Faculty Profiles - Tanaka Shota

Papers - Tanaka Shota

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Immune prognostic model for glioblastoma based on the ssGSEA enrichment score. International journal

Takanari Okamoto, Ryo Mizuta, Ayako Demachi-Okamura, Daisuke Muraoka, Eiichi Sasaki, Katsuhiro Masago, Rui Yamaguchi, Satoshi Teramukai, Yoshihiro Otani, Isao Date, Shota Tanaka, Yoshinobu Takahashi, Naoya Hashimoto, Hirokazu Matsushita

Cancer genetics 294-295 32 - 41 2025.3

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

PURPOSE: Few effective immune prognostic models based on the tumor immune microenvironment (TIME) for glioblastoma have been reported. Therefore, this study aimed to construct an immune prognostic model for glioblastoma by analyzing enriched biological processes and pathways in tumors. METHODS: A comprehensive single-sample gene set enrichment analysis (ssGSEA) of gene sets from the Molecular Signatures Database was performed using TCGA RNA sequencing data (141 glioblastoma cases). After evaluating gene sets associated with prognosis using univariable Cox regression, gene sets related to biological processes and tumor immunity in gliomas were extracted. Finally, the least absolute shrinkage and selection operator Cox regression refined the gene sets and a nomogram was constructed. The model was validated using CGGA (183 cases) and Aichi Cancer Center (42 cases) datasets. RESULTS: The immune prognostic model consisted of three gene sets related to biological processes (sphingolipids, steroid hormones, and intermediate filaments) and one related to tumor immunity (immunosuppressive chemokine pathways involving tumor-associated microglia and macrophages). Kaplan-Meier curves for the training (TCGA) and validation (CGGA) cohorts showed significantly worse overall survival in the high-risk group compared to the low-risk group (p < 0.001 and p = 0.04, respectively). Furthermore, in silico cytometry revealed a significant increase in macrophages with immunosuppressive properties and T cells with effector functions in the high-risk group (p < 0.01) across all cohorts. CONCLUSION: Construction of an immune prognostic model based on the TIME assessment using ssGSEA could potentially provide valuable insights into the prognosis and immune profiles of patients with glioblastoma and guide treatment strategies.

DOI： 10.1016/j.cancergen.2025.03.005

Repeated non-hemorrhagic and non-contusional mild traumatic brain injury in rats elicits behavioral impairment with microglial activation, astrogliosis, and tauopathy: Reproducible and quantitative model of chronic traumatic encephalopathy. International journal

Chiaki Sugahara, Kyohei Kin, Tatsuya Sasaki, Susumu Sasada, Satoshi Kawauchi, Satoru Yabuno, Takayuki Nagase, Takahiro Hirayama, Kaori Masai, Kakeru Hosomoto, Yosuke Okazaki, Koji Kawai, Shun Tanimoto, Yuichi Hirata, Hayato Miyake, Hiromichi Naito, Takao Yasuhara, Cesar V Borlongan, Isao Date, Shota Tanaka

Brain research 149412 - 149412 2024.12

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

Chronic traumatic encephalopathy (CTE) has attracted attention due to sports-related head trauma or repetitive mild traumatic brain injury (mTBI). However, the pathology of CTE remains underexplored. Reproducible and quantitative model of CTE has yet to be established. The aim of this study is to establish a highly reproducible model of CTE with behavioral and histological manifestations. First, the pathological symptoms of mTBI with no intracranial hemorrhage or contusion using the weight drop model of 52 g ball from a height of 30 cm was determined using hematoxylin and eosin staining. Adult rats that received single, double, or triple head impacts were compared with sham behaviorally and histologically. Results revealed that rats exposed to repetitive mTBI showed motor impairment with gradual recovery over time, which was prolonged as the number of head impact increased. Similarly, cognitive function was impaired by repetitive mTBI and the recovery depended on the number of head impact. Histologically, GFAP positive astrocytes increased with repetitive mTBI, although Iba-1 positive microglial aggregation was limited. At 4w, phosphorylated Tau significantly accumulated in the prefrontal cortex, corpus callosum, CA1, and dentate gyrus of rats that received triple mTBI, compared to sham or those exposed to single, or double mTBI. This repetitive mTBI rat model provides a highly reproducible and quantifiable brain and behavioral pathology reminiscent of CTE.

