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Faculty of Medicine College Hospital Neurosurgery |
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YAMASHITA Shinji
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Degree 【 display / non-display 】
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博士（医学） ( 2020.3 宮崎大学 )
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学士（医学） ( 2000.3 宮崎医科大学 )
Papers 【 display / non-display 】
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Takami H., Matsutani M., Suzuki T., Takabatake K., Fujimaki T., Okamoto M., Yamaguchi S., Kanamori M., Matsuda K., Sonoda Y., Natsumeda M., Ichinose T., Nakada M., Muroi A., Ishikawa E., Takahashi M., Narita Y., Tanaka S., Saito N., Higuchi F., Shin M., Mineharu Y., Arakawa Y., Kagawa N., Kawabata S., Wanibuchi M., Takayasu T., Yamasaki F., Fujii K., Ishida J., Date I., Miyake K., Fujioka Y., Kuga D., Yamashita S., Takeshima H., Shinojima N., Mukasa A., Asai A., Nishikawa R.
Neuro-Oncology 27 ( 3 ) 828 - 840 2025.3
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Neuro-Oncology
Background. A previous Phase II clinical trial, conducted from 1995 to 2003, evaluated CNS germ cell tumors (GCTs) using a three-group treatment stratification based on histopathology. The primary objective of the study was to assess the long-term efficacy of standardized treatment regimens, while the secondary objective focused on identifying associated long-term complications. Methods. A total of 228 patients were classified into 3 groups for treatment: germinoma (n = 161), intermediate prognosis (n = 38), and poor prognosis (n = 28), excluding one mature teratoma case. Treatment involved stratified chemotherapy regimens and varied radiation doses/coverage. Clinical data was retrospectively analyzed at a median follow-up of 18.5 years. Results. The treatment outcomes for germinoma, with or without syncytiotrophoblastic giant cells, were similar. The 10- and 20-year event-free survival rates for the germinoma, intermediate, and poor prognosis groups were 82/76/49% and 73/66/49%, respectively. Overall survival (OS) rates were 97/87/61% at 10 years and 92/70/53% at 20 years. Germinomas in the basal ganglia, treated without whole-brain radiation therapy (WBRT), frequently relapsed but were effectively managed with subsequent WBRT. Deaths in germinoma cases had varied causes, whereas deaths in the poor prognosis group were predominantly disease-related. Nineteen treatment-related complications were identified in 16 patients, with cumulative event rates of 1.9% at 10 years and 11.3% at 20 years. OS rates at 1 and 2 years post-relapse for tumors initially classified as germinoma, intermediate, and poor prognosis were 94/88/18% and 91/50/9%, respectively. Conclusions. Initial treatment intensity is crucial for managing non-germinomatous GCTs, while long-term follow-up for relapse and complications is imperative in germinomas. Irradiation extending beyond the immediate tumor site is essential for basal ganglia germinomas. Addressing relapse in non-germinomatous GCT remains a significant challenge.
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Motomura K., Sasaki K., Sugii N., Yamaguchi S., Inoue H., Oshima A., Tanaka K., Otani Y., Shirahata M., Shibahara I., Nagane M., Tsuzuki S., Matsutani T., Tsukamoto Y., Kijima N., Asano K., Ohno M., Inoue A., Mineharu Y., Miyake K., Mitobe Y., Hanihara M., Kawanishi Y., Deguchi S., Saito M., Matsuda R., Ujifuku K., Arita H., Sato Y., Yamashita S., Yonezawa U., Yamaguchi J., Momii Y., Ogawa T., Kambe A., Ohba S., Fukai J., Saito N., Kinoshita M., Sumi K., Otani R., Uzuka T., Takebe N., Koizumi S., Saito R., Arakawa Y., Narita Y.
Japanese Journal of Clinical Oncology 54 ( 10 ) 1123 - 1131 2024.10
Authorship：Lead author Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Clinical Oncology
Background: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. Methods: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. Results: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). Conclusions: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.
DOI： 10.1093/jjco/hyae116
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Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma
Yokogami Kiyotaka, Watanabe Takashi, Yamashita Shinji, Mizuguchi Asako, Takeshima Hideo
Journal of Neuro-Oncology 167 ( 3 ) 455 - 465 2024.3
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
PURPOSE
Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target.
METHODS
The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma's growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression.
RESULTS
Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results.
CONCLUSIONS
The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target. -
Matsumoto F., Yokogami K., Yamada A., Moritake H., Watanabe T., Yamashita S., Sato Y., Takeshima H.
