients with glioblastoma treated at five institutions during 2011–2023. Driver gene analysis was performed using a brain tumor-specific custom gene panel to verify the association between molecular and clinical information. Patients with mGBM had better preoperative KPS, lower Ki-67, and lower removal rates than did those with hGBM. Overall survival was longer in patients with mGBM than in those with hGBM (1207 vs 599 days, p = 0.037). TP53 mutation (hazard ratio: 5.33, 95% confidence interval: 0.26–108.7, p = 0.012) and histological grade 3 (p = 0.051) were poor prognostic factors for mGBM. Patients with mGBM had better preoperative KPS, worse removal rates, lower Ki-67 labeling index, and better overall survival than did those with hGBM. In addition, the histological grade of mGBM is potentially useful for estimating prognosis. In the WHO CNS5 2021, glioblastoma patients remain a heterogeneous population, and prognostic stratification based on the patient’s clinical background and molecular information is desirable.

    DOI： 10.1007/s10014-025-00500-8

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  • The cortical high-flow sign in oligodendroglioma, IDH-mutant and 1p/19q-codeleted is correlated with histological cortical vascular density

    Yamashita, K; Murayama, R; Itoyama, M; Kikuchi, K; Kusunoki, M; Kuga, D; Hatae, R; Fujioka, Y; Otsuji, R; Fujita, N; Yoshimoto, K; Ishigami, K; Togao, O

    NEURORADIOLOGY   67 ( 2 )   291 - 298   2025年1月   （ ISSN:0028-3940 eISSN:1432-1920 ）

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    記述言語：英語   出版者・発行元：Neuroradiology  

    Background and purpose: The cortical high-flow sign has been more commonly reported in oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG IDHm-codel) compared to diffuse glioma with IDH-wildtype or astrocytoma, IDH-mutant. Besides tumor types, higher grades of glioma might also contribute to the cortical high flow. Therefore, we investigated whether the histological cortical vascular density or CNS WHO grade was associated with the cortical high-flow sign in patients with ODG IDHm-codel. Materials and methods: This retrospective study consisted of pathologically confirmed 25 adult patients with ODG IDHm-codel. We implemented pseudo-continuous arterial spin labeling technique with background suppression. Subtraction images were generated from paired control and label images. Tumor-affecting cortices without intense contrast enhancement on conventional MR imaging were targeted for the determination of the cortical high-flow sign. Immunohistochemical staining of CD31 antibody was performed for the identification of vascular endothelial cells. A microscopic field of the most intense vascularization was captured in each specimen. The vessel number and the relative vascular density (%Vessel) were compared between the positive cortical high-flow sign (CHFS<sup>+</sup>) and the negative cortical high-flow sign (CHFS<sup>−</sup>) groups using the Mann–Whitney U test. Second, Fisher’s exact test was used to compare the difference between the presence or absence of cortical high-flow sign and CNS WHO grades. Finally, the vessel number and %Vessel were compared between the CNS WHO grade 2 and grade 3 using the Mann–Whitney U test. Results: The vessel number and %Vessel were higher in patients with the CHFS<sup>+</sup> group than in patients with CHFS<sup>−</sup> group (p = 0.016 and p = 0.005, respectively). We observed no significant differences (p = 1.00) in the frequency of cortical high-flow sign between the CNS WHO grade 2 and grade 3. In addition, no significant differences are found in the vessel number and %Vessel between the CNS WHO grade 2 and grade 3 (p = 0.121 and p = 0.475, respectively). Conclusion: The cortical high-flow sign on ASL, which is more commonly found in ODG IDHm-codel than in diffuse glioma with IDH-wildtype or astrocytoma, is associated with the histological cortical vascular density in patients with ODG IDHm-codel.

    DOI： 10.1007/s00234-024-03538-1

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  • Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

    Miki K, Yagi M, Hatae R, Otsuji R, Miyazaki T, Goto K, Setoyama D, Fujioka Y, Sangatsuda Y, Kuga D, Higa N, Takajo T, Hajime Y, Akahane T, Tanimoto A, Hanaya R, Kunisaki Y, Uchiumi T, Yoshimoto K

    Cancer & metabolism   12 ( 1 )   35   2024年11月   （ ISSN:2049-3002 eISSN:2049-3002 ）

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  • All-in-one bimodal DNA and RNA next-generation sequencing panel for integrative diagnosis of glioma

    Higa N., Akahane T., Kirishima M., Yonezawa H., Makino R., Uchida H., Yokoyama S., Takajo T., Otsuji R., Fujioka Y., Sangatsuda Y., Kuga D., Yamahata H., Hata N., Horie N., Kurosaki M., Yamamoto J., Yoshimoto K., Tanimoto A., Hanaya R.