DOI： 10.1016/j.brainres.2024.149412

Comparative analysis of intraoperative MRI and early postoperative MRI findings in glioma surgery patients. International journal

Yoshihiro Otani, Fumiyo Higaki, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryoji Imoto, Ryo Mizuta, Yasuhito Kegoya, Yohei Inoue, Tsuyoshi Umeda, Madoka Hokama, Takao Yasuhara, Takao Hiraki, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Shota Tanaka, Isao Date

Journal of neurosurgery 1 - 9 2024.12

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

OBJECTIVE: The extent of resection (EOR) is an important prognostic factor for both low- and high-grade gliomas. Intraoperative MRI (iMRI) has been used to increase the EOR in glioma surgery. While a recent study reported differences between iMRI and early postoperative MRI (epMRI), their specific relationship to postoperative clinical symptoms remains unclear. This study aims to compare the differences between iMRI and epMRI in glioma surgery. METHODS: A retrospective assessment was conducted on 43 patients with glioma who underwent surgery with iMRI and for whom no additional resection was performed after iMRI. The study evaluated the discrepancies in EOR, surgically induced contrast enhancement (SICE), and diffusion-weighted imaging (DWI) abnormality between iMRI and epMRI. EOR was defined as gross-total resection (GTR), near-total resection, subtotal resection (STR), or partial resection (PR) for enhancing lesions, and GTR, STR, or PR for nonenhancing lesions. In addition, the relationship between postoperative neurological findings and iMRI findings was evaluated. RESULTS: Discrepancies in EOR were observed in 2 (11.1%) of 18 cases with nonenhanced lesions and 1 (4.0%) of 25 cases with enhanced lesions. The positive rate of SICE was 25.0% on iMRI and 67.9% on epMRI. Enhancement at the resection cavity was the most frequent pattern in both iMRI and epMRI. The positive rate of enhancement of the resection cavity was strongly increased on epMRI compared with iMRI, potentially mimicking residual tumor. The positive rate of DWI abnormality was 73% on iMRI and 89.2% on epMRI. Among the 10 patients who showed no DWI abnormality on iMRI, 6 exhibited DWI abnormality on epMRI (the late-developing group). Two patients developed new neurological deficits postoperatively, and both showed DWI abnormality on both iMRI and epMRI. No patient in the late-developing group developed postoperative neurological deficits. CONCLUSIONS: Overall, iMRI demonstrated more accurate EOR and less SICE compared with epMRI. Although the positive rate of DWI abnormality was lower on iMRI than on epMRI, the late-developing group showed no postoperative neurological deficits. Therefore, iMRI is more useful in assessing accurate EOR and detecting postoperative neurological deficits than epMRI.

DOI： 10.3171/2024.7.JNS24784

Endoscopic Ventriculocisternostomy with Stent Placement for Trapped Temporal Horn International journal

Daisuke Sato, Shota Tanaka, Masahiro Shin, Taijun Hana, Hirokazu Takami, Shunsaku Takayanagi, Fumi Higuchi, Nobuhito Saito

