掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1111/cas.16127

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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  

Abstract

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

DOI： 10.1038/s41598-023-42842-3

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その他リンク： https://www.nature.com/articles/s41598-023-42842-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN.

DOI： 10.1007/s10014-023-00469-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. METHODS: The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics were retrospectively analyzed. RESULTS: The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor performance status were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant. CONCLUSIONS: The PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.

DOI： 10.1007/s11060-023-04411-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. METHODS: Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. RESULTS: A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). CONCLUSIONS: These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.

DOI： 10.1007/s11060-023-04381-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. CASE PRESENTATION: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. CONCLUSIONS: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

DOI： 10.1186/s12883-023-03274-8

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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）  

Plasma cell leukemia is a rare yet aggressive form of multiple myeloma characterized by high levels of plasma cells circulating in the peripheral blood. We recently experienced a case of plasma cell leukemia that had been in stringent complete remission for nine years after autologous stem cell transplantations with subsequent courses of lenalidomide maintenance therapy, and then relapsed as an extramedullary plasmacytoma in the central nervous system. Assessment of the bone marrow did not prove proliferation of plasma cells at relapse, but imbalanced elevation of serum levels of free light chains was observed without changes in other clinical biomarkers including immunoglobulin levels. Salvage chemotherapy with isatuximab, pomalidomide, and dexamethasone (IsaPD) was promptly initiated. After two courses of IsaPD, significant remission was achieved and the neuronal symptoms completely resolved. When excessive serum levels of clonotypic free light chains are noted, their significance should be carefully assessed even when plasma cell propagation in the bone marrow is not observed. In such cases, hematologists should search for extramedullary proliferation of plasma cells, including in the immune-privileged central nervous system.

DOI： 10.1007/s12185-023-03545-7

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記述言語：英語  

DOI： 10.1007/s10014-023-00449-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tumour-treating fields therapy is a locoregional, anti-cancer treatment. Efficacy and safety of tumour-treating fields therapy in adults with newly diagnosed glioblastoma were demonstrated in the pivotal phase 3 EF-14 study (NCT00916409). Here, we report post-approval data of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma. METHODS: Unsolicited post-marketing surveillance data from Japanese patients with newly diagnosed glioblastoma treated with tumour-treating fields therapy (December 2016-June 2020) were retrospectively analysed. The primary endpoints were skin, neurological and psychiatric adverse events. The secondary endpoints were 1- and 2-year overall survival rates, and the 6-month progression-free survival. adverse events were analysed using MedDRA v24.0. The overall survival and progression-free survival were assessed using the Kaplan-Meier survival analysis (log-rank testing). The Cox proportional hazard regression analyses were also performed. RESULTS: Forty patients with newly diagnosed glioblastoma were enrolled (62.5% male; median age 59 years; median baseline Karnofsky Performance Scale score 90). The most common tumour-treating-fields-therapy-related adverse event was beneath-array local skin reaction (60% of patients). The adverse events were mostly mild to moderate in severity. Neurological disorders were observed in 2.5% patients (one patient reported dysesthesia). No psychiatric disorders were reported. The 1- and 2-year overall survival rates were 77.9% (95% CI 60.6-88.3) and 53.6% (35.5-68.7%), respectively. The 6-month progression-free survival was 77.5% (61.2-87.6%). These survival rates compare favourably with those in the EF-14 trial (1- and 2-year overall survival rates: 73% [69-77%] and 43% [39-48%], respectively; 6-month progression-free survival rate: 56% (51-61%). CONCLUSION: This post-approval, real-world evidence study revealed no new safety signals and suggests the safety and efficacy of tumour-treating fields therapy in Japanese patients with newly diagnosed glioblastoma.

DOI： 10.1093/jjco/hyad001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent Todai OncoPanel as part of Advanced Medical Care B with approval by the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were performed in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those thirty transcripts, six had treatment implications and four had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

DOI： 10.1111/cas.15717

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

"Oligoastrocytoma" disappeared as of the revised fourth edition of the World Health Organization Classification of Tumours of the Central Nervous System, except where appended with "not otherwise specified (NOS)". However, histopathological and genetic backgrounds of cases with dual features of astrocytoma/oligodendroglioma have been sparsely reported. We encountered a 54-year-old man with right frontal glioma comprising two distinct parts on imaging and histopathological examination: grade 4 astrocytoma with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q; and oligodendroglioma with IDH1-R132H, intact ATRX, p53-negativity and partially deleted 1p/19q. At recurrence, histopathology showed low-grade mixed astrocytic and oligodendroglial features: the former with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q and the latter showing IDH1-R132H, intact ATRX, p53-negativity and 1p/19q codeletion. At second recurrence, histopathology was astrocytoma grade 4 with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q. Notably, 1p/19q codeletion was acquired at recurrence and CDKN2A was deleted at second recurrence. These findings suggest insights into tumorigenesis: (1) gliomas with two distinct lineages might mix to produce "oligoastrocytoma"; and (2) 1p/19q codeletion and CDKN2A deletion might be acquired during chemo-radiotherapy. Ultimately, astrocytic and oligodendroglial clones might co-exist developmentally or these two lineages might share a common cell-of-origin, with IDH1-R132H as the shared molecular feature.

DOI： 10.1007/s10014-022-00448-z

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記述言語：英語  

BACKGROUND: Glioblastoma is a malignant tumor, and its prognosis is as poor as 1.5 to 2 years. Most cases recur within one year even under the standard treatment. The majority of recurrences are local, and in rare cases, metastasize mostly within the centra nervous system. Extradural metastasis of glioma is exceedingly rare. Here, we present a case of vertebral metastasis of glioblastoma. CASE PRESENTATION: We present a 21-year-old man post total resection of the right parietal glioblastoma, diagnosed with lumbar metastasis. He originally presented with impaired consciousness and left hemiplegia and underwent gross total resection of the tumor. Given the diagnosis of glioblastoma, he was treated with radiotherapy combined with concurrent and adjuvant temozolomide. Six months after tumor resection, the patient presented with severe back pain, and was diagnosed as metastatic glioblastoma on the first lumbar vertebrae. Posterior decompression with fixation and postoperative radiotherapy were conducted. He went on to receive temozolomide and bevacizumab. However, at 3 months after the diagnosis of lumbar metastasis, further disease progression was noted, and his care was transitioned to best supportive care. Comparison on copy number status between primary and metastatic lesions on methylation array analysis revealed more enhanced chromosomal instability including 7p loss, 7q gain and 8 gain in the metastatic lesion. CONCLUSION: Based upon the literature review and our case, younger age of initial presentation, multiple surgical interventions, and long overall survival seem to be the risk factors of vertebral metastasis. As the prognosis of glioblastoma improves over time, its vertebral metastasis is seemingly more common. Therefore, extradural metastasis should be kept in mind in the treatment of glioblastoma. Further, detailed genomic analysis on multiple paired specimens is mandated to elucidate the molecular mechanisms of vertebral metastasis.

DOI： 10.3389/fonc.2023.1101552

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記述言語：英語  

BACKGROUND: Despite accumulating research on the molecular characteristics of meningiomas, no definitive molecularly targeted therapy for these tumors has been established to date. Molecular mechanisms underlying meningioma progression also remain unclear. Comprehensive genetic testing approaches can reveal actionable gene aberrations in meningiomas. However, there is still limited information on whether profiling the molecular status of subsequent recurrent meningiomas could influence the choice of molecular-targeted therapies. CASE PRESENTATION: We report a case of meningioma with malignant progression and multiple recurrences. We performed matched tumor pair analysis using the Todai OncoPanel to investigate the possibility of additional standard treatments. The loss of several chromosomal regions, including NF2 and CDKN2A, which is associated with aggressive meningiomas, was considered a significant driver event for malignant progression. Using additional matched tumor pair analysis, mutations in TRAF7, ARID1A, and ERBB3 were identified as subclonal driver events at the time of recurrence. No genetic aberrations were found for which evidence-based targeted therapy was applicable. We also reviewed previous reports of molecular therapies in meningioma to discuss issues with the current molecular testing approach. CONCLUSION: Gene panel testing platforms such as the Todai OncoPanel represent a powerful approach to elucidate actionable genetic alterations in various types of tumors, although their use is still limited to the diagnosis and prediction of prognosis in meningiomas. To enable targeted molecular therapy informed by gene-panel testing, further studies including matched tumor pair analyses are required to understand the molecular characteristics of meningiomas and develop treatments based on genetic abnormalities.

DOI： 10.3389/fneur.2023.1270046

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.

DOI： 10.3390/cancers14225522

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：(株)中外医学社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Pre-surgical diagnosis of skull base chondrosarcoma (SBC) is often challenging due to the resemblance to chordoma. The goal of this study was to develop an optimal method for predicting SBC diagnosis. METHODS: This retrospective study included patients with histologically diagnosed SBC and skull base chordoma. Their clinical and radiologic features were compared, and the predictive factors of SBC were examined. RESULTS: Forty-one patients with SBC and 41 with chordoma were included. Most SBCs exhibited hypointensity (25, 64.1%) or isointensity (12, 30.8%) on T1-weighted images, and hyperintensity (34, 87.1%) or mixed intensity (5, 12.8%) on T2-weighted images. MRI contrast enhancement was usually avid or fair (89.7%) with "arabesque"-like pattern (41.0%). The lateral/paramidline location was more common in SBC than in chordoma (85.4% vs. 9.8%; P < 0.01), while midline SBCs (14.6%) were also possible. Multivariate analysis demonstrated that higher apparent diffusion coefficient (ADC) value (unit odds ratio 1.01; 95% confidence interval 1.00-1.02; P < 0.01) was associated with an SBC diagnosis. An ADC value of ≥ 1750 × 10-6 mm2/s demonstrated a strong association with an SBC diagnosis (odds ratio 5.89 × 102; 95% confidence interval 51.0-6.80 × 103; P < 0.01) and yielded a sensitivity of 93.9%, specificity of 97.4%, positive predictive value of 96.9%, and negative predictive value of 95.0%. CONCLUSION: The ADC-based method is helpful in distinguishing SBC from chordoma and readily applicable in clinical practice. The prediction accuracy increases when other characteristics of SBC, such as non-midline location and arabesque-like enhancement, are considered together.

DOI： 10.1007/s11060-022-04097-2

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

DOI： 10.3390/cancers14174222

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Syringomyelia often accompanies spinal hemangioblastoma (SHB). It often shows progression to the medulla oblongata, dubbed as "syringobulbia", which presents critical symptoms such as dysphagia and respiratory compromise. Appropriate management of chronological syringomyelia progression toward syringobulbia is not set in stone. This study aims to unravel the clinical and chronological behavior of syringobulbia and its management. METHODS: A single-institution case series study of 5 patients operated for SHB with syringobulbia was conducted. Serial preoperative magnetic resonance imaging scans were analyzed in further details, especially focusing on the chronological progression of syringomyelia. A literature review was performed to describe clinical/imaging characteristics. RESULTS: Chronological imaging analyses revealed that despite the relatively steady progression of syringomyelia over years, it accelerated when developing syringobulbia. Intramedullary signal change ("presyringomyelia") was observed in the area where syringomyelia subsequently occurred. Literature review yielded another 15 cases of SHB with syringobulbia, totaling 20 cases. Bulbar dysfunction was seen in 4 cases (20%). Gross total resection was performed in all cases except 1, which underwent just syringotomy. Rapid postoperative symptom improvement was observed in all cases, as well as immediate imaging resolution of syringomyelia. CONCLUSIONS: The symptoms associated with syringobulbia often become life-threatening. Notably, its resolution may be near-synchronous to surgical resection of the spinal lesion. The speed of progression of syringomyelia is usually steady, but it may accelerate when extending to syringobulbia. Regular imaging follow-up is thus highly recommended to determine the best timing of intervention when presyringomyelia and syringomyelia are ascending toward the medulla oblongata.

DOI： 10.1016/j.wneu.2022.07.118

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tractography is one way to predict the distribution of cortical functional domains preoperatively. Diffusion tensor tractography (DTT) is commonly used in clinical practice, but is known to have limitations in delineating crossed fibers, which can be overcome by Q-ball imaging tractography (QBT). We aimed to compare the reliability of these 2 methods based on the spatial correlation between the arcuate fasciculus depicted by tractography and direct cortical stimulation during awake surgery. METHODS: In this study, 15 patients with glioma underwent awake surgery with direct cortical stimulation. Tractography was depicted in a three-dimensional computer graphic model preoperatively, which was integrated with a photograph of the actual brain cortex using our novel mixed-reality technology. The termination of the arcuate fasciculus depicted by either DTT or QBT and the results of direct cortical stimulation were compared, and sensitivity and specificity were calculated in speech-associated brain gyri: pars triangularis, pars opercularis, ventral precentral gyrus, and middle frontal gyrus. RESULTS: QBT had significantly better sensitivity and lower false-positive rate than DTT in the pars opercularis. The same trend was noted for the other gyri. CONCLUSIONS: QBT is more reliable than DTT in identification of the motor speech area and may be clinically useful in brain tumor surgery.

DOI： 10.1016/j.wneu.2022.05.041

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.

DOI： 10.2176/jns-nmc.2022-0027

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Chordoma and chondrosarcoma share common radiographic characteristics yet are distinct clinically. A radiomic machine learning model differentiating these tumors preoperatively would help plan surgery. MR images were acquired from 57 consecutive patients with chordoma (N = 32) or chondrosarcoma (N = 25) treated at the University of Tokyo Hospital between September 2012 and February 2020. Preoperative T1-weighted images with gadolinium enhancement (GdT1) and T2-weighted images were analyzed. Datasets from the first 47 cases were used for model creation, and those from the subsequent 10 cases were used for validation. Feature extraction was performed semi-automatically, and 2438 features were obtained per image sequence. Machine learning models with logistic regression and a support vector machine were created. The model with the highest accuracy incorporated seven features extracted from GdT1 in the logistic regression. The average area under the curve was 0.93 ± 0.06, and accuracy was 0.90 (9/10) in the validation dataset. The same validation dataset was assessed by 20 board-certified neurosurgeons. Diagnostic accuracy ranged from 0.50 to 0.80 (median 0.60, 95% confidence interval 0.60 ± 0.06%), which was inferior to that of the machine learning model (p = 0.03), although there are some limitations, such as the risk of overfitting and the lack of an extramural cohort for truly independent final validation. In summary, we created a novel MRI-based machine learning model to differentiate skull base chordoma and chondrosarcoma from multiparametric signatures.

