Research activity information

• Sep. 2021 日本分子脳神経外科学会, The 21st Annual Meeting of the Japan Society of Molecular Neurosurgery award, Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells


• Nov. 2020 日本脳腫瘍学会, Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells


• Sep. 2017 Japan Neurosurgical Society, Investigator Award, Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma

  Nagashima Hiroaki

• A morphological features-based nomogram for predicting facial nerve function in the immediate postoperative period after vestibular schwannoma surgery.

  Yuichi Fujita, Yoichi Uozumi, Yosuke Fujimoto, Hiroaki Nagashima, Masaaki Kohta, Kazuhiro Tanaka, Hidehito Kimura, Atsushi Fujita, Eiji Kohmura, Takashi Sasayama

  PURPOSE: Tumor morphology critically influences facial nerve (FN) outcomes following vestibular schwannoma (VS) surgery. This study aimed to develop a nomogram based on preoperative features for preoperative prediction of FN outcomes after VS surgery. METHODS: A retrospective analysis included patients with sporadic VS who underwent surgical resection via the retrosigmoid approach. Tumor size was assessed using the Koos grade, the intrameatal components using the fundal fluid cap (FFC) sign, and the cerebellopontine angle cisternal components using our modified morphological subclassification. Logistic regression analysis was performed to construct a nomogram for predicting immediate postoperative FN function. RESULTS: A total of 265 patients with VS met the inclusion criteria. Of these patients, 62 (23.4%) had poor FN function (House-Brackmann grade ≥ III) immediately after surgery. Univariate logistic regression analysis identified the Koos grade (p = 0.001), FFC sign (p = 0.023), and morphological subtype (p < 0.001) as significant predictors of poor FN function immediately after surgery. In multivariate logistic regression analysis, the FFC sign (OR 2.07, p = 0.042) and morphological subtype (OR 8.21, p < 0.001) remained statistically significant independent predictors of poor FN function. A nomogram constructed based on these indicators demonstrated good discrimination in the training cohort (area under the curve [AUC] 0.80), internal validation cohort (AUC 0.79), and external validation cohort (AUC 0.97). CONCLUSIONS: A simple and reliable nomogram incorporating the Koos grade, FFC sign, and morphological subtype accurately predicts the risk of FN injury during surgery aimed at total resection of VS. This clinically straightforward tool can assist in patient counseling and development of more individualized surgical strategies to improve FN outcomes in patients with VS.

  Mar. 2025, Journal of neuro-oncology, English, International magazine

  Scientific journal


• Clinical Benefits of Photodynamic Therapy Using Talaporfin Sodium in Patients With Isocitrate Dehydrogenase-Wildtype Diagnosed Glioblastoma: A Retrospective Study of 100 Cases.

  Yosuke Fujimoto, Yuichi Fujita, Kazuhiro Tanaka, Hiroaki Nagashima, Shunsuke Yamanishi, Yusuke Ikeuchi, Hirofumi Iwahashi, Shoji Sanada, Yoshihiro Muragaki, Takashi Sasayama

  BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) with talaporfin sodium is an intraoperative local therapy administered after the surgical removal of malignant gliomas. However, its clinical efficacy in a large patient population has not been determined. To analyze the clinical outcomes and prognosis in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients treated with PDT. METHODS: This retrospective study included patients with newly diagnosed IDH-wildtype glioblastoma treated at Kobe University Hospital between January 2013 and December 2022. PDT involves irradiation of the resection cavity with a 664-nm semiconductor laser after an intravenous infusion of talaporfin sodium. The main outcome measures were the recurrence patterns and survival times, which were compared between the PDT and non-PDT groups. Univariate and multivariate analyses were used to determine the prognostic factors. In addition, adverse events and prognostic factors in the PDT group were analyzed. RESULTS: A total of 44 and 56 patients were included in the PDT and non-PDT groups, respectively. The local recurrence rate was significantly lower in the PDT group than in the non-PDT group (51.3% vs 83.9%), whereas the distant recurrence and dissemination rates were significantly higher in the PDT group than in the non-PDT group (48.7% vs 16.1%). Two grade 3 adverse events were observed in the PDT group. The median progression-free survival and overall survival times were significantly longer in the PDT group than in the non-PDT group (progression-free survival: 10.8 vs 9.3 months, respectively, and overall survival: 24.6 vs 17.6 months, respectively). Multivariate analysis of the PDT groups revealed that younger age was an independent prognostic factor. CONCLUSION: PDT with talaporfin sodium provided effective local control with minimal adverse effects. The survival time of the patients treated with PDT was significantly longer than that of the patients who did not receive PDT. Therefore, a randomized controlled clinical trial on PDT is warranted.

  Nov. 2024, Neurosurgery, English, International magazine

  Scientific journal


• Association of preoperative seizures with reduced expression of soluble CD163, an M2 macrophage marker, in the cerebrospinal fluid in isocitrate dehydrogenase wild-type glioblastoma.

  Shunsuke Yamanishi, Hiroaki Nagashima, Kazuhiro Tanaka, Takiko Uno, Yusuke Ikeuchi, Hirofumi Iwahashi, Mitsuru Hashiguchi, Shintaro Horii, Tomoo Itoh, Yoshihiro Muragaki, Takashi Sasayama

  PURPOSE: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma. METHODS: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined. RESULTS: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures. CONCLUSIONS: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma.

  Oct. 2024, Journal of neuro-oncology, English, International magazine

  Scientific journal


• 播種にて発症した転移性脳腫瘍の特徴

  篠山 隆司, 田中 一寛, 長嶋 宏明, 山西 俊介, 池内 佑介

  (一社)日本癌治療学会, Oct. 2024, 日本癌治療学会学術集会抄録集, 62回, O88 - 5, English


• Potential of GSPT1 as a novel target for glioblastoma therapy

  Takashi Sasayama, Takeshi Hamada, Kazuhiro Tanaka, Hiroaki Nagashima, Shunsuke Yamanishi, Takehiko Ueyama

  Abstract Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.

  Springer Science and Business Media LLC, Aug. 2024, Cell Death & Disease, 15(8) (8)

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

  Avishay Spitzer, Simon Gritsch, Masashi Nomura, Alexander Jucht, Jerome Fortin, Ramya Raviram, Hannah R Weisman, L Nicolas Gonzalez Castro, Nicholas Druck, Rony Chanoch-Myers, John J Y Lee, Ravindra Mylvaganam, Rachel Lee Servis, Jeremy Man Fung, Christine K Lee, Hiroaki Nagashima, Julie J Miller, Isabel Arrillaga-Romany, David N Louis, Hiroaki Wakimoto, Will Pisano, Patrick Y Wen, Tak W Mak, Marc Sanson, Mehdi Touat, Dan A Landau, Keith L Ligon, Daniel P Cahill, Mario L Suvà, Itay Tirosh

  A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

  May 2024, Cancer cell, 42(5) (5), 904 - 914, English, International magazine

  Scientific journal


• CDKN2A/B homozygous deletion sensitizes IDH-mutant glioma to CDK4/6 inhibition.

  Ali M Nasser, Lisa Melamed, Ethan Wetzel, Chia-Chen Chang, Hiroaki Nagashima, Yosuke Kitagawa, Logan Muzyka, Hiroaki Wakimoto, Daniel P Cahill, Julie J Miller

  PURPOSE: Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcome. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi). EXPERIMENTAL DESIGN: Cell viability, proliferation assays and flow cytometry were used to examine the pharmacologic effect of two distinct CDKis, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine efficacy and tolerability of CDKi in vivo. RESULTS: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models. CONCLUSIONS: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support investigation of the use of these agents in a clinical setting.

  May 2024, Clinical cancer research : an official journal of the American Association for Cancer Research, English, International magazine

  Scientific journal


• 画像と病理2 播種にて発症した転移性脳腫瘍の特徴

  篠山 隆司, 田中 一寛, 長嶋 宏明, 山西 俊介, 池内 佑介, 伊藤 智雄

  日本脳腫瘍病理学会, May 2024, Brain Tumor Pathology, 41(Suppl.) (Suppl.), 092 - 092, Japanese


• 脳腫瘍の分子診断と治療1 Gliosarcoma with primitive neuronal componentに対するアレイCGH解析

  田中 一寛, 池内 佑介, 細田 弘吉, 長嶋 宏明, 山西 俊介, 神保 直江, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2024, Brain Tumor Pathology, 41(Suppl.) (Suppl.), 093 - 093, Japanese


• マイクロバブルテストが原因検索に有用であった心房中隔欠損症による脳膿瘍の1例

  金 永珠, 池内 佑介, 長嶋 宏明, 前山 昌博, 堀 達雄, 田中 一寛, 田中 秀和, 本岡 康彦, 篠山 隆司

  (株)メディカ出版, May 2024, 脳神経外科速報, 34(3) (3), e80 - e87, Japanese


• 悪性リンパ腫の診断・治療の現状と展望 Interleukin 10を元に分類した中枢神経原発悪性リンパ腫の網羅的解析

  池内 佑介, 田中 一寛, 細田 弘吉, 山西 俊介, 長嶋 宏明, 伊藤 智雄, 立石 健祐, 笹目 丈, 篠山 隆司

  日本脳腫瘍病理学会, May 2024, Brain Tumor Pathology, 41(Suppl.) (Suppl.), 104 - 104, Japanese


• 悪性リンパ腫の診断・治療の現状と展望 Interleukin 10を元に分類した中枢神経原発悪性リンパ腫の網羅的解析

  池内 佑介, 田中 一寛, 細田 弘吉, 山西 俊介, 長嶋 宏明, 伊藤 智雄, 立石 健祐, 笹目 丈, 篠山 隆司

  日本脳腫瘍病理学会, May 2024, Brain Tumor Pathology, 41(Suppl.) (Suppl.), 104 - 104, Japanese


• 脳腫瘍診断におけるliquid biopsyの可能性 グリオーマおよび中枢神経悪性リンパ腫患者の髄液中炎症性マーカーと予後

  篠山 隆司, 田中 一寛, 長嶋 宏明, 藤田 祐一, 岩橋 洋文, 小松 正人, 児玉 良典, 伊藤 智雄, 廣瀬 隆則

  日本脳腫瘍病理学会, May 2023, Brain Tumor Pathology, 40(Suppl.) (Suppl.), 068 - 068, Japanese


• Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

  Fumiyuki Yamasaki, Hirotaka Fudaba, Kenichiro Asano, Takashi Sasayama, Manabu Natsumeda, Taichi Shimabukuro, Kotaro Taguchi, Shinichiro Koizumi, Noriyuki Nakayama, Kentaro Fujii, Ikuno Nishibuchi, Kazuhiko Sugiyama, Kenji Yoshida, Ushio Yonezawa, Momii Yasutomo, Yukari Kawasaki, Kiyohide Kakuta, Kosuke Katayama, Kazuhiro Tanaka, Hiroaki Nagashima, Yoshihiro Tsukamoto, Makoto Ideguchi, Takafumi Nishizaki, Kazuhiko Kurozumi, Tomohiro Hosoya, Tomoyuki Akita, Atsushi Kambe

  INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

  Apr. 2023, BMJ open, 13(4) (4), e071350, English, International magazine

  Scientific journal


• 2-Hydroxyglutarate magnetic resonance spectroscopy in adult brainstem glioma.