World Neurosurgery 192 e447 - e453 2024.12

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

Background: Trapped temporal horn (TTH) is a subtype of focal obstructive hydrocephalus. Although a ventriculoperitoneal shunt is a traditional treatment approach, it poses risks of shunt failure and infection. The emergence of neuroendoscopy has led to an increased interest in ventriculocisternostomy as an alternative. This study aimed to evaluate the efficacy and safety of endoscopic ventriculocisternostomy with stent placement (EVSP) for TTH. Methods: We collected data of TTH cases treated with EVSP at our institutions between September 2013 and September 2021 and evaluated baseline characteristics and outcomes. A ventricular stoma was created at the medial wall of the abnormally enlarged temporal horn using a neuroendoscope, and a ventricular stent tube with multiple side holes was placed through the stoma to maintain patency. Results: The study included 10 patients (4 women and 6 men) with a mean age of 56.7 ± 19.7 years. The average follow-up period was 35.0 months (range, 1–96 months). The underlying pathologies were postoperative scarring (5 cases), intraventricular tumor (3 cases), and extraventricular tumor (2 cases). There were no procedural complications; however, one patient experienced recurrence and underwent additional cisternostomy. All patients exhibited partial or complete resolution of the preoperative symptoms and demonstrated shrinkage of the trapped ventricle, with a mean reduction rate of 84.5% ± 14.9%. Conclusions: EVSP is a safe and feasible option for the treatment of TTH and is a viable alternative to ventriculo-peritoneal shunt.

DOI： 10.1016/j.wneu.2024.09.124

Association between microenvironment-related genes and prognosis of primary central nervous system lymphoma. International journal

Keiichiro Hattori, Kenichi Makishima, Sakurako Suma, Yoshiaki Abe, Yasuhito Suehara, Tatsuhiro Sakamoto, Naoki Kurita, Ryota Ishii, Ryota Matsuoka, Masahide Matsuda, Takao Tsurubuchi, Ryo Nishikawa, Shota Tanaka, Akitake Mukasa, Yoshitaka Narita, Koichi Ichimura, Motoo Nagane, Shingo Takano, Bryan J Mathis, Eiichi Ishikawa, Daisuke Matsubara, Shigeru Chiba, Mamiko Sakata-Yanagimoto

EJHaem 5 ( 6 ) 1201 - 1214 2024.12

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

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients. METHODS: We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the "recurrence group (RG)" or "non-recurrence group (NRG)" were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30). RESULTS: Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells. CONCLUSION: These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.

DOI： 10.1002/jha2.1046

Cervical spinal cord stimulation exerts anti-epileptic effects in a rat model of epileptic seizure through the suppression of CCL2-mediated cascades International journal

Yosuke Okazaki, Tatsuya Sasaki, Kakeru Hosomoto, Shun Tanimoto, Koji Kawai, Takayuki Nagase, Chiaki Sugahara, Satoru Yabuno, Kyohei Kin, Susumu Sasada, Takao Yasuhara, Shota Tanaka, Isao Date

Scientific Reports 14 ( 1 ) 14543 - 14543 2024.12

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

Epidural spinal cord stimulation (SCS) is indicated for the treatment of intractable pain and is widely used in clinical practice. In previous basic research, the therapeutic effects of SCS have been demonstrated for epileptic seizure. However, the mechanism has not yet been elucidated. In this study, we investigated the therapeutic effect of SCS and the influence of epileptic seizure. First, SCS in the cervical spine was performed. The rats were divided into four groups: control group and treatment groups with SCS conducted at 2, 50, and 300 Hz frequency. Two days later, convulsions were induced by the intraperitoneal administration of kainic acid, followed by video monitoring to assess seizures. We also evaluated glial cells in the hippocampus by fluorescent immunostaining, electroencephalogram measurements, and inflammatory cytokines such as C–C motif chemokine ligand 2 (CCL2) by quantitative real-time polymerase chain reaction. Seizure frequency and the number of glial cells were significantly lower in the 300 Hz group than in the control group. SCS at 300 Hz decreased gene expression level of CCL2, which induces monocyte migration. SCS has anti-seizure effects by inhibiting CCL2-mediated cascades. The suppression of CCL2 and glial cells may be associated with the suppression of epileptic seizure.

