大学院医学系研究科
医学専攻
English
更新日：2024/12/26
助教
ﾔﾏｼﾀ　ﾀﾞｲｽｹ
山下　大介

経歴

  1. 2006/04-2008/03愛媛県立中央病院臨床研修医
  2. 2008/04-2014/03愛媛大学大学院 医学系研究科脳神経外科学医員
  3. 2013/06-2013/10北海道大学遺伝子病制御研究所 幹細胞生物学分野特別研究学生
  4. 2014/04-2017/04愛媛大学大学院 医学系研究科脳神経外科学助教
  5. 2014/06-2014/07北海道大学遺伝子病制御研究所 幹細胞生物学分野特別研究学生
  6. 2017/04-2017/10ブリガムアンドウィメンズホスピタル / ハーバード大学脳神経外科博士研究員
  7. 2017/11-2020/03アラバマ大学バーミングハム校脳神経外科博士研究員
  8. 2020/04-現在愛媛大学大学院 医学系研究科脳神経外科学助教

学歴

  1. 愛媛大学2006/03
  2. 愛媛大学大学院2015/03

学位

  1. 医学博士愛媛大学

研究分野

  1. ライフサイエンス腫瘍生物学
  2. ライフサイエンス腫瘍診断、治療学
  3. ライフサイエンス脳神経外科学

研究キーワード

  1. 老化
  2. アンチエイジング
  3. バイオマーカー
  4. エクソソーム
  5. グリオーマ幹細胞
  6. 脳腫瘍
  7. グリオーマ
  8. マイクロRNA

共同研究・競争的資金等の研究課題

  1. 老化に伴う脳腫瘍悪性化の脳内分子メカニズムの解明と新規治療戦略若手研究2022/04-2025/03競争的資金
  2. 北海道大学遺伝子病制御研究所一般共同研究老化が及ぼす脳腫瘍悪性化の脳内分子メカニズムの解明2022/04-2023/03
  3. 公益財団法人鈴木謙三記念医科学応用研究財団令和3年度調査研究老化に伴う脳腫瘍悪性化の脳内分子メカニズムの解明と新規治療戦略2022/01-2022/12競争的資金
  4. 北海道大学遺伝子病制御研究所一般共同研究社会的孤立がもたらす脳腫瘍悪性化のメカニズム2021/04-2022/03
  5. 北海道大学共同利用・共同研究拠点（一般共同研究）グリオーマの腫瘍辺縁における再発様式の解明と治療戦略2020/04-2021/03
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論文