DOI： 10.3390/cancers14133264

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stereotactic frame-based brain tumor biopsy (SFB) is a potent diagnostic tool considering its minimal invasiveness, though its diagnostic power and safety for brainstem lesions remain to be discussed. Here, we aimed to examine the usefulness of SFB for brainstem tumors. Twenty-two patients with brainstem tumors underwent 23 SFBs at our institution during 2002-2021. We retrospectively analyzed patient characteristics, tumor pathology, surgical procedures, and outcomes, including surgery-related complications and the diagnostic value. Seven (32%) tumors were located from the midbrain to the pons, eleven (50%) in the pons only, and four (18%) from the pons to the medulla oblongata. The target lesions were in the middle cerebellar peduncles in sixteen procedures (70%), the cerebellum in four (17%), the inferior cerebellar peduncles in two (9%), and the superior cerebellar peduncles in one (4%). A definitive diagnosis was made in 21 patients (95%) at the first SFB. The diagnoses were glioma in seventeen (77%) cases, primary central nervous system lymphoma in four (18%), and a metastatic brain tumor in one (5%). The postoperative complications (cranial nerve palsy in three [13%] cases, ataxia in one [4%]) were all transient. SFB for brainstem tumors yields a high diagnostic rate with a low risk of morbidity.

DOI： 10.3390/curroncol29070360

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Clinical Oncology (ASCO)  

2036

Background: Glioblastoma (GBM) is one of the worst prognostic cancers and there is no effective treatment after failure of bevacizumab. Eribulin is a microtubule inhibitor used for the treatment of patients with metastatic breast cancer and liposarcoma. We previously reported that eribulin strongly inhibits the RNA-dependent RNA polymerase (RdRP) activity of TERT protein in cancer cells, and has a strong anti-tumor effect against GBM cells with TERT promoter mutation. In this study we aim to investigate the efficacy and safety of eribulin in patients with bevacizumab-resistant recurrent GBM. Methods: This is an open-label, multicenter, single-arm phase II trial. Eligible patients aged 20-75 years with bevacizumab-resistant recurrent GBM were enrolled from 2018-2020. Patients received eribulin 1.4 mg/m² on days 1 and 8 of 21-day cycle until disease progression or intolerable toxicity was observed. The primary endpoint was one-year overall survival rate (1yOS%). The 35 patients are needed to achieve an 80% power at a one-sided alpha of 10%, under threshold 1yOS% of 10% and expected 1yOS% of 25%. Results: Thirty-seven patients aged 26-73 (median: 54) years were treated. Twenty-six of 37 (70.3%) patients were diagnosed as IDH-wildtype GBM, 4 (10.8%) were with IDH-mutant GBM and 7 (18.9%) were GBM, NOS. Thirty-four (91.9%) patients had a Karnofsky performance status of 70 or 80 at the registration. Thirty-one (83.8%) patients received additional treatments, including 28 (75.7%) bevacizumab, 11 (29.7%) re-irradiation and 3 (8.1%) resection after failure of eribulin. Among 37 subjects, 32 surgical specimens were analyzed for TERT promoter mutation and 15 for RdRP activity. 1yOS% was 29.7% [80% CI: 20.5 to 39.5 (p &lt; 0.0001), 95% CI: 16.1 to 44.6]. Median OS was 9.0 months [95% CI: 6.2 to 11.0] and median progression-free survival was 1.5 months [95% CI: 1.4 to 1.7]. Neither TERT nor RdRP statuses was associated with prolonged OS. Among all the target lesions evaluated, two lesions decreased more than 50% in size and the patients survived more than one year, however no obvious PR was confirmed at the final evaluation. The disease control rate was 25.7% [95% CI: 12.5 to 43.3]. Common ≥ grade 2 AEs were neutropenia (70.3%), leukopenia (56.8%), lymphopenia (27.0%), elevation of γ-GTP (13.5%), elevation of ALT (10.8%), elevation of AST (8.1%), alopecia (8.1%). Treatment-related grade 3 or 4 AEs occurred in 59.5% of subjects. There were no AEs leading to death. Conclusions: Eribulin was safely applied for the patients with recurrent GBM. This phase II study met its primary endpoint of 1yOS%, although no obvious response was observed. Further investigation to reveal the biomarkers related to longer survival is underway. Clinical trial information: UMIN000030359.

DOI： 10.1200/jco.2022.40.16_suppl.2036

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Clinical Oncology (ASCO)  

1551

Background: Cancer genomic profiling (CGP) tests have been approved in Japan since June 2019, with the requisite that all test results be discussed by molecular tumor boards (MTBs). More than 20,000 patients in over 200 designated hospitals have taken CGP tests by December 2021. As CGP tests have entered clinical practice, streamlining decision making by MTBs and standardizing interpretation of test results and treatment recommendations have become urgent issues. Here, we evaluated the utility of Chrovis, an annotation algorithm for reporting CGP tests to support MTBs make their recommendations. Methods: We retrospectively reviewed the reporting process of all approved CGP tests done at The University of Tokyo Hospital between December 2019 and November 2021. Chrovis provided annotation for each genetic variant by incorporating biologic, clinical, and therapeutic information by referencing several public knowledge databases and using natural language processing, and generated reports using the automated program. The MTB reviewed and made any necessary changes before finalizing the report. Changes in disclosure of germline findings were made according to the recommendations of a national guideline with consideration of past and family history. Results: Of the 243 tests, 91 changes in 81 Chrovis reports (33% of all reports) were made by the MTB. The most common type of change was germline disclosure with 26 changes (29%), followed by clinical trial information in Japan (18 changes, 20%) and recommendation of the patient-proposed national basket trial with multiple targeted agents (17 changes, 19%). Changes in germline disclosure increased from June 2021, when an update to a national guideline was released, while the proportion of changes in the latter two types remained unchanged. Gene alterations that led to the highest number of changes was TP53, with 13 changes. Changes in therapeutic recommendations were frequently observed in the RAS/MAPK pathway ( BRAF, KRAS, NF1, NRAS) with 12 changes. More changes were required with a tumor-only tissue CGP panel (57 of 149) compared with a matched tumor/normal tissue CGP panel (24 of 94, p = 0.04), mostly due to germline disclosure (24 vs. 2 changes). Conclusions: We observed that automated algorithm-based reporting was sufficient in 67% of reports. Recommendation for germline disclosure still requires manual supervision, particularly with tumor-only tissue CGP panels if algorithms do not incorporate medical history. The process of recommending clinical trials needs improvement, e.g., standardizing database formats for inclusion and exclusion criteria.

DOI： 10.1200/jco.2022.40.16_suppl.1551

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Background

Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs.

Methods

Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH).

Results

A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs.

Conclusions

12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

DOI： 10.1093/neuonc/noab246

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その他リンク： https://academic.oup.com/neuro-oncology/article-pdf/24/5/834/43548783/noab246.pdf

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：医歯薬出版(株)  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20220412010008&doc_link_id=issn%3D0039-2359%26volume%3D281%26issue%3D2%26spage%3D193&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D281%26issue%3D2%26spage%3D193&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while non-germinomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and non-germinoma/non-seminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

DOI： 10.1093/neuonc/noac021

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Craniopharyngioma is a pathologically benign but clinically malignant brain tumor typically located in the parasellar region. It is treated by surgical resection, but in most cases, total removal is not amenable due to its adhesion to the adjacent vital structures, such as the optic nerve, hypothalamus, and pituitary stalk. Often, tumor regrowth or recurrence occursand it is usually treated with either re-resection or radiotherapy, including stereotactic radiosurgery. Either treatment carries some important risks, including blindness, hypopituitarism, and cognitive impairment. A recent comprehensive genomic analysis revealed that the majority of papillary craniopharyngioma cases harbor a hotspot BRAF-V600E mutation. Several case reports have illustrated dramatic response of the residual or recurrent papillary craniopharyngioma to molecularly targeted therapy with a BRAF inhibitor(vemurafenib or dabrafenib)and a MEK inhibitor(trametinib), which are currently approved for melanoma and non-small cell lung carcinoma. This medical treatment can potentially be a wonderful treatment option for papillary craniopharyngioma, given its freedom from the aforementioned serious risks associated with surgery and radiotherapy.

DOI： 10.11477/mf.1436204542

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Hemangioblastoma(HB)is a tumor that frequently occurs in von Hippel-Lindau(VHL)disease, a hereditary tumor disease. It is a benign tumor and excision is the first choice of treatment, but in VHL disease, where HB occurs frequently, the emergence of more promising molecularly-targeted therapeutic agents has been desired. In this paper, we first explain HB and VHL disease and then outline the function of the VHL gene and the mechanism of onset of VHL disease. After that, we explain the analysis technology and frequency of VHL gene abnormalities and finally describe HIF2α inhibitors, which are promising as molecularly-targeted therapeutic agents for VHL disease. As the medical system for personalized medicine/precision medicine is being developed in Japan, it is expected that HB and VHL diseases will attract attention as target diseases in the future.

DOI： 10.11477/mf.1436204535

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Genomic and epigenomic analyses have progressed the exploration of the pathogenesis of CNS germ cell tumors(GCTs)in the past decade. GCTs are characterized by mutations in MAPK or PI3K pathways(55%)and unstable chromosomes, especially 12p gain(45%), as well as global hypomethylation in germinoma. Highly specific microRNA, miR-371a-3p, can be a diagnostic marker in serum and cerebrospinal fluid. Tumor cell content examined in H-E specimens has a prognostic value in germinoma: cases with higher tumor cell content show a worse prognosis. 12p gain in non-germinomatous GCTs(NGGCTs)has an unfavorable prognostic significance. PD-L1 and PD-1 are highly expressed in germinomas and the tumor cell microenvironment, respectively, highlighting the potential effectiveness of immune checkpoint inhibitors. Clinical trials from the Children's Oncology Group(COG)in the US and the Society for Paediatric Oncology(SIOP)in Europe and Japan have shown that whole ventricular irradiation is the most appropriate for germinomas, and that radiation fields can be reduced to the whole ventricle or a local area for localized NGGCTs. Toward personalized medicine, investigations into the structural abnormalities and variants in non-coding regions are needed to develop targeted therapy. A stratified treatment regimen is expected by incorporating newly-found biomarkers to reduce the treatment burden for generally young patients and circumvent late toxicity and sequelae. Establishing effective treatments is crucial for relapsed GCT that has a dismal prognosis.

DOI： 10.11477/mf.1436204530

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記述言語：英語  

Background: Solitary plasmacytoma is a localized lesion comprising monoclonal neoplastic proliferation of plasma cells. This disease is rarely encountered and few reports have described primary intracranial solitary plasmacytoma (PISP). Case Description: We report a case of PISP that presented initially as status epilepticus and exhibited massive intratumoral hemorrhage at the subcortical area. To the best of our knowledge, this is the first recorded presentation of this pathology in this manner. Following evacuation of the hematoma and decompressive craniectomy, the patient underwent radiation therapy and showed no sign of tumor recurrence at 3 years after diagnosis. Conclusion: This case reveals that PISP can present as subcortical intraparenchymal hemorrhage. It should be emphasized that the precise diagnosis of this disease is of utmost importance, because solitary plasmacytoma without a background of multiple myeloma responds well to radiation therapy.

DOI： 10.25259/SNI_66_2022

PubMed

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記述言語：英語  

Primary intracranial spindle cell sarcoma is an extremely rare mesenchymal tumor, the molecular pathogenesis of which is poorly understood. Because of the lack of specific markers, diagnosis sometimes relies on ruling out all possible differential diagnoses, often making it difficult to reach a definitive diagnosis. In this case study, we report a 69 year-old female patient for whom the integration of multi-layered molecular analyses contributed to making the diagnosis. The disease exhibited aggressive clinical behavior, requiring two sequential surgeries because of rapid regrowth within a short period. Primary and recurrent tumors exhibited similar histological features, in which spindle-shaped cells arranged in interlacing fascicles without any specific architectures, implicating sarcomatous tumors. In immunohistochemistry testing, tumor cells were immunopositive for vimentin but lacked any specific findings that contribute to narrowing down the differential diagnoses. Seeking further diagnostic clues, we performed DNA methylation-based analysis. The copy number analysis revealed MDM2 gene amplification and loss of heterozygosity of 22q. Moreover, dimension reduction clustering analysis implicated a methylation pattern comparable to aggressive types of sarcomas. In addition, an in-house next-generation sequencing panel ("Todai-OncoPanel") analysis identified somatic mutations in DICER1, NF2, and ATRX genes. Taken all together, we finally made the diagnosis of primary intracranial spindle cell sarcoma, DICER1-mutant, with MDM2 gene amplification. This case report suggests that even for the tumors with insufficient morphological and immuno-histological diagnostic clues, integration of multi-layered molecular analyses can contribute to making the diagnoses as well as to understanding the rare tumors by elucidating unexpected genetic and epigenetic features.

DOI： 10.1177/11795476221131189

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掲載種別：研究論文（学術雑誌）  

BACKGROUND: Image-guided systems improve the safety, functional outcome, and overall survival of neurosurgery but require extensive equipment. OBJECTIVE: To develop an image-guided surgery system that combines the brain surface photographic texture (BSP-T) captured during surgery with 3-dimensional computer graphics (3DCG) using projection mapping. METHODS: Patients who underwent initial surgery with brain tumors were prospectively enrolled. The texture of the 3DCG (3DCG-T) was obtained from 3DCG under similar conditions as those when capturing the brain surface photographs. The position and orientation at the time of 3DCG-T acquisition were used as the reference. The correct position and orientation of the BSP-T were obtained by aligning the BSP-T with the 3DCG-T using normalized mutual information. The BSP-T was combined with and displayed on the 3DCG using projection mapping. This mixed-reality projection mapping (MRPM) was used prospectively in 15 patients (mean age 46.6 yr, 6 males). The difference between the centerlines of surface blood vessels on the BSP-T and 3DCG constituted the target registration error (TRE) and was measured in 16 fields of the craniotomy area. We also measured the time required for image processing. RESULTS: The TRE was measured at 158 locations in the 15 patients, with an average of 1.19 ± 0.14 mm (mean ± standard error). The average image processing time was 16.58 min. CONCLUSION: Our MRPM method does not require extensive equipment while presenting information of patients' anatomy together with medical images in the same coordinate system. It has the potential to improve patient safety.

DOI： 10.1093/ons/opab353

Scopus

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記述言語：日本語   出版者・発行元：(一社)日本脳神経外科コングレス  

Myxoid glioneuronal tumor、PDGFRA p.K385-mutantは近年新たに提唱された中枢神経系腫瘍の概念である。その発生母地としては透明中隔や側脳室が考えられている。提唱後間もないため症例報告は少なく、その治療法や予後については一定の見解が得られていない。今回われわれは、透明中隔に生じたmyxoid glioneuronal tumor、PDGFRA p.K385-mutantに対し全摘出を行い、その後再発なく良好な経過を辿った1例を経験したので報告する。(著者抄録)

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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=J02632&link_issn=&doc_id=20211202230007&doc_link_id=1390572012410134912&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390572012410134912&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. METHODS: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. RESULTS: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27-66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4-17.7) and 1.5 (1.4-1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3-4 and 2.0% for Grade 5; most adverse events resolved and were manageable. CONCLUSIONS: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. CLINICAL TRIAL REGISTRATION: JapicCTI-152967.