  Hirofumi Iwahashi, Hiroaki Nagashima, Kazuhiro Tanaka, Takiko Uno, Mitsuru Hashiguchi, Masahiro Maeyama, Yuichiro Somiya, Masato Komatsu, Takanori Hirose, Tomoo Itoh, Ryohei Sasaki, Takashi Sasayama

  OBJECTIVE: Adult brainstem gliomas (BSGs) are rare tumors of the CNS that are poorly understood. Upregulation of the oncometabolite 2-hydroxyglutarate (2HG) in the tumor indicates the mutation of isocitrate dehydrogenase (IDH), which can be detected by magnetic resonance spectroscopy (MRS). Although histological examination is required for the definitive diagnosis of BSG, 2HG-optimized MRS (2HG-MRS) may be useful, considering the difficult nature of brainstem lesion biopsy. The aim of this study was to evaluate the utility of 2HG-MRS for diagnosing IDH-mutant adult BSG. METHODS: Patients with a radiographically confirmed brainstem tumor underwent 3T MRS. A single voxel was set in the lesion with reference to the T2 or fluid-attenuated inversion recovery image and analyzed according to the 2HG-tailored MRS protocol (point-resolved spectroscopic sequence; echo time 35 msec). All patients underwent intraoperative navigation-guided or CT-guided stereotactic biopsy for histopathological diagnosis. The status of IDH and H3K27M mutations was confirmed by immunohistochemistry and direct DNA sequencing. In addition, the authors examined the relationship between patients' 2HG concentrations and survival time. RESULTS: Ten patients (7 men, 3 women; median age 33.5 years) underwent 2HG-MRS and biopsy. Four patients had an H3K27M mutation and 4 had an IDH1 mutation (1 R132H canonical IDH mutation, 2 R132S and 1 R132G noncanonical IDH mutations). Two had neither H3K27M nor IDH mutations. The H3K27M and IDH mutations were mutually exclusive. Most tumors were located in the pons. There was no significant radiological difference between mutant H3K27M and IDH on a conventional MRI sequence. A 2HG concentration ≥ 1.8 mM on MRS demonstrated 100% (95% CI 28%-100%) sensitivity and 100% (95% CI 42%-100%) specificity for IDH-mutant BSG (p = 0.0048). The median overall survival was 10 months in IDH-wild-type BSG patients (n = 6) and could not be estimated in IDH-mutant BSG patients (n = 4) due to the small number of deaths (p = 0.008). CONCLUSIONS: 2HG-MRS demonstrated high sensitivity and specificity for the prediction of IDH-mutant BSG. In addition, 2HG-MRS may be useful for predicting the prognosis of adult BSG patients.

  Jan. 2023, Journal of neurosurgery, 1 - 8, English, International magazine

  Scientific journal


• Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell‐like property of glioblastoma cells

  Tomohiro Ishikawa, Yasuka Ogura, Kazuhiro Tanaka, Hiroaki Nagashima, Takashi Sasayama, Mitsuharu Endo, Yasuhiro Minami

  Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem-like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid-forming glioblastoma stem-like cells (GSCs), and Ror1 expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of Ror1 in the cells. Consistently, we show that both NICD and hypoxia-inducible factor 1 alpha bind to upstream regions within the Ror1 gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid-forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a-Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell-like property.

  Wiley, Nov. 2022, Cancer Science, 114(2) (2), 561 - 573, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• グリオブラストーマ細胞におけるRor1の発現制御とRor1による幹細胞性維持機構の解析(Molecular mechanism regulating expression of Ror1 in GSCs and the role of Ror1 in maintaining their stemness)

  石川 智弘, 遠藤 光晴, 田中 一寛, 長嶋 宏明, 篠山 隆司, 南 康博

  (一社)日本癌学会, Sep. 2022, 日本癌学会総会記事, 81回, P - 2118, English


• グリオーマの悪性化におけるRor2-Nrf2シグナル伝達系の重要な役割(Critical role of Ror2-Nrf2 signaling axis in regulating malignant progression of gliomas)

  遠藤 光晴, 長嶋 宏明, 田中 一寛, 篠山 隆司, 南 康博

  (一社)日本癌学会, Sep. 2022, 日本癌学会総会記事, 81回, P - 2047, English


• 脳腫瘍のsurrogate marker グリオーマおよび中枢神経悪性リンパ腫患者の髄液中炎症性マーカーの比較検討

  篠山 隆司, 田中 一寛, 長嶋 宏明, 藤田 祐一, 岩橋 洋文, 小松 正人, 児玉 良典, 伊藤 智雄, 廣瀬 隆則

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 063 - 063, Japanese


• 組織診断に難渋した高齢infratentorial IDH-mutant high-grade astrocytomaの1例

  長嶋 宏明, 芝野 綾香, 藤田 祐一, 山川 皓, 田中 一寛, 太田 耕平, 小松 正人, 廣瀬 隆則, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 088 - 088, Japanese


• 頭蓋内に多発病変を認めたRosai-Dorfman病の1例

  田中 一寛, 梅田 昴, 小松 正人, 長嶋 宏明, 藤田 祐一, 岩橋 洋文, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 123 - 123, Japanese


• 脳腫瘍のsurrogate marker グリオーマおよび中枢神経悪性リンパ腫患者の髄液中炎症性マーカーの比較検討

  篠山 隆司, 田中 一寛, 長嶋 宏明, 藤田 祐一, 岩橋 洋文, 小松 正人, 児玉 良典, 伊藤 智雄, 廣瀬 隆則

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 063 - 063, Japanese


• 組織診断に難渋した高齢infratentorial IDH-mutant high-grade astrocytomaの1例

  長嶋 宏明, 芝野 綾香, 藤田 祐一, 山川 皓, 田中 一寛, 太田 耕平, 小松 正人, 廣瀬 隆則, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 088 - 088, Japanese


• 頭蓋内に多発病変を認めたRosai-Dorfman病の1例

  田中 一寛, 梅田 昴, 小松 正人, 長嶋 宏明, 藤田 祐一, 岩橋 洋文, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2022, Brain Tumor Pathology, 39(Suppl.) (Suppl.), 123 - 123, Japanese


• Unilateral approach for bilateral middle cerebral artery aneurysms assisted by preoperative understandings of aneurysm wall properties:2-dimensional operative video.

  Hidehito Kimura, Kosuke Hayashi, Susumu Osaki, Ayaka Shibano, Yuichi Fujita, Hiroaki Nagashima, Akio Tomiyama, Takashi Sasayama

  Mar. 2022, World neurosurgery, English, International magazine

  Link to Kobe Univ. Repository (Kernel)


• Glutamic acid and total creatine as predictive markers for epilepsy in glioblastoma by using magnetic resonance spectroscopy prior to surgery.

  Mitsuru Hashiguchi, Kazuhiro Tanaka, Hiroaki Nagashima, Yuichi Fujita, Hirotomo Tanaka, Masaaki Kohta, Tomoaki Nakai, Yoichi Uozumi, Masahiro Maeyama, Yuichiro Somiya, Eiji Kohmura, Takashi Sasayama

  OBJECTIVE: Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. METHODS: Fifty-one patients with glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Single-voxel (1.5cm3) MRS, in an enhanced lesion, was acquired using a double-echo point-resolved spectroscopic sequence with chemical-shift selective water suppression. MRS data were quantified with linear combination model (LC-Model) software. We compared the MRS data between groups with and without epilepsy during the postoperative course (EP). RESULTS: The ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (Glu/tCr and Glx/tCr) in the tumor were associated with epilepsy history. The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of EP [area under curve: 0.82]. In the analysis excluding patients with preoperative epilepsy, a Glu/tCr value of 1.81 was 75% sensitive and 88% specific for the prediction [area under curve: 0.87]. CONCLUSIONS: Intratumoral metabolite concentrations measured using pretreatment 3.0-T MRI/1H-MRS changed characteristically in the group with EP. Our study suggests that the Glu/tCr ratio in tumors has adequate reliability in predicting EP. Pretreatment MRS is a minimally invasive and simple procedure that can provide useful information on glioblastoma patients.

  Jan. 2022, World neurosurgery, 160, e501-e510, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Efficacy of a High-definition Three-dimensional Exoscope in Simultaneous Transcranial and Endoscopic Endonasal Surgery: A Case Report.

  Ayaka Shibano, Hidehito Kimura, Shun Tatehara, Tatsuya Furukawa, Kazuki Inoue, Yuichi Fujita, Hiroaki Nagashima, Shunsuke Yamanishi, Tadashi Nomura, Ken-Ichi Nibu, Takashi Sasayama

  Owing to recent advances in medical optical technology, a high-definition (4K) three-dimensional (3D) exoscope has been developed as an alternative tool to using conventional microscopes for microscopic surgery, and its efficacy for neurosurgery has been reported. We report a case who underwent simultaneous surgery aiming for en bloc resection of an anterior skull base malignancy with concurrent exoscopic transcranial and endoscopic endonasal approaches using a 4K 3D exoscope. The patient was a 76-year-old woman who underwent en bloc resection for an anterior skull base olfactory neuroblastoma 13 years ago. After confirming the recurrence of progressive olfactory neuroblastoma, tumor resection was again decided to be performed. As with the first procedure, surgery was performed in an en bloc manner, using both transcranial and endonasal approaches. Exoscope provided enough space above the surgical field to allow us to perform transcranial and endonasal surgeries simultaneously. Moreover, the surgeons could maintain a comfortable posture throughout the procedure, and total tumor removal was successfully achieved without any abnormal event. To our knowledge, this is the first report of the introduction of an exoscope aiming for en bloc resection of an anterior skull base malignancy while performing simultaneous surgery with both transcranial and endonasal approaches. We believe that the more cases are accumulated, the more efficacy of a 4K 3D exoscope will be elucidated.

  2022, NMC case report journal, 9, 243 - 247, English, Domestic magazine

  Link to Kobe Univ. Repository (Kernel)


• Multidisciplinary treatment for glioblastoma

  篠山隆司, 田中一寛, 長嶋宏明

  Jan. 2022, Japanese journal of neurosurgery, 31(1) (1), 11 - 19, Japanese

  [Refereed]


• Hyperintense signal on diffusion-weighted imaging for monitoring the acute response and local recurrence after photodynamic therapy in malignant gliomas.

  Yuichi Fujita, Hiroaki Nagashima, Kazuhiro Tanaka, Mitsuru Hashiguchi, Tomoo Itoh, Takashi Sasayama

  PURPOSE: Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel localized treatment for malignant glioma that provides effective local control. The acute response of malignant glioma to PDT can be detected as linear transient hyperintense signal on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient values without symptoms. However, their long-term clinical significance has not yet been examined. The aim of this study was to clarify the link between hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. METHODS: Thirty patients (16 men; median age, 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed the signal changes on DWI after PDT and the relationship between these findings and the recurrence pattern. RESULTS: All patients showed linear hyperintense signal on DWI at the surface of the resected cavity from day 1 after PDT. These changes disappeared in about 30 days without any neurological deterioration. During a mean post-PDT follow-up of 14.3 months, 19 patients (63%) exhibited recurrence: 10 local, 1 distant, and 8 disseminated. All of the local recurrences arose from areas that did not show hyperintense signal on DWI obtained on day 1 after PDT. CONCLUSIONS: The local recurrence in malignant glioma after PDT occurs in an area without hyperintense signal on DWI as an acute response to PDT. This characteristic finding could aid in the monitoring of local recurrence after PDT.

  Sep. 2021, Journal of neuro-oncology, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• The histopathological and radiological features of T2-FLAIR mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas.

