Authorship：Lead author   Language：English  

DOI： 10.1227/neuprac.0000000000000040

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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

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.

DOI： 10.1136/bmjopen-2022-071350

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/10428194.2023.2199895

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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

BACKGROUND: Cerebellopontine angle (CPA) lipoma-associated hemifacial spasm (HFS) is rare. As the removal of CPA lipomas has a high risk of worsening the neurological symptoms, surgical exploration is warranted only in selected patients. Preoperative identification of the lipoma affected site of the facial nerve, and offending artery are crucial for patient selection and successful microvascular decompression (MVD). OBSERVATIONS: Presurgical simulation using three-dimensional (3D) multifusion imaging showed a tiny CPA lipoma wedged between the facial and auditory nerves, as well as an affected facial nerve by the anterior inferior cerebellar artery (AICA) at the cisternal segment. Although a recurrent perforating artery from the AICA anchored the AICA to the lipoma, successful MVD was achieved without lipoma removal. LESSONS: The presurgical simulation using 3D multifusion imaging could identify the CPA lipoma, affected site of the facial nerve, and offending artery. It was helpful for patient selection and successful MVD.

DOI： 10.3171/CASE2318

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

INTRODUCTION: Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE. MATERIALS AND METHODS: Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included. Patients with high grade gliomas were divided into isocitrate dehydrogenase (IDH)- wildtype and mutant groups, and the presence or absence of VTE and the intensity of PDPN by immunohistochemistry were confirmed. Platelet counts, as well as plasma sCLEC-2 and PDPN were measured in these patients. Furthermore, the levels of sCLEC-2 concentration were divided by the platelet count (C2PAC index) for comparison. RESULTS: IDH-wildtype glioma patients highly expressed PDPN (P < 0.001) compared to IDH-mutant glioma patients. In total, 9 (20.5 %) patients were diagnosed with VTE during the follow-up period, of which 8 patients harbored IDH-wildtype gliomas, and one patient an IDH-mutant glioma. Mean sCLEC-2 levels and C2PAC index in patients with IDH-wildtype gliomas were significantly higher than that of low or no PDPN expression group, which included patients with IDH-mutant gliomas (P = 0.0004, P = 0.0002). In patients with IDH-wildtype gliomas, the C2PAC index in patients with VTE was significantly higher than in patients without VTE (P = 0.0492). The optimal cutoff point of C2PAC for predicting VTE in IDH-wildtype glioma patients was 3.7 with a sensitivity of 87.5 % and specificity of 51.9 %. CONCLUSION: Platelet activation is strongly involved in the development of VTE in patients with IDH-wildtype high grade gliomas, and C2PAC index is a potential marker to detect VTE formation after surgery.

DOI： 10.1016/j.thromres.2023.01.018

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

Diffuse midline glioma(DMG)の80%以上がヒストンH3K27M変異を有する.橋に局在する病変は摘出術の適応はなく,針生検でも重篤な合併症が生じ得るためDMGに対してliquid biopsyの確立が切望される.我々は初発時に腰椎穿刺で採取した脳脊髄液よりH3K27Mを同定するのは困難と報告した.本稿では,多発病変および播種病変を有しliquid biopsyによりH3K27M変異と同定された2症例を紹介し,liquid biopsyの恩恵を受ける症例の特徴について迫る.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00650&link_issn=&doc_id=20230215270002&doc_link_id=10.34544%2Fjspn.47.4_358&url=https%3A%2F%2Fdoi.org%2F10.34544%2Fjspn.47.4_358&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

