掲載種別：研究論文（学術雑誌）   出版者・発行元：Edizioni Minerva Medica  

DOI： 10.23736/s1973-9087.25.08573-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Leptomeningeal disease (LMD) in diffuse midline gliomas (DMGs) can lead to devastating symptoms such as severe pain, urinary incontinence, and tetraparesis, with limited treatment options. We determined whether detecting H3F3A K27M-mutant droplets in cerebrospinal fluid (CSF) circulating tumor deoxyribonucleic acid (ctDNA) could be a biomarker for detecting LMD in DMGs. METHODS: Twenty-five CSF samples were obtained from 22 DMG patients. Histological confirmation of H3F3A K27M mutation was obtained in 10 (45.5%) cases. ctDNA was extracted from CSF, and H3F3A K27M-mutant and wildtype droplets were detected using digital droplet polymerase chain reaction (ddPCR). LMD was diagnosed by CSF cytology and pre- and post-contrast head and spine magnetic resonance (MR) imaging. RESULTS: The number of H3F3A K27M-mutant droplets (median 27 [range: 1-379] vs. median 0 [range: 0-1]; p < 0.0001) and variant allele frequency (VAF) (median 48.9% [range: 7.5%-87.5%] vs. median 0.0% [range: 0.0%-50.0%]; p < 0.0001) were significantly higher in the LMD/early-LMD group compared to no-LMD group. In two cases (Cases 4 and 11) without clinical evidence of LMD, multiple H3F3A K27M-mutant droplets were detected in CSF ctDNA. In those cases, extensive spinal dissemination was detected 6 months after the initial liquid biopsy. One case (Case 15) with high Schlafen11 (SLFN11) expression responded well to treatment for LMD and survived for 532 days after the diagnosis of LMD. CONCLUSION: This study provides evidence that detecting H3F3A K27M-mutant droplets in CSF ctDNA is diagnostic for LMD and is more sensitive than traditional methods such as CSF cytology and MR imaging.

DOI： 10.1002/pbc.31535

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

DOI： 10.1093/jjco/hyae116

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記述言語：日本語   出版者・発行元：(NPO)日本レーザー医学会  

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記述言語：日本語   出版者・発行元：日本脳神経CI学会  

当院で高精密3Dマルチモダリティ総合画像(HD-3DMFI)による双方向性仮想術前シミュレーション(IVS)を行った悪性神経神経膠腫56例(男性39例、女性17例、年齢中央値65歳)の手術成績について報告した。その結果、HD-3DMFIを用いたIVSの総合評点は2.70点で、特に脳表静脈や脳表動脈で十分な評点が得られていた。初発症例の摘出率は48例中24例(50%)が95%以上摘出され、4例(8%)が90～95%、20例(42%)が90%未満もしくは生検であった。また、再発症例の摘出率は8例中3例(38%)が95%以上摘出され、5例(62%)が90%未満、あるいは生検であった。KPSの変化としては、初発症例は術前中央値70から術後80に、再発症例は術前90が術後90であった。初発症例の予後はGrade IIIで無増悪生存期間中央値が19ヵ月、全生存期間中央値が未到達で、Grade IVではそれぞれ8ヵ月、20ヵ月であった。

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s10014-024-00483-y

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その他リンク： https://link.springer.com/article/10.1007/s10014-024-00483-y/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Molecular analysis of the growing teratoma syndrome has not been extensively studied. Here, we report a 14-year-old boy with a growing mass during treatment for a mixed germ cell tumor of the pineal region. Tumor markers were negative; thus, growing teratoma syndrome was suspected. A radical resection via the occipital transtentorial approach was performed, and histopathological examination revealed a teratoma with malignant features. Methylation classifier analysis confirmed the diagnosis of teratoma, and DMRT1 loss and 12p gain were identified by copy number variation analysis, potentially elucidating the cause of growth and malignant transformation of the teratoma. The patient remains in remission after intense chemoradiation treatment as a high-risk germ cell tumor.