DOI： 10.1038/s41598-024-64972-y

Image-based Re-evaluation of the JCOG0911 Study Focusing on Tumor Volume and Survival, Disease Progression Diagnosis, and Radiomic Prognostication for Newly Diagnosed Glioblastoma.

Manabu Kinoshita, Yasutaka Fushimi, Tomohiko Masumoto, Keita Sasaki, Tetsuya Sekita, Atsushi Natsume, Toshihiko Wakabashi, Takashi Komori, Shunsuke Tsuzuki, Yoshihiro Muragaki, Kazuya Motomura, Ryuta Saito, Kenichi Sato, Takaaki Beppu, Masamichi Takahashi, Jun-Ichiro Kuroda, Yukihiko Sonoda, Keiichi Kobayashi, Kazuhiko Mishima, Koichi Mitsuya, Fumiyuki Yamasaki, Akihiro Inoue, Tomoo Matsutani, Hideo Nakamura, Shigeru Yamaguchi, Eiichi Ishikawa, Masato Nakaya, Shota Tanaka, Kenta Ujifuku, Hiroyuki Uchida, Masayuki Kanamori, Ryohei Otani, Noriyuki Kijima, Namiko Nishida, Atsuo Yoshino, Yohei Mineharu, Yoshiki Arakawa, Haruhiko Fukuda, Yoshitaka Narita

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 2024.11

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

PURPOSE: To re-evaluate images recovered from JCOG0911, a randomized phase 2 trial for newly diagnosed glioblastoma (nGBM) conducted by the Japan Clinical Oncology Group (JCOG) Brain Tumor Study Group. METHODS: The correlation between tumor volumes and survival was evaluated, followed by progression-free survival (PFS) analysis by independent central review based on Response Assessment in Neuro-Oncology (RANO) criteria using MRI recovered from 118 nGBM patients enrolled in the JCOG0911 trial. A radiomic analysis was also performed to identify radiomic features predictive of nGBM prognosis. RESULTS: The distribution of the Gd-enhancing and T2-weighted image/fluid attenuated inversion recovery-high intensity lesions mainly occupied white matter. JCOG0911 consisted of more subjects with right-sided lesions. The median extent of resection of the Gd-enhancing lesions was 99%. The overall survival showed a nonsignificant negative trend with postoperative Gd-enhancing lesion volume (P = 0.22), with the hazard ratio increasing in parallel with its volume. The median PFS after registration was 302 and 308 days for local Response Evaluation Criteria in Solid Tumors (RECIST)-based and central RANO-based diagnoses. However, an apparent discrepancy was observed between the two in the early phase, presumably due to the misdiagnosis of pseudoprogression by local RECIST-based diagnosis. Radiomic analysis identified 28 radiomic features predictive of nGBM prognosis, 5 of which were those previously identified in a separate cohort. The constructed radiomics-based prognostic model stratified the cohort into high- and low-risk groups (P = 0.028). CONCLUSION: Novel analytical methods that could be incorporated into future clinical trials were successfully tested. RANO and RECIST may not differ in progression calls if pseudoprogression is appropriately handled.

DOI： 10.2463/mrms.mp.2024-0103

Phase II Trial of Pathology-based Tripartite Treatment Stratification for Patients with CNS Germ Cell Tumors: A Long-term Follow-up Study. International journal

Hirokazu Takami, Masao Matsutani, Tomonari Suzuki, Kazuhiko Takabatake, Takamitsu Fujimaki, Michinari Okamoto, Shigeru Yamaguchi, Masayuki Kanamori, Kenichiro Matsuda, Yukihiko Sonoda, Manabu Natsumeda, Toshiya Ichinose, Mitsutoshi Nakada, Ai Muroi, Eiichi Ishikawa, Masamichi Takahashi, Yoshitaka Narita, Shota Tanaka, Nobuhito Saito, Fumi Higuchi, Masahiro Shin, Yohei Mineharu, Yoshiki Arakawa, Naoki Kagawa, Shinji Kawabata, Masahiko Wanibuchi, Takeshi Takayasu, Fumiyuki Yamasaki, Kentaro Fujii, Joji Ishida, Isao Date, Keisuke Miyake, Yutaka Fujioka, Daisuke Kuga, Shinji Yamashita, Hideo Takeshima, Naoki Shinojima, Akitake Mukasa, Akio Asai, Ryo Nishikawa