DOI： 10.1093/neuonc/noac243

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

Background: Primary central nervous system lymphomas (PCNSLs) are sensitive to chemotherapy. The standard treatment is high-dose methotrexate (MTX)-based chemotherapy. There are no reports of successful treatment of acute uric acid nephropathy with rasburicase after MTX administration in PCNSLs. Case presentation: A 54-year-old man with a history of gout presented with a change in character and cognitive dysfunction. MRI showed a large enhancing mass spanning the bilateral frontal lobes and the right temporal lobe. After endoscopic biopsy, an MTX, procarbazine, and vincristine (MPV) regimen was initiated for the treatment of the PCNSL. After the initiation of chemotherapy, the patient experienced a gout attack, and blood examination revealed acute renal failure (ARF) and hyperuricemia. The considered causes of ARF included MTX toxicity and acute uric acid nephropathy. As the dramatic effect of MTX was observed, treatment was continued despite ARF, most probably due to acute hyperuricemia due to tumor lysis, which was treated in parallel. After an improvement in renal function, MTX was resumed, and rasburicase was initiated to control hyperuricemia. A complete response was obtained after induction chemotherapy. Hyperuricemia was controlled with rasburicase, and renal function was preserved. Conclusions: Acute uric acid nephropathy should be considered when ARF occurs after the initiation of MTX in PCNSLs, especially in newly diagnosed PCNSL patients with large tumors or hyperuricemia.

DOI： 10.3390/jcm11195548

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

BACKGROUND: Rehabilitation therapy during hospitalization is effective in improving activities of daily living (ADL) and physical function in patients with brain tumors. However, there are few studies on the effect of rehabilitation therapy on health-related quality of life (HRQOL) in patients with brain tumors. Additionally, the EuroQol-5Dimension-5Level (EQ-5D-5L) index score has not been reported as an outcome. This study aimed to investigate the HRQOL of patients with brain tumors who underwent rehabilitation therapy and investigated the factors affecting the EQ-5D-5L index score from various perspectives, including various brain tumor type and recurrence. In addition, we examined the relationship between the EQ-5D-5L index score, disease-specific HRQOL scale, and ADL. METHODS: Patients with brain tumors who underwent treatment and rehabilitation at Single tertiary care academic medical center were included in this cross-sectional study. We used the EQ-5D-5L, European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30, and EORTC quality of life questionnaire brain cancer module to evaluate HRQOL. ADL were assessed using the functional independence measure (FIM). The relationship between each HRQOL assessment score and the FIM was analyzed, and the influence of related factors was assessed by multiple regression analysis. RESULTS: This study included 76 patients. The EQ-5D-5L index score was 0.689 for all patients with brain tumors and 0.574 for those with glioblastomas, which was the lowest value. There was a moderate correlation between the EQ-5D-5L index score and FIM (r = 0.627, p < 0.001). In addition, the EQ-5D-5L index score was significantly correlated with most of the items of the disease-specific HRQOL scale. Multiple regression analysis revealed that glioblastoma histology (coefficient: - 0.373, p = 0.005) and recurrence (coefficient: - 0.273, p = 0.020) were independent factors affecting the EQ-5D-5L index score. CONCLUSIONS: Patients with glioblastoma undergoing rehabilitation have reduced HRQOL, which was influenced by glioblastoma histology and recurrence.

DOI： 10.1186/s41687-022-00499-y

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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

Multimodal therapy including surgery, radiation treatment, and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to examine the signal activation patterns in GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose-dependent manner. These effects on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of the O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1)-positive cells within the tumor. These results suggest that CLD suppressed GBM cell growth by inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.

DOI： 10.3390/cancers14030770

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We have previously published a study on the reliable detection of 2-hydroxyglutarate (2HG) in lower-grade gliomas by magnetic resonance spectroscopy (MRS). In this short article, we re-evaluated five glioma cases originally assessed as isocitrate dehydrogenase (IDH) wildtype, which showed a high accumulation of 2HG, and were thought to be false-positives. A new primer was used for the detection of IDH2 mutation by Sanger sequencing. Adequate tissue for DNA analysis was available in 4 out of 5 cases. We found rare IDH2 mutations in two cases, with IDH2 R172W mutation in one case and IDH2 R172K mutation in another case. Both cases had very small mutant peaks, suggesting that the tumor volume was low in the tumor samples. Thus, the specificity of MRS for detecting IDH1/2 mutations was higher (81.3%) than that originally reported (72.2%). The detection of 2HG by MRS can aid in the diagnosis of rare, non-IDH1-R132H IDH1 and IDH2 mutations in gliomas.