  1. Berberine as a potential enhancer for 5-ALA-mediated fluorescence in glioblastoma: increasing detectability of infiltrating glioma stem cells to optimize 5-ALA-guided surgery.2024/03/08Ohtsuka Yoshihiro,Suehiro Satoshi,Inoue Akihiro,Ohnishi Takanori,Nishikawa Masahiro,Yamashita Daisuke,Yano Hajime,Choudhury Mohammed E,Ozaki Saya,Sampetrean Oltea,Saya Hideyuki,Watanabe Hideaki,Tanaka Junya,Kunieda TakeharuJournal of neurosurgery1-1110.3171/2023.12.JNS231506The prognosis of glioblastoma (GBM) correlates with residual tumor volume after surgery. In fluorescence-guided surgery, 5-aminolevulinic acid (ALA) has been used to maximize resection while avoiding neurological morbidity. However, not all tumor cells, particularly glioma stem cells (GSCs), display 5-ALA-mediated protoporphyrin IX (PpIX) fluorescence (5-ALA fluorescence). The authors searched for repositioned drugs that affect mitochondrial functions and energy metabolism, identifying berberine (BBR) as a potential enhancer of 5-ALA fluorescence. In this study, they investigated whether BBR can enhance 5-ALA fluorescence in GSCs and whether BBR can be applied to clinical practice as a 5-ALA fluorescence enhancer.The effects of BBR on 5-ALA fluorescence in glioma and GSCs were evaluated by flow cytometry (fluorescence-activated cell sorting [FACS]) analysis. As 5-ALA is metabolized for heme synthesis, the effects of BBR on mRNA expressions of 7 enzymes in the heme-synthesis pathway were analyzed. Enzymes showing significantly higher expression than control in all cells were identified and protein analysis was performed. To examine clinical availability, the detectability and cytotoxicity of BBR in tumor-transplanted mice were analyzed.Fluorescence microscopy revealed much more intense 5-ALA fluorescence in both GSCs and non-stem cells with 5-ALA and BBR than with 5-ALA alone. FACS showed that BBR greatly enhanced 5-ALA fluorescence compared with 5-ALA alone, and enhancement was much higher for GSCs than for glioma cells. Among the 7 enzymes examined, BBR upregulated mRNA expressions of ALA synthetase 1 (ALAS1) more highly in all cells, and activated ALAS1 through deregulating ALAS1 activity inhibited by the negative feedback of heme. An in vivo study showed that 5-ALA fluorescence with 5-ALA and BBR was significantly stronger than with 5-ALA alone, and the sensitivity and specificity of BBR-enhanced fluorescence were both 100%. In addition, BBR did not show any cytotoxicity for normal brain tissue surrounding the tumor mass.BBR enhanced 5-ALA-mediated PpIX fluorescence by upregulating and activating ALAS1 through deregulation of negative feedback inhibition by heme. BBR is a clinically used drug with no side effects. BBR is expected to significantly augment fluorescence-guided surgery and photodynamic therapy.
  2. 専門医に求められる最新の知識 脳腫瘍 2021WHO分類に基づいた成人型びまん性グリオーマの分子分類 : 臨床応用における課題と将来展望2024/01山下 大介, 國枝 武治脳神経外科速報 : 臨床医の人生に伴走するlifetime journal34/ 1, 114-120URL大阪 : メディカ出版
  3. Identification of CD44 as a Reliable Biomarker for Glioblastoma Invasion: Based on Magnetic Resonance Imaging and Spectroscopic Analysis of 5-Aminolevulinic Acid Fluorescence.2023/08/24Inoue Akihiro,Ohnishi Takanori,Nishikawa Masahiro,Watanabe Hideaki,Kusakabe Kosuke,Taniwaki Mashio,Yano Hajime,Ohtsuka Yoshihiro,Matsumoto Shirabe,Suehiro Satoshi,Yamashita Daisuke,Shigekawa Seiji,Takahashi Hisaaki,Kitazawa Riko,Tanaka Junya,Kunieda TakeharuBiomedicines11/ 910.3390/biomedicines11092369Recurrent glioblastoma multiforme (GBM) is largely attributed to peritumoral infiltration of tumor cells. As higher CD44 expression in the tumor periphery correlates with higher risk of GBM invasion, the present study analyzed the relationship between CD44 expression and magnetic resonance imaging (MRI)-based invasiveness of GBM on a large scale. We also quantitatively evaluated GBM invasion using 5-aminolevulinic acid (5-ALA) spectroscopy to investigate the relationship between CD44 expression and tumor invasiveness as evaluated by intraoperative 5-ALA intensity. Based on MRI, GBM was classified as high-invasive type in 28 patients and low-invasive type in 22 patients. High-invasive type expressed CD44 at a significantly higher level than low-invasive type and was associated with worse survival. To quantitatively analyze GBM invasiveness, the relationship between tumor density in the peritumoral area and the spectroscopic intensity of 5-ALA was investigated. Spectroscopy showed that the 5-ALA intensity of infiltrating tumor cells correlated with tumor density as represented by the Ki-67 staining index. No significant correlation between CD44 and degree of 5-ALA-based invasiveness of GBM was found, but invasiveness of GBM as evaluated by 5-ALA matched the classification from MRI in all except one case, indicating that CD44 expression at the GBM periphery could provide a reliable biomarker for invasiveness in GBM.
  4. Usefulness of intraoperative rapid immunohistochemistry in the surgical treatment of brain tumors.2023/06Inoue Akihiro,Watanabe Hideaki,Kondo Takuya,Katayama Eiji,Miyazaki Yukihiro,Suehiro Satoshi,Yamashita Daisuke,Taniwaki Mashio,Kurata Mie,Shigekawa Seiji,Kitazawa Riko,Kunieda TakeharuNeuropathology : official journal of the Japanese Society of Neuropathology43/ 3, 209-22010.1111/neup.12864In the treatment of primary central nervous system lymphoma (PCNSL), intraoperative rapid pathological diagnosis can dramatically change the surgical strategy, and more accurate diagnostic methods are required. In April 2020, we adopted intraoperative rapid immunohistochemistry (IHC) in addition to conventional rapid intraoperative diagnosis based on morphological assessment, mainly for patients with PCNSL. Here, we investigate the usefulness and significance of intraoperative rapid IHC based on our initial experience. We performed intraoperative rapid IHC using antibodies for cluster of differentiation (CD)20, CD3, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) using enzyme-labeled antibody methods in 25 patients, including PCNSL patients, from April 2020 to July 2022. We examined the utility of this approach in determining treatment strategies for brain tumors. Postoperative final pathological diagnoses from paraffin-embedded sections were as follows: diffuse large B-cell lymphoma, 16 cases; glioblastoma, six cases; pilocytic astrocytoma, one case; adenocarcinoma, one case; and inflammatory disorder, one case. The entire process took 32 min and staining for CD20, CD3, LCA, and GFAP was comparable to that using paraffin-embedded sections. In all cases, the results of intraoperative rapid IHC were consistent with final pathological diagnoses from paraffin-embedded sections. In addition, in two cases, the results of conventional intraoperative rapid pathological diagnosis based on morphological assessments using frozen sections were drastically changed by adding intraoperative rapid IHC. Intraoperative rapid IHC contributes to deciding appropriate treatment strategies and facilitating early initiation of chemotherapy for PCNSL. This may allow new therapeutic strategies not only for PCNSL but also for other brain tumors.
  5. What is the Best Preoperative Quantitative Indicator to Differentiate Primary Central Nervous System Lymphoma from Glioblastoma?2023/04Inoue Akihiro,Matsumoto Shirabe,Ohnishi Takanori,Miyazaki Yukihiro,Kinnami Shingo,Kanno Kazuhisa,Honda Takatsugu,Kurata Mie,Taniwaki Mashio,Kusakabe Kosuke,Suehiro Satoshi,Yamashita Daisuke,Shigekawa Seiji,Watanabe Hideaki,Kitazawa Riko,Kunieda TakeharuWorld neurosurgery172, e517-e52310.1016/j.wneu.2023.01.065The role of surgery in primary central nervous system lymphoma (PCNSL) is to allow pathological diagnosis from tumor biopsy. However, PCNSL is often difficult to distinguish from other tumors, particularly glioblastoma multiforme (GBM). Quantitative evaluations to facilitate differentiation between PCNSL and GBM would be useful. Here, we investigated the best examinations for exact differentiation of PCNSL from GBM among preoperative examinations, including imaging studies and tumor markers.Various examinations were performed for 68 patients with PCNSL , including serum soluble interleukin 2 receptor, β2-microglobulin (MG) in cerebrospinal fluid (CSF), diffusion-weighted imaging, C-methionine-positron emission tomography (PET), and F-fluorodeoxyglucose (FDG)-PET. These results were compared with findings from 28 patients with consecutive GBM who underwent the same examinations to evaluate the utility and accuracy of different investigations.CSF β2-MG ≥2.0 mg/L was relatively specific for PCNSL, offering 95.0% sensitivity and 85.7% specificity. Tumor-to-contralateral normal brain tissue ratio ≥2.4 on F-FDG-PET was also quite specific for PCNSL, offering 83.8% sensitivity and 95.2% specificity. No other examinations displayed any significant differences in quantitative differential markers between PCNSL and GBM.Both β2-MG ≥2.0 mg/dL in CSF and tumor-to-contralateral normal brain tissue ratio ≥2.4 from F-FDG-PET allow quantitative differentiation of PCNSL from GBM, potentially representing clinically useful indicators. These findings could lead to innovative methods for differentiating PCNSL from GBM as well as new treatment strategies for other brain tumors.
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講演・口頭発表等