  Yuichi Fujita, Hiroaki Nagashima, Kazuhiro Tanaka, Mitsuru Hashiguchi, Takanori Hirose, Tomoo Itoh, Takashi Sasayama

  OBJECTIVE: The T2-FLAIR mismatch sign is a useful imaging sign in clinical MRI studies for detecting isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted astrocytomas. However, the association between the mismatch sign and pathological findings is poorly understood. Therefore, the aim of this study was to elucidate the relationship of histopathological and radiological features with the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. METHODS: We divided 17 IDH-mutant 1p/19q non-codeleted patients into two groups according to mismatch sign presence (WITH, n = 9; WITHOUT, n = 8) and retrospectively analyzed their pathological findings and apparent diffusion coefficient (ADC) values. We also compared these findings between the tumor Core (central area) and Rim (marginal area). RESULTS: In the pathological analysis, Core of the WITH group contained numerous microcysts whereas Rim had abundant neuroglial fibrils and cellularity. In contrast, Core of the WITHOUT group had highly concentrated neuroglial fibrils. In ADC analysis, Core of the WITH group had significantly higher ADC values compared with Rim (p < 0.001). However, there was no significant difference between Core and Rim in the WITHOUT group (p = 0.12). The WITH group had a significantly higher Core/Rim ratio of ADC values compared with the WITHOUT group (p < 0.001). CONCLUSIONS: This study provides evidence that a region-dependent microstructural difference could reflect the mismatch sign in IDH-mutant 1p/19q non-codeleted astrocytomas. Core of the mismatch sign characteristically had microcystic changes accompanied by higher ADC values, whereas Rim had abundant neuroglial fibrils and cellularity accompanied by lower ADC values.

  Feb. 2021, World neurosurgery, 149, e253-e260, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Glioma cells require one-carbon metabolism to survive glutamine starvation.

  Kazuhiro Tanaka, Takashi Sasayama, Hiroaki Nagashima, Yasuhiro Irino, Masatomo Takahashi, Yoshihiro Izumi, Takiko Uno, Naoko Satoh, Akane Kitta, Katsusuke Kyotani, Yuichi Fujita, Mitsuru Hashiguchi, Tomoaki Nakai, Masaaki Kohta, Yoichi Uozumi, Masakazu Shinohara, Kohkichi Hosoda, Takeshi Bamba, Eiji Kohmura

  Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around "pseudopalisading necrosis." Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results highlight a critical role for serine-dependent one-carbon metabolism in surviving glutamine starvation and suggest new therapeutic targets for glioma cells adapting to a low-nutrient microenvironment.

  Jan. 2021, Acta neuropathologica communications, 9(1) (1), 16 - 16, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Metabolic changes and anti-tumor effects of a ketogenic diet combined with anti-angiogenic therapy in a glioblastoma mouse model.

  Masahiro Maeyama, Kazuhiro Tanaka, Masamitsu Nishihara, Yasuhiro Irino, Masakazu Shinohara, Hiroaki Nagashima, Hirotomo Tanaka, Satoshi Nakamizo, Mitsuru Hashiguchi, Yuichi Fujita, Masaaki Kohta, Eiji Kohmura, Takashi Sasayama

  The ketogenic diet (KD) is a high fat and low carbohydrate diet that produces ketone bodies through imitation of starvation. The combination of KD and Bevacizumab (Bev), a VEGF inhibitor, is considered to further reduce the supply of glucose to the tumor. The metabolite changes in U87 glioblastoma mouse models treated with KD and/or Bev were examined using gas chromatography-mass spectrometry. The combination therapy of KD and Bev showed a decrease in the rate of tumor growth and an increase in the survival time of mice, although KD alone did not have survival benefit. In the metabolome analysis, the pattern of changes for most amino acids are similar between tumor and brain tissues, however, some amino acids such as aspartic acid and glutamic acid were different between tumors and brain tissues. The KD enhanced the anti-tumor efficacy of Bev in a glioblastoma intracranial implantation mouse model, based on lowest levels of microvascular density (CD31) and cellular proliferation markers (Ki-67 and CCND1) in KD + Bev tumors compared to the other groups. These results suggested that KD combined with Bev may be a useful treatment strategy for patients with GBM.

  Jan. 2021, Scientific reports, 11(1) (1), 79 - 79, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Local targeting of NAD+ salvage pathway alters the immune tumor microenvironment and enhances checkpoint immunotherapy in glioblastoma.

  Ming Li, Ameya R Kirtane, Juri Kiyokawa, Hiroaki Nagashima, Aaron Lopes, Zain A Tirmizi, Christine K Lee, Giovanni Traverso, Daniel P Cahill, Hiroaki Wakimoto

  The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunological changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma.

  Sep. 2020, Cancer research, English, International magazine

  [Refereed]

  Scientific journal


• IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice.

  Leland G Richardson, Linda T Nieman, Anat O Stemmer-Rachamimov, Xijin S Zheng, Khalifa Stafford, Hiroaki Nagashima, Julie J Miller, Juri Kiyokawa, David T Ting, Hiroaki Wakimoto, Daniel P Cahill, Bryan D Choi, William T Curry

  The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.

  Aug. 2020, Oncoimmunology, 9(1) (1), 1806662 - 1806662, English, International magazine

  [Refereed]

  Scientific journal


• Sirtuin activation targets IDH-mutant tumors.

  Julie J Miller, Alexandria Fink, Jack A Banagis, Hiroaki Nagashima, Megha Subramanian, Christine K Lee, Lisa Melamed, Shilpa S Tummala, Kensuke Tateishi, Hiroaki Wakimoto, Daniel P Cahill

  BACKGROUND: IDH-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. METHODS: The effect of inhibition or activation of Sirtuin activity, using small molecules, CRISPR/Cas9 gene editing and inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. RESULTS: We found that SIRT1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity, when combined with nicotinamide phosphoribosyltransferase inhibition (NAMPTi), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of SIRT1 through either genetic overexpression or pharmacologic SIRT1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. CONCLUSIONS: Activation of SIRT1 can selectively target IDH-mutant tumors. These findings indicate that relatively non-toxic STACs, administered either alone or in combination with NAMPTi, could alter the growth trajectory of IDH-mutant gliomas, while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.

  Jul. 2020, Neuro-oncology, 23(1) (1), 53 - 62, English, International magazine

  [Refereed]

  Scientific journal


• Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells.

  Hiroaki Nagashima, Christine K Lee, Kensuke Tateishi, Fumi Higuchi, Megha Subramanian, Seamus Rafferty, Lisa Melamed, Julie J Miller, Hiroaki Wakimoto, Daniel P Cahill

  Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. Poly(ADP-ribose) polymerases (PARPs) catalyze oligomerization of NAD+ monomers into poly(ADP-ribose) (PAR) chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here, we find that, in endogenous IDH1 mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation.

  Jun. 2020, Cancer discovery, 10(11) (11), 1672 - 1689, English, International magazine

  [Refereed]


• Intraoperative 3-T Magnetic Resonance Spectroscopy for Detection of Proliferative Remnants of Glioma.

  Yuichi Fujita, Masaaki Kohta, Takashi Sasayama, Kazuhiro Tanaka, Mitsuru Hashiguchi, Hiroaki Nagashima, Katsusuke Kyotani, Tomoaki Nakai, Tomoo Ito, Eiji Kohmura

  BACKGROUND: Few studies have examined the usefulness of intraoperative magnetic resonance spectroscopy (iMRS) for identifying abnormal signals at the resection margin during glioma surgery. The aim of this study was to assess the value of iMRS for detecting proliferative remnants of glioma at the resection margin. METHODS: Fifteen patients with newly diagnosed glioma underwent single-voxel 3-T iMRS concurrently with intraoperative magnetic resonance imaging-assisted surgery. Volumes of interest (VOIs) were placed at T2-hyperintense or contrast-enhancing lesions at the resection margin. In addition to technical verification, the correlation between the MIB-1 labeling index (a pathologic feature) and metabolites measured using iMRS (N-acetyl-L-aspartate [NAA], choline [Cho], and Cho/NAA ratio) was analyzed. RESULTS: iMRS was performed for 20 VOIs in 15 patients. Fourteen (70%) of these VOIs were confirmed to be MIB-1-positive. There was a significant positive correlation between the Cho/NAA ratio and MIB-1 index (r = 0.46, P = 0.04). Cho level (P = 0.003) and Cho/NAA ratio (P = 0.002) were significantly higher in VOIs that were MIB-1-positive than in those that were MIB-1-negative. Detection of a Cho level >1.074 mM and a Cho/NAA ratio >0.48 using iMRS resulted in high diagnostic accuracy for MIB-1-positive remnants (Cho level: sensitivity 86%, specificity 100%; Cho/NAA ratio: sensitivity 79%, specificity 100%). CONCLUSIONS: This study provides evidence that 3-T iMRS can detect proliferative remnants of glioma at the resection margin using the Cho level and Cho/NAA ratio, suggesting that intraoperative magnetic resonance imaging-assisted surgery with iMRS would be practicable in glioma.

  May 2020, World neurosurgery, 137, 149 - 157, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Restoration of Temozolomide Sensitivity by PARP Inhibitors in Mismatch Repair Deficient Glioblastoma is Independent of Base Excision Repair.

  Fumi Higuchi, Hiroaki Nagashima, Jianfang Ning, Mara V A Koerner, Hiroaki Wakimoto, Daniel P Cahill

  PURPOSE: Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects. EXPERIMENTAL DESIGN: Isogenic pairs of MSH6 wild-type and MSH6-inactivated human glioblastoma (GBM) cells (including both IDH1/2 wild-type and IDH1 mutant), as well as MSH6-null cells derived from a patient with recurrent GBM were treated with TMZ, the PARPi veliparib or olaparib, and combination thereof. Efficacy of PARPi combined with TMZ was assessed in vivo. We used genetic and pharmacological approaches to dissect the contribution of BER. RESULTS: While having no detectable effect in MSH6 wild-type GBMs, PARPi selectively restored TMZ sensitivity in MSH6-deficient GBM cells. This genotype-specific restoration of activity translated in vivo, where combination treatment of veliparib and TMZ showed potent suppression of tumor growth of MSH6-inactivated orthotopic xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated GBM cells to TMZ. Similarly, CRISPR PARP1 knockout did not re-sensitize MSH6-inactivated GBM cells to TMZ. CONCLUSIONS: PARPi restoration of TMZ chemosensitivity in MSH6-inactivated glioma represents a promising strategy to overcome acquired chemoresistance caused by MMR deficiency. Mechanistically, this PARPi-mediated synthetic phenotype was independent of BER blockage and was not recapitulated by loss of PARP1.

  Apr. 2020, Clinical cancer research : an official journal of the American Association for Cancer Research, 26(7) (7), 1690 - 1699, English, International magazine

  [Refereed]

  Scientific journal


• DWI for Monitoring the Acute Response of Malignant Gliomas to Photodynamic Therapy.

  Y Fujita, T Sasayama, K Tanaka, K Kyotani, H Nagashima, M Kohta, H Kimura, A Fujita, E Kohmura

  BACKGROUND AND PURPOSE: Photodynamic therapy is a novel treatment that provides effective local control, but little is known about photodynamic therapy-induced changes on MR imaging. The aim of this study was to assess the utility of DWI and ADC in monitoring the response of malignant gliomas to photodynamic therapy. MATERIALS AND METHODS: Time-dependent changes in DWI and ADC values after photodynamic therapy were analyzed in a group that received photodynamic therapy in comparison with a group that did not. RESULTS: Twenty-four patients were enrolled (photodynamic therapy, n = 14; non-photodynamic therapy, n = 10). In all patients who received photodynamic therapy, linear high signals on DWI in the irradiated area were detected adjacent to the resection cavity and were 5-7 mm in depth from 1 day posttreatment and disappeared in about 30 days without any neurologic deterioration. The non-photodynamic therapy group did not show this change. The photodynamic therapy group had significantly lower ADC values from 1 day posttreatment (P < .001), which increased steadily and disappeared by 30 days. There was no decline or time-dependent change in ADC values in the non-photodynamic therapy group. CONCLUSIONS: The acute response of malignant gliomas to photodynamic therapy was detected as linear high signals on DWI and as a decrease in ADC values. These findings were asymptomatic and transient. Although the photodynamic therapy-induced acute response on MR imaging disappeared after approximately 30 days, it may be helpful for confirming the photodynamic therapy-irradiated area.

