記述言語：英語   掲載種別：研究論文（学術雑誌）  

Diffuse midline glioma (DMG) H3K27-altered is one of the devastating childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation anti-tumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extra-terminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-seq and CUT & RUN showed that BET bromodomain inhibitors regulate the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation-response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

DOI： 10.1172/JCI174794

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Boron neutron capture therapy (BNCT) is a tumor cell-selective particle-radiation therapy. In BNCT, administered p-boronophenylalanine (BPA) is selectively taken up by tumor cells, and the tumor is irradiated with thermal neutrons. High-LET α-particles and recoil 7Li, which have a path length of 5-9 μm, are generated by the capture reaction between 10B and thermal neutrons and selectively kill tumor cells that have uptaken 10B. Although BNCT has prolonged the survival time of malignant glioma patients, recurrences are still to be resolved. miRNAs, that are encapsulated in small extracellular vesicles (sEVs) in body fluids and exist stably may serve critical role in recurrence. In this study, we comprehensively investigated microRNAs (miRNAs) in sEVs released from post-BNCT glioblastoma cells. METHOD: Glioblastoma U87 MG cells were treated with 25 ppm of BPA in the culture media and irradiated with thermal neutrons. After irradiation, they were plated into dishes and cultured for 3 days in the 5% CO2 incubator. Then, sEVs released into the medium were collected by column chromatography, and miRNAs in sEVs were comprehensively investigated using microarrays. RESULT: An increase in 20 individual miRNAs (ratio > 2) and a decrease in 2 individual miRNAs (ratio < 0.5) were detected in BNCT cells compared with non-irradiated cells. Among detected miRNAs, 20 miRNAs were associated with worse prognosis of glioma in Kaplan Meier Survival Analysis of overall survival in TCGA. CONCLUSION: These miRNA after BNCT may proceed tumors, modulate radiation resistance, or inhibit invasion and affect the prognosis of glioma.

DOI： 10.1007/s11060-024-04649-8

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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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担当区分：筆頭著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s10014-024-00483-y

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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Untethering surgery for lumbosacral lipoma is a preventive procedure, and avoidance of complications and good long-term outcomes are required. We introduced presurgical interactive virtual simulation (IVS) applying three-dimensional multifusion images using a haptic device aimed at improving operative outcomes. METHODS: Fourteen patients with newly diagnosed lumbosacral lipoma were recruited and underwent preoperative IVS. The median age at surgery was 8 months. A three-dimensional image analysis system was used to extract and fuse structures necessary for surgery, such as the lipoma, spinal cord and skin, from CT and MRI, and create three-dimensional multifusion images. The created images were individually converted to standard triangulated language format and loaded onto a workstation (Geomagic freeform™) that could be freely transformed, and the laminectomy range and lipoma extraction procedure were examined. Presurgical IVS was performed, and the actual surgery was performed. RESULTS: The disease types were dorsal, caudal, lipomyelomeningocele, transitional, and filum in 5, 5, 2, 1, and 1 patients, respectively. The surgical procedure and extent of the laminectomy were as planned for all patients. Resection of the lipomas tended to be less than expected preoperatively because of positive reactions on intraoperative monitoring. No postoperative complications were observed. The median postoperative follow-up period was 29 months, and there were no reoperations during the observation period. CONCLUSIONS: Although there are various types of lumbosacral lipoma, surgery can be safely performed by performing presurgical IVS. The short-term course is good; however, long-term follow-up is necessary for the appearance of neurological symptoms associated with growth and re-tethering.

DOI： 10.1007/s00381-023-06234-2

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3390/curroncol31040138

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

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

DOI： 10.1186/s40478-024-01723-0

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

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

DOI： 10.1007/s11060-023-04555-5

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

Abstract

Background

The EF-14 clinical trial demonstrated the safety and efficacy of tumor-treating fields (TTFields) for newly diagnosed glioblastoma. This study aimed to clarify the current status, safety, and efficacy of TTFields in Japanese patients who meet the EF-14 inclusion criteria.

Methods

This was a multicenter retrospective cohort study. Background, treatment, and outcome data of patients who satisfied the inclusion criteria of the EF-14 trial were collected from 45 institutions across Japan. The rate, determinants, and current status of TTField use, including its safety and efficacy in terms of progression and survival, were retrospectively investigated. This study was conducted in accordance with the STROBE checklist.

Results

Among the 607 patients enrolled, 70 were excluded due to progressive disease during radiation and temozolomide therapy, age &amp;gt; 80 years old, and Karnofsky Performance Status score of &amp;lt;70. Among the remaining 537 patients, 210 (39%) underwent TTField treatment. Multivariate analysis revealed younger age and spouse as a caregiver as significant factors for TTField use. The compliance rate of TTField use exceeded 75% in 60% of patients, with a median TTField usage duration of 11 months. Skin disorders requiring medical treatment occurred in 56% of patients. Multivariate Cox proportional hazards analysis in the whole series and propensity score-matched analysis revealed that TTField use was not a prognostic factor for progression-free survival (PFS) or overall survival (OS).

