Department of Neurosurgery and Neuro-Oncology

Yoshitaka Narita, Yasuji Miyakita, Masamichi Takahashi, Makoto Ohno, Shunsuke Yanagisawa, Yukie Tamura, Miu Kikuchi, Tomoyuki Nakano, Tomohiro Hosoya, Takaki Omura, Hitomi Sato

Introduction

We treat patients with primary and metastatic brain tumors. Approximately 300 patients were admitted and 202 craniotomies for tumor removal were performed in 2020 including 76 gliomas, 81 brain metastases, 7 primary CNS lymphomas, and 16 meningiomas (Table 1). The site of the craniotomy and the extent of tumor removal were visualized on an intraoperative MRI in real time, contributing to safer and more precise surgery. Intraoperative monitoring with motor- and sensory-evoked potential (MEP and SEP) recording as well as preoperative functional MRI and MR tractography were also used to preserve patient neurological function. Awake surgeries were also performed, particularly for removal of gliomas near the speech center. Patients with malignant brain tumors underwent postoperative radiotherapy and chemotherapy. In order to perform a more effective chemotherapy regimen, molecular biological studies for drug resistance and growth factors, cell kinetic studies on individual tumors and several clinical trials are ongoing.

The Team and What We Do

A weekly conference on treatment of patients with brain tumors is held with doctors of the Department of Radiation Oncology and Pathology, and of the Division of Brain Tumor Translational Research. Usually 10-15 patients are hospitalized and 3 or 4 of them undergo surgical treatment every week. The patients with malignant brain tumors receive postoperative radiotherapy and chemotherapy. Statistical analysis revealed that surgical removal of as much of the tumor as possible yielded better survival rates even for the most malignant glioblastomas, which usually recur soon after the surgery without radiotherapy. Concomitant use of chemotherapy is considered to enhance the anti-tumor effect of radiotherapy. Temozolomide has been given to all malignant glioma patients during radiotherapy and repeated every month for 1 year. R-MPV therapy is administered to the patients with primary CNS lymphoma before radiotherapy.

Fig 1


Table 1. Surgical cases for brain tumors

The decision on the indication for surgery of metastatic brain tumors is not simple. Multiplicity of brain metastasis, the stage of the primary malignancy and the patient performance status should be taken into careful consideration.

Research activities

An analysis of gene expression profiles in malignant gliomas is being carried out in order to determine specific genes that have an influence on the effects of chemotherapy and radiation therapy in cooperation with the Division of Brain Tumor Translational Research, the National Cancer Center Research Institute. The determination of the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) and the mutation of IDH1/2 and TERT are also being carried out to predict the prognosis of the patients with malignant gliomas.

Clinical trials

The Japan Clinical Oncology Group (JCOG)-Brain Tumor Study Group was organized in 2002 and multi-institutional randomized controlled trials are performed. “Randomized phase III study for unresectable WHO Grade II astrocytoma with radiotherapy alone or chemoradiotherapy with temozolomide (JCOG1303)” is ongoing, and so are a phase III randomized study for grade III gliomas (JCOG1016) and some phase III studies for glioblastoma (JCOG1308, JCOG1703 and JCOG1910). These studies, under the surveillance of JCOG, aim to set a standard protocol for treating malignant brain tumor patients. Moreover, a proper methodology for performing randomized studies will be established in the field of neuro-oncology.

An investigator-initiated phase II clinical trial of eribulin targeting TERT in patients with recurrent glioblastomas was completed and a phase II study of temozolomide and metformin for newly-diagnosed glioblastoma is also ongoing under an AMED grant.

Education

Our department plays a pivotal role in the JCOG-Brain Tumor Study Group and the brain tumor registry of Japan, and we conducted many clinical trials and ran the brain tumor registry. We educate many neurosurgeons and oncologists about surgical techniques of awake craniotomy and intraoperative MRI and the effective usage and adverse effects of many chemotherapeutic agents regarding malignant brain tumors.

Future prospects

Malignant brain tumors, especially glioblastoma, still have the worse prognosis among cancers. We continually strive to defeat these brain cancers through a variety of clinical work and research.

List of papers published

Journal

1. Narita Y, Sato S, Kayama T. Review of the diagnosis and treatment of brain metastases. Japanese journal of clinical oncology, 52:3-7, 2022

2. Nakano T, Fujimoto K, Tomiyama A, Takahashi M, Achiha T, Arita H, Kawauchi D, Yasukawa M, Masutomi K, Kondo A, Narita Y, Maehara T, Ichimura K. Eribulin prolongs survival in an orthotopic xenograft mouse model of malignant meningioma. Cancer science, 113:697-708, 2022

3. Arakawa Y, Sasaki K, Mineharu Y, Uto M, Mizowaki T, Mizusawa J, Sekino Y, Ono T, Aoyama H, Satomi K, Ichimura K, Kinoshita M, Ohno M, Ito Y, Nishikawa R, Fukuda H, Nishimura Y, Narita Y. A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII). BMC cancer, 21:1105, 2021