DOI： 10.1007/s10147-021-02028-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Image-guided systems improve the safety, functional outcome, and overall survival of neurosurgery but require extensive equipment. OBJECTIVE: To develop an image-guided surgery system that combines the brain surface photographic texture (BSP-T) captured during surgery with 3-dimensional computer graphics (3DCG) using projection mapping. METHODS: Patients who underwent initial surgery with brain tumors were prospectively enrolled. The texture of the 3DCG (3DCG-T) was obtained from 3DCG under similar conditions as those when capturing the brain surface photographs. The position and orientation at the time of 3DCG-T acquisition were used as the reference. The correct position and orientation of the BSP-T were obtained by aligning the BSP-T with the 3DCG-T using normalized mutual information. The BSP-T was combined with and displayed on the 3DCG using projection mapping. This mixed-reality projection mapping (MRPM) was used prospectively in 15 patients (mean age 46.6 yr, 6 males). The difference between the centerlines of surface blood vessels on the BSP-T and 3DCG constituted the target registration error (TRE) and was measured in 16 fields of the craniotomy area. We also measured the time required for image processing. RESULTS: The TRE was measured at 158 locations in the 15 patients, with an average of 1.19 ± 0.14 mm (mean ± standard error). The average image processing time was 16.58 min. CONCLUSION: Our MRPM method does not require extensive equipment while presenting information of patients' anatomy together with medical images in the same coordinate system. It has the potential to improve patient safety.

DOI： 10.1093/ons/opab353

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. The aim of this study was to further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior. METHODS: We compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. RESULTS: By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas, 102 up-regulated genes and 162 down-regulated genes were extracted. The down-regulated genes clustered heavily to 19q and 4p while the up-regulated genes clustered to 4q. It was noteworthy that fibroblast growth factor 1 associated with stem cell maintenance and multiple genes associated with glioma progression were down-regulated in 19q-loss astrocytomas, and these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, the expression pattern of the 19q-loss astrocytomas showed no shift toward oligodendrogliomas with 1p/19q codeletion but rather constituted a subgroup of astrocytoma. CONCLUSIONS: These findings suggested that 19q-loss in astrocytomas is more likely acquired event rather than an early event in oncogenesis like the 1p/19q-codeletion in oligodendrogliomas, and that the biological features of 19q-loss astrocytomas are possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

DOI： 10.1007/s11060-021-03816-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) is a subtype of primary CNS lymphoma (PCNSL). There are very few comprehensive reports on this extremely rare tumor. Therefore, it is necessary to investigate the clinical features and prognostic factors for primary ALCL of the CNS. We performed a systematic review of the published literature. Past cases were comprehensively searched using PubMed, Cochrane Library, and Web of Science. Clinical information, such as age, sex, anaplastic lymphoma kinase (ALK) status, lesion sites, treatment methods, and survivorship were extracted. Thirty-nine cases with information on ALK status and treatment course were identified. The average observation period was 13 months, and the overall 2-year survival rate was 58%. Univariate analyses showed a statistically significantly better prognosis among patients < 40 years of age (p = 0.039, HR 0.32 (0.11-0.95)) and in relation to ALK positivity (p = 0.010, HR 0.24 (0.08-0.71) and methotrexate treatment (p = 0.003, HR 0.17 (0.05-0.56)). Because of the sparsity of cases, it is necessary to accumulate cases in order to perform more detailed analyses.

DOI： 10.3390/cancers13174358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.

DOI： 10.1007/s00401-021-02337-9

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記述言語：日本語   出版者・発行元：(公社)日本医学放射線学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Five-aminolevulinic acid (5-ALA) is widely used as an intraoperative fluorescent probe for radical resection of high-grade glioma, and thus aids in extending progression-free survival of patients. However, there exist some cases where 5-ALA fails to fluoresce. In some other cases, it may undergo fluorescence quenching but cannot be orally readministered during surgery. This study aimed to develop a novel hydroxymethyl rhodamine green (HMRG)-based fluorescence labeling system that can be repeatedly administered as a topical spray during surgery for the detection of glioblastoma. EXPERIMENTAL DESIGN: We performed a three-stage probe screening using tumor lysates and fresh tumor tissues with our probe library consisting of a variety of HMRG probes with different dipeptides. We then performed proteome and transcript expression analyses to detect candidate enzymes responsible for cleaving the probe. Moreover, in vitro and ex vivo studies using U87 glioblastoma cell line were conducted to validate the findings. RESULTS: The probe screening identified proline-arginine-HMRG (PR-HMRG) as the optimal probe that distinguished tumors from peritumoral tissues. Proteome analysis identified calpain-1 (CAPN1) to be responsible for cleaving the probe. CAPN1 was highly expressed in tumor tissues which reacted to the PR-HMRG probe. Knockdown of this enzyme suppressed fluorescence intensity in U87 glioblastoma cells. In situ assay using a mouse U87 xenograft model demonstrated marked contrast of fluorescence with the probe between the tumor and peritumoral tissues. CONCLUSIONS: The novel fluorescent probe PR-HMRG is effective in detecting glioblastoma when applied topically. Further investigations are warranted to assess the efficacy and safety of its clinical use.

DOI： 10.1158/1078-0432.CCR-20-4518

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: In neurosurgery, it is important to inspect the spatial correspondence between the preoperative medical image (virtual space), and the intraoperative findings (real space) to improve the safety of the surgery. Navigation systems and related modalities have been reported as methods for matching this correspondence. However, because of the influence of the brain shift accompanying craniotomy, registration accuracy is reduced. In the present study, to overcome these issues, we developed a spatially accurate registration method of medical fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, and its registration accuracy was measured. Methods: The subjects included 16 patients with glioma. Nonrigid registration using the landmarks and thin-plate spline methods was performed for the fusion 3-dimensional computer graphics and the intraoperative brain surface photograph, termed mixed-reality computer graphics. Regarding the registration accuracy measurement, the target registration error was measured by two neurosurgeons, with 10 points for each case at the midpoint of the landmarks. Results: The number of target registration error measurement points was 160 in the 16 cases. The target registration error was 0.72 ± 0.04 mm. Aligning the intraoperative brain surface photograph and the fusion 3-dimensional computer graphics required ∼10 minutes on average. The average number of landmarks used for alignment was 24.6. Conclusions: Mixed-reality computer graphics enabled highly precise spatial alignment between the real space and virtual space. Mixed-reality computer graphics have the potential to improve the safety of the surgery by allowing complementary observation of brain surface photographs and fusion 3-dimensional computer graphics.

DOI： 10.1016/j.wnsx.2021.100102

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND IMPORTANCE: The occipital transtentorial approach is used to address lesions at the posterior incisural space or upper cerebellum. This approach is rarely used, making standardization of the surgical procedure challenging. Here we describe the effectiveness of indocyanine green (ICG) and dye markings before tentorial incision in charting a safe and bloodless surgical trajectory for improved manoeuvrability. CLINICAL PRESENTATION: The first case was a 40-year-old man with a residual pineal mass after chemoradiation therapy for pathologically-proven germinoma. Surgical resection was performed via left occipital craniotomy. Incision of the left cerebellar tentorium by a radiofrequency knife was preceded by visualization of the straight sinus and venous lake, which were marked with dye, enabling safe entry into the quadrigeminal cistern. Finally, total-resection of the mature teratoma was achieved. The second case was a 50-year-old man with an enhancing mass at the cerebellar vermis and left hemisphere. Left occipital craniotomy was followed by ICG administration, illuminating the straight sinus and a complex structure of dural venous channels, which were marked with dye. This visualization maximized the tentorial incision by carefully avoiding venous structures and widely exposed the upper cerebellum. Subtotal-resection of the tumor was achieved, with a diagnosis of glioblastoma. CONCLUSION: ICG administration and dye marking are feasible and useful methods for precise identification/visualization of venous structures. They enable maximization as well as safe and appropriate tentorial incision to provide a sufficient surgical corridor for the occipital transtentorial approach.

DOI： 10.1080/02688697.2021.1927982

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Glioblastoma, the most malignant and most common form of glioma, is known to portend very poor prognosis with the median overall survival of approximately 1.5 years. Its treatment requires a multidisciplinary approach, which consists of maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Bevacizumab is approved for newly diagnosed as well as recurrent malignant glioma in Japan. NovoTTF is a novel medical device that emits alternating electric fields; it inhibits the proliferation and growth of the tumor by interfering with tumor cell mitosis at anaphase. A photodynamic therapy with talaporfin sodium has been approved for primary malignant brain tumor including glioblastoma in Japan. For epilepsy secondary to glioblastoma, a novel class of antiepileptics such as levetiracetam and lacosamide is preferred given the lack of drug-drug interactions. Perampanel is a selective antagonist of AMPA receptors, the major subtype of ionotropic glutamate receptors; it may be a preferred antiepileptics for glioblastoma, given the in vitro and in vivo analyses suggesting that it decreases the proliferation and invasion of tumor cells. In this chapter, I describe the overview of the multidisciplinary treatments of glioblastoma. I also describe the future perspectives.

DOI： 10.11477/mf.1436204436

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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）  

Although the incidence of central nervous system (CNS) cancers is not high, it significantly reduces a patient's quality of life and results in high mortality rates. A low incidence also means a low number of cases, which in turn means a low amount of information. To compensate, researchers have tried to increase the amount of information available from a single test using high-throughput technologies. This approach, referred to as single-omics analysis, has only been partially successful as one type of data may not be able to appropriately describe all the characteristics of a tumor. It is presently unclear what type of data can describe a particular clinical situation. One way to solve this problem is to use multi-omics data. When using many types of data, a selected data type or a combination of them may effectively resolve a clinical question. Hence, we conducted a comprehensive survey of papers in the field of neuro-oncology that used multi-omics data for analysis and found that most of the papers utilized machine learning techniques. This fact shows that it is useful to utilize machine learning techniques in multi-omics analysis. In this review, we discuss the current status of multi-omics analysis in the field of neuro-oncology and the importance of using machine learning techniques.

DOI： 10.3390/biom11040565

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Machine learning models for automated magnetic resonance image segmentation may be useful in aiding glioma detection. However, the image differences among facilities cause performance degradation and impede detection. This study proposes a method to solve this issue. We used the data from the Multimodal Brain Tumor Image Segmentation Benchmark (BraTS) and the Japanese cohort (JC) datasets. Three models for tumor segmentation are developed. In our methodology, the BraTS and JC models are trained on the BraTS and JC datasets, respectively, whereas the fine-tuning models are developed from the BraTS model and fine-tuned using the JC dataset. Our results show that the Dice coefficient score of the JC model for the test portion of the JC dataset was 0.779 ± 0.137, whereas that of the BraTS model was lower (0.717 ± 0.207). The mean Dice coefficient score of the fine-tuning model was 0.769 ± 0.138. There was a significant difference between the BraTS and JC models (p < 0.0001) and the BraTS and fine-tuning models (p = 0.002); however, no significant difference between the JC and fine-tuning models (p = 0.673). As our fine-tuning method requires fewer than 20 cases, this method is useful even in a facility where the number of glioma cases is small.

DOI： 10.3390/cancers13061415

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. METHODS: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. RESULTS: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. CONCLUSION: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

DOI： 10.1093/neuonc/noaa199

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Background</title>
Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion?


</sec>
<sec>
<title>Methods</title>
Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI).


</sec>
<sec>
<title>Results</title>
A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI.


</sec>
<sec>
<title>Conclusion</title>
CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.


</sec>

DOI： 10.1093/noajnl/vdab086

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その他リンク： http://academic.oup.com/noa/article-pdf/3/1/vdab086/39555495/vdab086.pdf

掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Background</title>
Germinoma preferentially occurs in pediatric and young adult age groups. Although they are responsive to treatment with chemotherapy and radiation, the treatment may cause long-term sequelae in their later lives. Here, we searched for clinical and histopathological features to predict the prognosis of germinoma and affect treatment response.


</sec>
<sec>
<title>Methods</title>
A total of 114 germinoma cases were included in the analysis. We investigated the association between clinical factors, tumor cell content, and progression-free survival (PFS).


</sec>
<sec>
<title>Results</title>
The tumor cell content was widely distributed from &amp;lt;5% to 90% in the specimens, with a median value of 50%. Female patients showed higher tumor cell content in the specimens (P = .002). Cases with lesions at atypical sites showed shorter PFS than those with lesions at other sites (P = .03). Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (&amp;lt;50%) (P = .03). In multivariate analysis, tumor cell content was the only statistically significant prognostic factor (P = .04). Among the 7 cases treated with local radiation and chemotherapy, all 3 cases that recurred (2 outside of the radiation field, 1 unknown) had tumor cell content of ≥50% in the original specimen, whereas all 4 cases without recurrence had tumor cell contents of &amp;lt;50%.


</sec>
<sec>
<title>Conclusions</title>
We found that tumor cell content significantly affected the prognosis of germinomas. Although validation of these results using an independent and larger cohort is necessary, this potentially opens the possibility of leveraging this pathological factor in future clinical trials when stratifying the treatment intensity.


</sec>

DOI： 10.1093/noajnl/vdab110

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その他リンク： http://academic.oup.com/noa/article-pdf/3/1/vdab110/40404167/vdab110.pdf

記述言語：日本語   出版者・発行元：(株)中外医学社  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Down-regulated genes in the 19q-loss astrocytomas were heavily clustered to 19q and 4p, and up-regulated genes to 4q. It was noted that fibroblast growth factor 1 associated with stem cell maintenance was down-regulated in 19q-loss astrocytomas and genes associated with glioma progression were differentially expressed, these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, 19q-loss astrocytomas did not shift to oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas is more likely to be an acquired event rather than early event in oncogenesis like 1p/19q codeletion in oligodendrogliomas, and the biological and morphological features of 19q-loss astrocytomas were possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

DOI： 10.1093/noajnl/vdaa143.053

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p < 0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.

DOI： 10.1186/s40478-020-01078-2

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. To further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their clinical behavior, we compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. Comparing expression level of each genes between 19q-loss and 19q-intact astrocytomas,136 up-regulated genes and 203 down-regulated genes were extracted. Gene expression patterns of 19q-loss astrocytomas were partially different from that of 19q-intact astrocytomas. More down-regulated genes distributed on 19q and 4p, and more up-regulated genes distributed on 4q. Multiple genes associated with stem cell maintenance were down-regulated in 19q-loss astrocytomas, and genes associated with glioma progression were differentially expressed. Comparing expression patterns among 19q-loss astrocytomas and other IDH-mutant glioma subgroups using TCGA datasets by t-SNE analysis revealed that expression pattern of 19q-loss astrocytomas did not shift to that of oligodendrogliomas with 1p/19q codeletion but were a subgroup in astrocytomas. These results indicated that 19q-loss in astrocytomas was an acquired event different from 1p/19q codeletion in oligodendrogliomas, and better prognosis morphological features in 19q-loss astrocytomas were derived from differentially expressed genes associated with stem cell maintenance and glioma progression.