Conclusions

TTField use did not have a substantial effect on either PFS or OS in Japanese patients with glioblastoma, despite compliance rates comparable to those observed in the EF-14.

DOI： 10.1093/noajnl/vdae176

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その他リンク： https://academic.oup.com/noa/article-pdf/6/1/vdae176/60939346/vdae176.pdf

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

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

DOI： 10.1007/s11060-023-04484-3

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記述言語：日本語   出版者・発行元：(株)篠原出版新社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3171/CASE23361

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

Pediatric-type diffuse high-grade glioma is a new tumor class defined in the 5th edition of the WHO Classification of Tumors of the Central Nervous System(WHO2021). The class includes the following four tumor types: diffuse midline glioma, H3 K27-altered; diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and infant-type hemispheric glioma. Genetic detection of histone H3 mutations as well as detection of fusion genes and even methylation classifiers may be necessary to diagnose these tumors. Therefore, understanding their clinical and radiographical features is vital. Urgent establishment of new treatments is necessary for diffuse midline glioma, H3 K27-altered, as it is associated with very poor prognosis and is generally resistant to temozolomide. In this chapter, we focus on the clinical, radiographical, pathological, and molecular features of pediatric-type diffuse high-grade gliomas and introduce promising new treatments for diffuse midline glioma, H3 K27-altered.

DOI： 10.11477/mf.1436204829

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(NPO)日本レーザー医学会  

2018年7月に当科に光線力学療法(photodynamic therapy:PDT)を導入してから2021年6月まで,当科でPDTを施行した悪性脳腫瘍症例の臨床的特徴および無増悪生存期間(progression free survival:PFS),全生存期間(overall survival:OS),主な合併症について検討した.初発膠芽腫9例におけるPFSの中央値は14ヵ月,OS中央値は未達であった.死亡例は早期に遠隔再発を来した1例のみであった.主な合併症は光過敏症が1例,脳表に可逆性のFLAIR高信号が3例,術後うつ状態が5例に認め,いずれも一過性であった.術後の長期間遮光管理が原因と思われるうつ症状には,早期遮光解除などの工夫が必要と思われた.実際の症例を提示し我々のPDT初期治療経験を紹介し,また,次世代治療と考える近赤外光線免疫療法(near-infrared photoimmunotherapy:NIR-PIT)の研究に関しても紹介する.NIR-PITは,癌細胞の表面抗原を標識とし,近赤外線照射により生じた熱エネルギーにより腫瘍細胞の細胞膜を破壊する画期的な治療法である.今回,我々は膠芽腫細胞株に特異的な表面抗原Xに対する抗体を用いたNIR-PITを行い,殺細胞効果を確認した.(著者抄録)

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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

DOI： 10.1111/ene.15941

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

DOI： 10.1136/bmjopen-2022-071350

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担当区分：責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

DOI： 10.1080/10428194.2023.2199895

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.thromres.2023.01.018

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記述言語：日本語   出版者・発行元：新潟医学会  

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語  

DOI： 10.21037/tcr-22-2384

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), are among the most malignant and devastating childhood brain cancers. Despite aggressive treatment, nearly all children with these tumors succumb to their disease within 2 years of diagnosis. Due to the anatomical location of the tumors within the pons, surgery is not a treatment option, and distribution of most systematically administered drugs is limited by the blood-brain barrier (BBB). New drug delivery systems that bypass the BBB are desperately needed to improve outcomes of DIPG patients. Intranasal delivery (IND) is a practical and noninvasive drug delivery system that bypasses the BBB and delivers the drugs to the brain through the olfactory and trigeminal neural pathways. In this study, the authors evaluated the efficacy of nanoliposomal (LS) irinotecan (CPT-11) and an active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), using IND in DIPG patient-derived xenograft models. METHODS: In vitro responses to LS-CPT-11 and LS-SN-38 in DIPG cells were evaluated with cell viability, colony formation, and apoptosis assays. The cellular uptakes of rhodamine-PE (Rhod)-labeled LS-CPT-11 and LS-SN-38 were analyzed with fluorescence microscopy. Mice bearing DIPG patient-derived xenografts were treated with IND of LS-control (empty liposome), LS-CPT-11, or LS-SN-38 by IND for 4 weeks. In vivo responses were measured for tumor growth by serial bioluminescence imaging and animal subject survival. The concentration of SN-38 in the brainstem tumor administered by IND was determined by liquid chromatography-mass spectrometry (LC-MS). Immunohistochemical analyses of the proliferative and apoptotic responses of in vivo tumor cells were performed with Ki-67 and TUNEL staining. RESULTS: LS-SN-38 inhibited DIPG cell growth and colony formation and increased apoptosis, outperforming LS-CPT-11. Rhod-labeled LS-SN-38 showed intracellular fluorescence signals beginning at 30 minutes and peaking at 24 hours following treatment. LC-MS analysis revealed an SN-38 concentration in the brainstem tumor of 0.66 ± 0.25 ng/ml (5.43% ± 0.31% of serum concentration). IND of LS-SN-38 delayed tumor growth and significantly prolonged animal survival compared with IND of LS-control (p < 0.0001) and LS-CPT-11 (p = 0.003). IND of LS-SN-38 increased the number of TUNEL-positive cells and decreased the Ki-67-positive cells in the brainstem tumor. CONCLUSIONS: This study demonstrates that IND of LS-SN-38 bypasses the BBB and enables efficient and noninvasive drug delivery to the brainstem tumor, providing a promising therapeutic approach for treating DIPG.