Neuro-oncology 2024.11

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

BACKGROUND: A previous Phase II clinical trial, conducted from 1995 to 2003, evaluated CNS germ cell tumors (GCTs) using a three-group treatment stratification based on histopathology. The primary objective of the study was to assess the long-term efficacy of standardized treatment regimens, while the secondary objective focused on identifying associated long-term complications. METHODS: Total 228 patients were classified into three groups for treatment: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), excluding one mature teratoma case. Treatment involved stratified chemotherapy regimens and varied radiation doses/coverage. Clinical data was retrospectively analyzed at a median follow-up of 18.5 years. RESULTS: The treatment outcomes for germinoma, with or without syncytiotrophoblastic giant cell, were similar. The 10- and 20-year event-free survival rates for the germinoma, intermediate, and poor prognosis groups were 82/76/49% and 73/66/49%, respectively. Overall survival (OS) rates were 97/87/61% at 10 years and 92/70/53% at 20 years. Germinomas in the basal ganglia, treated without whole-brain radiation therapy (WBRT), frequently relapsed but were effectively managed with subsequent WBRT. Deaths in germinoma cases had varied causes, whereas deaths in the poor prognosis group were predominantly disease-related. Nineteen treatment-related complications were identified in 16 patients, with cumulative event rates of 1.9% at 10 years and 11.3% at 20 years. OS rates at 1 and 2 years post-relapse for tumors initially classified as germinoma, intermediate, and poor prognosis were 94/88/18% and 91/50/9%, respectively. CONCLUSIONS: Initial treatment intensity is crucial for managing non-germinomatous GCTs, while long-term follow-up for relapse and complications is imperative in germinomas. Irradiation extending beyond the immediate tumor site is essential for basal ganglia germinomas. Addressing relapse in non-germinomatous GCT remains a significant challenge.

DOI： 10.1093/neuonc/noae229

がん診療ガイドライン作成・改訂に関する問題点と対応について脳腫瘍診療ガイドラインの現状と課題

園田順彦, 中田光俊, 田中將太, 篠山隆司, 吉本幸司, 成田善孝, 荒川芳輝, 山崎文之, 齋藤竜太, 阿部竜也, 黒住和彦, 市川智継, 永根基雄

日本癌治療学会学術集会抄録集 62回 GL - 4 2024.10

Novel case of ependymoma-like tumor with mesenchymal differentiation harboring ZFTA::RELA fusion in an adult

Hirohisa Yajima, Shunsaku Takayanagi, Hirokazu Takami, Shota Tanaka, Masashi Nomura, Kaishi Satomi, Masako Ikemura, Sumihito Nobusawa, Ryuta Saito, Akihide Kondo, Nobuhito Saito

Brain Tumor Pathology 41 ( 3-4 ) 139 - 144 2024.10

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

High-grade supratentorial tumors harboring ZFTA::NCOA1/2 fusion in infants presenting with mixed histology of embryonal-appearing components resembling ependymoma and mesenchymal sarcomatous components have recently been reported as ependymoma-like tumors with mesenchymal differentiation (ELTMDs). In contrast, we describe herein a pathologically similar case with a novel ZFTA::RELA fusion in an adult. A frontal lobe lesion was resected from a 30-year-old woman and displayed mixed components on pathological examination, showing ependymoma-like and sarcomatous parts. The absence of perivascular pseudorosettes was inconsistent with a diagnosis of ependymoma. Fluorescence in situ hybridization analysis confirmed ZFTA::RELA fusion. The DKFZ methylation classifier (v12.8) did not categorize this case among established methylation classes. In addition, t-distributed stochastic neighbor embedding analysis using DNA methylation data revealed that the present case was distant from ependymomas but close to two previously reported cases of ELTMD involving ZFTA::NCOA1/2 fusion. Taken together, we concluded that this tumor should be considered under the entity of ELTMD. This represents the first description of an adult patient with ELTMD harboring ZFTA::RELA fusion analyzed by DNA methylation profiling, supporting the establishment of ELTMD as a possible new tumor type.