DOI： 10.3390/diagnostics11112129

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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

Detection of BRAF V600E mutation in glioblastomas (GBMs) is important because of potential therapeutic implications. Still, the relative paucity of these mutations makes molecular detection in all GBMs controversial. In the present study, we analyzed clinical, radiographic and pathologic features of 12 BRAF V600E-mutant GBMs and 12 matched controls from 2 institutions. We found that a majority of BRAF V600E-mutant GBMs displayed a combination of well-circumscribed lesions, large cystic components with thin walls and solid cortical component on MRI, but with some overlap with matched BRAF wildtype controls (p = 0.069). BRAF V600E-mutant GBMs were also apt to gross total resection (83% vs 17%, p = 0.016) and morphologically displayed epithelioid features (83% vs 0%, p < 0.0001). Identification of these clinical, radiographic, and pathologic characteristics should prompt testing for BRAF V600E in IDH-wildtype GBM.

DOI： 10.1007/s10014-021-00407-0

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

There is growing interest in liquid biopsy, the less-invasive detection of circulating tumor DNA(ctDNA)or circulating tumor cells(CTCs)from cerebrospinal fluid(CSF)and/or serum of patients, for the diagnosis of brain tumors. We share our experience of detecting hot spot point mutations using droplet digital PCR(ddPCR)in ctDNA obtained from the CSF of patients with brain tumors. The detection of mutations such as IDH1 R132H, BRAF V600E, and TERT promoter mutations in gliomas can be diagnostic. For optimal detection of ctDNA, which is only seen at very low concentrations, proper handling and storage of CSF, high-yield extraction of ctDNA, and usage of sensitive PCR methods for detection are imperative. We discuss which mutations can be assessed when diagnosing brain tumors, with a specific focus on gliomas. Finally, we look at what the near future holds for liquid biopsy of brain tumor patients, including next-generation sequencing panel analysis and accurate assessment of fusion genes.

DOI： 10.11477/mf.1436204425

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞Point ・脳腫瘍の低侵襲診断法liquid biopsyには,ddPCRによるctDNAの解析が有用である.・ctDNAの検出精度を向上させるためには,脳脊髄液サンプル採取後に適正な処理が重要である.・将来的には次世代シーケンスゲノムパネル検索や融合遺伝子解析が可能となると期待される.

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01228&link_issn=&doc_id=20210608210011&doc_link_id=10.11477%2Fmf.1436204425&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436204425&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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

Recent studies have suggested the feasibility of detecting H3K27M mutations in the cerebrospinal fluid of diffuse midline glioma (DMG) patients. However, cerebrospinal fluid from patients in these studies were collected mainly during biopsy, ventriculo-peritoneal shunt procedures or postmortem. We assessed circulating tumor DNA (ctDNA) extracted from cerebrospinal fluid (CSF) and plasma in a series of 12 radiographically suspected and/or pathologically confirmed diffuse midline glioma patients and assessed for H3F3A K27M mutation using digital droplet PCR. In 10 patients, CSF was obtained by lumbar puncture at presentation. A definitive detection of H3F3A K27M mutation was achieved in only one case (10%); H3F3A K27M mutation was suspected in three other cases (30%). H3F3A K27M mutation was detected in two patients in CSF obtained by ventricular tap during a ventriculo-peritoneal shunt for obstructive hydrocephalus. Cases in which a definitive assessment was possible (definite H3F3A K27M or definite H3F3A wildtype) tended to be younger (median 7.5 years vs. 40.5 years; p = 0.07) and have a higher concentration of CSF protein (median 123 mg/dL vs. 27.5 mg/dL; p = 0.21) compared to nondefinite cases. Low proliferation and apoptotic rates seemed to be characteristics of DMG unfavorable for liquid biopsy. More advanced lesions with necrosis and evidence of dissemination were unlikely to be candidates for lumbar puncture due to the fear of exacerbating obstructive hydrocephalus. Methods to safely sample CSF and a more sensitive detection of ctDNA are necessary for reliable liquid biopsy of DMG at presentation.