4. Fujimoto K, Arita H, Satomi K, Yamasaki K, Matsushita Y, Nakamura T, Miyakita Y, Umehara T, Kobayashi K, Tamura K, Tanaka S, Higuchi F, Okita Y, Kanemura Y, Fukai J, Sakamoto D, Uda T, Machida R, Kuchiba A, Maehara T, Nagane M, Nishikawa R, Suzuki H, Shibuya M, Komori T, Narita Y, Ichimura K. TERT promoter mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic glioma with molecular features of glioblastoma. Acta neuropathologica, 142:323-338, 2021

5. Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, Kitagawa J, Aoi A, Nishikawa R. Phase I/II study of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro-oncology, 23:122-133, 2021

6. Narita Y, Muragaki Y, Kagawa N, Asai K, Nagane M, Matsuda M, Ueki K, Kuroda J, Date I, Kobayashi H, Kumabe T, Beppu T, Kanamori M, Kasai S, Nishimura Y, Xiong H, Ocampo C, Yamada M, Mishima K. Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial. Cancer science, 112:5020-5033, 2021

7. Ohno M, Hayashi Y, Aikawa H, Hayashi M, Miyakita Y, Takahashi M, Matsushita Y, Yoshida A, Satomi K, Ichimura K, Hamada A, Narita Y. Tissue 2-Hydroxyglutarate and Preoperative Seizures in Patients With Diffuse Gliomas. Neurology, 97:e2114-e2123, 2021

8. Yonezawa H, Ohno M, Igaki H, Miyakita Y, Takahashi M, Tamura Y, Shima S, Matsushita Y, Ichimura K, Narita Y. Outcomes of salvage fractionated re-irradiation combined with bevacizumab for recurrent high-grade gliomas that progressed after bevacizumab treatment*. Japanese journal of clinical oncology, 51:1028-1035, 2021

9. Aoki T, Kagawa N, Sugiyama K, Wakabayashi T, Arakawa Y, Yamaguchi S, Tanaka S, Ishikawa E, Muragaki Y, Nagane M, Nakada M, Suehiro S, Hata N, Kuroda J, Narita Y, Sonoda Y, Iwadate Y, Natsumeda M, Nakazato Y, Minami H, Hirata Y, Hagihara S, Nishikawa R. Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study. International journal of clinical oncology, 26:2205-2215, 2021

10. Oort Q, Dirven L, Sikkes SAM, Aaronson N, Boele F, Brannan C, Egeter J, Grant R, Klein M, Lips I, Narita Y, Sato H, Sztankay M, Stockhammer G, Talacchi A, Uitdehaag BMJ, Reijneveld JC, Taphoorn MJB . Development of an EORTC questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumours: phase I-III. Quality of life research: an international journal of quality of life aspects of treatment, care and rehabilitation, 30:1491-1502, 2021

11. Kawaguchi RK, Takahashi M, Miyake M, Kinoshita M, Takahashi S, Ichimura K, Hamamoto R, Narita Y, Sese J. Assessing Versatile Machine Learning Models for Glioma Radiogenomic Studies across Hospitals. Cancers, 13:2021

12. Kanamori M, Takami H, Suzuki T, Tominaga T, Kurihara J, Tanaka S, Hatazaki S, Nagane M, Matsuda M, Yoshino A, Natsumeda M, Yamaoka M, Kagawa N, Akiyama Y, Fukai J, Negoto T, Shibahara I, Tanaka K, Inoue A, Mase M, Tomita T, Kuga D, Kijima N, Fukami T, Nakahara Y, Natsume A, Yoshimoto K, Keino D, Tokuyama T, Asano K, Ujifuku K, Abe H, Nakada M, Matsuda KI, Arakawa Y, Ikeda N, Narita Y, Shinojima N, Kambe A, Nonaka M, Izumoto S, Kawanishi Y, Kanaya K, Nomura S, Nakajima K, Yamamoto S, Terashima K, Ichimura K, Nishikawa R. Necessity for craniospinal irradiation of germinoma with positive cytology without spinal lesion on MR imaging-A controversy. Neuro-oncology advances, 3:vdab086, 2021

13. Oya S, Ikawa F, Ichihara N, Wanibuchi M, Akiyama Y, Nakatomi H, Mikuni N, Narita Y. Nation-wide Brain Tumor Registry-based Study of Intracranial Meningioma in Japan: Analysis of Surgery-related Risks. Neurologia medico-chirurgica, 61:98-106, 2021

14. Takahashi S, Takahashi M, Tanaka S, Takayanagi S, Takami H, Yamazawa E, Nambu S, Miyake M, Satomi K, Ichimura K, Narita Y, Hamamoto R. A New Era of Neuro-Oncology Research Pioneered by Multi-Omics Analysis and Machine Learning. Biomolecules, 11:2021