DOI： 10.1007/s10014-024-00489-6

深層学習による悪性脳腫瘍の高b値拡散強調画像の再構成(Deep-Learning-Based Reconstruction of High b-Value Diffusion Weighted Images of Malignant Brain Tumors)

坂口雄亮, 高橋慧, 石黒尚明, 鈴木雄一, 高橋雅道, 高柳俊作, 三宅基隆, 高見浩数, 野村昌志, 田中將太, 成田善孝, 齊藤延人, 浜本隆二, 斉藤延人

日本癌学会総会記事 83回 P - 3288 2024.9

覚醒下開頭腫瘍切除術後の言語・高次脳機能の短～長期変化及び術前言語機能との関連に関する調査

荻野亜希子, 兼岡麻子, 橋本龍一郎, 藤原清香, 高見浩数, 高柳俊作, 國井尚人, 田中將太, 緒方徹

言語聴覚研究 21 ( 3 ) 352 - 352 2024.9

脳腫瘍に対する全ゲノム解析(Whole-genome sequencing analysis of brain tumors)

鈴木啓道, 中島拓真, 舟越勇介, 金森政之, 柴原一陽, 鈴木智成, 木下学, 園田順彦, 荒川芳輝, 永根基雄, 田中將太, 石田穣治, 齋藤竜太, 花谷亮典, 吉本幸司, 成田善孝

日本癌学会総会記事 83回 S08 - 3 2024.9

AB019. Detailed analysis of DNA hydroxymethylation observed with the malignant progression of IDH-mutant gliomas. International journal

Taijun Hana, Akitake Mukasa, Masashi Nomura, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Shota Tanaka, Takahide Nejo, Yosuke Kitagawa, Erika Yamazawa, Satoshi Takahashi, Tsukasa Koike, Yoshihiro Kushihara, Hirokazu Takami, Shunsaku Takayanagi, Hiroyuki Aburatani, Nobuhito Saito

Chinese clinical oncology 13 ( Suppl 1 ) AB019 2024.8

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

BACKGROUND: Gliomas vary in prognosis with World Health Organization (WHO) grade. Low-grade gliomas can undergo malignant progression (MP), becoming aggressive high-grade tumors, worsening prognosis. This is prevalent in isocitrate dehydrogenase-mutant (IDH-mt) gliomas like astrocytoma and oligodendroglioma, but the mechanism of MP is still not fully understood. High-grade IDH-mt gliomas have been reported to exhibit TET-mediated DNA hydroxymethylation, which is suggested to potentially influence gene expression. We hypothesized that hydroxymethylation in specific regions could be implicated in triggering MP. METHODS: We collected glioma tumor samples over a decade, using WHO 2021 classification to study IDH-mt astrocytoma grade 2 progression to grades 3 or 4, indicating MP. Samples from five patients, demonstrating MP, were analyzed for DNA hydroxymethylation status across more than 850,000 genomic locations using the oxidative bisulfite process and Infinium EPIC methylation array. This was complemented by RNA sequencing for gene expression analysis and its correlation with hydroxymethylation, and motif-enrichment analysis to infer transcription factor involvement in hydroxymethylation-based gene regulation. Additionally, to delve into the fundamental causes of hydroxymethylation, we exposed an IDH-mt glioma cell line to hypoxic conditions and systematically explored the genomic locations where hydroxymethylation occurred. RESULTS: Our comprehensive analysis identified a significant overlap of hydroxymethylated genomic regions across samples during MP, with a notable enrichment in open sea and intergenic regions (P<0.001). These regions were significantly associated with cancer-related signalling pathways. Integration with RNA sequencing data revealed 91 genes with significant correlations between hydroxymethylation and gene expression, implying roles in cell cycle regulation and antineoplastic functions. Furthermore, motif-enrichment analysis suggested the potential regulatory role of KLF4 in these processes. The cell culture results revealed that a certain similarity exists between the hydroxymethylation patterns observed during MP and those in glioma cells cultured under hypoxic conditions. CONCLUSIONS: This study elucidates the importance of region-specific DNA hydroxymethylation in the MP of IDH-mt astrocytomas, suggesting its potential impact on gene expression relevant to cancer malignancy. Our findings propose a complex interplay between hydroxymethylation and gene regulation, which may offer new insights into the mechanisms driving glioma progression and highlight potential targets for therapeutic intervention.