DOI： 10.3390/diagnostics11040681

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.

DOI： 10.1093/jnen/nlaa141

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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

© Copyright © 2020 Abe, Natsumeda, Okada, Watanabe, Tsukamoto, Kanemaru, Yoshimura, Oishi, Hashizume, Kakita and Fujii. Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with HIST1H3B K27M and ACVR1 G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with H3F3A gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze MGMT promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated MGMT promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with H3F3A gene mutation showed MGMT promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment in vitro. We confirmed in vitro that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.

DOI： 10.3389/fonc.2019.01568

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Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6 months and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations - BRAF V600E mutation, TERT promoter mutations, and homozygous deletions of CDKN2A/2B. Emerging evidence support the effectiveness of targeted therapies for brain tumors with BRAF V600E mutation. Here we describe a dramatic radiographical response to combined therapy with BRAF and MEK inhibitors in a patient with epithelioid GBM harboring BRAF V600E mutation, characterized by thick spinal dissemination. From relapsed tumor procured at autopsy, we established a cell line retaining the BRAF V600E mutation, TERT promoter mutation and CDKN2A/2B loss. Intracranial implantation of these cells into mice resulted in tumors closely resembling the original, characterized by epithelioid tumor cells and dissemination, and invasion into the perivascular spaces. We then confirmed the efficacy of treatment with BRAF and MEK inhibitor both in vitro and in vivo. Epithelioid GBM with BRAF V600E mutation can be considered a good treatment indication for precision medicine, and this patient-derived cell line should be useful for prediction of the tumor response and clarification of its biological characteristics.

DOI： 10.1186/s40478-019-0774-7

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OBJECTIVE: Venous thromboembolism (VTE) often is encountered in patients with high-grade gliomas. The underlying mechanisms are unclear, as is the optimal prophylactic protocol. The purpose of the present study was to identify risk factors of VTE and examine the validity of early VTE detection in high-grade gliomas. METHODS: We reviewed the medical records of 165 patients with newly diagnosed high-grade glioma treated at Niigata University Hospital during the years 2009 to 2016. If the serum D-dimer levels increased to 5.0 μg/mL or more, computed tomography was performed to detect VTE. Furthermore, immunohistochemistry with antibodies against podoplanin was performed on available 101 tumor tissues. RESULTS: Of the 165 patients, 44 (26.7%) developed VTE. Of the 44 patients, 34 (79.5%) developed VTE within 7 days after surgery. No fatal VTE occurred and major complications secondary to anticoagulation occurred in only 2 (1.2%) patients. On multivariate analysis, lower Karnofsky Performance Scale status, podoplanin expression, and isocitrate dehydrogenase-wildtype status were independently associated with the risk of VTE (P < 0.05). CONCLUSIONS: We found that most VTEs occurred early in the postoperative period and commonly in patients with lower Karnofsky Performance Scale status and isocitrate dehydrogenase-wildtype gliomas, which expressed podoplanin.