  Dec. 2019, AJNR. American journal of neuroradiology, 40(12) (12), 2045 - 2051, English, International magazine

  Scientific journal


• 脳性麻痺の成人期におけるITB治療

  森下 暁二, 長嶋 宏明, 山川 皓, 相原 英夫, 足立 昌夫, 甲村 英二

  (一社)日本定位・機能神経外科学会, Dec. 2019, 機能的脳神経外科, 58, 53 - 57, Japanese

  [Refereed]


• 脳性麻痺の成人期におけるITB治療

  森下 暁二, 長嶋 宏明, 山川 皓, 相原 英夫, 足立 昌夫, 甲村 英二

  (一社)日本定位・機能神経外科学会, Dec. 2019, 機能的脳神経外科, 58, 53 - 57, Japanese

  [Refereed]


• Tumor-associated macrophage related interleukin-6 in cerebrospinal fluid as a prognostic marker for glioblastoma.

  Tatsuo Hori, Takashi Sasayama, Kazuhiro Tanaka, Yu-Ichiro Koma, Masamitsu Nishihara, Hirotomo Tanaka, Satoshi Nakamizo, Hiroaki Nagashima, Masahiro Maeyama, Yuichi Fujita, Hiroshi Yokozaki, Takanori Hirose, Eiji Kohmura

  Interleukin-6 (IL-6) is one of the pleiotropic cytokines and has received attention as a critical factor implicated in the invasion and the angiogenesis of various cancers. In glioma, IL-6 is known to be associated with the prognosis; however, the roles of IL-6 in cerebrospinal fluid (CSF) has not been studied sufficiently. We examined the concentration of CSF IL-6 using 75 CSF samples of glioma (54 glioblastomas (GBMs) and 21 other grades of gliomas) and analyzed the association CSF IL-6 with infiltration levels of tumor-associated macrophages (TAMs) and prognosis. The concentration of CSF IL-6 in GBM patients was significantly higher than that in other grades of gliomas. CSF IL-6 levels were associated with the infiltration rate of TAMs in GBMs, and IL-6 levels were increased in the GBM cells co-cultured with TAM-like macrophages. The CSF of GBM patients, which contained high concentration of IL-6, promoted the migration ability of GBM cells, and neutralization antibodies of IL-6 inhibited its migration ability. Finally, in both univariate and multivariate analysis, higher CSF IL-6 levels were associated with poorer prognosis in GBM patients. These results indicated that the concentration of CSF IL-6 is associated with TAMs' infiltration level and may be a useful prognostic biomarker for the GBM patients.

  Oct. 2019, Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 68, 281 - 289, English, International magazine

  [Refereed]

  Scientific journal


• MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.

  Junichi Sakata, Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Mitsutoshi Nakada, Hirotomo Tanaka, Naoya Hashimoto, Naoki Kagawa, Manabu Kinoshita, Satoshi Nakamizo, Masahiro Maeyama, Masamitsu Nishihara, Kohkichi Hosoda, Eiji Kohmura

  BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment. METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed. RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level. CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.

  Apr. 2019, Journal of neuro-oncology, 142(2) (2), 241 - 251, English, International magazine

  [Refereed]

  Scientific journal


• 脊髄係留症候群による疼痛に対してspinal cord stimulation(SCS)を併用した1例

  森下 暁二, 相原 英夫, 長嶋 宏明, 藤田 祐一, 松尾 和哉, 小山 淳二

  (一社)日本定位・機能神経外科学会, Dec. 2018, 機能的脳神経外科, 57, 25 - 29, Japanese

  [Refereed]


• グリオーマにおけるマイクロRNAの役割

  篠山 隆司, 田中 一寛, 長嶋 宏明, 田中 宏知, 坂田 純一, 西原 賢在, 甲村 英二

  近畿脳腫瘍病理検討会, Aug. 2018, Neuro-Oncologyの進歩, 25(2) (2), 8 - 18, Japanese

  [Refereed]


• 頸椎損傷に伴う椎骨動脈損傷の臨床像と治療戦略

  藤田 祐一, 相原 英夫, 長嶋 宏明, 森下 暁二, 青木 謙二, 高山 博行, 原田 俊彦, 当麻 美樹, 原 淑恵, 甲村 英二

  (株)医学書院, Aug. 2018, Neurological Surgery, 46(8) (8), 663 - 671, Japanese

  [Refereed]


• [Clinical Features and Treatment Strategy of Vertebral Artery Injury Associated with Cervical Spine Trauma].

  Yuichi Fujita, Hideo Aihara, Hiroaki Nagashima, Akitsugu Morishita, Kenji Aoki, Hiroyuki Takayama, Toshihiko Harada, Yoshiki Tohma, Yoshie Hara, Eiji Kohmura

  OBJECTIVE: Vertebral artery injury(VAI)associated with cervical spine trauma has the potential to cause catastrophic vertebrobasilar stroke. However, there are no well-defined treatment recommendations for VAI. The purpose of this study was to identify an effective treatment strategy for VAI following cervical spine trauma. METHODS: Ninety-seven patients with blunt cervical spine trauma were treated at Hyogo Prefectural Kakogawa Medical Center between January 2013 and September 2017. Of these patients, 49 underwent computed tomographic angiography or magnetic resonance angiography for evaluation of the vertebral artery. Eighteen patients(36.7%)had a diagnosis of VAI. We retrospectively analyzed the clinical features, treatment, and outcomes in these 18 patients. RESULTS: Seven patients(38.9%)had bilateral VAI, 16(88.9%)had cervical dislocation, and 2(11.1%)had transverse process fractures extending into the transverse foramen. Surgical reduction was performed in 14 patients. Five patients with either bilateral or unilateral occlusion underwent parent artery occlusion before reduction. There were no complications after this procedure. Two patients with bilateral VAI had a stroke before treatment. There were no infarctions in the distribution of the vertebrobasilar artery after intervention. The perioperative stroke rate was relatively good, and almost all Glasgow Outcome Scale scores were related to the degree of spinal cord injury. CONCLUSIONS: Aggressive screening for VAI is important in patients with cervical spine trauma in order to ensure adequate treatment. Although the treatment strategy described here could yield good results, it may require modification according to the needs of the individual patient.

  Aug. 2018, No shinkei geka. Neurological surgery, 46(8) (8), 663 - 671, Japanese, Domestic magazine

  [Refereed]

  Scientific journal


• Pentose phosphate pathway activation via HSP27 phosphorylation by ATM kinase: A putative endogenous antioxidant defense mechanism during cerebral ischemia-reperfusion.

  Yusuke Yamamoto, Kohkichi Hosoda, Taichiro Imahori, Jun Tanaka, Kazuya Matsuo, Tomoaki Nakai, Yasuhiro Irino, Masakazu Shinohara, Naoko Sato, Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Masaaki Kohta, Eiji Kohmura

  Molecular mechanism underlying ischemic stroke remains poorly understood. We previously reported glucose 6-phosphate dehydrogenase (G6PD) activity in pentose phosphate pathway (PPP) is activated via heat shock protein 27 (HSP27) phosphorylation at serine 85 (S85) by ataxia telangiectasia mutated (ATM) kinase during cerebral ischemia. This mechanism seems to be endogenous antioxidative system. To determine whether this system also works during reperfusion, we performed comparative metabolic analysis of reperfusion effect on metabolism in rat cortex using middle cerebral artery occlusion (MCAO). Metabolic profiling using gas-chromatography/mass-spectrometry analysis showed changes in metabolic state that depended on reperfusion time. Enrichment analysis showed PPP was significantly upregulated during ischemia-reperfusion. Significant increases in fructose 6-phosphate and ribulose 5-phosphate after reperfusion also suggested enhancement of PPP. In relation to PPP, ischemia-reperfusion induced an increase of up to 69-fold in HSP27 transcripts after 24-h reperfusion. Immunoblotting showed gradual increase in HSP27 protein and marked increase in HSP27 phosphorylation (S85) that were time-dependent (4.5-fold after 24-h reperfusion). G6PD activity was significantly elevated after 1-h MCAO (20%), reduced after 1-h reperfusion, increased gradually thereafter and significantly elevated after 24-h reperfusion. The NADPH/NAD+ ratio displayed similar increasing pattern. Intracerebroventricular injection of ATM kinase inhibitor (KU-55933) significantly reduced HSP27 phosphorylation and G6PD activity, significantly increased protein carbonyl, and resulted in increase in infarct size (100%) 24-h after reperfusion following 90-min MCAO. Consequently, G6PD activation via HSP27 phosphorylation by ATM kinase may be part of endogenous antioxidant defense neuroprotection mechanism that is activated during ischemia-reperfusion. These findings have important implications for treatment of stroke.

  May 2018, Brain research, 1687, 82 - 94, English, International magazine

  [Refereed]

  Scientific journal


• 頸椎損傷に伴う椎骨動脈損傷の治療戦略

  藤田 祐一, 長嶋 宏明, 森下 暁二, 相原 英夫, 青木 謙二, 高山 博行, 原田 俊彦, 当麻 美樹, 原 淑恵, 甲村 英二

  (一社)日本脳神経外傷学会, Feb. 2018, 日本脳神経外傷学会プログラム・抄録集, 41回, 96 - 96, Japanese


• Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma.

  Hiroaki Nagashima, Takashi Sasayama, Kazuhiro Tanaka, Katsusuke Kyotani, Naoko Sato, Masahiro Maeyama, Masaaki Kohta, Junichi Sakata, Yusuke Yamamoto, Kohkichi Hosoda, Tomoo Itoh, Ryohei Sasaki, Eiji Kohmura

  It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628-3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.

  Jan. 2018, Journal of neuro-oncology, 136(2) (2), 317 - 326, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Cerebrospinal fluid leakage and Chiari I malformation with Gorham's disease of the skull base: A case report

  Hiroaki Nagashima, Katsu Mizukawa, Masaaki Taniguchi, Yusuke Yamamoto, Eiji Kohmura

  Lead, Sep. 2017, NEUROLOGIA I NEUROCHIRURGIA POLSKA, 51(5) (5), 427 - 431, English

  [Refereed]

  Scientific journal


• COMBINED METABOLIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES PENTOSE PHOSPHATE PATHWAY ACTIVATION BY HSP27 PHOSPHORYLATION DURING CEREBRAL ISCHEMIA (vol 349, pg 1, 2017)

  Taichiro Imahori, Kohkichi Hosoda, Tomoaki Nakai, Yusuke Yamamoto, Yasuhiro Irino, Masakazu Shinohara, Naoko Sato, Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Masaaki Kohta, Eiji Kohmura

  Aug. 2017, NEUROSCIENCE, 357, 414 - 414, English, International magazine


• Magnetic Resonance Spectroscopy Findings in Patients with Dural Arteriovenous Fistulas: Three Case Reports.

  Hiroaki Nagashima, Atsushi Fujita, Jun Tanaka, Masaaki Kohta, Takashi Sasayama, Kazuhiro Tanaka, Kohkichi Hosoda, Eiji Kohmura

  BACKGROUND: Magnetic resonance spectroscopy (MRS) is a potentially useful modality for evaluating brain metabolites in patients with dural arteriovenous fistula (dAVF). Here we describe a different pattern of MRS-based cerebral metabolism findings in patients with dAVF. CASE DESCRIPTIONS: We performed MRS in 3 patients with transverse sigmoid sinus dAVF associated with cortical venous reflux. In case 1, which was associated with vasogenic edema on T2-weighted magnetic resonance imaging (MRI), decreased preoperative N-acetylaspartate (NAA)/creatine (Cr) and myo-inositol (mIns)/Cr and increased lactate (Lac)/Cr ratios improved after treatment. In case 2, a decreased preoperative NAA/Cr ratio improved after treatment. These 2 patients presented with seizures. In case 3, the patient presented with headache and showed no metabolic changes on preoperative or postoperative MRS. CONCLUSIONS: Our results suggest that patients with dAVF can be classified based on a combination of metabolic and signal changes seen on T2-weighted MRI. MRS may allow significantly expanded evaluation of the metabolic changes associated with dAVF for appropriate classification and management.