    Pathology, research and practice   263   155598   2024年11月   （ ISSN:0344-0338 eISSN:1618-0631 ）

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    記述言語：英語   出版者・発行元：Pathology, research and practice  

    Previously, we constructed a DNA-based next-generation sequencing (NGS) panel for an integrated diagnosis of gliomas according to the 2021 World Health Organization classification system. The aim of the current study was to evaluate the feasibility of a modified panel to include fusion gene detection via RNA-based analysis. Using this bimodal DNA/RNA panel, we analyzed 210 cases of gliomas and others to identify fusion genes in addition to gene alterations, including TERT promoter (TERTp) mutation and 1p/19q co-deletion, in formalin-fixed paraffin-embedded tissues. Of the 210 patients, fusion genes were detected in tumors of 35 patients. Eighteen of 112 glioblastomas (GBs) harbored fusion genes, including EGFR and FGFR3 fusions. In IDH-mutant astrocytoma, 6 of 30 cases showed fusion genes such as MET and NTRK2 fusions. Eleven molecular GBs and 20 not-elsewhere-classified cases harbored no gene fusions. Other 11 tumors including ependymoma, pilocytic astrocytoma, diffuse hemispheric glioma, infant-type hemispheric glioma, and solitary fibrous tumors exhibited diagnostic fusion genes. Overall, our results suggest that the all-in-one bimodal DNA/RNA panel is reliable for detecting diagnostic gene alterations in accordance with the latest WHO classification. The integrative pathological and molecular strategy could be valuable in confirmation of diagnosis and selection of treatment options for brain tumors.

    DOI： 10.1016/j.prp.2024.155598

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  • In-house molecular diagnosis of diffuse glioma updating the revised WHO classification by a platform of the advanced medical care system, Senshin-Iryo

    Hata, N; Fujioka, Y; Otsuji, R; Kuga, D; Hatae, R; Sangatsuda, Y; Amemiya, T; Noguchi, N; Sako, A; Fujiki, M; Mizoguchi, M; Yoshimoto, K

    NEUROPATHOLOGY   44 ( 5 )   344 - 350   2024年10月   （ ISSN:0919-6544 eISSN:1440-1789 ）

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    記述言語：英語   出版者・発行元：Neuropathology  

    Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in-house, molecular diagnostic platform using Senshin-Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin-Iryo as “Drug resistance gene testing for anticancer chemotherapy” and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation-dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin-Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system.

    DOI： 10.1111/neup.12970

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  • 改訂WHO分類が更新する過程で、先進医療制度のプラットフォームで実施したびまん性神経膠腫の施設内分子診断(In-house molecular diagnosis of diffuse glioma updating the revised WHO classification by a platform of the advanced medical care system, Senshin-Iryo)

    Hata Nobuhiro, Fujioka Yutaka, Otsuji Ryosuke, Kuga Daisuke, Hatae Ryusuke, Sangatsuda Yuhei, Amemiya Takeo, Noguchi Naoki, Sako Aki, Fujiki Minoru, Mizoguchi Masahiro, Yoshimoto Koji

    NEUROPATHOLOGY   44 ( 5 )   344 - 350   2024年10月   （ ISSN:0919-6544 ）

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    記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