DOI： 10.1093/neuonc/noaa215.692

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The factors associated with health-related quality of life in patients with glioma remain unclear; particularly, the impact of symptoms on quality of life has not been studied comprehensively. This study aims to document the quality of life of patients with glioma and clarify the impact of symptoms. METHODS: In this cross-sectional study, participants were recruited from patients at The University of Tokyo Hospital and from patients who were registered at the Japan Brain Tumor Alliance. We included adult patients with World Health Organization grade II-IV glioma and excluded those with disturbances of consciousness or aphasia. We used the European Organization for Research and Treatment of Cancer QLQ-C30 and BN20 to evaluate quality of life and the symptoms. Multiple regression analyses were performed to investigate the impact of symptoms on European Organization for Research and Treatment of Cancer global health status and QLQ-C30 social functioning. In addition, we performed univariate subgroup analyses classified by World Health Organization grade and history of chemotherapy. RESULTS: This study included 76 patients. Seven symptoms occurred in more than 50% of the patients: fatigue, future uncertainty, drowsiness, communication deficit, financial difficulties, motor dysfunction and weakness of legs. Multiple regression analyses showed that insomnia affected their global health status, and appetite loss, financial difficulties and motor dysfunction were significantly related to their social functioning. In subgroup analysis, the number of symptom subscales that were significantly related to global health status and social functioning was larger in World Health Organization grade II patients compared with grade III/IV patients. CONCLUSIONS: In addition to neurological deficits, symptoms were associated with poor quality of life in patients with glioma. This study provided the basis on further investigation of usefulness of symptom evaluation on quality of life improvement.

DOI： 10.1093/jjco/hyaa068

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記述言語：日本語   出版者・発行元：(一社)日本言語聴覚士協会  

＜文献概要＞1.はじめに 覚醒下腫瘍摘出手術は,脳腫瘍周辺の機能領域に対する損傷を避けつつ,腫瘍を最大限に切除することを目的とした術式で,通常の開頭腫瘍摘出術に比べて腫瘍摘出率,術後後遺症,生命予後の点で優位とされる.言語野近傍の腫瘍に対する覚醒下手術では,術中に患者を覚醒させ,言語タスクを実施する間に患者の脳表に電気刺激を与えてその機能を一時的に低下させ,電気刺激によって誘発または抑制される言語症状から患者の機能領域を同定する(図1).術者はこの皮質マッピングの結果を考慮して腫瘍の切除範囲を決定する.また,言語に関わる神経線維近傍の腫瘍切除術では,脳白質に電気刺激を与えて陽性反応を観察する皮質下マッピングも行われる.本邦では,2012年に日本Awake Surgery学会が世界初の英語版覚醒下手術ガイドラインを,また翌年には日本語版ガイドラインを発表した.さらに,2014年には覚醒下脳手術施設認定制度が始まり,2015年には脳腫瘍覚醒下マッピング加算の算定が可能となった.2016年には全国で105件,2017年には185件の覚醒下腫瘍摘出術が施行され,今後覚醒下手術を行う施設はさらに増えるものと予想される.覚醒下手術は多職種によるチーム医療であり,言語・高次脳機能の専門職として言語聴覚士もその一端を担う.当院においても,2016年より言語聴覚士が覚醒下手術に参加し,術前評価,術中マッピング,術後評価とリハビリテーションを行っている.覚醒下手術は世界的に広く行われているが,各国の覚醒下手術における言語聴覚士の役割を知る機会は少ない.今回,英米の2大学病院に勤務する言語聴覚士とともに,当院を含めた3大学病院の覚醒下手術における言語聴覚士の業務内容を比較し,課題や今後の展望について考察したので報告する.なお,本稿の要旨は,The American Speech-Language-Hearing Association Convention 2019において,各病院の言語聴覚士と共同で発表した.また,言語聴覚士の職名は各国で異なるが(英国:Speech Language Therapist,SLT/米国:Speech Language Pathologist,SLP/日本:Speech Therapist,ST),本稿では便宜上,一律に「言語聴覚士」と記載した.

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

NCCオンコパネルやFoundationOneといった、多数のがん関連遺伝子の異常を一度に解析できるがん遺伝子パネル検査が日本でも保険診療で行えるようになり、わが国のがんゲノム医療体制は急速に整備されてきた。パネル検査により、脳腫瘍領域でも、治療に有用と思われる多数の遺伝子異常が同定できる。例えばEGFR、IDH、H3F3A、HIST1H3B、BRAF遺伝子、NTRK融合遺伝子などである。これらの遺伝子異常に対応した分子標的薬は、現状ではまだまだ少ない状況である。しかし、NTRK融合遺伝子陽性腫瘍に対するエヌトレクチニブは保険承認され、さらにIDH阻害薬やBRAF阻害薬などの臨床試験も行われており、少しずつではあるが、脳腫瘍領域においてもパネル検査結果に基づく個別化医療が推進されていくことが予想される。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J03120&link_issn=&doc_id=20200826180004&doc_link_id=issn%3D0917-1495%26volume%3D30%26issue%3D9%26spage%3D970&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0917-1495%26volume%3D30%26issue%3D9%26spage%3D970&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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：日本がん免疫学会  

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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：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：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）  

OBJECTIVE: The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). METHODS: Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. RESULTS: Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5-30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach's coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test-retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. CONCLUSIONS: The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.

DOI： 10.1093/jjco/hyaa036

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記述言語：英語  

BACKGROUND: Primary central nervous system (CNS) anaplastic large cell lymphoma (ALCL) is an uncommon type of brain tumor, usually treated with a regimen that includes high-dose methotrexate (MTX). Only a few cases of primary CNS anaplastic lymphoma kinase (ALK)-positive ALCL have been reported so far, with no reported cases of a small cell variant. CASE DESCRIPTION: A 26-year-old man presenting with headache and visual field impairment was found to have a supratentorial mass mimicking meningioma. Craniotomy was performed for tumor resection, and postoperative histologic examination revealed atypical cells that were nonenlarged lymphocytes with irregularly shaped and enlarged nuclei; these cells were cluster of differentiation 30 and ALK-positive, leading to the diagnosis of a small cell variant of ALK-positive ALCL. In this case, the tumor exhibited an aggressive behavior with MTX resistance with metastases in the pelvis but responded well to cytarabine and etoposide (CYVE). CONCLUSIONS: In general, CNS ALK-positive ALCL responds well to MTX, but small cell variants show aggressive behavior and may be resistant to MTX. For small cell variants of ALCL that are resistant to MTX therapy, as in this case, CYVE therapy may be an effective treatment.

DOI： 10.1016/j.wneu.2020.02.171

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glioma is characterized by a high heterogeneity in the brain tumor. Abundant tumor-associated macrophages (TAMs) exist as neoplastic tissues, implicating tumor plasticity and thus leading to therapeutic challenges. Vascular adhesion protein (VAP-1) potentially serves as a mediator for TAM immunity in tumor milieu. We previously demonstrated that VAP-1 could contribute to tumor malignancy, but its characteristics in TAM immunity of glioma progression are still unclear. This study explored the association of VAP-1 expression with TAM distribution as well as the resulting clinical significance and prognostic value in human gliomas. An in-depth analysis of AOC3 (VAP-1) gene expression was performed using 695 glioma samples derived from the cancer genome atlas (TCGA)-lower grade glioma and glioblastoma (GBMLGG) cohort. Bioinformatic analysis confirmed that VAP-1 expression is associated with poor prognosis of glioma patients (p = 0.0283). VAP-1 and TAM biomarkers (CD68, iNOS, and CD163) were evaluated by immunohistochemistry in 108 gliomas from Kaohsiung Medical University Hospital. VAP-1+ was expressed in 56 (51.85%) cases and this phenotype revealed a significant association with overall survival in Kaplan-Meier analysis (p < 0.0001). Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature. We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas (p < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both p < 0.0001). Furthermore, VAP-1/CD163 coexpression exhibited excellent diagnostic accuracy in gliomas (AUC = 0.8008). In conclusion, VAP-1 and TAM CD163 M2 coexpression was found in glioma tissues belonging to a highly malignant subgroup that was associated with poor prognosis. These results implied VAP-1 abundance is closely linked to alternative M2 activation during glioma progression. From the aforementioned data, a reasonable inference is that VAP-1 combined with targeting M2 immunity might be an effective therapeutic target for human gliomas.

DOI： 10.3390/diagnostics10050256

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記述言語：英語  

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41598-020-60086-3

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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：SAGE Publications  

Medical care-related decision-making among patients with malignant brain tumors has not been sufficiently discussed. This study aimed to develop a framework for understanding patients’ experiences in the decision-making process. Semi-structured interviews with 14 patients were analyzed using a grounded theory approach, focusing on their 48 decision-making points. Additionally, interviews with two family members and seven healthcare providers, and participant observations were used to gain contextual insight into patients’ experiences. Patients faced decisions while they struggled in vulnerability under shock, fear, and anxiety while hoping. Under this context, they showed four decision-making patterns: (1) led by the situation, (2) controlled by others, (3) entrusted someone with the decision, and (4) myself as a decision-making agent. Across these patterns, the patients were generally satisfied with their decisions even when they did not actively participate in the process. Healthcare providers need to understand patients’ contexts and their attitudes toward yielding decision-making to others.

DOI： 10.1177/2333393620960059

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/2333393620960059

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS: We retrospectively explored whether previously described EGFR extracellular domain (ECD)-sensitizing mutations in the context of EGFR gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS: We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of EGFRvIII or EGFR ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION: While dacomitinib was not effective in most patients with EGFR-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, EGFRvIII and EGFR ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.

DOI： 10.1200/PO.19.00295

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We conducted a feasibility study to predict malignant glioma grades via radiomic analysis using contrast-enhanced T1-weighted magnetic resonance images (CE-T1WIs) and T2-weighted magnetic resonance images (T2WIs). We proposed a framework and applied it to CE-T1WIs and T2WIs (with tumor region data) acquired preoperatively from 157 patients with malignant glioma (grade III: 55, grade IV: 102) as the primary dataset and 67 patients with malignant glioma (grade III: 22, grade IV: 45) as the validation dataset. Radiomic features such as size/shape, intensity, histogram, and texture features were extracted from the tumor regions on the CE-T1WIs and T2WIs. The Wilcoxon-Mann-Whitney (WMW) test and least absolute shrinkage and selection operator logistic regression (LASSO-LR) were employed to select the radiomic features. Various machine learning (ML) algorithms were used to construct prediction models for the malignant glioma grades using the selected radiomic features. Leave-one-out cross-validation (LOOCV) was implemented to evaluate the performance of the prediction models in the primary dataset. The selected radiomic features for all folds in the LOOCV of the primary dataset were used to perform an independent validation. As evaluation indices, accuracies, sensitivities, specificities, and values for the area under receiver operating characteristic curve (or simply the area under the curve (AUC)) for all prediction models were calculated. The mean AUC value for all prediction models constructed by the ML algorithms in the LOOCV of the primary dataset was 0.902 ± 0.024 (95% CI (confidence interval), 0.873-0.932). In the independent validation, the mean AUC value for all prediction models was 0.747 ± 0.034 (95% CI, 0.705-0.790). The results of this study suggest that the malignant glioma grades could be sufficiently and easily predicted by preparing the CE-T1WIs, T2WIs, and tumor delineations for each patient. Our proposed framework may be an effective tool for preoperatively grading malignant gliomas.

DOI： 10.1038/s41598-019-55922-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: A noninvasive diagnostic method to predict the degree of malignancy accurately would be of great help in glioma management. This study aimed to create a highly accurate machine learning model to perform glioma grading. METHODS AND MATERIALS: Preoperative magnetic resonance imaging acquired for cases of glioma operated on at our institution from October 2014 through January 2018 were obtained retrospectively. Six types of magnetic resonance imaging sequences (T2-weighted image, diffusion-weighted image, apparent diffusion coefficient [ADC], fractional anisotropy, and mean kurtosis [MK]) were chosen for analysis; 476 features were extracted semiautomatically for each sequence (2856 features in total). Recursive feature elimination was used to select significant features for a machine learning model that distinguishes glioblastoma from lower-grade glioma (grades 2 and 3). RESULTS: Fifty-five data sets from 54 cases were obtained (14 grade 2 gliomas, 12 grade 3 gliomas, and 29 glioblastomas), of which 44 and 11 data sets were used for machine learning and independent testing, respectively. We detected 504 features with significant differences (false discovery rate <0.05) between glioblastoma and lower-grade glioma. The most accurate machine learning model was created using 6 features extracted from the ADC and MK images. In the logistic regression, the area under the curve was 0.90 ± 0.05, and the accuracy of the test data set was 0.91 (10 out of 11); using a support vector machine, they were 0.93 ± 0.03 and 0.91 (10 out of 11), respectively (kernel, radial basis function; c = 1.0). CONCLUSIONS: Our machine learning model accurately predicted glioma tumor grade. The ADC and MK sequences produced particularly useful features.

DOI： 10.1016/j.ijrobp.2019.07.011

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

PURPOSE

Diffusion tensor-based tractography (DTT) is a method to estimate the direction of white matter fibers, but it is difficult to verify the relationship with brain function spatially with high accuracy. We developed a registration method to fuse the real space (brain surface photograph) and preoperative fused 3D image (virtual space) using the landmark method and thin plate spline method. In our previous study, this method was able to achieve highly accurate alignment registration error 0.7±0.1mm (mean±SE) even after brain shift due to craniotomy. In this study, we proposed a method to examine spatial errors of DTT and direct cortical stimulation (DCS) and verify its accuracy.

METHODS

We included 7 gliomas performed awake surgery. We created the fused three – dimensional image before surgery and acquired the brain surface photograph immediately after craniotomy, then we aligned them using the proposed method. Sites that showed speech arrest by DCS were plotted on the fused image. A circle with a radius of 15 mm centered on the same site was taken as the range over which the current spreads. The surface area of each of the circles was calculated to make it true if there was arcuate fasciculus drawn with DTT in the circle, and false if it did not exist. By using this method, the accuracy of the DTT was verified. RESULT: In 7 cases, speech arrest was shown at 21 DCS plots. The probability of the presence of DTT within the current spread of DCS was 64.4%.