DOI： 10.3171/2022.9.JNS22715

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. METHODS: An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ± 10 Gy boost (arm A) or WBRT ± boost with concomitant and maintenance TMZ for two years (arm B). The primary endpoint was overall survival (OS). RESULTS: Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, two-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. CONCLUSIONS: This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.

DOI： 10.1093/neuonc/noac246

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

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

DOI： 10.1093/neuonc/noac243

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.3174/ajnr.A7666

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記述言語：英語  

Neurenteric cyst (NC) shows benign histopathology and rarely demonstrate malignant transformation. We herein describe a case of NC that exhibited malignant transformation. A 65-year-old female presented with gait disturbance due to compression by a cystic mass on the dorsal surface of the medulla oblongata. Partial resection was performed twice, leading to improvement of her symptoms. Two years after the second surgery, gadolinium-perfused T1-weighted magnetic resonance imaging revealed an invasive lesion with contrast enhancement at the trigone of the left lateral ventricle for which partial resection followed by radiotherapy was performed. However, mass regrowth was observed, with the patient eventually succumbing to her disease 11 months after her third surgery. Histopathological analyses of the first and second surgical specimens identified pseudostratified cuboidal epithelial cells, with no nuclear or cellular atypia resembling gastrointestinal mucosa, lining the inner surface of the cystic wall. Based on these findings the lesion was diagnosed as NC. The third surgical specimen exhibited apparent malignant features of the epithelial cells with elongated and hyperchromatic nuclei, several mitotic figures, small necrotic foci, and a patternless or sheet-like arrangement. Based on these findings, the lesion was diagnosed as NC with malignant transformation. Next-generation sequencing revealed KRAS p.G12D mutation in all specimens. Additionally, the third surgical specimen harbored the following 12 de novo gene alterations: ARID1A loss, BAP1 p.F170L, CDKN1B loss, CDKN2A loss, CDKN2B loss, FLCN loss, PTCH1 loss, PTEN loss, PTPRD loss, SUFU loss, TP53 loss, and TSC1 loss. The aforementioned results suggest that KRAS mutation is associated with the development of the NC, and that the additional gene alterations contribute to malignant transformation of the NC.

DOI： 10.1111/neup.12822

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担当区分：責任著者   記述言語：英語  

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

DOI： 10.3390/jcm11195548

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1186/s41687-022-00499-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E mutant high-grade gliomas (HGGs); however, the therapeutic effect is limited by the emergence of drug resistance. EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E mutant HGG patient-derived xenograft (PDX) models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the re-activation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3β (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular-targeted therapy. CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E mutant HGG.

DOI： 10.1158/1078-0432.CCR-21-3622

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan-Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p = 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (p = 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p < 0.001, HR = 5.455), and Epstein-Barr virus infection (p = 0.031, HR = 5.304) were the pathological risk factors.

DOI： 10.1007/s10014-022-00427-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We therefore determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.