    先進医療制度を利用して確立した、びまん性神経膠腫の施設内分子診断プラットフォームを5年間使用して得た成果をまとめた。本プラットフォームでは、IDH・BRAF・H3の各遺伝子の点突然変異、染色体1p/19q・10番染色体・17番染色体のヘテロ接合性喪失(LOH)、およびMGMT遺伝子のメチル化を解析する検査をワンセットにして先進医療の「抗悪性腫瘍剤治療における薬剤耐性遺伝子検査」として申請し、2018年8月に承認された。2021年10月にはTERT遺伝子プロモーター変異を標的とするSanger法塩基配列検査も上記の検査セットに追加した。同時にLOH解析法をMLPA法に置き換える変更も加えた。MLPA法での検査対象は、1p/19q共欠失と、WHO分類2021年版で新たに必要となったEGFR、PTEN、CDKN2Aといった遺伝子マーカーとした。WHO分類2021年改訂後、本先進医療検査での分子マーカー所見によって診断が確定した症例は54名中38名(70.1%)に上った。残り16名のうち4名(7.4%)は「びまん性神経膠腫、NEC」と診断され、12名は膠芽腫と病理組織診断された。これまで日本の医療制度下では、改訂を続けるWHO分類の移行期に臨床現場でジレンマが発生してきた。本研究で行った先進医療の試みは、その移行期を乗り切るための救済システムとして機能したことが示された。

  • OUTCOME IMPACT OF THE CDKN2A/B HEMI-ZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA

    Otsuji, R; Hata, N; Yamamoto, H; Kuga, D; Hatae, R; Sangatsuda, Y; Fujioka, Y; Noguchi, N; Nakamizo, A; Mizoguchi, M; Yoshimoto, K

    NEURO-ONCOLOGY   25   2023年11月   （ ISSN:1522-8517 eISSN:1523-5866 ）

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  • Supramaximal resectionは皮質神経膠腫患者の生存期間を延長させる　容積測定による研究(Supramaximal Resection Can Prolong the Survival of Patients with Cortical Glioblastoma: A Volumetric Study)

    Otsuji Ryosuke, Hata Nobuhiro, Funakoshi Yusuke, Kuga Daisuke, Togao Osamu, Hatae Ryusuke, Sangatsuda Yuhei, Fujioka Yutaka, Takigawa Kosuke, Sako Aki, Kikuchi Kazufumi, Yoshitake Tadamasa, Yamamoto Hidetaka, Mizoguchi Masahiro, Yoshimoto Koji

    Neurologia medico-chirurgica   63 ( 8 )   364 - 374   2023年8月   （ ISSN:0470-8105 ）

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    記述言語：英語   出版者・発行元：(一社)日本脳神経外科学会  

    膠芽腫患者を対象とした後ろ向き研究を実施し、FLAIR病変切除率を評価することで、supramaximal resection(SMR)の臨床効果について検討した。2006年12月～2018年8月に神経膠腫と診断された成人患者のうち、肉眼的全切除(GTR)が施行された成人33例(年齢中央値64歳、男性19例)を対象とした。評価項目は腫瘍切除率(手術前後のFLAIRおよびガドリニウム強調T1強調画像の腫瘍体積を3D画像体積分析装置により測定)、SMR率(0%から10%刻み)などとした。腫瘍を皮質灰白質との接触により、皮質群23例(SMR 8例、GTR 15例)、深在性群10例(SMR 4例、全切除6例)に分けて検討した。その結果、SMR閾値が30%以上の場合に全生存期間の改善が観察された。皮質群ではGTRと比較してSMRで全生存期間が延長する傾向が認められた(69.6ヵ月対22.1ヵ月)。一方、深在群ではGTRと比較してSMRで全生存期間が有意に短縮していた(10.2ヵ月対27.9ヵ月、p=0.0221)。以上から、FLAIR病変のsupramaximal resectionは神経膠腫患者の生存期間を延長可能であることが示された。

  • 急速な自然血栓化をきたし親血管閉塞にいたった右内頸動脈海綿静脈洞部大型動脈瘤の1例

    尾辻 亮介, 天野 敏之, 宮松 雄一郎, 原 健太, 徳永 聡, 中溝 玲

    脳卒中の外科   51 ( 4 )   302 - 306   2023年8月   （ ISSN:0914-5508 ）

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    記述言語：日本語   出版者・発行元：(一社)日本脳卒中の外科学会  