DOI： 10.3390/curroncol31040138

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

DOI： 10.1186/s40478-024-01723-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

DOI： 10.1007/s11060-023-04555-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Choroid plexus carcinomas (CPCs) are extremely rare brain tumors and carry a dismal prognosis. Treatment options are limited and there is an urgent need to develop models to further research. In the present study, we established two CPC cell lines and performed multi-omics analyses. These cell lines serve as valuable models to propose new treatments in these rare but deadly brain tumors. METHODS: Multi-omic profiling including, (i) methylation array (EPIC 850 K), (ii) whole genome sequencing (WGS), (iii) CANCERPLEX cancer genome panel testing, (iv) RNA sequencing (RNA-seq), and (v) proteomics analyses were performed in CCHE-45 and NGT131 cell lines. RESULTS: Both cell lines were classified as methylation class B. Both harbored pathogenic TP53 point mutations; CCHE-45 additionally displayed TP53 loss. Furthermore, alterations of the NOTCH and WNT pathways were also detected in both cell lines. Two protein-coding gene fusions, BZW2-URGCP, and CTTNBP2-ERBB4, mutations of two oncodrivers, GBP-4 and KRTAP-12-2, and several copy number alterations were observed in CCHE-45, but not NGT131. Transcriptome and proteome analysis identified shared and unique signatures, suggesting that variability in choroid plexus carcinoma tumors may exist. The discovered difference's importance and implications highlight the possible diversity of choroid plexus carcinoma and call for additional research to fully understand disease pathogenesis. CONCLUSION: Multi-omics analyses revealed that the two choroid plexus carcinoma cell lines shared TP53 mutations and other common pathway alterations and activation of NOTCH and WNT pathways. Noticeable differences were also observed. These cell lines can serve as valuable models to propose new treatments in these rare but deadly brain tumors.

DOI： 10.1007/s11060-023-04484-3

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

DOI： 10.3171/CASE23361

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記述言語：日本語   出版者・発行元：(NPO)日本レーザー医学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01213&link_issn=&doc_id=20230803380003&doc_link_id=10.2530%2Fjslsm.jslsm-44_0024&url=https%3A%2F%2Fdoi.org%2F10.2530%2Fjslsm.jslsm-44_0024&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

BACKGROUND:

Pleomorphic xanthoastrocytoma (PXA) (World Health Organization grade II) is classified as a relatively benign and circumscribed glioma; however, anaplastic PXA (APXA, World Health Organization grade III) has a poorer prognosis, and differentiating from glioblastoma can be difficult both histologically and molecularly.

OBJECTIVE:

To describe the clinical, pathological, and molecular characteristics of diffusely infiltrating gliomas with histological APXA-like features.

METHODS:

Four diffusely infiltrating gliomas in adult patients histologically diagnosed as APXAs at a single institute were retrospectively reviewed. We analyzed their clinical, radiological, pathological, genetic, epigenetic, and prognostic characteristics.

RESULTS:

All tumors histologically showed classical characteristic PXA-like appearance with BRAF wildtype, mitotic figure, necrosis, and an increased mindbomb E3 ubiquitin-protein ligase 1 labeling index and were initially diagnosed as APXAs; moreover, they underwent high-grade glioma treatment. Three patients with TERT promotor mutations died within 18 months. These patients' MRIs showed widespread infiltrating fluid-attenuated inversion recovery hyperintense lesions and Gd-enhancing lesions in the bilateral cerebral hemispheres in 2 of the patients. Contrastingly, a patient with the wildtype TERT promotor has survived for 2.5 years without recurrence. MRI revealed an unilateral fluid-attenuated inversion recovery hyperintense and Gd-enhancing lesion. By methylation classifier analysis, all 4 cases clustered toward GBM, IDH-wildtype, mesenchymal type, although one was deemed unclassifiable due to a low calibrated score.

CONCLUSION:

In diffusely infiltrating gliomas showing histological characteristics of APXA, methylation classification should be performed as these tumors may be difficult to differentiate between glioblastoma, IDH-wildtype by histological or genetic analysis. The aggressive nature of these tumors should be expected, especially in cases that are BRAF-wildtype and TERT promotor mutant.

DOI： 10.1227/neuprac.0000000000000040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

DOI： 10.1080/10428194.2023.2199895

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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その他リンク： 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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(NPO)日本レーザー医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

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その他リンク： 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

記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fonc.2019.01568

Scopus

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40478-019-0774-7

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.wneu.2019.05.049

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1200/PO.18.00308.