DOI： 10.1158/1535-7163.MCT-21-0646

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To develop an innovative brain mapping and neuromonitoring method during neurosurgery, the authors set out to establish intraoperative flavoprotein fluorescence imaging (iFFI) to directly visualize cortical activations in human brain. The significance of iFFI was analyzed by comparison with intraoperative perfusion-dependent imaging (iPDI), which is considered the conventional optical imaging, and by performing animal experiments. METHODS: Seven patients with intracerebral tumors were examined by iFFI and iPDI following craniotomy, using a single operative microscope equipped with a laser light source for iFFI and xenon lamp for iPDI. Images were captured by the same charge-coupled device camera. Responses to bipolar stimulation at selected points on the cortical surface were analyzed off-line, and relative signal changes were visualized by overlaying pseudocolor intensity maps onto cortical photographs. Signal changes exceeding 3 SDs from baseline were defined as significant. The authors also performed FFI and PDI on 10 mice using similar settings, and then compared signal patterns to intraoperative studies. RESULTS: Signals acquired by iFFI exhibited biphasic spatiotemporal changes consisting of an early positive signal peak (F1) and a delayed negative signal peak (F2). In contrast, iPDI signals exhibited only 1 negative peak (P1) that was significantly delayed compared to F1 (p < 0.02) and roughly in phase with F2. Compared to F2 and P1, F1 was of significantly lower amplitude (p < 0.02) and located closer to the bipolar stimulus center (p < 0.03), whereas F2 and P1 were more widespread, irregular, and partially overlapping. In mice, the spatiotemporal characteristics of FFI and PDI resembled those of iFFI and iPDI, but the early positive signal was more robust than F1. CONCLUSIONS: This is the first report in humans of successful intraoperative visualization of cortical activations by using iFFI, which showed rapid evoked cortical activity prior to perfusion-dependent signal changes. Further technical improvements can lead to establishment of iFFI as a real-time intraoperative tool.

DOI： 10.3171/2022.1.JNS212542

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

DOI： 10.1007/s12328-022-01599-4

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

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

DOI： 10.3390/cancers14030770

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Elderly patients with primary central nervous system malignant lymphoma (EL-PCNSL) may not be given sufficient treatment due to their poor pre-treatment Karnofsky Performance Status (KPS) and comorbidities. Therefore, a retrospective, cohort study was performed to evaluate risk factors associated with a poor prognosis of EL-PCNSL in the Tohoku Brain Tumor Study Group. METHODS: Patients aged ≥ 71 years with PCNSL were enrolled from eight centers. Univariate analysis was performed with the log-rank test. A Cox proportional hazards model was used for multivariate analysis. RESULTS: Three of the total 142 cases received best supportive care (BSC). Treatment was given to 30 cases without a pathological diagnosis, 3 cases with cerebrospinal fluid (CSF) cytology, and 100 cases with a pathological diagnosis. After confirmation of no differences in progression-free survival (PFS) and overall survival (OS) between the group treated without pathology and the groups diagnosed by pathology or CSF cytology and between median age ≥ 76 years and < 76 years, a total of 133 patients were studied. The median pre-treatment KPS was 50%. Median PFS and median OS were 16 and 24 months, respectively. Risk factors associated with poor prognosis on Cox proportional hazards model analysis were pre-treatment cardiovascular disease and central nervous system disease comorbidities, post-treatment pneumonia and other infections, and the absence of radiotherapy or chemotherapy. CONCLUSIONS: Pre-treatment comorbidities and post-treatment complications would affect the prognosis. Radiation and chemotherapy were found to be effective, but no conclusions could be drawn regarding the appropriate content of chemotherapy and whether additional radiotherapy should be used.

DOI： 10.1007/s10147-021-02042-3

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記述言語：英語  

Meningoencephalocele in the lateral sphenoid sinus (SS) has been determined to be a rare entity often detected by cerebrospinal fluid (CSF) rhinorrhea. To date, the pathology of meningoencephalocele in the lateral SS has remained to be unclear in many cases. In this study, we report on a case of a 72-year-old woman with an arteriovenous malformation who presented with CSF rhinorrhea. Radiologic investigations revealed a left temporal meningoencephalocele in the lateral SS. We removed the meningoencephalocele and performed skull base repair, after which the CSF rhinorrhea resolved. Pathological examination showed congenital cortical abnormalities with dysmorphic neurons in various shapes and acquired chronic tissue alterations including fibrillary gliosis and scattered Rosenthal fibers. These findings may further aid in understanding the etiopathogenesis of meningoencephalocele in the lateral SS.

DOI： 10.2176/jns-nmc.2022-0152

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

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

DOI： 10.3390/diagnostics11112129

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The selective provocative test (SPT) under local anesthesia aids in protecting against ischemic complications during endovascular treatment. However, the use of this test under general anesthesia is not well described. Herein, we present a case of a 51-year-old man with a ruptured fusiform aneurysm in the middle cerebral artery M4 segment, which was thought to possibly supply the motor cortex. Internal trapping of the affected vessel and aneurysm by endovascular intervention was successfully performed after SPT using transcranial motor evoked potential (MEP) monitoring under general anesthesia. Transcranial MEP is suitable for neurological assessment during SPT under general anesthesia.

DOI： 10.1007/s00701-021-05001-z

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

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

DOI： 10.1007/s10014-021-00407-0

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担当区分：筆頭著者,　責任著者   記述言語：英語  

Spinal dissemination in epithelioid glioblastoma can be diagnosed by cerebrospinal fluid cytology and liquid biopsy to detect BRAF V600E mutation.