    脳動脈瘤に血栓化が生じることがあるが,親動脈まで血栓が進展し閉塞にいたることはまれである.右内頸動脈海綿静脈洞部大型動脈瘤で内頸動脈偽閉塞をきたした1例を経験した.症例は55歳女性.原発性アルドステロン症に対し通院治療中であった.無症候であったが,頭部MRIで右内頸動脈海綿静脈洞部に大型脳動脈瘤を指摘された.血管撮影,バルーン閉塞試験(BOT)を含めた精査を行った.初回の血管撮影では動脈瘤内に血栓はなかった.BOT後7日目に突然頭痛,嘔吐,右眼痛,右眼瞼下垂をきたした.画像検査の結果,動脈瘤の血栓化と右内頸動脈の血栓による血流遅延および右中大脳動脈領域の梗塞をきたしていた.本例は側副血行路が発達しており,梗塞は血栓による遠位塞栓と考えた.さらなる血栓化と順行性の血流による塞栓症増悪の危険があると評価した.BOTでは対側比で10%程度の脳血流低下の所見であり,浅側頭動脈-中大脳動脈(STA-M4)bypass併用下で頸部内頸動脈結紮術を施行する方針とした.術後,右眼痛,眼瞼下垂は消失し,神経脱落症状はなく,新規梗塞巣もなかった.大型脳動脈瘤による親血管の閉塞はまれであり,原因は不明である.その一因としてBOTによる一時的な内頸動脈遮断が血行動態に変化を生じ血栓形成に影響した可能性がある.(著者抄録)

  • Induction of glioblastoma cell ferroptosis using combined treatment with chloramphenicol and 2-deoxy-d-glucose

    Miki, K; Yagi, M; Noguchi, N; Do, Y; Otsuji, R; Kuga, D; Kang, DC; Yoshimoto, K; Uchiumi, T

    SCIENTIFIC REPORTS   13 ( 1 )   10497   2023年6月   （ ISSN:2045-2322 ）

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    記述言語：英語   出版者・発行元：Scientific Reports  

    Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-d-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.

    DOI： 10.1038/s41598-023-37483-5

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  • Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma

    Higa, N; Akahane, T; Yokoyama, S; Makino, R; Yonezawa, H; Uchida, H; Takajo, T; Kirishima, M; Hamada, T; Noguchi, N; Otsuji, R; Kuga, D; Nagasaka, S; Yamahata, H; Yamamoto, J; Yoshimoto, K; Tanimoto, A; Hanaya, R

    NEURO-ONCOLOGY ADVANCES   5 ( 1 )   vdad078   2023年1月   （ eISSN:2632-2498 ）

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    記述言語：英語   出版者・発行元：Neuro-Oncology Advances  

    Background: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas. Methods: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH. Results: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients. Conclusions: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

    DOI： 10.1093/noajnl/vdad078

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  • 中硬膜動脈塞栓術に続いて施行した開頭術後に生じた慢性硬膜下血腫　1症例報告(Chronic Subdural Hematoma after Craniotomy with Preoperative Embolization of Middle Meningeal Artery: A Case Report)

    Otsuji Ryosuke, Amano Toshiyuki, Matsuo Satoshi, Miyamatsu Yuichiro, Hara Kenta, Tokunaga So, Nakamizo Akira

    NMC Case Report Journal   9 ( 1 )   151 - 155   2022年12月

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    記述言語：英語   出版者・発行元：(一社)日本脳神経外科学会  

    症例は56歳男性で、複視を訴えて受診した。MRIで右蝶形骨縁に3cm径の腫瘍を認め、右中硬膜動脈の選択的血管造影でanterior convexity branchからの腫瘍濃染像を認めた。まずトリスアクリルゼラチンマイクロスフィアおよびプラチナコイルを用いて右中硬膜動脈のanterior convexity branchに塞栓術を施行し、翌日に腫瘍の完全切除を施行した。病理診断はgrade IIの蝶形骨縁髄膜腫であった。2ヵ月後、頭痛と左片麻痺を訴え、CTで15mm厚の慢性硬膜下血腫とmidline shiftを認めた。穿頭洗浄ドレナージ術を行った。その結果、頭痛と左片麻痺は速やかに消失した。3ヵ月経過時点で血腫は認めていない。

  • Changes in the Relapse Pattern and Prognosis of Glioblastoma After Approval of First-Line Bevacizumab: A Single-Center Retrospective Study

    Funakoshi, Y; Takigawa, K; Hata, N; Kuga, D; Hatae, R; Sangatsuda, Y; Fujioka, Y; Otsuji, R; Sako, A; Yoshitake, T; Togao, O; Hiwatashi, A; Iwaki, T; Mizoguchi, M; Yoshimoto, K