  Aug. 2017, World neurosurgery, 104, 1050.e7-1050.e11, English, International magazine

  [Refereed]

  Scientific journal


• Combined metabolic and transcriptional profiling identifies pentose phosphate pathway activation by HSP27 phosphorylation during cerebral ischemia.

  Taichiro Imahori, Kohkichi Hosoda, Tomoaki Nakai, Yusuke Yamamoto, Yasuhiro Irino, Masakazu Shinohara, Naoko Sato, Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Masaaki Kohta, Eiji Kohmura

  The metabolic pathophysiology underlying ischemic stroke remains poorly understood. To gain insight into these mechanisms, we performed a comparative metabolic and transcriptional analysis of the effects of cerebral ischemia on the metabolism of the cerebral cortex using middle cerebral artery occlusion (MCAO) rat model. Metabolic profiling by gas-chromatography/mass-spectrometry analysis showed clear separation between the ischemia and control group. The decreases of fructose 6-phosphate and ribulose 5-phosphate suggested enhancement of the pentose phosphate pathway (PPP) during cerebral ischemia (120-min MCAO) without reperfusion. Transcriptional profiling by microarray hybridization indicated that the Toll-like receptor and mitogen-activated protein kinase (MAPK) signaling pathways were upregulated during cerebral ischemia without reperfusion. In relation to the PPP, upregulation of heat shock protein 27 (HSP27) was observed in the MAPK signaling pathway and was confirmed through real-time polymerase chain reaction. Immunoblotting showed a slight increase in HSP27 protein expression and a marked increase in HSP27 phosphorylation at serine 85 after 60-min and 120-min MCAO without reperfusion. Corresponding upregulation of glucose 6-phosphate dehydrogenase (G6PD) activity and an increase in the NADPH/NAD+ ratio were also observed after 120-min MCAO. Furthermore, intracerebroventricular injection of ataxia telangiectasia mutated (ATM) kinase inhibitor (KU-55933) significantly reduced HSP27 phosphorylation and G6PD upregulation after MCAO, but that of protein kinase D inhibitor (CID755673) did not affect HSP27 phosphorylation. Consequently, G6PD activation via ischemia-induced HSP27 phosphorylation by ATM kinase may be part of an endogenous antioxidant defense neuroprotection mechanism during the earliest stages of ischemia. These findings have important therapeutic implications for the treatment of stroke.

  May 2017, Neuroscience, 349, 1 - 16, English, International magazine

  [Refereed]

  Scientific journal


• Cisterna magna meningiomas without dural attachment: Report of two cases

  Masaaki Kohta, Takashi Sasayama, Tomoaki Nakai, Masaaki Taniguchi, Hiroaki Nagashima, Kazuhiro Tanaka, Katsu Mizukawa, Tomoo Itoh, Eiji Kohmura

  Meningiomas within the cisterna magna without dural attachment are extremely rare. To the best of our knowledge, only three cases of meningiomas within the cisterna magna have been reported in the literature. The authors present two cases of patient with the cisterna magna meningioma without dural attachment. (Case 1) A 36-year-old female presented with a 10-month history of numbness in the left hand. Magnetic resonance imaging (MRI) disclosed the presence of a contrast-enhanced tumor in the posterior fossa. A suboccipital craniectomy was performed, and the tumor located within the cisterna magna with no attachment to the dura. Diagnosis is made as clear cell meningioma. The postoperative course was uneventful, and a recurrence has not been observed for three years. (Case 2) A 58-year-old man presented with a well-circumscribed mass in the posterior fossa. At surgery, the tumor located within the cisterna magna with a connection to the right tenia. The tumor was totally removed without neurological deficits. At a 7-year follow-up, no evidence of a recurrence was observed. It is quite difficult to preoperatively diagnose as a cisterna magna meningioma without dural attachment. However, complete removal of the tumor should be achieved. (C) 2017 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved.

  ELSEVIER URBAN & PARTNER SP Z O O, May 2017, NEUROLOGIA I NEUROCHIRURGIA POLSKA, 51(3) (3), 247 - 251, English

  [Refereed]

  Scientific journal


• 中枢神経原発悪性リンパ腫診断における髄液マーカーの有用性

  篠山 隆司, 田中 一寛, 西原 賢在, 長嶋 宏明, 甲村 英二

  近畿脳腫瘍病理検討会, Feb. 2017, Neuro-Oncologyの進歩, 23(3) (3), 9 - 15, Japanese

  [Refereed]


• Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma.

  Hiroaki Nagashima, Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Naoko Sato, Yukiko Takeuchi, Katsusuke Kyotani, Akitake Mukasa, Katsu Mizukawa, Junichi Sakata, Yusuke Yamamoto, Kohkichi Hosoda, Tomoo Itoh, Ryohei Sasaki, Eiji Kohmura

  BACKGROUND: Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS. METHODS: Forty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas. RESULTS: A metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma. CONCLUSIONS: IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.

  Nov. 2016, Neuro-oncology, 18(11) (11), 1559 - 1568, English, International magazine

  [Refereed]


• キアリ1型奇形の治療

  長嶋 達也, 河村 淳史, 小山 淳二, 阿久津 宣行, 長嶋 宏明

  (一社)日本小児神経外科学会, Jul. 2016, 小児の脳神経, 40(6) (6), 419 - 427, Japanese

  [Refereed]


• Tumor-Associated Macrophages Associate with Cerebrospinal Fluid Interleukin-10 and Survival in Primary Central Nervous System Lymphoma (PCNSL).

  Takashi Sasayama, Kazuhiro Tanaka, Takashi Mizowaki, Hiroaki Nagashima, Satoshi Nakamizo, Hirotomo Tanaka, Masamitsu Nishihara, Katsu Mizukawa, Takanori Hirose, Tomoo Itoh, Eiji Kohmura

  Increased tumor-associated macrophages (TAMs) have been reported to be associated with poor prognosis in various tumors; however, the importance of TAMs in primary central nervous system lymphoma (PCNSL) has not been clarified. In 47 patients with PCNSL who were treated with high-dose methotrexate (MTX) and radiotherapy, the relationships between the infiltration levels of TAMs and the clinicopathological parameters were analyzed. Univariate analysis of the Cox proportional hazards model using continuous scales revealed that increased CD68 positive (+) TAMs was significantly associated with inferior progression-free survival (PFS) (P = 0.04), and trends were observed for the increased CD163(+)  TAMs and having shorter PFS (P = 0.05). However, increased TAMs were not associated with overall survival. Because TAMs are known to produce various cytokines, we examined the relationships between cerebrospinal fluid (CSF) cytokines and TAMs. CSF interleukin-6 (IL-6) and soluble IL-2 receptor were not correlated with the infiltration rate of TAMs; however, CSF IL-10 level was correlated with infiltration levels of CD68 and CD163(+)  TAMs. We also confirmed the expression of IL-10 in CD68(+)  and CD163(+)  TAMs by double immunostaining analysis. Our results indicate that a high level of IL-10 in CSF may be positively associated with the infiltration level of TAMs in PCNSLs.

  Jul. 2016, Brain pathology (Zurich, Switzerland), 26(4) (4), 479 - 87, English, International magazine

  [Refereed]

  Scientific journal


• Radiographic occult cerebellar germinoma presenting with progressive ataxia and cranial nerve palsy.

  Noriaki Minami, Kazuhiro Tanaka, Hidehito Kimura, Takanori Hirose, Tatsuya Mori, Masahiro Maeyama, Hiroaki Sekiya, Takeshi Uenaka, Satoshi Nakamizo, Hiroaki Nagashima, Katsu Mizukawa, Tomoo Itoh, Takashi Sasayama, Eiji Kohmura

  BACKGROUND: Although the usefulness of susceptibility-weighted imaging (SWI) for detecting basal ganglia germinoma has been reported, the technique is not widely used. We recently encountered an unusual case of primary cerebellar germinoma, presenting with progressive ataxia and cranial nerve palsy, characterized by gradually enlarging low-intensity lesions visible with both T2*-weighted imaging (T2*WI), which were the key to the diagnosis. CASE PRESENTATION: A 30-year-old man was referred to our hospital because of slowly progressive dizziness and mild ataxia. Magnetic resonance imaging (MRI) revealed a small, low-intensity spot in the left cerebellar peduncle on the T2*WI and SWI without enhancement. Cerebral angiography revealed no vascular abnormality. The serum α-fetoprotein value was normal. A steroid-pulse was administered as a therapeutic and diagnostic trial, but the symptoms improved little. The patient was discharged from the hospital but soon developed brainstem dysfunction, characterized by dyspnea or hiccups, and he was readmitted. T2*WI imaging revealed expanded and extended spotty lesions in the cerebellum and brainstem, which had not enhanced with contrast agent previously. Targeted stereotactic biopsy of the newly enhanced cerebellar lesion was performed; histopathological examination of the tissue revealed pure germinoma. Serum and cerebral spinal fluid values of beta-human chorionic gonadotropin were not significantly elevated. Chemotherapy with carboplatin and etoposide was initiated. The enhanced lesion disappeared promptly, but the patient continued to require assisted automatic ventilation because of paralysis of respiratory muscles. CONCLUSIONS: We conclude that enlarging low-intensity lesions on T2*WI and SWI may be a reliable clue to the diagnosis of germinomas, irrespective of their location, even without enhancement. Biopsy of the tumor at an early stage is the only way to make the diagnosis conclusively and enable prompt start of treatment.

  Jan. 2016, BMC neurology, 16, 4 - 4, English, International magazine

  [Refereed]


• Medulloblastoma with suprasellar solitary massive metastasis: Case report.

  Hiroaki Nagashima, Tatsuya Nagashima, Atsufumi Kawamura, Kazuki Yamamoto, Makiko Yoshida, Daiichiro Hasegawa, Yoshiyuki Kosaka, Eiji Kohmura

  It is extremely rare for metastasised medulloblastoma to form a large tumour in the suprasellar region. We present a case of medulloblastoma with large suprasellar metastasis at initial presentation. A 3-year and 5-month-old boy presented with a 1-month history of vomiting and loss of appetite, and body weight. Computed tomography and magnetic resonance imaging revealed a 20 mm × 20 mm mass in the suprasellar region and a 30 mm × 30 mm mass in the fourth cerebral ventricle. We performed endoscopic biopsy of the suprasellar tumour, and subsequently totally removed the vermian tumour through a suboccipital craniotomy. The histopathological findings revealed that both the suprasellar and vermian tumours were classic type and non SHH/WNT type medulloblastoma. The postoperative course was uneventful. The patient showed complete remission after chemotherapy. The tumour in the suprasellar region was most likely metastatic from the vermis. Endoscopic biopsy of the tumour in the suprasellar region and total removal of the tumour in the vermis in a one-stage operation followed by intensive chemotherapy with reduced dose radiotherapy may provide a satisfactory outcome.