DOI： 10.1016/j.wneu.2019.05.049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

PURPOSE Biopsy is the gold standard for the diagnosis of primary CNS lymphoma (PCNSL). However, surgical biopsy has problems of morbidity related to hemorrhagic complications and false-negative findings, so safer and more reliable diagnostic methods are required. The aim of this study is to detect the MYD88 mutation, an important driver mutation, in the cerebrospinal fluid (CSF) of patients with CNS lymphoma.PATIENTS AND METHODS Twenty-six patients with CNS lymphoma (20 primary CNS lymphoma and six CNS relapse from systemic lymphoma) were studied. We extracted cell-free DNA (cfDNA) from CSF by lumbar puncture. cfDNA was extracted from 1 mL of CSF, and Sanger sequencing and droplet digital polymerase chain reaction (ddPCR) were performed. Furthermore, we performed DNA sequencing of MYD88 in 21 cases with available surgically obtained formalin-fixed paraffin-embedded (FFPE) tissue and compared the results.RESULTS The median cfDNA amount extracted from 1 mL CSF was 219 ng/mL (25th to 75th percentile, 129 to 333 ng/mL). MYD88 mutations were detected from CSF in 76.9% (20 of 26 cases), and L265P in exon 5 was the most frequent mutation in 19 out of 20 (95.0%) cases. S219C in exon 3 was detected in one case. In four patients, MYD88 mutation was confirmed by ddPCR but not by Sanger sequencing. In all 21 cases with sufficient FFPE tissue for DNA analysis, the detection of MYD88 mutation from cfDNA was consistent with those of tumor-derived DNA from FFPE tissue.CONCLUSION This pilot study provided evidence that the somatic driver mutation MYD88 can be reliably detected by combination of Sanger sequencing and ddPCR in the cfDNA taken from 1 mL of CSF in patients with CNS lymphomas. (C) 2019 by American Society of Clinical Oncology

DOI： 10.1200/PO.18.00308.

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

We present the case of an 11-month-old girl with linear nevus sebaceous syndrome who underwent posterior quadrantectomy(PQ)for intractable epilepsy due to cortical dysplasia extending from the temporal, parietal, and occipital lobes in the right hemisphere. Epileptic spasms started at 4 months after birth, and the frequency of her seizures gradually increased to 10 episodes per day. Electroencephalograms in the interictal periods showed hypsarrhythmia. Magnetic resonance imaging(MRI)suggested cortical dysplasia in the right temporal, parietal, and occipital lobes. Ictal single-photon emission computed tomography revealed increased cerebral blood flow in similar areas as the cortical dysplasia suggested on MRI. Several antiepileptic drugs were administered to control the epileptic spasms, without success. In addition, her developmental delay gradually became evident. Because the epileptic foci extended into the posterior region of the right hemisphere, we did not execute a focused resection, but performed a PQ. The epileptic spasms completely disappeared after surgery and her developmental delay gradually improved. Early surgical intervention via PQ is useful in patients with drug-resistant epilepsy in whom the epileptic foci have extended into the temporal, parietal, and occipital lobes. This intervention not only controls intractable seizures but also helps to facilitate normal development.

DOI： 10.11477/mf.1436203943

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Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface antigen often expressed in glioblastoma and has drawn much attention as a possible therapeutic target. We performed immunohistochemistry on histology sections of surgical specimens taken from 67 cases with glioblastoma, isocitrate dehydrogenase-wild type, and evaluated the morphological characteristics and distribution of the EGFRvIII-positive tumor cells. We then evaluated the localization of EGFRvIII-expression within the tumor and peritumoral areas. EGFRvIII immunopositivity was detected in 15 specimens taken from 13 patients, including two recurrent specimens taken from the same patient at relapse. Immunofluorescence staining demonstrated that EGFRvIII-positive cells were present in cells positive for glial fibrillary acidic protein (GFAP), and some showed astrocytic differentiation with multiple fine processes and others did not shown. The EGFRvIII-positive cells were located in cellular areas of the tumor, but not in the invading zone. In the two recurrent cases, EGFRvIII-positive cells were markedly decreased in one case and retained in the other. With regard to overall survival, univariate analysis indicated that EGFRvIII-expression in patients with glioblastoma was not significantly associated with a favorable outcome. Double-labeling immunofluorescence staining of EGFRvIII and GFAP showed that processes of large, well differentiated, GFAP-positive glia extend to and surround less differentiated, EGFRvIII-positive glial cells in cellular areas of tumor. However, in the tumor periphery, EGFRvIII-positive tumor cells were not observed. This finding suggests that EGFRvIII is involved in tumor proliferation, but that invading glioma cells lose their EGFRvIII expression.