Web of Science

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11477/mf.1436203943

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2176/nmc.oa.2018-0078

PubMed

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記述言語：英語  

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2176/nmc.ra.2018-0044

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語  

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jjco/hyw171

Web of Science

PubMed

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記述言語：英語  

DOI： 10.1080/10428194.2016.1201570

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ehpc.2016.01.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/stem.2380

Web of Science

PubMed

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記述言語：英語  

DOI： 10.1111/neup.12276

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/neup.12196

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3171/2014.4.PEDS13628

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40478-014-0158-y

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2176/nmc.oa2013-0195

Scopus

PubMed

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記述言語：英語  

DOI： 10.1007/s00701-010-0891-3

Web of Science

PubMed

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：新潟医学会  

【はじめに】Temozolomide (TMZ)治療中に再発したGlioblastoma (GBM)は,TMZへの耐性を獲得していると思われる．現在までに様々なTMZ耐性機序が報告されているが，臨床応用には至っていない．我々は, human GBM-initiating cells (GICs)からTMZ耐性GIC細胞(GICR)を樹立し，薬剤ライブラリスクリーニングによりGICRに有効な新規治療候補薬の同定を試みた．その結果,GICRの増殖に強い抑制効果を示す化合物， 1－ （3－C-ethynyｌ-βーD-ribopentofuranosyl uracil (EUrd)を同定し，その分子機序を解析したので報告する．【材料と方法】TMZ含有培地でGICを培養してGICRを樹立した．北海道大学薬学研究院所有の1,342種の化合物を用いて,GICRに増殖抑制/細胞死誘導効果を示す薬剤群を同定する薬剤スクリーニングを行った．GBMに対して未検討のEUrdの作用機序を解析した．更に,GICRをNOD/SCIDマウスの皮下に移植した担がんマウスモデルを用いて,EUrdの治療効果を検討した． またEUrdの代謝に関わると思われるリン酸化酵素と脱リン酸化酵素のノックアウト株と強制発現株を作製し，その分子機構を検討した．【結果】化合物スクリーニングによりGICRに増殖抑制/細胞死誘導効果を持つEUrdを同定した.EUrdは,U87MG等のGBM細胞株に対しても増殖抑制/細胞死誘導効果を示すことを確認した．その作用機序は核酸合成阻害であり,Eurd存在下でGICRはG0/G1期にcell cycle arrestする．更に, 担がんマウスモデルでもEUrdは腫瘍増殖抑制効果を認めた．またEUrdはuridine-cytidine kinase-like1 (UCKL1) と5'-nucleotide cytosolic Ⅲ (NT5C3)によってリン酸化の制御を受ける可能性が示された．【考察と結論】我々は,GICRに対する薬剤スクリーニングを遂行し,GICRに増殖阻害を引き起こす化合物EUrdを同定した.EUrdは,GBM以外の悪性腫瘍に対して抗腫瘍効果が報告されているが，未だ臨床応用されていない化合物である．今後, TMZ維持療法中の再発性GBMに対する新規治療薬として臨床応用が期待される．

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その他リンク： http://hdl.handle.net/10191/44832

記述言語：日本語   出版者・発行元：北関東医学会  

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記述言語：日本語   出版者・発行元：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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記述言語：日本語   出版者・発行元：(株)インナービジョン  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

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その他リンク： http://search.jamas.or.jp/link/ui/2015187840

記述言語：日本語   出版者・発行元：(株)インナービジョン  

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2014333897

記述言語：日本語   出版者・発行元：新潟県医師会  

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記述言語：日本語   出版者・発行元：(NPO)日本脳神経血管内治療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2013333130

記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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記述言語：日本語   出版者・発行元：新潟医学会  

CiNii Article

CiNii Books

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開催年月日： 2022年4月

記述言語：日本語  

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開催年月日： 2021年5月

記述言語：日本語  

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その他リンク： 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

開催年月日： 2021年5月

記述言語：日本語  

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開催年月日： 2021年5月

記述言語：日本語  

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開催年月日： 2021年5月

記述言語：日本語  

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開催年月日： 2021年5月

記述言語：日本語  

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開催年月日： 2021年4月

記述言語：日本語  

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開催年月日： 2020年10月

記述言語：日本語  

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開催年月日： 2020年10月

記述言語：日本語  

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開催年月日： 2020年8月

記述言語：日本語  

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開催年月日： 2017年9月

記述言語：日本語  

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その他リンク： 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

開催年月日： 2017年5月

記述言語：日本語  

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その他リンク： 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

開催年月日： 2016年5月

記述言語：日本語  

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