  2016, Neurologia i neurochirurgia polska, 50(3) (3), 211 - 4, English, International magazine

  [Refereed]

  Scientific journal


• STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

  Takashi Mizowaki, Takashi Sasayama, Kazuhiro Tanaka, Katsu Mizukawa, Kumi Takata, Satoshi Nakamizo, Hirotomo Tanaka, Hiroaki Nagashima, Masamitsu Nishihara, Takanori Hirose, Tomoo Itoh, Eiji Kohmura

  Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

  Sep. 2015, Journal of neuro-oncology, 124(2) (2), 165 - 74, English, International magazine

  [Refereed]

  Scientific journal


• 局所放射線治療後に頭蓋内主幹動脈狭窄による脳梗塞を呈した成人神経膠腫の2例

  南 徳明, 水川 克, 岩橋 洋文, 長嶋 宏明, 田中 一寛, 篠山 隆司, 細田 弘吉, 椋本 成俊, 佐々木 良平, 甲村 英二

  (株)医学書院, Apr. 2015, Neurological Surgery, 43(4) (4), 344 - 351, Japanese

  [Refereed]


• Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment.

  Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Kumi Takata, Hiroaki Nagashima, Naoko Satoh, Katsusuke Kyotani, Takashi Mizowaki, Taichiro Imahori, Yasuo Ejima, Kenta Masui, Beatrice Gini, Huijun Yang, Kohkichi Hosoda, Ryohei Sasaki, Paul S Mischel, Eiji Kohmura

  The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.

  Apr. 2015, The Journal of clinical investigation, 125(4) (4), 1591 - 602, English, International magazine

  [Refereed]

  Scientific journal


• [Two cases of cerebral infarction due to focal irradiation for glioma in adults].

  Noriaki Minami, Katsu Mizukawa, Hirofumi Iwahashi, Hiroaki Nagashima, Kazuhiro Tanaka, Takashi Sasayama, Kohkichi Hosoda, Naritoshi Mukumoto, Ryohei Sasaki, Eiji Kohmura

  Radiation-induced vasculopathy is a complication of radiation therapy. Most reports regarding post-irradiation ischemic stroke with intracranial tumors are restricted to pediatric cases. Here we report two adult cases of delayed brain infarction due to anterior and middle cerebral artery stenosis or occlusion seemingly caused by focal radiation therapy for malignant glioma. Although radiation-induced ischemic stroke in adults is relatively uncommon, it is possible that the morbidity rate of radiation-induced stroke in malignant glioma patients will increase with prolonged survival due to advances in therapy. Therefore, regular evaluation of intracranial vasculature following radiation therapy is necessary.

  Apr. 2015, No shinkei geka. Neurological surgery, 43(4) (4), 344 - 51, Japanese, Domestic magazine

  [Refereed]


• A large cavernous malformation of the third ventricle floor: A case report.

  Hiroaki Nagashima, Kazuhiro Tanaka, Takashi Sasayama, Yusuke Okamura, Masaaki Taniguchi, Kyoko Otani, Takashi Yamasaki, Tomoo Itoh, Eiji Kohmura

  Suprasellar and third ventricular region cavernous malformations originating from the floor of the third ventricle are extremely rare. We report a case of third ventricular cavernous malformation arising from the ventricle floor in a 24-year-old woman who presented with short-term memory loss and disorientation. Computed tomography revealed a suprasellar mass with calcification in the posterior chiasmatic region. T2-weighted magnetic resonance imaging revealed a mass with heterogeneous intensity and without hydrocephalus. The mass was slightly enhanced subsequent to gadolinium infusion. Using a basal interhemispheric translamina terminalis approach and a neuroendoscope, we confirmed that the tumor was located at the floor of the third ventricle and removed it. Histopathological examination confirmed the diagnosis of cavernous malformation. The postoperative course was uneventful, but the patient's short-term memory loss persisted. Despite its rarity, cavernous malformation should be suspected when a tumor is detected in the vicinity of the third ventricle floor. It is treatable through surgical resection.

  2015, Neurologia i neurochirurgia polska, 49(6) (6), 446 - 50, English, International magazine

  [Refereed]

  Scientific journal


• 顔面外傷に対する外頸動脈塞栓術 6症例の検討

  長嶋 宏明, 相原 英夫, 当麻 美樹, 高岡 諒, 甲村 英二

  (一社)日本脳神経外傷学会, Dec. 2014, 神経外傷, 37(2) (2), 128 - 133, Japanese

  [Refereed]


• 脊髄播種・転移を起こした膠芽腫のマイクロRNA発現に関する検討

  篠山 隆司, 田中 一寛, Mizukawa Katsu, 溝脇 卓, 長嶋 宏明, 堀 達雄, Kohmura Eiji

  日本脳腫瘍病理学会, May 2014, Brain Tumor Pathology, 31(Suppl.) (Suppl.), 080 - 080, Japanese


• 【小児脳神経外科領域におけるトピックス】小児悪性脳腫瘍の集学的治療

  長嶋 達也, 河村 淳史, 山元 一樹, 長嶋 宏明

  日本脳神経外科コングレス, May 2014, 脳神経外科ジャーナル, 23(5) (5), 409 - 417, Japanese

  [Refereed]


• 顔面外傷に対する外頸動脈塞栓術 6症例の検討

  長嶋 宏明, 相原 英夫, 森下 暁二, 中井 友昭, 当麻 美樹, 高岡 諒, Kohmura Eiji

  (一社)日本脳神経外傷学会, Mar. 2014, 日本脳神経外傷学会プログラム・抄録集 37回, 37回, 89 - 89, Japanese


• Multidisciplinary treatment of malignant pediatric brain tumors

  Tatsuya Nagashima, Atsufumi Kawamura, Kazuki Yamamoto, Hiroaki Nagashima

  Japanese Congress of Neurological Surgeons, 2014, Japanese Journal of Neurosurgery, 23(5) (5), 409 - 417, English

  [Refereed]

  Scientific journal


• Brain abscess associated with ethmoidal sinus osteoma: A case report

  Hiroaki Nagashima, Hideo Aihara, Takashi Tashiro, Eiji Kohmura

  Lead, Elsevier, 2014, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 1(4) (4), 97 - 100, English

  [Refereed]

  Scientific journal


• 重症頭部外傷に対する初療室穿頭術53例の検討

  長嶋 宏明, 相原 英夫, 当麻 美樹, 高岡 諒, 甲村 英二

  (一社)日本脳神経外傷学会, Dec. 2013, 神経外傷, 36(2) (2), 188 - 195, Japanese

  [Refereed]


• 頭蓋内海綿状血管腫連続12例の検討

  長嶋 宏明, 前山 昌博, 井口 基, 澤 秀樹, 木村 充, 大洞 慶郎

  (NPO)日本脳神経外科救急学会, Jun. 2013, Neurosurgical Emergency, 18(1) (1), 75 - 80, Japanese

  [Refereed]


• 重症頭部外傷の臨床像 びまん性脳損傷と局所性脳損傷との比較

  長嶋 宏明, 相原 英夫, 高岡 諒, 当麻 美樹

  (一社)日本脳神経外傷学会, Dec. 2012, 神経外傷, 35(2) (2), 119 - 124, Japanese

  [Refereed]


• Pediatric orbital schwannoma originating from the oculomotor nerve.

  Hiroaki Nagashima, Kazuki Yamamoto, Atsufumi Kawamura, Tatsuya Nagashima, Koji Nomura, Makiko Yoshida

  Intraorbital schwannoma is a rare tumor that constitutes approximately 1%-8% of all orbital tumors. The authors report a case of orbital schwannoma in a 5-year-old boy who was admitted to their institute with exophthalmos and ptosis of the right eye. Computed tomography scanning and MR imaging revealed a retroocular mass in the right orbit. The tumor was successfully removed via a transcranial approach. The pathological diagnosis was schwannoma that appeared to originate from the superior branch of the oculomotor nerve. Despite the rarity of these intraorbital extraocular tumors in children, schwannomas should be differentiated from other intraorbital tumors.

  Feb. 2012, Journal of neurosurgery. Pediatrics, 9(2) (2), 165 - 8, English, International magazine

  [Refereed]


• 先天奇形シリーズ(第7回) キアリ奇形

  長嶋 達也, 山元 一樹, 河村 淳史, 長嶋 宏明

  (株)医学書院, Jun. 2011, Neurological Surgery, 39(6) (6), 617 - 628, Japanese

  [Refereed]


• 【全面改訂版 必携!けいれん、意識障害 その時どうする】けいれん・意識障害を起こす疾患の治療管理のポイント 虐待による乳幼児頭部外傷 いわゆる揺すぶられっ子症候群

  長嶋 達也, 山元 一樹, 河村 淳史, 長嶋 宏明

  (株)東京医学社, Mar. 2011, 小児内科, 43(3) (3), 633 - 637, Japanese

  [Refereed]


• 3歳未満の脳腫瘍に対する集学的治療体制の確立に向けて

  長嶋 達也, 河村 淳史, 山元 一樹, 長嶋 宏明

  (一社)兵庫県医師会, Mar. 2011, 兵庫県医師会医学雑誌, 53(2) (2), 64 - 65, Japanese

  [Refereed]


• 外傷性頭蓋内出血における抗凝固薬・抗血小板薬内服の影響

  小山 淳二, 長嶋 宏明, 三宅 茂, 相原 英夫, 甲村 英二

  (一社)日本脳神経外傷学会, Dec. 2010, 神経外傷, 33(1) (1), 48 - 54, Japanese

  [Refereed]


• 慢性硬膜下血腫の再発因子についての検討

  長嶋 宏明, 坂田 純一, 石井 大嗣, 千葉 義幸, 三宅 茂

  日本脳神経外科コングレス, Nov. 2010, 脳神経外科ジャーナル, 19(11) (11), 845 - 849, Japanese

  [Refereed]


• Recurrence factors for chronic subdural hematoma after burr-hole surgery

  Hiroaki Nagashima, Junichi Sakata, Taiji Ishii, Yoshiyuki Chiba, Shigeru Miyake

  Japanese Congress of Neurological Surgeons, 2010, Japanese Journal of Neurosurgery, 19(11) (11), 845 - 849, Japanese

  [Refereed]

  Scientific journal

• Multiinstitutional research to identify the blood biomarkers for diagnosing the state of glioblastoma after standard treatment

  中田光俊, 大槻純男, 内田康雄, 中嶋理帆, 篠山隆司, 長嶋宏明, 立石健祐, 齋藤紀彦, 平井希, 棗田学, 塚本佳広, 吉本幸司, 花谷亮典, 比嘉那優大, 近藤聡英, 石川栄一, 武笠晃丈, 廣瀬雄一, 荒川芳輝, 黒住和彦, 阿部竜也, 川端信司, 田中將太, 木下雅史

  2022, 日本脳腫瘍学会学術集会プログラム・抄録集, 40th


• 円蓋部に限局するくも膜下出血で発症した脳静脈血栓症の3症例

  上月惇, 十河正弥, 岡山公宣, 千原典夫, 上田健博, 関口兼司, 藤本陽介, 長嶋宏明, 篠山隆司, 松本理器

  2022, 日本内科学会雑誌, 111


• 2-HYDROXYGLUTARATE MAGNETIC RESONANCE SPECTROSCOPY IN ADULT BRAINSTEM GLIOMA PATIENTS

  Hiroaki Nagashima, Kazuhiro Tanaka, Yuichi Fujita, Mitsuru Hashiguchi, Mashahiro Maeyama, Yuichiro Somiya, Takanori Hirose, Tomoo Itoh, Takashi Sasayama

  Nov. 2021, NEURO-ONCOLOGY, 23, 131 - 131, English

  Summary international conference


• GLIOMA CELLS REPROGRAM SERINE-DEPENDENT ONE-CARBON METABOLISM TO SURVIVE GLUTAMINE STARVATION

  Kazuhiro Tanaka, Hiroaki Nagashima, Yuichi Fujita, Mitsuru Hashiguchi, Takashi Sasayama

