研究者詳細 - 石田　穣治

論文 - 石田　穣治

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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

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