DOI： 10.2176/nmc.oa.2018-0078

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

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O6-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.

DOI： 10.2176/nmc.ra.2018-0044

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

We have previously reported that reliable detection of 2-hydroxyglutarate (2HG) in isocitrate dehydrogenase (IDH)-mutant WHO grade 2 and 3 gliomas is possible utilizing 3.0-T single-voxel magnetic resonance spectroscopy (SVMRS). We set out to determine whether the same method could be applied to detect 2HG in IDH-mutant glioblastoma. Forty-four patients harboring glioblastoma underwent pre-operative MRS evaluation to detect 2HG and other metabolites. Presence of IDH-mutations was determined by IDH1 R132H immunohistochemical analysis and DNA sequencing of surgically obtained tissues. Six out of 44 (13.6%) glioblastomas were IDH-mutant. IDH-mutant glioblastoma exhibited significantly higher accumulation of 2HG (median 3.191 vs. 0.000 mM, p < 0.0001, Mann-Whitney test). A cutoff of 2HG = 0.897 mM achieved high sensitivity (100.0%) and specificity (92.59%) in determining IDH-mutation in glioblastoma. Glioblastoma with high 2HG accumulation did not have significantly longer overall survival than glioblastoma with low 2HG accumulation (p = 0.107, log-rank test). Non-invasive and reliable detection of 2HG in IDH-mutant glioblastoma was possible by 3.0-T SVMRS.

DOI： 10.1007/s10143-017-0908-y

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00990&link_issn=&doc_id=20180209010018&doc_link_id=%2Fdg3nigta%2F2017%2Fs13109%2F014%2F0563-0563%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2017%2Fs13109%2F014%2F0563-0563%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00990&link_issn=&doc_id=20170929080007&doc_link_id=%2Fdg3nigta%2F2017%2Fs13105%2F002%2F0311-0312%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2017%2Fs13105%2F002%2F0311-0312%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

Objective: In this study, we provide long-term outcome data of patients with primary central nervous system lymphoma
Methods: The long-term outcomes of PCNSL patients diagnosed between 1982 and 2006 were reviewed. Neurological late neurotoxicity symptoms, neuroradiological brain atrophy and leukoen-cephalopathy were evaluated. Surviving patients completed the Quality of Life Questionnaire-30 and Brain Cancer Module-20. The differences in overall survival were assessed using the Kaplan-Meier method and log-rank test. The differences between groups in terms of each investigated parameter were analyzed using the Wilcoxon signed-rank test
Results: Among 112 PCNSL patients, there were 33 (29.4%) long-term (&gt; 5 years) survivors. The median survival of all long-term survivors was 105.7 months; of these, 8 (7.1%) were alive at the latest follow-up, with a mean survival time of 170.2 months (range, 121.8-286.4). Clinical assessment revealed severe neurotoxicity in 14 patients (42.4%), moderate neurotoxicity in 5 (15.1%), and normal status in 14 (42.4%). Correlations were seen between the neuroradiological imaging score changes and neurocognitive condition (P= 0.0001), neurocognitive condition and the whole brain irradiation dose (P= 0.0004), and atrophy and the whole brain irradiation dose (P= 0.0035).
Conclusions: A more severe clinical condition was found to be associated with increasing age and whole brain irradiation dose in long-term survivors with PCNSL.