  Nov. 2021, NEURO-ONCOLOGY, 23, 202 - 202, English

  Summary international conference


• 脳腫瘍遺伝子異常の画像診断 MR Spectroscopyを用いた2HG測定による成人脳幹グリオーマの遺伝子診断

  長嶋 宏明, 田中 一寛, 橋口 充, 藤田 祐一, 前山 昌博, 曽宮 雄一郎, 廣瀬 隆則, 伊藤 智雄

  日本脳腫瘍病理学会, May 2021, Brain Tumor Pathology, 38(Suppl.) (Suppl.), 060 - 060, Japanese


• 癌ゲノム医療 神戸大学医学部附属病院におけるがんゲノム医療の現状と課題

  篠山 隆司, 田中 一寛, 金原 史朗, 小松 正人, 児玉 良典, 山本 暢之, 長嶋 宏明, 南 博信, 廣瀬 隆則, 伊藤 智雄

  日本脳腫瘍病理学会, May 2021, Brain Tumor Pathology, 38(Suppl.) (Suppl.), 067 - 067, Japanese


• グリオーマと栄養飢餓環境 グルタミン飢餓におけるセリン合成と一炭素代謝の調整

  田中 一寛, 長嶋 宏明, 宇野 滝子, 橘田 明音, 藤田 祐一, 橋口 充, 廣瀬 隆則, 伊藤 智雄, 篠山 隆司

  日本脳腫瘍病理学会, May 2021, Brain Tumor Pathology, 38(Suppl.) (Suppl.), 086 - 086, Japanese


• ポリ(ADP-リボース)グリコヒドロラーゼ阻害はNAD⁺を隔離し,IDH変異腫瘍細胞におけるアルキル化化学療法の代謝致死性を増強する

  長嶋宏明, 長嶋宏明, LEE Christine, 立石建祐, 樋口芙未, 田中一寛, 篠山隆司, MILLERT Julie, 脇本浩明, CAHILL Daniel

  2021, 日本分子脳神経外科学会プログラム・抄録集, 21st


• PARG阻害はNAD+を隔離し,IDH変異腫瘍細胞におけるアルキル化化学療法の代謝致死性を増強する

  長嶋宏明, 長嶋宏明, 田中一寛, 篠山隆司

  2021, 日本癌学会学術総会抄録集(Web), 80th


• 膠芽腫に対するVEGF阻害剤とケトン食療法併用の有用性

  篠山隆司, 長嶋宏明, 入野康宏, 田中一寛

  2021, 日本癌学会学術総会抄録集(Web), 80th


• グルタミン飢餓環境にあるグリオーマ細胞のセリン合成と一炭素代謝の調整

  田中一寛, 長嶋宏明, 篠山隆司

  2021, 日本癌学会学術総会抄録集(Web), 80th


• 膠芽腫摘出術での脳室開放は播種を促進するか?

  篠山隆司, 田中一寛, 長嶋宏明, 藤田祐一, 岩橋洋文, 橋口充, 西原賢在

  2021, 日本脳腫瘍の外科学会プログラム・抄録集, 26th


• 専門医に求められる最新の知識 脳腫瘍 COVID-19大流行下の脳腫瘍臨床と研究の現況 米国ボストンより

  長嶋 宏明, 脇本 浩明

  (株)メディカ出版, Jul. 2020, 脳神経外科速報, 30(7) (7), 731 - 737, Japanese


• THE RELATION BETWEEN T2-FLAIR MISMATCH SIGN AND ADC VALUES REFLECTING PATHOLOGICAL MICROSTRUCTURE IN LOWER-GRADE GLIOMAS

  Yuichi Fujita, Takashi Sasayama, Hiroaki Nagashima, Kazuhiro Tanaka, Mitsuru Hashigutchi, Eiji Kohmura

  Nov. 2019, NEURO-ONCOLOGY, 21, 164 - 164, English

  Summary international conference


• MODULATION OF NAD PATHWAYS AS A THERAPEUTIC STRATEGY FOR TARGETING IDH MUTANT GLIOMA

  Julie Miller, Hiroaki Nagashima, Alexandria Fink, Kensuke Tateishi, Hiroaki Wakimoto, Jack Banagis, Daniel Cahill

  Nov. 2019, NEURO-ONCOLOGY, 21, 43 - 43, English

  Summary international conference


• PREDICTORS OF SENSITIVITY TO COMBINED TEMOZOLOMIDE AND PARP INHIBITOR IN GLIOMA

  Hiroaki Nagashima, Fumi Higuchi, Christine Lee, Seamus Rafferty, Julie Miller, Hiroaki Wakimoto, Daniel Cahill

  Nov. 2019, NEURO-ONCOLOGY, 21, 72 - 72, English

  Summary international conference


• 慢性硬膜下血腫の再発因子の検討

  中原 正博, 魚住 洋一, 斧渕 夏那, 長嶋 宏明, 荒井 篤, 三宅 茂, 甲村 英二

  (一社)日本脳神経外傷学会, Feb. 2019, 日本脳神経外傷学会プログラム・抄録集, 42回, 81 - 81, Japanese


• MMR欠損TMZ抵抗性神経膠腫に対するPARP阻害剤併用によるTMZ抵抗性の克服

  樋口芙未, 樋口芙未, 長嶋宏明, 脇本浩明, カーヒル ダニエル

  2019, 日本脳腫瘍学会プログラム・抄録集, 37th


• 抗血栓薬と頭部外傷 抗血栓治療中の頭部外傷の治療と管理 救命センターにおける重症例での成績から

  相原 英夫, 森下 暁二, 長嶋 宏明, 当麻 美樹, 甲村 英二

  (一社)日本脳神経外傷学会, Feb. 2018, 日本脳神経外傷学会プログラム・抄録集, 41回, 57 - 57, Japanese


• 救命救急センターにおける外傷性てんかん

  長嶋 宏明, 藤田 祐一, 森下 暁二, 相原 英夫, 当麻 美樹

  (一社)日本脳神経外傷学会, Feb. 2018, 日本脳神経外傷学会プログラム・抄録集, 41回, 75 - 75, Japanese


• 頭部外傷後における外傷後水頭症の検討

  森下 暁二, 長嶋 宏明, 相原 英夫

  (一社)日本脳神経外傷学会, Feb. 2018, 日本脳神経外傷学会プログラム・抄録集, 41回, 79 - 79, Japanese


• INTRAOPERATIVE MAGNETIC RESONANCE SPECTROSCOPY (iMRS) FOR GLIOMA SURGERY

  Takashi Sasayama, Masaaki Kohta, Kazuhiro Tanaka, Masahiro Maeyama, Hiroaki Nagashima, Eiji Kohmura

  Nov. 2017, NEURO-ONCOLOGY, 19, 238 - 238, English

  Summary international conference


• 受傷早期に形成外科と合同手術を行った開放性顔面・前頭部陥没骨折を伴う頭部外傷の治療経験

  林 成人, 長嶋 宏明, 太田 耕平, 小川 晴生, 時吉 貴宏, 原田 知明, 原 淑惠, 山下 晴央, 田原 真也, 甲村 英二

  (一社)日本脳神経外傷学会, Feb. 2017, 日本脳神経外傷学会プログラム・抄録集, 40回, 95 - 95, Japanese


• CXCL13 AND IL-10 IN CEREBROSPINAL FLUID (CSF) AS AN IMPORTANT BIOMARKER FOR PRIMARY CENTRAL NERVOUS SYSTEM CELL LYMPHOMA (PCNSL)

  Takashi Sasayama, Kazuhiro Tanaka, Masamitsu Nishihara, Hiroaki Nagashima, Katsu Mizukawa, Junichi Sakata, Masahiro Maeyama, Eiji Kohmura

  Nov. 2016, NEURO-ONCOLOGY, 18, 111 - 111, English

  Summary international conference


• STANNIOCALCIN-1 EXPRESSION IN GLIOBLASTOMA IS ASSOCIATED WITH LEPTOMENINGEAL DISSEMINATION OR METASTASIS

  Junichi Sakata, Takashi Sasayama, Kazuhiro Tanaka, Mitsutoshi Nakada, Naoya Hashimoto, Manabu Kinoshita, Naoki Kagawa, Katsu Mizukawa, Hiroaki Nagashima, Naoko Sato, Eiji Kohmura

  Nov. 2016, NEURO-ONCOLOGY, 18, 15 - 15, English

  Summary international conference


• 脳腫瘍 グリオーマに対する治療戦略 グリオーマ摘出術における3.0-Tesla術中MRスペクトロスコピーの有用性の検討

  篠山 隆司, 甲田 将章, 水川 克, 長嶋 宏明, 中井 友昭, 坂田 純一, 前山 昌博, 甲村 英二

  (一社)日本癌治療学会, Oct. 2016, 日本癌治療学会学術集会抄録集, 54回, WS15 - 5, Japanese


• MR Spectroscopyによる原発性中枢神経リンパ腫とグリオーマの鑑別

  長嶋 宏明, 篠山 隆司, 田中 一寛, 佐藤 直子, 坂田 純一, 京谷 勉輔, 伊藤 智雄, 甲村 英二

  日本脳腫瘍病理学会, May 2016, Brain Tumor Pathology, 33(Suppl.) (Suppl.), 112 - 112, Japanese


• 中枢神経原発悪性リンパ腫(PCNSL)での腫瘍関連マクロファージ浸潤と臨床学的解析

  篠山 隆司, 坂田 純一, 長嶋 宏明, 前山 昌博, 田中 一寛, 水川 克, 西原 賢在, 廣瀬 隆則, 伊藤 智雄, 甲村 英二

  日本脳腫瘍病理学会, May 2016, Brain Tumor Pathology, 33(Suppl.) (Suppl.), 112 - 112, Japanese


• 頭蓋外転移を呈したgliosarcomaの一例

  坂田 純一, 篠山 隆司, 前山 昌博, 田中 一寛, 長嶋 宏明, 伊藤 智雄, 廣瀬 隆則, 甲村 英二

  日本脳腫瘍病理学会, May 2016, Brain Tumor Pathology, 33(Suppl.) (Suppl.), 137 - 137, Japanese


• GLUTAMINASE-MEDIATED METABOLIC PATHWAY INVOLVES GLIOBLASTOMA RESISTANCE TO mTOR-TARGETED THERAPIES

  Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Kumi Takata, Hiroaki Nagashima, Kenta Masui, Beatrice Gini, Huijun Yang, Paul S. Mischel, Eiji Kohmura

  Nov. 2014, NEURO-ONCOLOGY, 16, English

  Summary international conference


• 特異な経過を辿った原発不明の転移性脳腫瘍の1例

  長嶋 宏明, 石井 大嗣, 篠山 隆司, 近藤 威, 原 重雄, 伊藤 智雄, 甲村 英二

  日本脳腫瘍病理学会, May 2014, Brain Tumor Pathology, 31(Suppl.) (Suppl.), 118 - 118, Japanese


• 頭部外傷の画像診断とモニタリング ショック合併の重症頭部外傷症例に対する集学的初期治療とICP指向性治療

  相原 英夫, 森下 暁二, 中井 友昭, 当麻 美樹, 長嶋 宏明, 阿久津 宣行, 甲村 英二

  (一社)日本脳神経外傷学会, Mar. 2014, 日本脳神経外傷学会プログラム・抄録集, 37回, 58 - 58, Japanese


• Cerebrospinal fluid interleukin-10 is associated with molecular subtype, tumor-associated macrophage infiltration and STAT3 activation in primary central nervous system diffuse large B-cell lymphoma

  Takashi Mizowaki, Takashi Sasayama, Kazuhiro Tanaka, Katsu Mizukawa, Kumi Takata, Satoshi Nakamizo, Hirotomo Tanaka, Hiroaki Nagashima, Masamitsu Nishihara, Takanori Hirose, Tomoo Itoh, Eiji Kohmura

  2014, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 34, S125 - S125, English

  Summary international conference


• Glutaminase-mediated metabolic pathway involves glioblastoma resistance to mTOR-targeted therapies

  Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Kumi Takata, Hiroaki Nagashima, Kenta Masui, Beatrice Gini, Huijun Yang, Paul S. Mischel, Eiji Kohmura

  2014, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 34, S73 - S73, English

  Summary international conference


• 神経外傷におけるモニタリング 重症頭部外傷に対するICP指向性管理と外科的減圧優先の治療

  相原 英夫, 長嶋 宏明, 阿久津 宣行, 高岡 諒, 当麻 美樹, 甲村 英二

  (一社)日本脳神経外傷学会, Mar. 2012, 日本脳神経外傷学会プログラム・抄録集, 35回, 47 - 47, Japanese


• 重症頭部外傷の臨床像 びまん性脳損傷と局所性脳損傷との比較

  長嶋 宏明, 相原 英夫, 高岡 諒, 当麻 美樹

  (一社)日本脳神経外傷学会, Mar. 2012, 日本脳神経外傷学会プログラム・抄録集, 35回, 70 - 70, Japanese


• 重症頭部外傷に対する人工真皮を用いた減圧皮膚形成術

  阿久津 宣行, 相原 英夫, 長嶋 宏明, 櫻井 敦, 日下 淳子, 小山 淳二, 甲村 英二

  (一社)日本脳神経外傷学会, Mar. 2012, 日本脳神経外傷学会プログラム・抄録集, 35回, 72 - 72, Japanese


• 外傷性頭蓋内出血における抗凝固薬・抗血小板薬内服の影響

  小山 淳二, 長嶋 宏明, 三宅 茂, 相原 英夫, 甲村 英二

  (一社)日本脳神経外傷学会, Mar. 2010, 日本脳神経外傷学会プログラム・抄録集, 33回, 80 - 80, Japanese

• 小児脳神経外科学 第2版

  長嶋 達也、長嶋 宏明

  Contributor, 新生児・乳児期の脳腫瘍 p680-687, 金芳堂, Oct. 2015


• 最新ガイドライン準拠 小児科診断、治療指針

  長嶋 達也、長嶋 宏明

  頭部外傷, 中山書店, 2012

• Predictors of sensitivity to combined temozolomide and PARP inhibitor in glioma

  Hiroaki Nagashima, Fumi Higuchi, Christine K. Lee, Seamus Rafferty, Julie J. Miller, Hiroaki Wakimoto, Daniel P. Cahill

  24th Society of Neuro-oncology annual meeting, Nov. 2019, English

  Poster presentation


• Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells

  : Hiroaki Nagashima, Christine K. Lee, Kensuke Tateishi, Fumi Higuchi, Megha Subramanian, Seamus Rafferty, Lisa Melamed, Julie J. Miller, Hiroaki Wakimoto, Daniel P. Cahill

  32nd EORTC-NCI-AACR Symposium, Oct. 2020, English

  [Invited]

  Oral presentation


• Magnetic resonance spectroscopy of glutamate and 2-hydroxyglutarate in patients with the IDH1 mutant glioma: A prospective validation study

  Kazuhiro Tanaka, Takashi Sasayama, Hiroaki Nagashima, Masahiro Maeyama, Eiji Kohmura

  22nd International Conference on Brain Tumor Research and Therapy (ICBTRT), Jun. 2018


• 術前MR SpectroscopyによるグリオーマIDH1遺伝子変異予測の検討

  田中 一寛, 篠山 隆司, 長嶋 宏明, 前山 昌博, 甲村 英二

  第47回日本神経放射線学会, Feb. 2018

  [Invited]


• 脳幹グリオーマに対するMR Spectroscopyを用いたIDH遺伝子変異診断の有用性

  田中 一寛, 長嶋 宏明, 篠山 隆司, 前山 昌博, 佐藤 直子, 小山 淳二, 河村 淳史, 京谷 勉輔, 伊藤 智雄, 甲村 英二

  第35回日本脳腫瘍学会, Nov. 2017


• MR Spectroscopyを用いた2HG測定によるIDH遺伝子変異陽性脳幹グリオーマ診断の有用性

  田中 一寛, 長嶋 宏明, 篠山 隆司, 前山 昌博, 佐藤 直子, 京谷 勉輔, 伊藤 智雄, 甲村 英二

  日本脳神経外科学会第76回学術総会, Oct. 2017


• 術前MR SpectroscopyによるグリオーマIDH1変異の予測可能性

  長嶋 宏明, 田中 一寛, 篠山 隆司, 佐藤 直子, 入野 康宏, 京谷 勉輔, 甲村 英二

  第33回日本脳腫瘍学会学術集会, Dec. 2015


• 悪性グリオーマのmTORシグナル阻害薬に対する代償的グルタミン代謝機構

  田中 一寛, 篠山 隆司, 入野 康宏, 佐藤 直子, 長嶋 宏明, 甲村 英二

  第20回日本脳腫瘍の外科学会, Dec. 2015


• Preoperative prediction of IDH1 mutation in glioma tissue by MR Spectroscopy

  Hiroaki Nagashima, Kazuhiro Tanaka, Takashi Sasayama, Naoko Satoh, Yasuhiro Irino, Katsusuke Kyotani, Eiji Kohmura

  20th Society of Neuro-oncology annual meeting, Nov. 2015, English

  Oral presentation


• Increasing expression of glutaminase C (GAC) mRNA in malignant gliomas

  Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Hiroaki Nagashima, Naoko Satoh, Paul S. Mischel, Eiji Kohmura

  20th Annual Society for Neuro-OncologyAnnual Scientific Meeting and Education Day, Nov. 2015, English

  Poster presentation


• 悪性グリオーマのmTORシグナル阻害薬に対する代償的グルタミン代謝機構

  田中 一寛, 篠山 隆司, 入野 康宏, 佐藤 直子, 長嶋 宏明, 甲村 英二

  第74回日本脳神経外科学会学術総会, Oct. 2015, Japanese

  Oral presentation


• 再発膠芽腫に対する再摘出術の有効性および問題点

  篠山 隆司, 田中 一寛, 水川 克, 田中 宏知, 坂田 純一, 長嶋 宏明, 甲村 英二

  第20回日本脳腫瘍の外科学会, Sep. 2015


• 初発・再発時に覚醒下手術を2度行った優位半球言語野近傍グリオーマの1例

  田中 一寛, 篠山 隆司, 後藤田 政子, 長嶋 宏明, 山本 祐輔, 甲田 将章, 水川 克, 甲村 英二

  第13回日本Awake surgery学会, Sep. 2015


• 中枢神経原発悪性リンパ腫での腫瘍関連マクロファージ浸潤と髄液サイトカインとの関連性

  篠山 隆司, 坂田 純一, 溝脇 卓, 田中 一寛, 田中 宏知, 長嶋 宏明, 水川 克, 西原 賢在, 廣瀬 隆則, 伊藤 智雄, 甲村 英二

  第16回日本分子脳神経外科学会, Aug. 2015


• MR SpectroscopyによるグリオーマIDH1変異の予測可能性

  長嶋 宏明, 田中 一寛, 篠山 隆司, 入野 康宏, 京谷 勉輔, 甲村 英二

  第18回日本臨床脳神経外科学会, Jul. 2015

  Public symposium


• グリオーマでのmiR-183によるIDH2発現調節と代謝との関連

  篠山 隆司, 田中 宏知, 田中 一寛, 長嶋 宏明, 入野 康宏, 甲村 英二

  第3回がんと代謝研究会, Jul. 2015


• 悪性グリオーマのグルタミン代謝による代償的mTOR阻害薬耐性機構

  田中 一寛, 篠山 隆司, 入野 康宏, 佐藤 直子, 長嶋 宏明, 甲村 英二

  第3回がんと代謝研究会, Jul. 2015

• Microbiota of ketogenic diet in glioblastoma patients and enhancement effect of synbiotics

  篠山 隆司, 長嶋 宏明, 藤田 祐一, 田中 一寛

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2024 - 31 Mar. 2027


• Molecular mechanism of membrane lipid remodeling in hypoxic glioma cells

  田中 一寛, 長嶋 宏明, 篠山 隆司, 高橋 政友

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2023 - 31 Mar. 2026

  悪性グリオーマでは網羅的DNA解析の発達によって多くの遺伝子異常や癌シグナル経路が 明らかとなってきたが、細胞内代謝に関する分子生物学的メカニズムは不明な点が多い。特に、腫瘍微小環境における酸素・栄養状態はグリオーマ細胞の悪性化や治療抵抗性の獲得に繋がると考えられる。本研究では低酸素環境下のグリオーマ細胞の膜脂質代謝変化（リモデリング）を明らかにすべく、リピドーム解析や分子生物学的解析で、細胞膜を構成するリン脂質やコレステロール、脂肪酸の組成変化および機能解析を行うことである。また、悪性グリオーマに対する標準的治療薬であるテモゾロミド（アルキル化剤）はDNA損傷によりアポトーシスを誘導するが、低酸素環境下においてグリオーマ細胞が治療抵抗性を獲得する機序について、膜脂質代謝の変化に着目して細胞膜の機能を解明する。 グリオーマ培養細胞（U87およびT98グリオーマ細胞）を用いたリピドーム定量分析法では、低酸素状態においてコレステロールやホスファチジルセリン（PS）やホスファチジルエタノールアミン（PE）の含有率が増加していた。また、ホスファチジルコリン（PC）の含有率は変化しないが、リン脂質の疎水性尾部を形成する2本の脂肪酸について不飽和脂肪酸より飽和脂肪酸の割合が増加していた。また、膜脂質代謝に関与する遺伝子発現解析をリアルタイムPCR法やWestern blot法で行い、低酸素によって飽和脂肪酸を含むホスファチジルコリン（PC）の生合成に強く関与するリゾリン脂質アシル転移酵素LPCAT1の発現が増加していることを確認した。


• Development of new treatments for medulloblastoma targeting macrophage

  西原 賢在, 長嶋 宏明, 篠山 隆司, 藤田 祐一, 田中 一寛

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Kobe University, 01 Apr. 2022 - 31 Mar. 2025


• Targeting PARG in malignant glioma therapy

  長嶋 宏明

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Kobe University, 01 Apr. 2021 - 31 Mar. 2025

  申請者は、先行研究においてIDH遺伝子変異を持つ低悪性度神経膠腫に対してテモゾロミド（TMZ)とPARG阻害薬を併用すると、IDH変異遺伝子特有の代謝脆弱性により顕著な抗腫瘍効果を示すことを発見した。高悪性度IDH野生型神経膠腫においても、PARG阻害薬によりTMZの抗腫瘍効果が著しく増強されるサブグループが存在することが明らかとなった。これらの研究を踏まえ本研究では、患者由来神経膠腫幹細胞株を用い、TMZとPARG阻害薬の併用療法が有効な悪性神経膠腫の特徴・遺伝子異常を明らかにすることを目標に研究を開始した。まず、 IDH野生型神経膠腫の中で、 PARG阻害薬の追加によってTMZの殺効果が増強されるサブグループを明らかにするべく、ハイスループットジェノタイピング法を用いて、患者由来神経膠腫幹細胞株の遺伝子変異や共欠失などの網羅的解析を行った。その結果、WEE1遺伝子の発現状態やリン酸化状態がPARG阻害薬単独やTMZとの併用に対する感受性に関与していることが示唆された。また、WEE1阻害薬によりTMZ+PARG阻害薬の薬剤感受性が変化することが確認された。IDH野生型神経膠腫では、PARG阻害薬単独やTMZ＋PARG阻害薬併用療法は代謝脆弱性を利用し細胞死を誘導するのではなく、DNA損傷応答、特にWEE1経路の応答を介して細胞死に至る可能性が示唆された。また、TMZのDNA損傷応答経路にWEE1の発現が関与している可能性があり、TMZ耐性化に関与している可能性が示唆された。