DOI： 10.21037/cco-24-ab019

[Preoperative Embolization of Intracranial Meningioma].

Yuta Soutome, Kenji Sugiu, Masafumi Hiramatsu, Jun Haruma, Yuki Ebisudani, Ryo Kimura, Hisanori Edaki, Masato Kawakami, Juntaro Fujita, Shota Tanaka

No shinkei geka. Neurological surgery 52 ( 4 ) 794 - 804 2024.7

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

Preoperative embolization(POE)of intracranial meningioma is performed worldwide. Although clear evidence of the effectiveness of POE has not been reported in the literature, the technique plays an important role in open surgery, especially for large or skull base meningiomas. The purposes of embolization include: 1)induction of tumor necrosis, resulting in a safer operation, 2)reduction in intraoperative bleeding, and 3)decrease in operative time. Knowledge of the functional vascular anatomy, embolic materials, and endovascular techniques is paramount to ensure safe embolization. Our standard procedure is as follows: 1)embolization is performed several days before open surgery; 2)in cases with strong peritumoral edema, steroid administration or embolization may be performed immediately prior to surgery; 3)patients undergo the procedure under local anesthesia; 4)the microcatheter is inserted as close as possible to the tumor; 5)particulate emboli are the first-line material; 6)embolization is occasionally performed with N-butyl cyanoacrylate(NBCA)glue; and 7)if possible, additional proximal feeder occlusion with coils is performed. The JR-NET study previous showed the situation regarding intracranial tumor embolization in Japan. Endovascular neurosurgeons should fully discuss the indications and strategies for POE with tumor neurosurgeons to ensure safe and effective procedures.

DOI： 10.11477/mf.1436204978

Accurate Preoperative and Intraoperative Evaluation Reduces Surgical Costs and Patient Invasiveness in Ventriculoperitoneal Shunt Revision. International journal

Marina Takahashi, Taijun Hana, Shota Tanaka, Nobuhito Saito

Cureus 16 ( 6 ) e62334 2024.6

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

The ventriculoperitoneal (VP) shunt is one of the most common surgical procedures in neurosurgery, frequently resulting in malfunctions. Shunt malfunctions, which can include mechanical failure, obstruction, infection, or disconnection, occur in a significant percentage of patients, often necessitating multiple revisions. These revisions can lead to increased healthcare costs due to additional surgeries or treatments. Therefore, addressing the economic impacts of these revisions is crucial. Our report presents a cost-effective approach to shunt revisions, demonstrated through a case study of an 82-year-old woman with hydrocephalus. Although initially treated with a VP shunt, she required a revision after six years due to shunt malfunction. Through comprehensive preoperative and intraoperative evaluations, including a shuntogram with iodine contrast and meticulous examination, we identified the cause of malfunction as a connective tissue sac blocking the peritoneal catheter. The surgery involved flushing the catheter lumen with saline to confirm the obstruction and careful removal of the obstructive tissue. This accurate diagnosis facilitated a minimally invasive revision, enabling the reuse of existing shunt components and avoiding the need for new devices, thus reducing costs and surgical invasiveness. Our study serves as a call to action for healthcare providers and surgeons to consider more cost-effective and patient-friendly approaches in managing VP shunt malfunctions, ultimately benefiting both the healthcare system and the patients it serves.

