Faculty Profiles - Tanaka Shota

IDH変異型腫瘍におけるTERT変異と1p/19q共欠失の予後因子としての意義の比較

有田英之, 大野誠, 中村大志, 田村郁, 三宅勇平, 齊藤邦昭, 田中將太, 樋口芙未, 金村米博, 市村幸一

Brain Tumor Pathology 35 ( Suppl. ) 141 - 141 2018.9

拡散画像のRadiomics解析と機械学習モデルによるIDH1遺伝子変異の同定 Reviewed

高橋慧, 高橋渉, 田中将太, 芳賀昭弘, 仲本宗泰, 鈴木雄一, 武笠晃丈, 高柳俊作

Brain Tumor Pathology 35 ( Suppl. ) 142 - 142 2018.9

IDH変異グリオーマに於けるシトシンメチル化状態の変化と腫瘍発生メカニズムの解明(Analyses of the cytosine methylation status among IDH mutated gliomas and the mechanism of gliomagenesis) Reviewed

花大洵, 野村昌志, 武笠晃丈, 田中將太, 永江玄太, 油谷浩幸

日本癌学会総会記事 77回 2307 - 2307 2018.9

右モンロー孔近傍diffuse midline gliomaの一剖検例

池村雅子, 近藤篤史, 阿部浩幸, 牛久哲男, 高柳俊作, 辛正廣, 田中將太, 深山正久

Brain Tumor Pathology 35 ( Suppl. ) 157 - 157 2018.9

がん遺伝子パネル検査を施行した成人の左側頭後頭部gliofibromaの1例

高柳俊作, 野村昌志, 田中將太, 池村雅子, 牛久綾, 高阪真路, 油谷浩幸, 間野博行

Brain Tumor Pathology 35 ( Suppl. ) 189 - 189 2018.9

クリニカルシークエンスによりNF2変異とATRXの遺伝子変異を認めた頭蓋内線維肉腫症例

根城尭英, 高柳俊作, 田中將太, 牛久綾, 高阪真路, 楚良繁雄, 油谷浩幸, 間野博行, 武笠晃丈, 斉藤延人

Brain Tumor Pathology 35 ( Suppl. ) 173 - 173 2018.9

神経膠腫におけるネオアンチゲンと免疫微小環境の経時変化に関するマルチオミクス解析 Reviewed

根城尭英, 松下博和, 唐崎隆弘, 野村昌志, 永江玄太, 高柳俊作, 田中將太, 成田善孝, 永根基雄, 西川亮, 植木敬介, 油谷浩幸, 武笠晃丈, 垣見和宏, 齊藤延人

日本がん免疫学会総会プログラム・抄録集 22回 84 - 84 2018.7

IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis. Reviewed International journal

Ryohei Otani, Takeo Uzuka, Fumi Higuchi, Hadzki Matsuda, Masashi Nomura, Shota Tanaka, Akitake Mukasa, Koichi Ichimura, Phyo Kim, Keisuke Ueki

Cancer science 109 ( 7 ) 2327 - 2335 2018.7

Language：English Publishing type：Research paper (scientific journal)

IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II-IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas). Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival compared to 19q-intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q-loss GBM and 19q-intact GBM (P = .4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas.

DOI： 10.1111/cas.13635

Response Invited

Ryohei Otani, Akitake Mukasa, Masahiro Shin, Mayu Omata, Shunsaku Takayanagi, Shota Tanaka, Keisuke Ueki, Nobuhito Saito

Journal of Neurosurgery 129 ( 1 ) 274 - 275 2018.7

Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma. Reviewed International journal

Ryohei Otani, Akitake Mukasa, Masahiro Shin, Mayu Omata, Shunsaku Takayanagi, Shota Tanaka, Keisuke Ueki, Nobuhito Saito

Journal of neurosurgery 128 ( 5 ) 1428 - 1437 2018.5

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma. METHODS Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression. RESULTS All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line. CONCLUSIONS Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.

DOI： 10.3171/2016.12.JNS161444

Spinal Cord Astrocytoma with Isocitrate Dehydrogenase 1 Gene Mutation. Reviewed International journal

Keisuke Takai, Shota Tanaka, Takashi Sota, Akitake Mukasa, Takashi Komori, Makoto Taniguchi

World neurosurgery 108 991.e13-991.e16 - 991.e16 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

BACKGROUND: In 2016, the World Health Organization updated its classification of tumors, adding genetic profiles to the conventional histopathologic typing. CASE DESCRIPTION: The authors present herein the first case of a 44-year-old female with isocitrate dehydrogenase-mutant World Health Organization grade II diffuse spinal astrocytoma diagnosed on the basis of both histopathologic and genetic findings. CONCLUSIONS: The present case underscores the significant role of a molecular genetic analysis in the differential diagnosis of intramedullary spinal gliomas.