DOI： 10.1002/ccr3.4551

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.inat.2021.101118

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

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

DOI： 10.11477/mf.1436204425

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

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

DOI： 10.3390/diagnostics11040681

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously reported observing GLI3 in medulloblastomas expressing neuronal markers (NM) and/or glial fibrillary acidic protein (GFAP). Furthermore, patients with medulloblastomas expressing NM or GFAP tended to show favorable or poor prognosis, respectively. In the present study, we focused on the role of topoisomerase IIβ (TOP2β) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2β expressions in a larger population. We divided 124 medulloblastomas into three groups (NM-/GFAP-, NM +/GFAP-, and GFAP +) based on their immunoreactivity (IR) against NM and GFAP. The relationship among GLI3, NM, GFAP, and TOP2β was evaluated using fluorescent immunostaining and a publicly available single-cell RNA sequencing dataset. In total, 87, 30, and 7 medulloblastomas were classified as NM-/GFAP-, NM + /GFAP-, and GFAP +, and showed intermediate, good, and poor prognoses, respectively. GLI3-IR was frequently observed in NM +/GFAP-  and GFAP + , and TOP2β-IR was frequently observed only in NM +/GFAP-  medulloblastomas. In fluorescent immunostaining, TOP2β-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2β expression was elevated in CMAS/DCX-positive, but not in GFAP-positive, cells. NM-IR and GFAP-IR are important for estimating the prognosis of patients with medulloblastoma; hence they should be assessed in clinical practice.

DOI： 10.1007/s10014-021-00396-0

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Multinodular and vacuolating neuronal tumors of the cerebrum(MVNTs)are rare brain tumors that were described first in 2013. MVNTs have been added to the World Health Organization Classification of Tumors of the Central Nervous System in 2016(2016WHO), although an MVNT is a clinical-pathological lesion with uncertain class assignment. It remains unclear whether MVNTs should be considered a true neoplasm or malformative lesion. Their prevalence and pathophysiology are unknown. MVNTs typically occur in adults, predominantly in the cerebral subcortical region, and are most frequently associated with seizures or seizure equivalents. MVMTs can also present incidentally without seizures. MVNTs have been reported to show highly suggestive imaging features, especially on MRI scans. MVNTs consist of small T2 and T2-FLAIR hyperintense nodules in subcortical and juxtacortical areas with rare or no post-contrast enhancement. Most MVNTs reported in the literature involve the supratentorial part of the brain. Recently, lesions exhibiting a remarkably similar pattern of imaging findings were described in the posterior fossa, which are referred to as multinodular and vacuolating posterior fossa of unknown significance(MV-PLUS). Both MVNT and MV-PLUS are considered "leave-me-alone" lesions because of the absence of malignancy criteria and the lack of evolutivity on follow-up MRI scans.

DOI： 10.11477/mf.1436204402

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Primary melanocytic neoplasms of the central nervous system(CNS)presumably arise from leptomeningeal melanocytes that are derived from the neural crest. Melanocytic neoplasms associated with neurocutaneous melanosis likely derive from melanocyte precursor cells that reach the CNS after somatic mutations, mostly, of the NRAS. They should be distinguished from other melanotic tumors involving the CNS, including metastatic melanoma and other primary tumors that undergo melanization, such as melanocytic schwannomas, medulloblastomas, paragangliomas, and various gliomas, because these lesions require different patient workups and therapy. Primary melanocytic neoplasms of the CNS that are diffuse and do not form macroscopic masses are called melanocytoses, whereas malignant diffuse or multifocal lesions are collectively called melanomatoses. Benign and intermediate-grade tumoral lesions are called melanocytomas. Discrete malignant tumors are called melanomas. CT and MRI of melanocytosis and melanomatosis show diffuse thickening and enhancement of the leptomeninges, often with focal or multifocal nodularity. Depending on the melanin content, diffuse and circumscribed melanocytic tumors of the CNS may show some characteristics on CT and MRI: iso- to hyperattenuation on CT and paramagnetic properties of melanin on MRI resulting in an isointense signal on T1WIs and iso- to hypointensity on T2WIs.

DOI： 10.11477/mf.1436204403

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Dysplastic cerebellar gangliocytoma or Lhermitte-Duclos disease(LDD)is a rare benign cerebellar lesion composed of dysplastic ganglion cells that conform to the existing cortical architecture. In this disease, the enlarged ganglion cells are predominantly located within the internal granular layer, and they thicken the cerebellar folia. The architecture of the affected cerebellar hemisphere with the enlarged cerebellar folia and the cystic changes, in some cases, present as "tiger-striped striations," a characteristic imaging finding that is not specific to LDD. This imaging feature may be observed in medulloblastoma and isolated cerebellar Rosai-Dorfman disease. This cerebellar lesion is a major central nervous system manifestation of Cowden syndrome, an autosomal dominant condition that causes various hamartomas and neoplasms. A molecular-based study estimated the prevalence of Cowden syndrome to be 1 case per 200,000. In a study involving 211 patients with Cowden syndrome, 32% developed LDD. LDD can be diagnosed in young children and older adults within the eighth decades of life. PTEN mutations have been identified in virtually all adult-onset LDDs, but not in childhood-onset cases.