Human Cell 37 ( 2 ) 523 - 530 2024.3
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Human Cell
Atypical teratoid/rhabdoid (AT/RT) is a rare and highly malignant tumor of the central nervous system (CNS). It is most commonly found in children less than 5 years of age and is associated with inactivation of loss of function of SMARCB1/INI1. An experimental model for AT/RT is necessary to develop new and effective therapies. We established a patient-derived new cell line (MZ611ATRT), which showed loss of BAF-47. MZ611ATRT genetically features somatic heterozygous deletion of SMARCB1 and single nucleotide deletion of the residual allele, exon 5 ([c.541delC]), resulting in a stop codon at codon 954 by frameshift. We assessed the RNA-sequencing data of the other two AT/RT cell lines with forced expression of SMARCB1 available from public databases. We found SMARCB1 overexpression significantly down-regulates the expression of a group of enzymes related to cholesterol biosynthesis. Simvastatin was highly sensitive against MZ611ATRT cells and induced apoptosis (IC50 was 3.098 µM for MZ611ATRT, 41.88uM for U-87 MG, 23.34uM for IOMM-Lee, and 18.12uM for U-251 MG.). Pathways involved in cholesterol biosynthesis may be new targets for adjuvant therapy of AT/RT.
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TAKEISHI Go, YAMASHITA Shinji, MATSUMOTO Fumitaka, SAITO Kiyotaka, WATANABE Takashi, YONEYAMA Takumi, HINOURA Takuji, OHTA Hajime, YOKOGAMI Kiyotaka, KURODA Yoshiki, TAKESHIMA Hideo, Miyazaki Brain Tumor Research Group
Neurologia medico-chirurgica 64 ( 2 ) 87 - 92 2024.2
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：The Japan Neurosurgical Society
Advances in cancer treatment have improved the survival of patients with cancer, with a concomitant increase in the proportion of patients with metastatic brain tumors (MBTs). In this study, we used cancer registries established in Japan after 2016 and available patient data by organ in order to conduct an accurate epidemiological study. To the best of our knowledge, this is the first study to report on the detailed epidemiological data on MBT at the prefectural level in Japan using the Miyazaki Brain Tumor Database and Miyazaki Cancer Registry. This study included 425 new cases of MBTs diagnosed in Miyazaki Prefecture from 2007 to 2016. As per our findings, the most frequent primary tumor in Miyazaki Prefecture was found to be in the lung (49.4%), followed by colon/rectum/anus (9.4%) and breast (8.5%). Among patients with MBTs, 59.1% were males, a number closely similar to that of Japan, as shown in the Japanese Brain Tumor Registry (55.5%). The median age at diagnosis was 68 and 63 years in Miyazaki Prefecture and Japan, respectively. Although more patients were symptomatic in Miyazaki Prefecture than in Japan (88.5% vs. 15.5%), fewer patients opted for surgery (33.6% vs. 61.9%), probably because of their advanced age at diagnosis. As per the findings of this study, the annual incidence rate of new MBTs (i.e., ratio of the number of new cancer registrations to that of new MBT patients in Miyazaki Prefecture) was at 0.41%. The number of tumor sites in MBTs was independent of the total number of cancers per organ. Considering the expansion of cancer registries worldwide, including those on brain tumors, further epidemiological analysis of MBTs is deemed warranted.
Books 【 display / non-display 】
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悪性脳腫瘍のすべて 化学療法2 中枢神経系胚細胞腫
山下真治 竹島秀雄（ Role： Joint author）
MC メディカ出版 2020.10
Language：Japanese Book type：Scholarly book
Presentations 【 display / non-display 】
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紹介脳生検で脳炎の診断となった悪性リンパ腫頭蓋内再発の1例
山下 真治
第39回日本脳腫瘍学会 2021.12
Event date： 2021.12.4 - 2021.12.6
Presentation type：Poster presentation
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オプチューン 長期使用例と再発例
山下 真治
第4回オプチューンラウンドテーブル 2021.11.23
Event date： 2021.11.23
Presentation type：Oral presentation (general)
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T2-FLAIR mismatch signを呈するlower grade gliomaに関する臨床病理学的検討
山下 真治
第80回日本脳神経外科学会総会 2021.10
Event date： 2021.10.27 - 2021.10.30
Presentation type：Poster presentation
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ベバシズマブ投与終了後に発生し、急速な増大を認めた放射線誘発腫瘍の1例
山下 真治
第139回日本脳神経外科学会九州支部会
Event date： 2021.9.4
Presentation type：Oral presentation (general)
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治療難治例に対するチラブルチニブ使用経験
山下 真治
九州PCNSL研究会 2021.8
Event date： 2021.8.20
Presentation type：Oral presentation (general)
Grant-in-Aid for Scientific Research 【 display / non-display 】
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EVI1によるPDGFRβ転写制御とグリオブラストーマ血管新生機構について
Grant number：22K09237 2022.04 - 2027.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
水口 麻子、
Authorship：Coinvestigator(s)
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代謝経路再編成が概日リズム経路を介し、幹細胞性維持、細胞死回避に及ぼす影響の解明
Grant number：22K09262 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
Authorship：Coinvestigator(s)
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オルガノイドーシングルセル解析法によるグリオーマ血管擬態の分子機構解明
Grant number：22K16692 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費基金 若手研究
Authorship：Principal investigator