DOI： 10.1016/j.wneu.2017.08.142

Distinct molecular profile of diffuse cerebellar gliomas. Reviewed International journal

Masashi Nomura, Akitake Mukasa, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Tomonari Suzuki, Ryohei Otani, Keiichi Kobayashi, Takashi Maruyama, Shota Tanaka, Shunsaku Takayanagi, Takahide Nejo, Satoshi Takahashi, Koichi Ichimura, Taishi Nakamura, Yoshihiro Muragaki, Yoshitaka Narita, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Junji Shibahara, Hiroyuki Aburatani, Nobuhito Saito

Acta neuropathologica 134 ( 6 ) 941 - 956 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

DOI： 10.1007/s00401-017-1771-1

CHARACTERISTIC MOLECULAR PROFILE CHANGES IN PRIMARY AND RECURRENT GLIOMAS DEPENDING ON THEIR HISTOPATHOLOGY Reviewed

Akitake Mukasa, Masashi Nomura, Kuniaki Saito, Koki Aihara, Genta Nagae, Takahide Nejo, Shota Tanaka, Shunsaku Takayanagi, Satoshi Takahashi, Mayu Omata, Taishi Nakamura, Yoshitaka Narita, Yoshihiro Muragaki, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Nobuhito Saito

NEURO-ONCOLOGY 19 94 - 94 2017.11

Definitive surgical treatment of osteomalacia induced by skull base tumor and determination of the half-life of serum fibroblast growth factor 23. Reviewed

Taijun Hana, Shota Tanaka, Hirofumi Nakatomi, Masaaki Shojima, Seiji Fukumoto, Masako Ikemura, Nobuhito Saito

Endocrine journal 64 ( 10 ) 1033 - 1039 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN ENDOCRINE SOC

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome often associated with fibroblast growth factor 23 (FGF23)-producing tumors such as phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) affecting the bone and soft tissue. We experienced a patient with progressive bone and muscle pain due to FGF23-related TIO. Venous sampling had strongly suggested the anterior skull base as a source of FGF23, which led to the discovery of a small tumor in the ethmoid sinus extending intracranially. Radical surgical resection confirmed the histological diagnosis of PMTMCT with FGF23 immunopositivity and achieved durable tumor control with complete resolution of symptoms. We serially measured serum FGF23 level before, during and after surgery and analyzed the data to determine the half-life of FGF23. Serum FGF23 level sharply declined as early as 20 minutes after en bloc tumor resection and completely normalized after surgery. The half-life of FGF23 was calculated to be approximately 18.5 minutes using single phase exponential decay model as well as semilog transformation formula. Serial measurements of serum FGF23 level can potentially declare "complete" resection of a FGF23-producing tumor and total cure of TIO; in this regard, development of its intraoperative measurement would be helpful in the management of this endocrine tumor.

DOI： 10.1507/endocrj.EJ17-0177

Differences in genetic and epigenetic alterations between von Hippel-Lindau disease-related and sporadic hemangioblastomas of the central nervous system. Reviewed International journal

Shunsaku Takayanagi, Akitake Mukasa, Shota Tanaka, Masashi Nomura, Mayu Omata, Shunsuke Yanagisawa, Shogo Yamamoto, Koichi Ichimura, Hirofumi Nakatomi, Keisuke Ueki, Hiroyuki Aburatani, Nobuhito Saito

Neuro-oncology 19 ( 9 ) 1228 - 1236 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