DOI： 10.11477/mf.1436204404

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Proton magnetic resonance spectroscopy(1H-MRS)is a non-invasive method for evaluating brain function and metabolism. 1H-MRS can quantify low-molecular-weight metabolites in a living brain; it shows their spectra without tracer administration. In this paper, we introduce 1H-MRS and MRS for imaging the distribution of metabolites. The applications of 1H-MRS imaging for several neurological disorders will be outlined.

DOI： 10.11477/mf.1436204411

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

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

DOI： 10.1093/jnen/nlaa141

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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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

DOI： 10.1080/15548627.2020.1797280

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記述言語：日本語   出版者・発行元：日本サイトメトリー学会  

<p>For post-translational protein modifications such as phosphorylation, the involved residues have been recently identified by mass spectrometers. However, it is not easy to efficiently detect the therapeutic target from the vast amount of proteomic data. Neuronal growth cones are specialized, highly motile structures formed at the tip of axons, that are indispensable for synaptogenesis in the developing brain and for neuronal plasticity in the adult brain. However, there is lack of information on the molecular basis of growth cones in the mammalian brain. We performed a phosphoproteomic analysis of growth cone membrane fractions (2 mg) isolated from the rat forebrain on postnatal day 1. We chose the more abundant peptides as research-targets, based on the hypothesis that abundant phosphorylated sites are involved in important biological functions. The phosphopeptides detected with high frequency at the 1st (Serine [S] 96) and 9th (Threonine [T] 172) positions were the phosphorylation sites of neuronal growth-associated protein - 43 kDa (GAP 43). C-jun N-terminal kinase (JNK) was responsible for phosphorylation at these sites, which increased during neuronal development and axonal regeneration. T172 phosphorylation was also confi rmed in rodents and primates. This review introduces our methodology for fi nding novel phospho-proteins as therapeutic molecular targets for specifi c diseases, along with their regulatory kinases. We believe that our serial approach, as illustrated here, can be applied to various research fi elds. In future research, we propose to demonstrate that pT172 antibody can be utilized as an axonal growth and regeneration marker in humans.</p>

DOI： 10.18947/cytometryresearch.31.1_7

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記述言語：英語  

We report for the first time a case of choroid plexus papilloma (CPP) of the fourth ventricle associated with adrenal pheochromocytoma. A large tumor was found in the fourth ventricle of a 24-year-old man who presented with symptoms of increased intracranial pressure due to obstructive hydrocephalus. A systemic search revealed that the patient also had an asymptomatic left adrenal tumor. Both tumors were resected. The pathological diagnosis of the brain tumor was CPP and that of the adrenal tumor was pheochromocytoma, both of which showed no pathological signs of malignancy. Genetic testing for von Hippel-Lindau disease was negative. There have been no reports of cases of CPP associated with pheochromocytoma. In this report, we discuss the relationship between both tumors.

DOI： 10.2176/nmccrj.cr.2021-0151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

DOI： 10.1158/0008-5472.CAN-20-2425

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pleomorphic xanthoastrocytoma (PXA) is a rare glial tumor, however, its histological differentiation from high-grade gliomas is often difficult. Molecular characteristics may contribute to a better diagnostic discrimination. Prognostic factors of PXA are also important but few relevant reports have been published. This study investigated the molecular features and prognostic factors of PXAs. Seven university hospitals participated in this study by providing retrospective clinical data and tumor samples of PXA cases between 1993 and 2014. Tumor samples were analyzed for immunohistochemical (IHC) neuronal and glial markers along with Ki67. The status of the BRAF and TERT promoter (TERTp) mutation was also evaluated using the same samples, followed by feature extraction of PXA and survival analyses. In all, 19 primary cases (17 PXA and 2 anaplastic PXA) were included. IHC examination revealed the stable staining of nestin and the close association of synaptophysin to NFP. Of the PXA cases, 57% had the BRAF mutation and only 7% had the TERTp mutation. On univariate analysis, age (≥60 years), preoperative Karnofsky performance status (KPS) (≤80%), and marked peritumoral edema were significantly associated with progression-free survival (PFS). No independent factor was indicated by the multivariate analysis. In conclusion, PXA was characterized by positive nestin staining and a few TERTp mutations. The neuronal differential marker and BRAF status may help in diagnosis. Patient age, preoperative KPS, and marked perifocal edema were associated with PFS. The present study is limited because of small number of cases and its retrospective nature. Further clinical study is needed.