DOI： 10.1093/jjco/hyw171

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Language：English   Publisher：TAYLOR & FRANCIS LTD  

DOI： 10.1080/10428194.2016.1201570

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DOI： 10.1016/j.ehpc.2016.01.002

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

Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multi-modal treatment with surgery and chemo/radiotherapies. GBM-initiating cells (GICs) are the likely cell-of-origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)-resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine-cytidine kinase-like 1 (UCKL1) and the decreased one of 5'-nucleotidase cytosolic III (NT5C3), which regulate uridine-monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3.

DOI： 10.1002/stem.2380

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Language：English   Publisher：WILEY-BLACKWELL  

Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomasmimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

DOI： 10.1111/neup.12276

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O-6-methylguanine-DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1-positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT-negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1-positive/MGMT-negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1-negative/MGMT-negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA.

DOI： 10.1111/neup.12196

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

The authors report a rare case of a huge hypervascular tentorial cavernous angioma treated with preoperative endovascular embolization, followed by successful gross-total removal. A 15-year-old girl presented with scintillation, diplopia, and papilledema. Computed tomography and MRI studies revealed a huge irregularly shaped tumor located in the right occipital and suboccipital regions. The tumor, which had both intra- and extradural components, showed marked enhancement and invasion of the overlying occipital bone. Angiography revealed marked tumor stain, with blood supply mainly from a large branch of the left posterior meningeal artery. Therefore, this lesion was diagnosed as a tentorium-based extraaxial tumor. For differential diagnosis, meningioma, hemangiopericytoma, and malignant skull tumor were considered. Tumor feeders were endovascularly embolized with particles of polyvinyl alcohol. On the following day, the tumor was safely gross totally removed with minimum blood loss. Histopathological examination confirmed the diagnosis of cavernous angioma. To date, there have been no reports of tentorium-based cavernous angiomas endovascularly embolized preoperatively. A tentorial cavernous angioma is most likely to show massive intraoperative bleeding. Therefore, preoperative embolization appears to be quite useful for safe maximum resection. Hence, the authors assert that the differential diagnosis of tentorium-based tumors should include tentorial cavernous angioma, for which preoperative endovascular embolization should be considered.

DOI： 10.3171/2014.4.PEDS13628

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Introduction: Previous magnetic resonance spectroscopy (MRS) and mass spectroscopy studies have shown accumulation of 2-hydroxyglutarate (2HG) in mutant isocitrate dehydrogenase (IDH) gliomas. IDH mutation is known to be a powerful positive prognostic marker in malignant gliomas. Hence, 2HG accumulation in gliomas was assumed to be a positive prognostic factor in gliomas, but this has not yet been proven. Here, we analyzed 52 patients harboring World Health Organization (WHO) grade II and III gliomas utilizing 3.0-tesla MRS.
Results: Mutant IDH gliomas showed significantly higher accumulation of 2HG (median 5.077 vs. 0.000, p = 0.0002, Mann-Whitney test). 2HG was detectable in all mutant IDH gliomas, whereas in 10 out of 27 (37.0%) wild-type IDH gliomas, 2HG was below the detectable range (2HG = 0) (p = 0.0003, chi-squared test). Screening for IDH mutation by 2HG analysis was highly sensitive (cutoff 2HG = 1.489 mM, sensitivity 100.0%, specificity 72.2%). Gliomas with high 2HG accumulation had better overall survival than gliomas with low 2HG accumulation (p = 0.0401, Kaplan-Meier analysis).
Discussion: 2HG accumulation detected by 3.0-tesla MRS not only correlates well with IDH status, but also positively correlates with survival in WHO grade II and III gliomas.