DOI： 10.7759/cureus.62334

Embryonal tumor with multilayered rosettes arising from the internal auditory canal of an adult: Illustrative case with molecular investigations

Adam Sheriff, Hirokazu Takami, Shunsaku Takayanagi, Yosuke Kitagawa, Shota Tanaka, Masako Ikemura, Reiko Matsuura, Yuko Matsushita, Koichi Ichimura, Nobuhito Saito

Neuropathology 44 ( 3 ) 208 - 215 2024.6

Publishing type：Research paper (scientific journal)

Embryonal tumors with multilayered rosettes (ETMRs) are aggressive central nervous system (CNS) tumors that usually occur in young children. Here, we describe the first incidence of ETMR in an adult patient that also originated in the novel location of the internal auditory canal (IAC). The 36-year-old patient initially presented with unsteadiness, diplopia, and tinnitus. The tumor in the IAC was discovered on brain magnetic resonance imaging, and gross total resection was performed followed by pathological and molecular diagnosis. The patient received whole brain and spinal cord radiotherapy after an intracranial recurrence and adjuvant chemotherapy consisting of four cycles of ifosfamide, cisplatin, and etoposide. Progression was rapid; however, the patient survived for 22 months after diagnosis before succumbing to the disease. Molecular investigation revealed a DICER1 mutation at exon 25, and methylation classification categorized the tumor as ETMR, non-C19MC-altered. This case underscores the diverse possible presentations of ETMR, DICER1-mutated and the importance of molecular techniques to characterize and promptly treat atypical ETMR.

DOI： 10.1111/neup.12951

Region-specific DNA hydroxymethylation along the malignant progression of IDH-mutant gliomas International journal

Taijun Hana, Akitake Mukasa, Masashi Nomura, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Shota Tanaka, Takahide Nejo, Yosuke Kitagawa, Erika Yamazawa, Satoshi Takahashi, Tsukasa Koike, Yoshihiro Kushihara, Hirokazu Takami, Shunsaku Takayanagi, Hiroyuki Aburatani, Nobuhito Saito

Cancer Science 115 ( 5 ) 1706 - 1717 2024.5

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

The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.

DOI： 10.1111/cas.16127

[Angioarchitecture and Associated Dural Arteriovenous Fistulas of the Superior Petrosal Sinus and Petrosal Vein].

Masafumi Hiramatsu, Jun Haruma, Kenji Sugiu, Shota Tanaka

No shinkei geka. Neurological surgery 52 ( 3 ) 596 - 604 2024.5

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

The superior petrosal sinus and petrosal vein are important drainage routes for the posterior cranial fossa, with some variations and collateral vessels. An anterolateral-type tentorial dural arteriovenous fistula, which occurs around the petrosal vein, often develops aggressive symptoms due to venous reflux to the brainstem and cerebellum. Neuroendovascular treatment of this fistula is usually challenging because transarterial embolization has a high risk and indications for transvenous embolization are limited. In the cavernous sinus and transverse sinus/sigmoid sinus dural arteriovenous fistulas, venous reflux to the petrosal vein is dangerous, and a treatment strategy with the occlusion of the petrosal vein is indispensable. Furthermore, attention should be paid to venous approaches through the superior petrosal sinus.

DOI： 10.11477/mf.1436204953

Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors. International journal

Yosuke Kitagawa, Ami Kobayashi, Daniel P Cahill, Hiroaki Wakimoto, Shota Tanaka

Biochimica et biophysica acta. Reviews on cancer 1879 ( 3 ) 189102 - 189102 2024.4

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

Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.

DOI： 10.1016/j.bbcan.2024.189102

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