CONCLUSION

The proposed method indicates that DTT does not necessarily match the DCS results by verification using real space and virtual space. We present some illustrative cases.

DOI： 10.1093/neuonc/noz175.718

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10014-019-00352-z

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II-IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II-III astrocytoma, IDH-mutant, n = 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the "neoantigen expression ratio," decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for "high-affinity," "clonal," and "passenger gene-derived" neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.

DOI： 10.1158/2326-6066.CIR-18-0599

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記述言語：英語  

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

DOI： 10.1038/s41598-019-43790-7

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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）  

Phosphatidylinositol 3-kinase signaling promotes cell growth and survival and is frequently activated in infiltrative gliomas. Activating mutations in PIK3CA gene are observed in 6-15% of glioblastomas, although their clinical significance is largely undescribed. The objective of this study was to examine whether PIK3CA mutations are associated with a specific clinical phenotype in glioblastoma. We retrospectively reviewed 157 consecutive newly diagnosed glioblastoma patients from December 2009 to June 2012 who underwent molecular profiling consisting of targeted hotspot genotyping, fluorescence in situ hybridization for gene amplification, and methylation-specific PCR for O6-methylguanine-DNA methyltransferase promoter methylation. Molecular alterations were correlated with clinical features, imaging and outcome. The Cancer Genome Atlas data was analyzed as a validation set. There were 91 males; median age was 58 years (range, 23-85). With a median follow-up of 20.9 months, median progression-free survival (PFS) and estimated overall survival (OS) were 11.9 and 24.0 months, respectively. Thirteen patients (8.3%) harbored PIK3CA mutation, which was associated with younger age (mean 49.4 vs. 58.1 years, p = 0.02). PIK3CA mutation correlated with shorter PFS (median 6.9 vs. 12.4 months, p = 0.01) and OS (median 21.2 vs. 24.2 months, p = 0.049) in multivariate analysis. A significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions, was observed (46.2% vs. 11.1%, p = 0.004). In conclusion, despite the association with younger age, PIK3CA activating mutations are associated with earlier recurrence and shorter survival in adult glioblastoma. The aggressive course of these tumors may be related to their propensity for disseminated presentation.

DOI： 10.1186/s40478-019-0720-8

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記述言語：日本語   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE OF THE REPORT: This study aimed to determine the most effective metabolic index of FDG-PET and MET-PET to differentiate high- and low-grade gliomas, and then to characterize tumor metabolism according to the 2016 WHO classification. We also developed a new calculation method of potential infiltrative tumor volume to overcome the current limitations of tumor evaluation according to metabolic index, which focuses solely on tumor core area. MATERIALS AND METHODS: Patients who underwent both FDG-PET and MET-PET, as well as surgical treatment, were retrospectively identified. All tumors were diagnosed histologically and included 44 high-grade and 19 low-grade gliomas. Metabolic indices of tumor-to-normal (T/N) ratio and maximum value within the tumor itself were compared between high- and low-grade tumors. A calculation method for potential infiltrative tumor volume was developed and compared between these 2 grades. RESULTS: T/N, calculated as tumor value divided by normal cortex value, was the most effective (area under the curve, 0.800 for FDG-PET; area under the curve, 0.773 for MET-PET) for differentiating high- and low-grade gliomas. Potential infiltrative volume effectively distinguished between high- and low-grade glioma (43.8 ± 30.2 mL vs 14.0 ± 12.6 mL; P = 0.005 [t test]). A combination of T/N, with a cutoff value of 0.9 or higher on FDG-PET and/or 3.0 or higher on MET-PET, and potential infiltrative volume, with a cutoff value of 20.0 mL or higher, provided a diagnostic accuracy of 89% in distinguishing high- from low-grade gliomas. CONCLUSIONS: Evaluation of potential infiltrative volume surrounding the tumor core area, in addition to the T/N ratio of the tumor core, may help distinguish between high- and low-grade gliomas.

DOI： 10.1097/RLU.0000000000002460

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

DOI： 10.1038/s41598-019-38510-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In conducting medical research, a system which can objectively predict the future trends of the given research field is awaited. This study aims to establish a novel and versatile algorithm that predicts the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected with computational sorting methods such as text-mining analyses. Thirty journals that represent the recent trends in neuro-oncology were also selected. As a novel concept, the annual impact (AI) of each year was calculated for each journal and field (number of articles published in the journal × impact factor of the journal). The AI index (AII) for the year was defined as the sum of the AIs of the 30 journals. The AII trends of the 79 fields from 2008 to 2017 were subjected to machine learning predicting analyses. The accuracy of the predictions was validated using actual past data. With this algorithm, the latest trends in neuro-oncology were predicted. As a result, the linear prediction model achieved relatively good accuracy. The predicted hottest fields in recent neuro-oncology included some interesting emerging fields such as microenvironment and anti-mitosis. This algorithm may be an effective and versatile tool for prediction of future trends in a particular medical field.

DOI： 10.3390/cancers11020178

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intratumoural heterogeneity underlies tumour escape from molecularly targeted therapy in glioblastoma. A cell-based model preserving the evolving molecular profiles of a tumour during treatment is key to understanding the recurrence mechanisms and development of strategies to overcome resistance. In this study, we established a matched pair of glioblastoma stem-like cell (GSC) cultures from patient glioblastoma samples before and after epidermal growth factor receptor (EGFR)-targeted therapy. A patient with recurrent glioblastoma (MGG70R) harboring focal, high-level EGFR amplification received the irreversible EGFR tyrosine kinase inhibitor dacomitinib. The tumour that subsequently recurred (MGG70RR) showed diploid EGFR, suggesting inhibitor-mediated elimination of EGFR-amplified tumour cells and propagation of EGFR non-amplified cell subpopulations. The MGG70R-GSC line established from MGG70R formed xenografts retaining EGFR amplification and EGFR overexpression, while MGG70RR-GSC established from MGG70RR generated tumours that lacked EGFR amplification and EGFR overexpression. MGG70R-GSC-derived intracranial xenografts were more proliferative than MGG70RR-GSC xenografts, which had upregulated mesenchymal markers, mirroring the pathological observation in the corresponding patient tumours. In vitro MGG70R-GSC was more sensitive to EGFR inhibitors than MGG70RR-GSC. Thus, these molecularly distinct GSC lines recapitulated the subpopulation alteration that occurred during glioblastoma evasion of targeted therapy, and offer a valuable model facilitating therapeutic development for recurrent glioblastoma.

DOI： 10.1038/s41598-018-37437-2

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記述言語：英語  

Brain metastasis frequently develops in non-small-cell lung cancer (NSCLC). Here, we report a patient who developed brain metastasis from ALK-positive NSCLC which mimicked brain abscess. He was admitted for suspected obstructive pneumonia nine months after curative lung resection. Head magnetic resonance imaging revealed a cavitary lesion, which was compatible with brain abscess but rare in brain metastasis. However, after treatment with antibiotics, the brain lesion increased in size. Aspiration of the liquid content of the brain lesion revealed cancer cells. When a brain lesion suggestive of abscess develops in a patient with ALK-positive NSCLC, aspiration may be necessary to differentiate metastasis from abscess.

DOI： 10.1155/2019/9141870

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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.2019.00727

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記述言語：英語  

Maffucci syndrome (MS) and Ollier disease (OD) are nonhereditary congenital diseases characterized by multiple enchondromas and/or chondrosarcomas. Recent studies have implicated somatic mosaic mutations of isocitrate dehydrogenase 1 or 2 (IDH1/2) as contributing to the pathogenesis of MS and OD. Occasionally, patients with these disorders may also present with central nervous system (CNS) tumors; however, detailed genetic analyses are limited. In this article, the authors report on a male patient with MS, harboring three CNS tumors that share a common genetic alteration. Over a 9-year period, three separate tumor resections were conducted for sellar, intraparenchymal brainstem, and osseous clival tumors. The histopathological diagnoses were pituitary adenoma, diffuse astrocytoma, and chondrosarcoma, respectively. Sanger sequencing revealed a common IDH1 R132C mutation among all three CNS tumors but not in blood DNA. Administering chemotherapy (nimustine) and subsequent radiation therapy to the brainstem glioma and the residual lesion in the clivus have kept the patient progression free for 18 months. This is the first report demonstrating an IDH1 mutation shared among three different CNS tumors in a single patient with MS. The findings support the hypothesis that in MS and OD, a single common IDH1 mutation triggers tumorigenesis in cells of different origins and locations in a somatic mosaic fashion.

DOI： 10.3171/2018.6.JNS18729

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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   出版者・発行元：日本癌学会  

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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：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：日本がん免疫学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II-IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas). Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival compared to 19q-intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q-loss GBM and 19q-intact GBM (P = .4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas.

DOI： 10.1111/cas.13635

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記述言語：英語  

DOI： 10.3171/2017.9.JNS172108

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma. METHODS Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression. RESULTS All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line. CONCLUSIONS Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.

DOI： 10.3171/2016.12.JNS161444

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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：ELSEVIER SCIENCE INC  

BACKGROUND: In 2016, the World Health Organization updated its classification of tumors, adding genetic profiles to the conventional histopathologic typing. CASE DESCRIPTION: The authors present herein the first case of a 44-year-old female with isocitrate dehydrogenase-mutant World Health Organization grade II diffuse spinal astrocytoma diagnosed on the basis of both histopathologic and genetic findings. CONCLUSIONS: The present case underscores the significant role of a molecular genetic analysis in the differential diagnosis of intramedullary spinal gliomas.

DOI： 10.1016/j.wneu.2017.08.142

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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：SPRINGER  

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

DOI： 10.1007/s00401-017-1771-1

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記述言語：英語   出版者・発行元：OXFORD UNIV PRESS INC  

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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：JAPAN ENDOCRINE SOC  

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome often associated with fibroblast growth factor 23 (FGF23)-producing tumors such as phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) affecting the bone and soft tissue. We experienced a patient with progressive bone and muscle pain due to FGF23-related TIO. Venous sampling had strongly suggested the anterior skull base as a source of FGF23, which led to the discovery of a small tumor in the ethmoid sinus extending intracranially. Radical surgical resection confirmed the histological diagnosis of PMTMCT with FGF23 immunopositivity and achieved durable tumor control with complete resolution of symptoms. We serially measured serum FGF23 level before, during and after surgery and analyzed the data to determine the half-life of FGF23. Serum FGF23 level sharply declined as early as 20 minutes after en bloc tumor resection and completely normalized after surgery. The half-life of FGF23 was calculated to be approximately 18.5 minutes using single phase exponential decay model as well as semilog transformation formula. Serial measurements of serum FGF23 level can potentially declare "complete" resection of a FGF23-producing tumor and total cure of TIO; in this regard, development of its intraoperative measurement would be helpful in the management of this endocrine tumor.

DOI： 10.1507/endocrj.EJ17-0177

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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：OXFORD UNIV PRESS INC  

Background: Although inactivation of the von Hippel-Lindau gene (VHL), located on chromosome 3p25, is considered to be a major cause of hemangioblastomas (HBs), the incidence of biallelic inactivation of VHL is reportedly low. The aim of this study was to determine the prevalence of VHL alterations in HBs, as well as to identify additional molecular aberrations. Methods: Genetic and epigenetic alterations were comprehensively and comparatively analyzed in 11 VHL-related and 21 sporadic HBs. Results: VHL alterations detected by sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were more frequent in VHL-related HBs than in sporadic HBs (100% vs 62%; P = 0.029). VHL alterations were found only in 4 sporadic HBs by direct sequencing; however, targeted deep sequencing detected 9 additional alterations. Loss of heterozygosity (LOH) on chromosome 3 was found in 64% and 57% of VHL-related and sporadic HBs, respectively, by single nucleotide polymorphism (SNP) array analysis. Among 19 tumors with chromosome 3 LOH, 5 were classified as copy-neutral LOH. VHL promoter hypermethylation was detected only in sporadic HBs (33%), indicating that epigenetic suppression of VHL is a common mechanism in sporadic HBs. The rate of biallelic VHL inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. LOH on either chromosome 6 or 10 was detected only in sporadic HBs (43%). Conclusion: Although biallelic inactivation of VHL is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB.

DOI： 10.1093/neuonc/nox034

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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：AMER ASSOC CANCER RESEARCH  

IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102-15. ©2017 AACR.

DOI： 10.1158/0008-5472.CAN-16-2263

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記述言語：日本語   出版者・発行元：日本がん免疫学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE The management of vestibular schwannoma (VS) remains controversial. One commonly cited advantage of microsurgery over other treatment modalities is that tumor removal provides the greatest chance of long-term cure. However, there are very few publications with long-term follow-up to support this assertion. The purpose of the current study is to report the very long-term risk of recurrence among a large historical cohort of patients who underwent microsurgical resection. METHODS The authors retrospectively reviewed the medical records of patients who had undergone primary microsurgical resection of unilateral VS via a retrosigmoid approach performed by a single neurosurgeon-neurotologist team between January 1980 and December 1999. Complete tumor removal was designated gross-total resection (GTR), and anything less than complete removal was designated subtotal resection (STR). The primary end point was radiological recurrence-free survival. Time-to-event analyses were performed to identify factors associated with recurrence. RESULTS Four hundred fourteen patients met the study inclusion criteria and were analyzed. Overall, 67 patients experienced recurrence at a median of 6.9 years following resection (IQR 3.9-12.1, range 1.2-22.5 years). Estimated recurrence-free survival rates at 5, 10, 15, and 20 years following resection were 93% (95% CI 91-96, 248 patients still at risk), 78% (72-85, 88), 68% (60-77, 47), and 51% (41-64, 22), respectively. The strongest predictor of recurrence was extent of resection, with patients who underwent STR having a nearly 11-fold greater risk of recurrence than the patients treated with GTR (HR 10.55, p < 0.001). Among the 18 patients treated with STR, 15 experienced recurrence at a median of 2.7 years following resection (IQR 1.9-8.9, range 1.2-18.7). Estimated recurrence-free survival rates at 5, 10, 15, and 20 years following GTR were 96% (95% CI 93-98, 241 patients still at risk), 82% (77-89, 86), 73% (65-81, 46), and 56% (45-70, 22), respectively. Estimated recurrence-free survival rates at 5, 10, and 15 years following STR were 47% (95% CI 28-78, 7 patients still at risk), 17% (5-55, 2), and 8% (1-52, 1), respectively. CONCLUSIONS Long-term surveillance is required following microsurgical resection of VS even after GTR. Subtotal resection alone should not be considered a definitive long-term cure. These data emphasize the importance of long-term follow-up when reporting tumor control outcomes for VS.