DOI： 10.2176/nmc.oa.2020-0155

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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 1) pineal and neurohypophyseal bifocal lesion, 2) with diabetes insipidus, and 3) 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 three 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 two cases, and granulomatous inflammation in two cases. Histological diagnosis was not established in two cases. Although no tumors other than GCTs were identified, three (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 three criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no less 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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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Although blunt carotid artery injury is known as an important cause of ischemic stroke, the role of the endovascular treatment for acute ischemic stroke related to blunt carotid injuries remains unclear. We report the case of a patient with acute ischemic stroke secondary to blunt carotid artery injury who was treated with endovascular revascularization. A 46-year-old man suffered from sudden left-sided hemiparesis a day after a strike from a Japanese fencing staff on his right neck. 3D-CT angiography revealed tandem internal carotid artery occlusions of the cervical and C1 portions. We performed endovascular revascularization with carotid artery stenting and direct aspiration of the thrombus and achieved complete recanalization. The patient recovered almost completely. We conclude that endovascular revascularization should not be withheld from patients with acute ischemic stroke related to blunt carotid injury.

DOI： 10.11477/mf.1436204223

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

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

DOI： 10.3389/fonc.2019.01568

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担当区分：責任著者   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 SOC CLINICAL ONCOLOGY  

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

DOI： 10.1200/PO.18.00308

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担当区分：責任著者   記述言語：英語  

DOI： 10.1080/10428194.2019.1639169

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

DOI： 10.1186/s40478-019-0774-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Schizencephaly is a rare congenital central nervous system malformation characterized by linear, thickened clefts of the cerebral mantle. Recently, germline mutations in collagen type IV alpha 1 (COL4A1) have been reported to be a genetic cause of schizencephaly as a result of prenatal stroke. Patients with COL4A1 mutation demonstrate a variety of disease phenotypes. However, little is known about the potential complications of patients with COL4A1 mutations before and after neurologic surgery. CASE DESCRIPTION: A 9-month-old boy with schizencephaly and a congenital cataract underwent a ventriculoperitoneal shunt for progressive hydrocephalus. Postoperatively, he developed malignant hyperthermia and cerebral venous thrombosis. Early treatment with dantrolene sodium and hydration was effective. Genetic testing revealed a germline COL4A1 mutation. CONCLUSIONS: To our knowledge, malignant hyperthermia and cerebral venous thrombosis have not been reported in the literature in patients with COL4A1 mutations after surgery. Schizencephaly arising from COL4A1 mutations might be a disease prone to these adverse effects because this mutation is known to be associated with venous tortuosity, venous vulnerability, and muscle spasms due to basement membrane protein abnormalities. We need to better understand the wide spectrum of clinical phenotypes of COL4A1 mutations and potential complications in order to better manage surgery of patients with schizencephaly.

DOI： 10.1016/j.wneu.2019.04.156

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.wneu.2019.05.049

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

DOI： 10.1111/neup.12534

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

DOI： 10.2176/nmc.oa.2018-0078

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

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

DOI： 10.2176/nmc.ra.2018-0044

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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 Inc.  

Introduction: A prospective study was designed to elucidate incidence and predictors of deep venous thrombosis (DVT) in patients undergoing craniotomies. Materials and Methods: Ninety-two patients who underwent craniotomies received pre- and postoperative venous ultrasonography and/or contrast-enhanced spiral computed tomography for diagnosis of DVT. The primary endpoint was DVT occurrence. Serial levels of serum D-dimer, soluble fibrin, and thrombin–antithrombin complex (TAT) were analyzed. Results: Twenty-four of 92 patients (26.1%) had DVT, of whom 10 (41.7%) were diagnosed preoperatively. In patients with preoperative DVT, age, incidence of decreased performance status and leg paresis, levels of D-dimer, soluble fibrin, and TAT were significantly greater. In patients with postoperative DVT, length of surgery, incidence of decreased postoperative performance status, levels of D-dimer on postoperative days (POD) 3, 7, and 14, and TAT on POD7 were significantly greater. Patients with postoperative DVT had elevated D-dimer levels on POD 7 compared with POD 3. The D-dimer cutoff of 2.65 μg/mL at POD 7 could be used to identify DVT with 85.7% sensitivity and 72.3% specificity. A cutoff of 5.25 μg/mL at POD 7 yielded a specificity of 96.9%. Decreased performance status and elevated D-dimer were independent predictors for preoperative DVT, prolonged operation time, and elevated D-dimer on POD 7 for postoperative DVT. Conclusions: DVT frequently was observed in patients before and after undergoing craniotomies. Patients with decreased performance status should be preoperatively screened for DVT by checking D-dimer levels. Elevated D-dimer levels on POD 7 compared with POD 3 and D-dimer levels greater than 2.65 μg/mL at POD7 suggest the presence of DVT.