  1. 複数本のEnterprise VRDを用いて治療した破裂椎骨動脈解離性動脈瘤の1例STOROKE 20162016/04/15
  2. 神経膠腫の悪性度診断におけるMRSの有用性－連続100例による検討－第39回 日本脳神経CI学会総会2016/01/29
  3. エクソソーム内microRNAプロファイリングによるグリオーマ幹細胞特異的microRNAの同定第33回 日本脳腫瘍学会学術集会2015/12/06
  4. miR-340 acts as a tumor suppressor in tumorigenesis of human glioma-initiating cells by targeting tissue plasminogen activator20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology2015/11/20
  5. 自験例によるanaplastic hemangiopericytoma の臨床病理学的特徴に関する検討第74回 日本脳神経外科学会学術総会2015/10/16
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産業財産権

  1. 特許権グリオーマ形成阻害作用を有するmicroRNA特願2013-2382792013/11/18特開2015-0984442015/05/28
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受賞

  1. 2017/02第25回愛媛医学会賞
  2. 2016/03第39回 日本脳神経CI学会総会　優秀演題賞
  3. 2016/03平成27年度 愛媛大学大学院医学系研究科　優秀論文賞
  4. 2015/03平成27年度 愛媛大学大学院医学系研究科　研究奨励賞
  5. 2014/12第32回 日本脳腫瘍学会学術集会　会長賞（優秀ポスター）
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担当授業科目

  1. 2024脳神経外科学
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所属学協会

  1. 2023/01-現在脳神経外科手術と機器学会
  2. 2022/11-現在日本老年脳神経外科学会
  3. 2020/10-現在日本小児神経外科学会
  4. 2020/05-現在日本認知症予防学会
  5. 2020/05-現在日本認知症学会
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