DOI： 10.3171/2016.11.JNS16498

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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：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：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）   出版者・発行元：BIOMED CENTRAL LTD  

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

DOI： 10.1186/s40478-017-0422-z

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

Primary spinal germ cell tumors are rare, and spinal nongerminomatous germ cell tumors represent an even rarer subset for which no standard therapy has been established. The authors report the case of a 24-year-old woman with multifocal primary spinal germ cell tumors scattered from T-12 to L-5 that consisted of yolk sac tumor and mature teratoma. After diagnostic partial resection, the patient was treated with 30 Gy of craniospinal irradiation and 30 Gy of local spinal irradiation, followed by 8 courses of chemotherapy based on ifosfamide, cisplatin, and etoposide (ICE). Salvage surgery was also performed for residual mature teratoma components after the third course of ICE chemotherapy. Chemotherapy was continued after the operation, but ifosfamide was entirely eliminated from the ICE regimen because severe myelosuppression was observed after previous courses. The patient remains recurrence free as of more than 5 years after the completion of chemotherapy. This case suggests that this treatment strategy is an effective option for primary spinal yolk sac tumor.

DOI： 10.3171/2016.8.SPINE16465

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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：TAYLOR & FRANCIS INC  

OBJECTIVE: The present study clarified factors related to mother-child communication openness when fathers suffer neurobehavioural sequelae after stroke or traumatic brain injury. RESEARCH DESIGN: A cross-sectional study using self-report anonymous questionnaires was conducted. METHODS AND PROCEDURES: Forty-one mothers with 6-22-year-old children participated. The questionnaire examined personal factors (mother's psychological distress), social/family factors (family support functioning), illness-related factors (father's time at home and neurobehavioural sequelae severity) and mother's perceived level of open communication. Multiple regression was used to analyse factors related to mother-child communication openness. RESULTS: Mother-child open communication was explained by family support functioning (β = 0.449), father's time at home (β = -0.325) and mother's psychological distress (β = -0.303). Neurobehavioural sequelae severity was not associated with mother-child open communication. CONCLUSIONS: Personal, social/family and illness-related factors were related to mother-child communication about paternal illness. Professionals should promote optimal family support functioning, connect families with external resources and assess families' interaction processes.

DOI： 10.1080/02699052.2016.1225986

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DOI： 10.1093/neuonc/now090

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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：ELSEVIER SCIENCE INC  

BACKGROUND: Myofibroma is a fibrous tumor of infancy that sometimes affects a single patient in a multiple fashion (infantile myofibromatosis). Its intracranial involvement is extremely rare, and its clinical picture has been poorly characterized. Here we report an interesting case of myofibromatosis with an intracranial lesion that behaved like an aggressive tumor and yet demonstrated very benign pathology. CASE DESCRIPTION: A 36-year-old man had never been diagnosed with infantile myofibromatosis despite his lifelong history of multiple tumors of various diagnoses. He presented with simple partial seizure and progressive right finger paresis. A series of brain magnetic resonance imaging scans revealed a rapidly growing lesion at his left frontal convexity, which corresponded to a high uptake area on a (18)F-fluorodeoxyglucose-positron emission tomography scan, highly suspicious of malignancy. He underwent complete tumor resection and his symptoms quickly resolved postoperatively. The pathological diagnosis was myofibroma with a MIB-1 labeling index of 1%-2%. A retrospective review of his previous tumors demonstrated the same pathology, which led to the diagnosis of myofibromatosis. Follow-up magnetic resonance imaging illustrated stabilization or regression of other preexisting lesions as well as formation of a new intracranial lesion. CONCLUSIONS: The discrepancy between rapid tumor growth associated with increased uptake on metabolic imaging and benign pathologic findings with a low proliferative index is noteworthy and should be recognized in the management of an intracranial lesion in a patient with infantile myofibromatosis. Given de novo formation of a lesion in this adult patient, long-term follow-up is essential in this disease.

DOI： 10.1016/j.wneu.2016.06.105

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECTIVE The etiology of intraneural ganglion cysts has been controversial. In recent years, substantial evidence has been presented to support the articular (synovial) theory for their pathogenesis. The authors sought to 1) perform a systematic review of the world's literature on intraneural cysts, and 2) reinterpret available published MR images in articles by other authors to identify unrecognized joint connections. METHODS In Part 1, all cases were analyzed for demographic data, duration of symptoms, the presence of a history of trauma, whether electromyography or nerve conduction studies were performed, the type of imaging, surgical treatment, presence of a joint connection, intraneural cyst recurrence, and postoperative imaging. Two univariate analyses were completed: 1) to compare the proportion of intraneural ganglion cyst publications per decade and 2) to assess the number of recurrences from 1914 to 2003 compared with the years 2004-2015. Three multivariate regression models were used to identify risk factors for intraneural cyst recurrence. In Part 2, the authors analyzed all available published MR images and obtained MR images from selected cases in which joint connections were not identified by the original authors, specifically looking for unrecognized joint connections. Two univariate analyses were done: 1) to determine a possible association between the identification of a joint connection and obtaining an MRI and 2) to assess the number of joint connections reported from 1914 to 2003 compared with 2004 to 2015. RESULTS In Part 1, 417 articles (645 patients) were selected for analysis. Joint connections were identified in 313 intraneural cysts (48%). Both intraneural ganglion cyst cases and cyst recurrences were more frequently reported since 2004 (statistically significant difference for both). There was a statistically significant association between cyst recurrence and percutaneous aspiration as well as failure to disconnect the articular branch or address the joint. In Part 2, the authors identified 43 examples of joint connections that initially went unrecognized: 27 based on their retrospective MR image reinterpretation of published cases and 16 of 16 cases from their sampling of original MR images from published cases. Overall, joint connections were more commonly found in patients who received an MRI examination and were more frequently reported during the years 2004 to 2015 (statistically significant difference for both). CONCLUSIONS This comprehensive review of the world's literature and the MR images further supports the articular (synovial) theory and provides baseline data for future investigators.

DOI： 10.3171/2015.9.JNS141368

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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：ELSEVIER SCI LTD  

Progression of anaplastic glioma (World Health Organization [WHO] grade III) is typically determined radiographically, and transformation to glioblastoma (GB) (WHO grade IV) is often presumed at that time. However, the frequency of actual histopathologic transformation of anaplastic glioma and the subsequent clinical impact is unclear. To determine these associations, we retrospectively reviewed all anaplastic glioma patients who underwent surgery at our center at first radiographic progression, and we examined the effects of histological diagnosis, clinical history, and molecular factors on transformation rate and survival. We identified 85 anaplastic glioma (39 astrocytoma, 24 oligodendroglioma, 22 oligoastrocytoma), of which 38.8% transformed to GB. Transformation was associated with shorter overall survival (OS) from the time of diagnosis (3.4 vs. 10.9years, p=0.0005) and second surgery (1.0 vs. 3.5years, p<0.0001). Original histologic subtype did not significantly impact the risk of transformation or OS. No other factors, including surgery, adjuvant therapy or molecular markers, significantly affected the risk of transformation. However, mutations in isocitrate dehydrogenase 1 (IDH1) was associated with longer time to progression (median 4.6 vs. 1.4years, p=0.008) and OS (median 10.0 vs. 4.2years, p=0.046). At radiographic progression, tissue diagnosis may be warranted as histologic grade may provide valuable prognostic information and affect therapeutic clinical trial selection criteria for this patient population.

DOI： 10.1016/j.jocn.2016.02.019

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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：BIOMED CENTRAL LTD  

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

DOI： 10.1186/s40478-016-0351-2

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記述言語：英語  

DOI： 10.1186/s40478-016-0351-2

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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）   出版者・発行元：CELL PRESS  

Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.

DOI： 10.1016/j.ccell.2015.11.006

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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：ELSEVIER SCIENCE INC  

BACKGROUND: Endoscopic ventriculostomy is an attractive surgical alternative to ventriculoperitoneal shunt in the treatment of focal hydrocephalus, including trapped temporal horn (TTH). The major concern of this surgical approach is closure of a stoma, the risk of which may be minimized by placement of a stent after ventriculostomy. CASE DESCRIPTION: The authors report a case of a 60-year-old man with glioblastoma in the corpus callosum and the parietal lobe who developed TTH after partial tumor resection. After the failure of a ventriculoperitoneal shunt, endoscopic ventriculocisternostomy was chosen over the revision of the shunt. A stoma was placed at the medial wall of the dilated temporal horn. Endoscopic inspection confirmed communication with the interpeduncular cistern, but the collapsed lateral ventricle after fenestration suggested the risk of stoma closure. Therefore, a ventricular tube was placed through the stoma as a stent to secure its flow. No further surgical intervention was needed, and the patient was able to complete radiochemotherapy without cessation. CONCLUSIONS: The risk of recurrence of TTH after endoscopic ventriculocisternostomy may be minimized by combining ventriculostomy with stent placement. This surgical procedure would be beneficial, particularly in cases of TTH associated with malignant brain tumors, where the risk of delay or interruption of adjuvant oncologic treatments may negatively impact patient prognosis.

DOI： 10.1016/j.wneu.2015.08.019

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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：WILEY-BLACKWELL  

The etiology of intraneural ganglion cysts has been poorly understood. This has resulted in the development of multiple surgical treatment strategies and a high recurrence rate. We sought to analyze these recurrences in order to provide a pathoanatomic explanation and staging classification for intraneural cyst recurrence. An expanded literature search was performed to identify frequencies and patterns in cases of intraneural ganglion cyst recurrences following primary surgery. Two univariate analyses were completed to identify associations between the type of revision surgery and repeat cyst recurrences. The expanded literature search found an 11% recurrence rate following primary surgery, including 64 recurrences following isolated cyst decompression (Group 1); six after articular branch resection (Group 2); and none following surgical procedures that addressed the joint (Group 3). Eight cases did not specify the type of primary surgery. In group 1, forty-eight of the recurrences (75%) were in the parent nerve, three involved only the articular branch, and one travelled along the articular branch in a different distal direction without involving the main parent nerve. In group 2, only one case (17%) recurred/persisted within the parent nerve, one recurred within a persistent articular branch, and one formed within a persistent articular branch and travelled in a different distal direction. Intraneural recurrences most commonly occur following surgical procedures that only target the main parent nerve. We provide proven or theoretical explanations for all identified cases of intraneural recurrences for an occult or persistent articular branch pathway.

DOI： 10.1002/ca.22615

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DOI： 10.1158/1538-7445.AM2015-1072

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DOI： 10.1093/neuonc/nou254.13

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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：AMER ASSOC CANCER RESEARCH  

PURPOSE: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. METHODS: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. RESULTS: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). CONCLUSION: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898-909. ©2014 AACR.

DOI： 10.1158/1078-0432.CCR-13-3052

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記述言語：日本語   出版者・発行元：日本家族性腫瘍学会  

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECT: Meningiomas treated by subtotal or partial resection are associated with significantly shorter recurrence-free survival than those treated by gross-total resection. The Simpson grading system classifies incomplete resections into a single category, namely Simpson Grade IV, with wide variations in the volume and location of residual tumors, making it complicated to evaluate the achievement of surgical goals and predict the prognosis of these tumors. Authors of the present study investigated the factors related to necessity of retreatment and tried to identify any surgical nuances achievable with the aid of modern neurosurgical techniques for meningiomas treated using Simpson Grade IV resection. METHODS: This retrospective analysis included patients with WHO Grade I meningiomas treated using Simpson Grade IV resection as the initial therapy at the University of Tokyo Hospital between January 1995 and April 2010. Retreatment was defined as reresection or stereotactic radiosurgery due to postoperative tumor growth. RESULTS: A total of 38 patients were included in this study. Regrowth of residual tumor was observed in 22 patients with a mean follow-up period of 6.1 years. Retreatment was performed for 20 of these 22 tumors with regrowth. Risk factors related to significantly shorter retreatment-free survival were age younger than 50 years (p = 0.006), postresection tumor volume of 4 cm(3) or more (p = 0.016), no dural detachment (p = 0.001), and skull base location (p = 0.016). Multivariate analysis revealed that no dural detachment (hazard ratio [HR] 6.42, 95% CI 1.41-45.0; p = 0.02) and skull base location (HR 11.6, 95% CI 2.18-218; p = 0.002) were independent risk factors for the necessity of early retreatment, whereas postresection tumor volume of 4 cm(3) or more was not a statistically significant risk factor. CONCLUSIONS: Compared with Simpson Grade I, II, and III resections, Simpson Grade IV resection includes highly heterogeneous tumors in terms of resection rate and location of the residual mass. Despite the difficulty in analyzing such diverse data, these results draw attention to the favorable effect of dural detachment (instead of maximizing the resection rate) on long-term tumor control. Surgical strategy with an emphasis on detaching the tumor from the affected dura might be another important option in resection of high-risk meningiomas not amenable to gross-total resection.

DOI： 10.3171/2013.8.JNS13832

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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：W B SAUNDERS CO-ELSEVIER INC  

This article presents an overview of stereotactic radiosurgery for intracranial glioma. It assists readers in reviewing up-to-date literature on this topic and determining indications of radiosurgery in the treatment of glioma. Discussion also includes its recent advances and future perspectives.

DOI： 10.1016/j.nec.2013.05.010

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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：ELSEVIER SCIENCE INC  

OBJECTIVE: To assess the outcome of stereotactic radiosurgery (SRS) for patients with benign skull base tumors and trigeminal-related facial pain.
METHODS: We undertook a retrospective review of 31 consecutive patients (25 women, 6 men) with benign skull base tumors and trigeminal pain who underwent SRS between 1991 and 2008. The tumors included 17 posterior fossa meningiomas, 9 cavernous sinus meningiomas, and 5 trigeminal schwannomas. The median patient age was 62 years (range, 17-81 years). In all cases the tumor was the primary target for SRS. The median follow-up after SRS was 50 months (range, 12-184 months).
RESULTS: The actuarial tumor control rate after SRS was 95% at both 3 years and 5 years. Eighteen patients (58%) initially achieved complete resolution of trigeminal pain. Higher maximum dose was associated with initial complete pain resolution on a multivariate analysis. However, 7 patients had recurrent pain during follow-up. At last follow-up, only 7 patients (23%) remained pain-free off medications. Further treatment in addition to medical therapy was required for 6 patients (19%).
CONCLUSION: Although SRS offers excellent radiographic tumor control for benign skull base tumors, durable relief of tumor-related trigeminal pain without medication was noted in only one-fourth of patients at last follow-up.

DOI： 10.1016/j.wneu.2012.01.057

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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：Japanese Congress of Neurological Surgeons  

Despite the use of maximal standard treatments, the prognosis of patients with glioblastoma remains poor
hence novel therapies are desperately needed. Molecular targeted therapies have shown some promise in other malignancies, while they have not demonstrated remarkable tumor response or improved patient survival in glio-blastoma to date, due, in part, to the redundancy and crosstalk of multiple overactive molecular pathways and the lack of validated predictive biomarkers. At present, a comprehensive cancer genotyping platform that can reveal potentially targetable genes is being implemented into clinical practice at some cancer institutions in the United States. This may allow us to rationally tailor therapies to specific tumor genotypes that we predict may be susceptible. In this paper, an overview of current glioblastoma treatment strategies in the United States is presented.