Background: Although inactivation of the von Hippel-Lindau gene (VHL), located on chromosome 3p25, is considered to be a major cause of hemangioblastomas (HBs), the incidence of biallelic inactivation of VHL is reportedly low. The aim of this study was to determine the prevalence of VHL alterations in HBs, as well as to identify additional molecular aberrations. Methods: Genetic and epigenetic alterations were comprehensively and comparatively analyzed in 11 VHL-related and 21 sporadic HBs. Results: VHL alterations detected by sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were more frequent in VHL-related HBs than in sporadic HBs (100% vs 62%; P = 0.029). VHL alterations were found only in 4 sporadic HBs by direct sequencing; however, targeted deep sequencing detected 9 additional alterations. Loss of heterozygosity (LOH) on chromosome 3 was found in 64% and 57% of VHL-related and sporadic HBs, respectively, by single nucleotide polymorphism (SNP) array analysis. Among 19 tumors with chromosome 3 LOH, 5 were classified as copy-neutral LOH. VHL promoter hypermethylation was detected only in sporadic HBs (33%), indicating that epigenetic suppression of VHL is a common mechanism in sporadic HBs. The rate of biallelic VHL inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. LOH on either chromosome 6 or 10 was detected only in sporadic HBs (43%). Conclusion: Although biallelic inactivation of VHL is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB.

DOI： 10.1093/neuonc/nox034

The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion-Mediated Cytotoxicity. Reviewed International journal

Kensuke Tateishi, Fumi Higuchi, Julie J Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy T Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill

Cancer research 77 ( 15 ) 4102 - 4115 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102-15. ©2017 AACR.

DOI： 10.1158/0008-5472.CAN-16-2263

グリオーマ複数回手術症例のオミクス解析によるネオアンチゲンと免疫微小環境の経時変化の検討

根城尭英, 松下博和, 唐崎隆弘, 相原功輝, 野村昌志, 高柳俊作, 田中將太, 永江玄太, 山本尚吾, 上田宏生, 辰野健二, 成田善孝, 永根基雄, 西川亮, 植木敬介, 油谷浩幸, 武笠晃丈, 垣見和宏, 齊藤延人

日本がん免疫学会総会プログラム・抄録集 21回 84 - 84 2017.6

Long-term risk of recurrence and regrowth after gross-total and subtotal resection of sporadic vestibular schwannoma. Reviewed International journal

Hirofumi Nakatomi, Jeffrey T Jacob, Matthew L Carlson, Shota Tanaka, Minoru Tanaka, Nobuhito Saito, Christine M Lohse, Colin L W Driscoll, Michael J Link

Journal of neurosurgery 1 - 7 2017.5

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE The management of vestibular schwannoma (VS) remains controversial. One commonly cited advantage of microsurgery over other treatment modalities is that tumor removal provides the greatest chance of long-term cure. However, there are very few publications with long-term follow-up to support this assertion. The purpose of the current study is to report the very long-term risk of recurrence among a large historical cohort of patients who underwent microsurgical resection. METHODS The authors retrospectively reviewed the medical records of patients who had undergone primary microsurgical resection of unilateral VS via a retrosigmoid approach performed by a single neurosurgeon-neurotologist team between January 1980 and December 1999. Complete tumor removal was designated gross-total resection (GTR), and anything less than complete removal was designated subtotal resection (STR). The primary end point was radiological recurrence-free survival. Time-to-event analyses were performed to identify factors associated with recurrence. RESULTS Four hundred fourteen patients met the study inclusion criteria and were analyzed. Overall, 67 patients experienced recurrence at a median of 6.9 years following resection (IQR 3.9-12.1, range 1.2-22.5 years). Estimated recurrence-free survival rates at 5, 10, 15, and 20 years following resection were 93% (95% CI 91-96, 248 patients still at risk), 78% (72-85, 88), 68% (60-77, 47), and 51% (41-64, 22), respectively. The strongest predictor of recurrence was extent of resection, with patients who underwent STR having a nearly 11-fold greater risk of recurrence than the patients treated with GTR (HR 10.55, p < 0.001). Among the 18 patients treated with STR, 15 experienced recurrence at a median of 2.7 years following resection (IQR 1.9-8.9, range 1.2-18.7). Estimated recurrence-free survival rates at 5, 10, 15, and 20 years following GTR were 96% (95% CI 93-98, 241 patients still at risk), 82% (77-89, 86), 73% (65-81, 46), and 56% (45-70, 22), respectively. Estimated recurrence-free survival rates at 5, 10, and 15 years following STR were 47% (95% CI 28-78, 7 patients still at risk), 17% (5-55, 2), and 8% (1-52, 1), respectively. CONCLUSIONS Long-term surveillance is required following microsurgical resection of VS even after GTR. Subtotal resection alone should not be considered a definitive long-term cure. These data emphasize the importance of long-term follow-up when reporting tumor control outcomes for VS.

DOI： 10.3171/2016.11.JNS16498