    WORLD NEUROSURGERY   159   E479 - E487   2022年3月   （ ISSN:1878-8750 eISSN:1878-8769 ）

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    記述言語：英語   出版者・発行元：World Neurosurgery  

    Background: Controversies exist regarding the aggressive recurrence of glioblastoma after bevacizumab treatment. We analyzed the clinical impact of bevacizumab approval in Japan by evaluating the clinical course and relapse pattern in patients with glioblastoma. Methods: We included 100 patients with IDH-wild-type glioblastoma from September 2006 to February 2018 in our institution. The patients were classified into the pre-bevacizumab (n = 51) and post-bevacizumab (n = 49) groups. Overall, progression-free, deterioration-free, and postprogression survivals were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were evaluated. Results: Significant improvement in progression-free (pre-bevacizumab, 7.5 months; post-bevacizumab, 9.9 months; P = 0.0153) and deterioration-free (pre-bevacizumab, 8.5 months; post-bevacizumab, 13.8 months; P = 0.0046) survivals was seen. These survival prolongations were strongly correlated (r: 0.91, P < 0.0001). The nonenhancing tumor pattern was novel in the post-bevacizumab era (5 of 33). The presence of a nonenhancing tumor did not indicate poor postprogression survival (hazard ratio: 0.82 [0.26–2.62], P = 0.7377). The rate of early focal recurrence was significantly lower (P = 0.0155) in the post-bevacizumab (4 of 33) than in the pre-bevacizumab (18 of 39) era. There was a significant decrease in early focal recurrence after approval of bevacizumab in patients with unresectable tumors (P = 0.0110). The treatment era was significantly correlated with a decreased rate of early focal recurrence (P = 0.0021, univariate analysis; P = 0.0144, multivariate analysis). Conclusions: Approval of first-line bevacizumab in Japan for unresectable tumors may prevent early progression and clinical deterioration of glioblastoma without worsening the clinical course after relapse.

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  • Prognostic impact of PDGFRA gain/amplification and MGMT promoter methylation status in patients with IDH wild-type glioblastoma

    Higa, N; Akahane, T; Yokoyama, S; Yonezawa, H; Uchida, H; Takajo, T; Otsuji, R; Hamada, T; Matsuo, K; Kirishima, M; Hata, N; Hanaya, R; Tanimoto, A; Yoshimoto, K

    NEURO-ONCOLOGY ADVANCES   4 ( 1 )   vdac097   2022年1月   （ eISSN:2632-2498 ）

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    記述言語：英語   出版者・発行元：Neuro-Oncology Advances  

    Background: Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM. Methods: Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status. Results: We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P =. 003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P =. 031), higher Ki-67 score (P =. 019), and lower extent of surgical resection (P =. 033). Unmethylated MGMTp also predicted poor prognosis (P =. 005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P <. 001). Conclusions: Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.

    DOI： 10.1093/noajnl/vdac097

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講演・口頭発表等

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MISC

  • Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid 査読 国際誌

    Otsuji, R; Fujioka, Y; Hata, N; Kuga, D; Hatae, R; Sangatsuda, Y; Nakamizo, A; Mizoguchi, M; Yoshimoto, K

    CANCERS   16 ( 5 )   2024年3月   （ ISSN:2072-6694 eISSN:2072-6694 ）

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    担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：Cancers  

    Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood–brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.

    DOI： 10.3390/cancers16051009

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  • 【Endosome、Lysosome、Exosome-小胞とは?】Exosomeと疾患　脳腫瘍

    尾辻 亮介, 藤岡 寛, 溝口 昌弘

    Clinical Neuroscience   40 ( 7 )   885 - 888   2022年7月   （ ISSN:0289-0585 ）

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    記述言語：日本語   出版者・発行元：(株)中外医学社  

所属学協会

  • 日本脳神経外科学会

  • 日本脳腫瘍学会

  • 日本脳腫瘍病理学会

  • 日本神経内視鏡学会

  • 日本脳卒中学会

  • 日本脳卒中の外科学会

  • 日本脳血管内治療学会

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共同研究・競争的資金等の研究課題

専門診療領域

  • 生物系／医歯薬学／外科系臨床医学／脳神経外科学

臨床医資格

  • 専門医

    日本脳神経外科学会

  • 指導医

    日本脳卒中学会

  • 専門医

    日本脳神経血管内治療学会