DOI： 10.7887/jcns.22.590

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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：SPRINGER  

Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score <70 was associated with poor OS (median 9.5 vs. 20.5 months, p = 0.02). Higher histologic grade was associated with poor progression-free survival (PFS; median for WHO grades II, III, and IV: 21.5, 6.5, and 4 months; p = 0.03) and OS (median 34, 15.5, and 8.5 months; p < 0.05). Radiation therapy was strongly associated with better prognosis (PFS 16.5 vs. 4.5 months, p < 0.01; OS 27.5 vs. 6.5, p < 0.01), but chemotherapy was not. Gliomatosis cerebri patients have a poor prognosis. Lower KPS upon presentation and higher histologic grade predict decreased survival. Surgery's role is limited beyond biopsy for diagnostic purposes. Radiotherapy appears beneficial, although selection bias could be present in this retrospective study. Chemotherapy's value is not as clear but this must be interpreted with caution given variable treatment regimens in this series.

DOI： 10.1007/s11060-013-1058-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECT: Optimum management for elderly patients with newly diagnosed glioblastoma (GBM) in the temozolomide (TMZ) era is not well defined. The object of this study was to clarify outcomes in this population. METHODS: The authors retrospectively reviewed 105 consecutive cases involving elderly patients (age ≥ 65 years) with newly diagnosed GBM who were treated at the Mayo Clinic between 2003 and 2008. RESULTS: The patients' median age was 74 years (range 66-87 years), and the median Karnofsky Performance Status (KPS) score was 80 (range 40-90). Half of the patients underwent biopsy and half underwent resection. Patients with deep-seated lesions (19 patients [18%]) or multifocal lesions (34 patients [32%]) were more likely to have biopsy than resection (p = 0.0001 and 0.0009, respectively). New persistent neurological deficits developed in 7 patients (6.7%). Postoperative hemorrhage occurred in 6 patients (5.7%), all of whom underwent biopsy. Complete follow-up data regarding adjuvant treatment was available in 84 patients. Forty-one (49%) were treated with chemotherapy (mostly TMZ) and radiation therapy (RT), and 23 (27%) with RT alone. Nineteen (23%) received only palliative care after surgery (more common with biopsy, p = 0.03). Chemotherapy complications occurred in 28.6% (Grade 3 or 4 hematological complications in 11.9%). The median values for progression-free survival (PFS) and overall survival (OS) were 3.5 and 5.5 months. In a multivariate analysis, younger age (p = 0.03, risk ratio [RR] 0.34, 95% CI 0.13-0.89), single lesion (p = 0.02, RR 0.51, 95% CI 0.30-0.89), resection (p = 0.04, RR 0.54, 95% CI 0.31-0.94), and adjuvant treatment (p = 0.0001, RR 0.24, 95% CI 0.11-0.49) were associated with better OS. Only adjuvant treatment was significantly associated with prolonged PFS (p = 0.0007, RR 0.27, 95% CI 0.13-0.57). With combined therapy with resection, RT, and chemotherapy, the median PFS and OS were 8 and 12.5 months, respectively. CONCLUSIONS: The prognosis for GBM worsens with increasing age in elderly patients. With important risks, resection and adjuvant treatment are associated with prolonged survival. Although selection bias cannot be excluded in this retrospective study, advanced age alone should not necessarily preclude optimal resection followed by adjuvant radiochemotherapy.

DOI： 10.3171/2012.10.JNS112268

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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：NATURE PUBLISHING GROUP  

Glioblastomas are heterogeneous neoplasms that are driven by complex signalling pathways, and are among the most aggressive and challenging cancers to treat. Despite standard treatment with resection, radiation and chemotherapy, the prognosis of patients with glioblastomas remains poor. An increasing understanding of the molecular pathogenesis of glioblastomas has stimulated the development of novel therapies, including the use of molecular-targeted agents. Identification and validation of diagnostic, prognostic and predictive biomarkers has led to the advancement of clinical trial design, and identification of glioblastoma subgroups with a more-favourable prognosis and response to therapy. In this Review, we discuss common molecular alterations relevant to the biology of glioblastomas, targeted, antiangiogenic and immunotherapies that have impacted on the treatment of this disease, and the challenges and pitfalls associated with these therapies. In addition, we emphasize current biomarkers relevant to the management of patients with glioblastoma.

DOI： 10.1038/nrclinonc.2012.204

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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：Oxford University Press (OUP)  

BACKGROUND: Frameless stereotaxy commonly registers preoperative magnetic resonance imaging (MRI) to patients by using surface scalp anatomy or adhesive fiducial scalp markers. Patients' scalps may shift slightly between preoperative imaging and final surgical positioning with pinion placement, introducing error. This might be reduced when frameless stereotaxy is performed in a high-field intraoperative MRI (iMRI), as patients are positioned before imaging. This could potentially improve accuracy.
OBJECTIVE: To compare frameless stereotactic accuracy using a high-field iMRI with that using standard preoperative MRI.
METHODS: Data were obtained in 32 adult patients undergoing frameless stereotactic-guided brain tumor surgery. Stereotactic images were obtained with 1.5T MRI scanner either preoperatively (14 patients) or intraoperative (18 patients). System-generated accuracy measurements and distances from the actual center of each fiducial marker to that represented by neuronavigation were recorded. Finally, accuracy at multiple deep targets was assessed by using a life-sized human head stereotactic phantom in which fiducials were placed on deformable foam to mimic scalp.
RESULTS: System-generated accuracy measurements were significantly better for the iMRI group (mean +/- SEM = 1.04 +/- 0.05 mm) than for the standard group (1.82 +/- 0.09 mm; P &lt; .001). Measured distances from the actual center of scalp fiducial markers to that represented by neuronavigation were also significantly smaller for iMRI (1.72 +/- 0.10 mm) in comparison with the standard group (3.17 +/- 0.22 mm; P &lt; .001). Deep accuracy in the phantom model was significantly better with iMRI (1.67 +/- 0.12 mm) than standard imaging (2.28 +/- 0.14 mm; P = .003).
CONCLUSION: Frameless stereotactic accuracy is increased by using high-field iMRI compared with standard preoperative imaging.

DOI： 10.1227/neu.0b013e31826a88a9

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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：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: Frameless stereotaxy commonly registers preoperative magnetic resonance imaging (MRI) to patients by using surface scalp anatomy or adhesive fiducial scalp markers. Patients' scalps may shift slightly between preoperative imaging and final surgical positioning with pinion placement, introducing error. This might be reduced when frameless stereotaxy is performed in a high-field intraoperative MRI (iMRI), as patients are positioned before imaging. This could potentially improve accuracy. OBJECTIVE: To compare frameless stereotactic accuracy using a high-field iMRI with that using standard preoperative MRI. METHODS: Data were obtained in 32 adult patients undergoing frameless stereotactic-guided brain tumor surgery. Stereotactic images were obtained with 1.5T MRI scanner either preoperatively (14 patients) or intraoperative (18 patients). System-generated accuracy measurements and distances from the actual center of each fiducial marker to that represented by neuronavigation were recorded. Finally, accuracy at multiple deep targets was assessed by using a life-sized human head stereotactic phantom in which fiducials were placed on deformable foam to mimic scalp. RESULTS: : System-generated accuracy measurements were significantly better for the iMRI group (mean ± SEM = 1.04 ± 0.05 mm) than for the standard group (1.82 ± 0.09 mm; P < .001). Measured distances from the actual center of scalp fiducial markers to that represented by neuronavigation were also significantly smaller for iMRI (1.72 ± 0.10 mm) in comparison with the standard group (3.17 ± 0.22 mm; P < .001). Deep accuracy in the phantom model was significantly better with iMRI (1.67 ± 0.12 mm) than standard imaging (2.28 ± 0.14 mm; P = .003). CONCLUSION: Frameless stereotactic accuracy is increased by using high-field iMRI compared with standard preoperative imaging.

DOI： 10.1227/NEU.0b013e31826a88a9

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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：SPRINGER  

Few studies have assessed the presentation, management, and outcome of anaplastic astrocytoma (AA) in elderly patients in the temozolomide era. We retrospectively reviewed 42 consecutive patients aged >65 years with newly-diagnosed AA who underwent surgical resection or biopsy between 2003 and 2008. Median age and KPS score were 73 years (range, 66-88) and 80 (range, 50-90), respectively. Thirty-two patients (76 %) presented with focal deficits. Twenty patients (48 %) experienced seizures before surgery. Tumor enhanced diffusely in 24 patients (57 %) and sparsely in 18 patients (43 %). Biopsy (79 %) was more common than resection. Post-operatively, new persistent neurological deficits and hemorrhage were seen in two (4.8 %) and three (7.1 %) patients, respectively. Complete follow-up data regarding adjuvant treatment was available in 31 patients. Sixteen patients (52 %) received temozolomide and radiation therapy (RT), while nine patients (29 %) received RT alone. Chemotherapy-related grade 3/4 hematologic complication rate was 17.6 %. Median overall survival (OS) was 6.5 months (12 months with resection; 3.5 months with biopsy). Resection (P = 0.007, risk ratio = 0.21) and sparse enhancement (P = 0.007, risk ratio = 0.13) were associated with longer OS in multivariate analysis. Similarly, chemoradiation was associated with longer survival compared to RT alone (OS: P = 0.01, progression-free survival (PFS): P = 0.02) after adjusting for age, KPS, enhancement, and surgery. Resection was associated with longer survival among elderly patients with AA, although this could reflect selection bias. Similarly, adding chemotherapy to RT was associated with prolonged survival but carried important complication risks. In appropriately selected AA patients, aggressive treatments with radical resection and chemoradiation may be appropriate even in this age group.

DOI： 10.1007/s11060-012-0956-7

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECT: Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population. METHODS: Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5-220 months). RESULTS: Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression-free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression. CONCLUSIONS: Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.

DOI： 10.3171/2012.4.JNS11214

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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：HUMANA PRESS INC  

BACKGROUND: Angiographic vasculitis affecting the spine has been rarely described. The use of immunosuppression as a primary treatment and a review of the literature is presented. METHODS: Case report. RESULTS: A 61-year-old female presented with sudden onset back pain and headache. The patient was found to have acute spinal epidural hemorrhage and subsequent work-up demonstrated angiographic spinal vasculitis. Immunosuppression with cyclophosphamide resulted in clinical and radiographic improvement. CONCLUSIONS: Immunomodulating therapy should be considered in the management of select patients with spinal vasculitis which may lead to improved clinical outcome and potentially disease resolution.

DOI： 10.1007/s12028-011-9667-8

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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：SPRINGER  

Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher's exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) experienced hemorrhage, of which four hemorrhages (6%) were serious (grade ≥ 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated.

DOI： 10.1007/s11060-011-0642-1

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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/jns.0.0.0.jns10189

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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：ELSEVIER SCIENCE INC  

OBJECTIVE: To evaluate the efficacy of stereotactic radiosurgery (SRS) for patients with prolactin (PRL)-secreting pituitary adenomas that were refractory to medical management. METHODS: Retrospective review of 22 patients treated with SRS from 1994 until 2006. All patients were either intolerant or their tumors were unresponsive to dopamine agonist therapy. Nine patients (41%) had undergone prior transsphenoidal surgery. The median serum PRL concentration before SRS was 88.4 ng/mL (range, 25-943). The median treatment volume was 2.2 cm(3) (range, 0.4-29.0); the median margin radiation dose was 25 Gy (range, 16-30). The median endocrinologic follow-up was 60 months (range, 16-129). RESULTS: Tumor control after SRS was 100%. Serum PRL concentration was significantly lower (median, 28.4 ng/mL) (P = 0.006) at last follow-up, but the 4-year actuarial rate of biochemical remission off medications was only 17%. No tested variable was associated with biochemical remission off medications. Overall, four patients (18%) had biochemical remission off medications and clinical improvement, three patients (14%) had normal serum PRL concentrations and clinical improvement on dopamine agonist therapy, seven patients (32%) had improved symptoms off medications but continued to have elevated serum PRL levels, and eight patients (36%) continued to be symptomatic with elevated PRL levels either on (n = 3) or off (n = 5) dopamine agonist therapy. The incidence of new anterior pituitary deficits was 42% at 4 years. CONCLUSIONS: SRS was effective in controlling tumor growth for patients with PRL-secreting pituitary adenomas, and the majority of patients were clinically improved.

DOI： 10.1016/j.wneu.2010.05.007

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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：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: To analyze the factors associated with anterior pituitary deficits after pituitary adenoma stereotactic radiosurgery (SRS). METHODS: The tumor, pituitary stalk, and pituitary gland were segmented on the dose plans of 82 patients (secreting tumors, n = 53; nonsecreting tumors, n=29) for dose-volume analysis. No patient had undergone prior radiation therapy and all patients had at least 12 months of endocrinological follow-up (median, 63 months; mean, 69 months; range, 13-134). RESULTS: Thirty-four patients (41%) developed new anterior pituitary deficits at a median of 32 months (range, 2-118) after SRS. The risk of developing new anterior pituitary deficits was 16% and 45% at 2 and 5 years, respectively. Multivariate analysis of the entire group showed that poor visualization of the pituitary gland (hazard ratio [HR]=2.63, 95% confidence interval [CI]=1.10-6.25, P=.03) was associated with a higher rate of new anterior pituitary deficits. Dosimetric analysis of 60 patients whose pituitary gland could be clearly identified showed that increasing mean pituitary gland radiation dose correlated with new anterior pituitary deficits (HR=1.11, 95% CI=1.02-1.20, P=.02). New anterior pituitary deficits stratified by mean pituitary gland radiation dose: <or=7.5 Gy, 0% (0/7); 7.6 to 13.2 Gy, 29% (7/24); 13.3 to 19.1 Gy, 39% (9/23); >19.1 Gy, 83% (5/6). CONCLUSION: New endocrine deficits after pituitary adenoma radiosurgery were correlated with increasing radiation dose to the pituitary gland. Methods that limit the radiation dose to the pituitary gland during SRS may increase the probability of preserving pituitary function.