DOI： 10.1186/s40478-014-0158-y

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

The efficacy and toxicity of high-dose methotrexate (HD-MTX)-based chemotherapy were retrospectively reviewed in patients with primary central nervous system lymphoma (PCNSL). All immunocompetent patients with histologically or radiographically diagnosed PCNSL treated between 2006 and 2012 at Niigata University Hospital were enrolled. Thirty-eight patients with a diagnosis of PCNSL were treated with one of two regimens during different time periods. During the first period, from 2006 to 2009, three 3-week cycles of MPV (MTX + procarbazine + vincristine) were administered (MPV3 group). In the second period, from 2010 to 2012, five 2-week cycles of MTX were administered (MTX5 group). High-dose cytarabine was used in both groups following HD-MTX-based chemotherapy. Whole-brain radiotherapy was used for patients who did not attain a complete response (CR) based on magnetic resonance images. In the MPV3 group, 20 out of 23 patients (87%) completed the planned treatment. The CR rate after chemotherapy was 30%, and 57% after radiation therapy. Thirteen out of 15 patients (87%) in the MTX5 group completed the planned treatment. The CR rates after chemotherapy and radiation therapy were 53% and 93%, respectively. Renal dysfunction was assessed by measuring creatinine clearance rates, which were very similar in both groups. In terms of hematologic toxicity and other adverse reactions, there was no significant difference between the two groups. In conclusion, dose-dense MTX chemotherapy improved outcome with acceptable toxicity compared with the treatment schedule for three cycles of MPV treatment.

DOI： 10.2176/nmc.oa2013-0195

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Language：English   Publisher：SPRINGER WIEN  

DOI： 10.1007/s00701-010-0891-3

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：Japanese  

J-GLOBAL

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Other Link： http://hdl.handle.net/10191/44832

Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：日本脳神経CI学会  

2-ヒドロキシグルタル酸(2HG)は正常組織では殆ど検出されないが、IDH変異を有するグリオーマでは蓄積する。IDH変異を有するグリオーマ症例で、3T-single voxel Magnetic Resonance Spectroscopy(3T-SVMRS)を用いて、2HGを検出できることを報告した。その内容を、1)IDH変異と2HG、2)IDH変異を有するグリオーマの特異なbiology、3)3T-SVMRSの撮像条件、4)SVMRSによる2HGの検出、5)2HGの測定の臨床的意義、の5項目に分けて解説した。

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Language：Japanese   Publisher：(株)インナービジョン  

新潟大学脳研究所は、脳神経外科と神経内科の臨床2科、神経病理部門、そして統合脳機能研究センターなどを有している。同センターの中田力名誉教授(当時・教授/センター長)の発案により実現した、3T MRIを用いた死後画像解析システムが稼働している。われわれのポリシーは、死亡時画像診断(以下、Ai)施行後直ちに病理解剖を行い、画像情報と組織所見を統合して病態理解につなげようとするものである。Aiを剖検の代替手段として行おうとするものではない。本稿では、神経疾患を対象として当研究所が取り組んでいる死後画像解析システムと病理解剖について紹介する。(著者抄録)

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2015187840

Language：Japanese   Publisher：(株)インナービジョン  

脳腫瘍の画像診断は、(1)存在・局在診断(腫瘍性病変の検出と部位・進展範囲の把握)、(2)質的(腫瘍の組織型と悪性度)診断推定と鑑別診断、(3)術前情報取得、(4)術後評価、(5)治療効果判定のいずれにも大きく関与する。CTは、(1)(2)における腫瘍の石灰化の検出、(3)での頭蓋骨描出などにおいて有用であるが、MRI情報はすべての過程において重要である。本稿では、神経膠腫の(2)(3)における当施設でのMRI撮像について、症例を提示して示す。なお、3T MRI装置を用いたMRスペクトロスコピー(MRS)、arterial spin labeling(ASL)法による灌流MRI、拡散テンソル画像(DTI)、three dimensional anisotropy contrast(3D-AC)法による神経線維描出は、本学脳研究所統合脳機能研究センターの協力を得て行っている。(著者抄録)

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2014333897

Language：Japanese   Publisher：新潟県医師会  

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Language：Japanese   Publisher：(NPO)日本脳神経血管内治療学会  

J-GLOBAL

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Language：Japanese   Publisher：日本脳腫瘍病理学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2013333130

Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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