15. Takami H, Graffeo CS, Perry A, Ohno M, Ishida J, Giannini C, Narita Y, Nakazato Y, Saito N, Nishikawa R, Matsutani M, Ichimura K, Daniels DJ. Histopathology and prognosis of germ cell tumors metastatic to brain: cohort study. Journal of neuro-oncology, 154:121-130, 2021

16. Takami H, Satomi K, Fukuoka K, Fukushima S, Matsushita Y, Yamasaki K, Nakamura T, Tanaka S, Mukasa A, Saito N, Suzuki T, Yanagisawa T, Nakamura H, Sugiyama K, Tamura K, Maehara T, Nakada M, Nonaka M, Asai A, Yokogami K, Takeshima H, Iuchi T, Kanemura Y, Kobayashi K, Nagane M, Kurozumi K, Yoshimoto K, Matsuda M, Matsumura A, Hirose Y, Tokuyama T, Kumabe T, Narita Y, Shibui S, Nakazato Y, Nishikawa R, Matsutani M, Ichimura K. Low tumor cell content predicts favorable prognosis in germinoma patients. Neuro-oncology advances, 3:vdab110, 2021

17. Wakabayashi T, Hirose Y, Miyake K, Arakawa Y, Kagawa N, Nariai T, Narita Y, Nishikawa R, Tsuyuguchi N, Fukami T, Sasaki H, Sasayama T, Kondo A, Iuchi T, Matsuda H, Kubota K, Minamimoto R, Terauchi T, Nakazato Y, Kubomura K, Wada M. Determining the extent of tumor resection at surgical planning with 18F-fluciclovine PET/CT in patients with suspected glioma: multicenter phase III trials. Annals of nuclear medicine, 35:1279-1292, 2021

18. Yamagishi Y, Sasaki N, Nakano Y, Matushita Y, Omura T, Shimizu S, Saito K, Kobayashi K, Narita Y, Kondo A, Shiokawa Y, Nagane M, Ichimura K. Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma. Cancer science, 112:4702-4710, 2021

19. Yamamuro S, Takahashi M, Satomi K, Sasaki N, Kobayashi T, Uchida E, Kawauchi D, Nakano T, Fujii T, Narita Y, Kondo A, Wada K, Yoshino A, Ichimura K, Tomiyama A. Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance. Cancer science, 112:4736-4747, 2021

20. Yazaki S, Yoshida T, Kojima Y, Yagishita S, Nakahama H, Okinaka K, Matsushita H, Shiotsuka M, Kobayashi O, Iwata S, Narita Y, Ohba A, Takahashi M, Iwasa S, Kobayashi K, Ohe Y, Yoshida T, Hamada A, Doi T, Yamamoto N. Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA oncology, 7:1141-1148, 2021

21. Takahashi J, Nagasawa S, Doi M, Takahashi M, Narita Y, Yamamoto J, Ikemoto MJ, Iwahashi H. In Vivo Study of the Efficacy and Safety of 5-Aminolevulinic Radiodynamic Therapy for Glioblastoma Fractionated Radiotherapy. International journal of molecular sciences, 22:2021

22. Kobayashi K, Miyake M, Takahashi M, Hamamoto R. Observing deep radiomics for the classification of glioma grades. Scientific reports, 11:10942, 2021

23. Kawauchi D, Takahashi M, Satomi K, Yamamuro S, Kobayashi T, Uchida E, Honda-Kitahara M, Narita Y, Iwadate Y, Ichimura K, Tomiyama A. The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death. Cancer science, 112:2442-2453, 2021

24. Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Narita Y, Ichimura K, Yoshida A. Utility of methylthioadenosine phosphorylase immunohistochemical deficiency as a surrogate for CDKN2A homozygous deletion in the assessment of adult-type infiltrating astrocytoma. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc, 34:688-700, 2021

25. Matsumoto F, Miyakita Y, Sakai A, Akamatsu M, Matsumoto Y, Matsumura S, Omura G, Kobayashi K, Narita Y, Yoshimoto S. Resection of carcinoma of the external auditory canal in a patient with a high jugular bulb using temporal craniotomy. Auris, nasus, larynx, 48:535-538, 2021

26. Ozawa T, Kaneko S, Szulzewsky F, Qiao Z, Takadera M, Narita Y, Kondo T, Holland EC, Hamamoto R, Ichimura K. C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation. Acta neuropathologica communications, 9:36, 2021

27. Takahashi S, Takahashi M, Kinoshita M, Miyake M, Kawaguchi R, Shinojima N, Mukasa A, Saito K, Nagane M, Otani R, Higuchi F, Tanaka S, Hata N, Tamura K, Tateishi K, Nishikawa R, Arita H, Nonaka M, Uda T, Fukai J, Okita Y, Tsuyuguchi N, Kanemura Y, Kobayashi K, Sese J, Ichimura K, Narita Y, Hamamoto R. Fine-Tuning Approach for Segmentation of Gliomas in Brain Magnetic Resonance Images with a Machine Learning Method to Normalize Image Differences among Facilities. Cancers, 13:2021