DOI： 10.1227/01.NEU.0000370978.31405.A9

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記述言語：英語   出版者・発行元：AMER ASSOC NEUROLOGICAL SURGEONS  

DOI： 10.3171/2010.3.JNS10189

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

OBJECT: Intraneural ganglia are nonneoplastic mucinous cysts contained within the epineurium of peripheral nerves. Their pathogenesis has been controversial. Historically, the majority of authors have favored de novo formation (degenerative theory). Because of their rarity, intraneural ganglia affecting the upper limb have been misunderstood. This study was designed to critically analyze the literature and to test the hypothesis that intraneural ganglia of the upper limb act analogously to those in the lower limb, being derived from an articular source (synovial theory). METHODS: Two patients with digital intraneural cysts were included in the study. An extensive literature review of intraneural ganglia of the upper limb was undertaken to provide the historical basis for the study. RESULTS: In both cases, the digital intraneural ganglia were demonstrated to have joint connections; the one patient in whom an articular branch was not appreciated initially had evidence on postoperative MR images of persistence of intraneural cyst after simple decompression was performed. Eighty-six cases of intraneural lesions were identified in varied locations of the upper limb: the most common sites were the ulnar nerve at the elbow and wrist, occurring 38 and 22 times, respectively. Joint connections were present in only 20% of the cases published by other groups. CONCLUSIONS: The authors believe that the fundamental principles of the unifying articular (synovial) theory (that is, articular branch connections, cyst fluid following a path of least resistance, and the role of pressure fluxes) previously described to explain intraneural ganglia in the lower limb apply to those cases in the upper limb. In their opinion, the joint connection is often not identified because of the cysts' rarity, radiologists' and surgeons' inexperience, and the difficulty visualizing and demonstrating it because of the small size of the cysts. Furthermore, they believe that recurrence (subclinical or clinical) is not only underreported but also predictable after simple decompression that fails to address the articular branch. In contrast, intraneural recurrence can be eliminated with disconnection of the articular branch.

DOI： 10.3171/FOC.2009.26.2.E10

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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：ELSEVIER SCIENCE INC  

BACKGROUND: Cerebral ischemia associated with chronic CCA occlusion is a rare condition and raises strategic dilemma when the revascularization is needed. METHODS: Two patients with CCA occlusion presented with ischemic symptom associated with the affected side. Both patients underwent vascular reconstruction by direct carotid endarterectomy to achieve primary restoration of CCA to ICA flow. RESULTS: Successful reopening of the vessels was obtained in both patients without the evidence of postsurgical ischemic event. Follow-up MRA was obtained at later than 6 months after surgery, which demonstrated patent CCA-ICA in both patients. CONCLUSIONS: Direct carotid endarterectomy of the occluded CCA can be safely performed if the preoperative angiography suggest still patent vessels distal to carotid bifurcation and the substantial "back flow" is obtained from ICA during arteriotomy.

DOI： 10.1016/j.surneu.2007.01.034

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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：ELSEVIER SCIENCE INC  

BACKGROUND: The management of the unruptured AcomA aneurysm associated with atherosclerotic occlusion of the unilateral internal carotid artery (ICA) raises several strategic dilemmas. METHODS: Two such patients with unruptured aneurysm on the AcomA, which supply cross-flow toward the hemisphere with ICA occlusion, are presented. RESULTS: Both patients were treated with STA-M2 bypass followed by clipping of the unruptured AcomA aneurysm in 1 stage through the transsylvian route. Both patients were doing well without neurological deficit nor cognitive impairment at 1 year follow-up. CONCLUSIONS: In the surgical treatment of unruptured AcomA aneurysm with atherosclerotic ICA occlusion, preceding bypass would be ideal in case of intraoperative rupture as well as to reduce perioperative ischemia if the bypass procedure itself could be performed with minimal risk. Enough and atraumatic exposure of the sylvian fissure contributed to reduce brain retraction during the clipping of AcomA aneurysm and, in addition, to ease the STA-M2 bypass.

DOI： 10.1016/j.surneu.2006.10.031

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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：AMER ASSOC NEUROLOGICAL SURGEONS  

DOI： 10.3171/jns.2007.106.3.514

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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：ELSEVIER SCIENCE INC  

BACKGROUND: Cerebral revascularization in the deep surgical field is technically challenging. Especially, side-to-side anastomosis like A3-A3 could be technically more difficult compared with end-to-side anastomosis. To improve surgeon's dexterity and maneuverability in the deep surgical field, the authors developed an easily accessible and well-simulating training system using prosthetic tubes and a box. METHODS: Two prosthetic tubes (silicon tube, 1.2 mm in diameter) are mounted in parallel on the bottom of 6.5-cm-deep emptied 'tissue paper box.' The orifice of the box is restricted to 2 x 2 cm to simulate a deep and narrow surgical corridor. Using bayonet-shaped micro needle holder and forceps, the side-to-side anastomosis of the tubes is performed with 10-0 nylon under operative microscope. RESULTS: Prosthetic tubes well simulated real A3-A3 anastomosis. From the standpoint of technical difficulty, this training system needed slightly higher level of dexterity compared with real A3-A3 anastomosis because of narrower and deeper surgical corridor, and the wall of prosthetic tube was slightly thicker and more inflexible. After this training, the surgical technique in real A3-A3 anastomosis was improved. CONCLUSIONS: This training system worked well to ease the transition from anastomosis in shallow surgical field to deep and narrow surgical field. The prosthetic tube we used approximates real A3 relatively well, and the ease in setting up this system enabled repeated practice, which resulted in steep learning curve of the technique.

DOI： 10.1016/j.surneu.2006.03.035

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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：JAPAN NEUROSURGICAL SOC  

Temporary intraluminal shunt was used during 72 consecutive carotid endarterectomies (CEAs) in 61 patients (bilateral CEA in 11 patients) during October 2001 and September 2005. The medical records of these patients were retrospectively reviewed. All procedures were performed with routine shunt insertion without monitoring such as electroencephalography. Pre- and postoperative diffusion-weighted magnetic resonance (MR) imaging was used to detect ischemic complications. Postoperative angiography was performed in 70 cases to detect abnormalities such as major stenosis or dissection of the distal end. Symptomatic ischemic complication occurred in one patient at 1 month. Postoperative diffusion-weighted MR imaging detected new hyperintense lesions in three patients including the symptomatic patient. Postoperative angiography confirmed that the distal end was satisfactory in all cases. The incidence of ischemic lesions of embolic origin after CEA with routine shunt usage is acceptably low if the procedure of shunt device insertion and removal is meticulously conducted.

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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：ELSEVIER SCIENCE INC  

BACKGROUND: Microvascular anastomosis using 10-0 nylon needs a higher level of technical dexterity compared with routine neurosurgical maneuvers. Although this technique remains an important part of treating complex intracranial aneurysms or cerebrovascular disease, the surgeon's clinical experience in using this technique is not so common. METHODS: To improve dexterity and maneuverability in the limited clinical case volume, we developed an easily accessible training system, using commercially available desk type microscope and simply suturing neighboring fibers of the gauze with 10-0 nylon under fixed and highest (x 20) magnification. RESULT: This training system is somewhat of a drawback compared to the simulation of a real clinical setting. However, because of the extremely easy availability and accessibility of the dark type microscope repeated training and the accumulation of more than 10000 stitches, on average, was accomplished. This resulted in a steep learning curve of the technique. CONCLUSION: For residency and post-residency year young neurosurgeons, who need to brush up their skills due to lower surgical case volume compared with what senior neurosurgeons have experienced this easily available training would contribute to establishing daily and long-lasting microsurgical practice.

DOI： 10.1016/j.surneu.2005.11.064

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記述言語：日本語   出版者・発行元：The Japanese Society on Surgery for Cerebral Stroke  

The effectiveness of CEA in preventing further stroke of the patient with high grade carotid stenosis is well known. However, controversy still exists as for the choice of CEA or low flow bypass in the cases of near occlusion because of the uncertainty of the patency of distal ICA as well as the risk for postoperative hyperperfusion. We experienced 7 consecutive cases of near occlusion between May and November 2004 and performed CEA. In all cases, the flexible shunt (Furui shunt) was employed to reduce the risk of hemodynamic ischemia during clamping. To prevent distal embolism during distal shunt tube insertion, great care was taken to secure the "true distal lumen" high enough above the stenotic site. If necessary, arteriotomy was added on the distal wall and then connected toward the proximal. The use of a shunt tube was helpful in gaining a fine view of the distal end during endarterectomy because it held the collapsed lumen round open. There were no ischemic complications. Good patencies were demonstrated by postoperative DSAs in all cases. In our experiences, CEA could be safely performed as long as the angiography shows patent ICA distal to stenotic site even in delayed fashion.

DOI： 10.2335/scs.34.27

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00273987947?from=CiNii

記述言語：日本語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：Japanese Congress of Neurological Surgeons  

Ultra-early surgical treatments are expected to be established, in which the associated brain injury is minimized and a maximal volume of hematoma is removed shortly after onset with secure hemostasis. We developed a transparent guiding sheath and other surgical instruments for endoscopic surgery, and we established a novel surgical procedure in the ultra-early stage using those instruments. This procedure has the following characteristics: (1) the capability of burr hole opening under local anesthesia, (2) a transparent sheath improves the surgical field visualization of the parenchyma and the hematoma, (3) free-hand surgery without fixing an endoscope and a sheath to a frame facilitates three-dimensional operation, (4) the capability of secure hemostasis by electric coagulation (When bleeding from a perforating artery occurs, a suction tube is placed at the bleeding point and hemostasis is achieved by electric coagulation), (5) easy preparation of relatively simple surgical instruments. We have performed this procedure on 85 patients with intracerebral or intraventricular hemorrhage. Among these 85 patients, 24 patients received our treatment in the ultra-early stage, or within 3 hours after onset. The mean duration of surgery was 63 minutes, the mean hematoma reduction rate was 96%, and no perioperative hemorrhage with deterioration of symptoms and/or signs occurred. Thus, we believe that endoscopic hematoma evacuation with our surgical procedure is a promising ultra-early-stage treatment for intracerebral hemorrhage, and that it may improve the long-term prognosis of patents with intracerebral hemorrhage.

DOI： 10.7887/jcns.14.401

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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：HUMANA PRESS INC  

Ultra-early surgical treatment in which associated brain injury is minimized and maximal volume of hematoma is removed shortly after onset with secure hemostasis is expected to be established. We developed a transparent guiding sheath and other surgical instruments for endoscopic surgery and established a novel, ultra-early stage surgical procedure using those instruments. This procedure has the following characteristics: (a) burr hole opening under local anesthesia is possible; (b) a transparent sheath improves the visualization of the surgical field in the parenchyma and the hematoma; (c) free-hand surgery without fixing an endoscope and a sheath to a frame facilitates three-dimensional operation; (d) secure hemostasis by electric coagulation is possible; (e) relatively simple surgical instruments are easy to prepare. We have performed this procedure in 82 patients with intracerebral or intraventricular hemorrhage (44 with putaminal hemorrhage, 12 with thalamic hemorrhage, 8 with subcortical hemorrhage, 8 with cerebellar hemorrhage, 10 with intraventricular hemorrhage). Twenty-four of those patients received our treatment in the ultra-early stage (within 3 hours after onset). The mean duration of surgery was 63 minutes, the mean hematoma reduction rate was 96%, and no peri-operative hemorrhage with deterioration of symptoms and/or signs occurred. Therefore, we believe that endoscopic hematoma evacuation with our surgical procedure is a promising ultra-early stage treatment for intracerebral hemorrhage and that it may improve the long-term prognosis in patents with intracerebral hemorrhage.

DOI： 10.1385/NCC:2:1:067

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞Point ・網羅的遺伝子解析により,乳頭上皮型頭蓋咽頭腫の大半にBRAF-V600E変異がみられることが判明した.・他癌腫で承認済のBRAF阻害薬,MEK阻害薬が,BRAF変異陽性乳頭上皮型頭蓋咽頭腫に著効するという症例報告がなされた.・頭蓋咽頭腫は難治な脳腫瘍であり,乳頭上皮型においては従来の手術・放射線治療に分子標的治療を加えた集学的治療が重要となろう.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01228&link_issn=&doc_id=20220216220019&doc_link_id=10.11477%2Fmf.1436204542&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436204542&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：(株)医学書院  

＜文献概要＞Point ・遺伝子変異解析により,中枢神経胚細胞腫症例の55%においてMAPKとPI3K経路に変異がみつかり,両者は相互排他的であった.ターゲット治療はまだ開発されていない.・欧米・日本の臨床試験により,ジャーミノーマでは全脳室照射,非ジャーミノーマでは全脳室または局所照射の方向になりつつある.・腫瘍含有率の高いジャーミノーマ,12p gainのある非ジャーミノーマの予後が不良であることが報告され,今後の層別化治療につながる可能性がある.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01228&link_issn=&doc_id=20220216220007&doc_link_id=10.11477%2Fmf.1436204530&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436204530&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

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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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）   出版者・発行元：WILEY  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：英語   出版者・発行元：日本癌学会  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：(一社)日本言語聴覚士協会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J04306&link_issn=&doc_id=20171005130223&doc_link_id=10.11477%2Fmf.6001200137&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.6001200137&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   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：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：(一社)日本高次脳機能障害学会  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語  

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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：医歯薬出版  

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その他リンク： http://search.jamas.or.jp/link/ui/2016058733

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/jco.2015.33.15_suppl.e17658

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

DOI： 10.1093/neuonc/nou253.30

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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）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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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）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

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記述言語：英語   出版者・発行元：AMER ASSOC NEUROLOGICAL SURGEONS  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：英語   出版者・発行元：日本脳神経外科コングレス  

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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）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1227/01.NEU.0000387049.61328.AD

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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）   出版者・発行元：DUKE UNIV PRESS  

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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）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：The Japanese Society on Surgery for Cerebral Stroke  

Preoperative angiography is basically essential for a patient of intracerebral hematoma, so as to check any underlying vascular anomaly such as a ruptured aneurysm or an arteriovenous malformation (AVM). When the hematoma causes impending herniation, however, we omit preoperative angiography to save time and perform emergency surgery even if a ruptured aneurysm or an AVM is highly suspected. We experienced 8 such cases during 2.5 years: 6 cases of ruptured aneurysm and 2 of AVM. Three of them achieved good recovery and none died.<br> Some special considerations and tactics are required before and during surgery to ensure safety. When a ruptured aneurysm is suspected, a microscope, a self-retractor and clips should be ready prior to surgery. The superficial temporal artery should be preserved just in case. After the craniotomy, the hematoma is evacuated partially for decompression away from the suspected aneurysm. Then, in case of premature rupture, the dissection is performed directly toward the bleeding site; otherwise sylvian fissure is dissected for aneurysm exploration. When an AVM is suspected, care must be taken not to injure the draining veins. It is safer to finish the emergency surgery after evacuating the hematoma and to go on to cerebral angiography. The resection of an AVM should then be performed in the chronic period.<br> In our experiences, we were able to perform emergency surgery safely for a ruptured aneurysm or an AVM, even when we had to omit preoperative angiography because of impending herniation.<br>

DOI： 10.2335/scs.35.204

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