DOI： 10.1016/j.wneu.2017.12.139

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

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

DOI： 10.1007/s10143-017-0908-y

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記述言語：日本語   出版者・発行元：信州医学会  

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

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type.
Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKT(S473) and p-S6(S240/244) and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis.
TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.canlet.2017.04.019

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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：OXFORD UNIV PRESS  

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

DOI： 10.1093/jjco/hyw171

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記述言語：英語   出版者・発行元：TAYLOR & FRANCIS LTD  

DOI： 10.1080/10428194.2016.1201570

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Glioblastomas are highly aggressive tumors that contain treatment resistant stem-like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the -secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B-II/LC3B-I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors.

DOI： 10.1111/bpa.12343

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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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  

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

DOI： 10.1002/stem.2380

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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  

Wingless (Wnt) signaling is an important pathway in gliomagenesis and in the growth of stem-like glioma cells. Using immunohistochemistry to assess the translocation of beta-catenin protein, we identified intranuclear staining suggesting Wnt pathway activation in 8 of 43 surgical samples (19%) from adult patients with glioblastoma and in 9 of 30 surgical samples (30%) from pediatric patients with glioblastoma. Wnt activity, evidenced by nuclear beta-catenin in our cohort and high expression of its target AXIN2 (axis inhibitor protein 2) in published glioma datasets, was associated with shorter patient survival, although this was not statistically significant. We determined the effects of the porcupine inhibitor LGK974 on 3 glioblastoma cell lines with elevated AXIN2 and found that it reduced Wnt pathway activity by 50% or more, as assessed by T-cell factor luciferase reporters. Wnt inhibition led to suppression of growth, proliferation in cultures, and modest induction of cell death. LGK974 reduced NANOG messenger RNA levels and the fraction of cells expressing the stem cell marker CD133 in neurosphere cultures, induced glial differentiation, and suppressed clonogenicity. These data indicate that LGK974 is a promising new agent that can inhibit the canonical Wnt pathway in vitro, slow tumor growth, and deplete stem-like clonogenic cells, thereby providing further support for targeting Wnt in patients with glioblastoma.

DOI： 10.1097/NEN.0000000000000227

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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  

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

DOI： 10.1111/neup.12196

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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  

Medulloblastoma (MB) is a malignant cerebellar tumor arising in children, and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re-evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation-free (DF) MB. Gli3-immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells. The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P&lt;0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3-IR was observed at the nuclear membrane. The overall survival and event-free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

DOI： 10.1111/neup.12052

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担当区分：筆頭著者   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  

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

DOI： 10.1186/s40478-014-0158-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non-treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47 000 genes). Twenty-five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n = 488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12214

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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 present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non-treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47000 genes). Twenty-five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n=488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading.

DOI： 10.1111/cas.12214

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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  

Primary central nervous system lymphoma (PCNSL) expressing T-cell markers is rare, among which nasal-type extranodal NK/T-cell lymphoma is an extremely rare subtype associated with Epstein-Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV-associated PCNSL showing a cytotoxic T-cell phenotype. The patient, a 73-year-old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and slightly hyperintense on diffusion-weighted images. Biopsy specimens from the temporal region showed many medium-sized anaplastic lymphocytic cells with perivascular and angio-invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T-cell-restricted intracellular antigen-1 (TIA-1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV-encoded RNAs in the tumor cell nuclei. A rearrangement study showed T-cell receptor g-chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T-cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV-associated T-cell lymphoma.

DOI： 10.1111/neup.12005

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 28-year-old man presented with osteosarcoma of the occipital bone 16 years after 24 Gy of craniospinal irradiation for acute lymphocytic leukemia. The tumor had both intra- and extracranial components. However, the affected skull appeared to be normal on imaging because of permeative infiltration by the tumor. Subtotal resection was achieved and the tumor was verified histologically as an osteosarcoma. The residual tumor soon showed remarkable enlargement and disseminated to the spinal cord. Both of the enlarged and disseminated tumor masses were treated by surgical intervention and chemotherapy. However, the patient deteriorated due to the tumor regrowth and died 11 months after the initial diagnosis. This patient had previously developed a leukemia, a colon cancer, a rectal cancer and a hepatocellular carcinoma. His brother also died of leukemia. The patient had a heterozygous TP53 germ-line mutation of codon 248 in the exon 7. In conclusion, we consider the present tumor to be a rare example of radiation-induced skull osteosarcoma in a member of the cancer-prone family with TP53 germline mutation which is associated with Li-Fraumeni syndrome.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five controls of cortical tissue taken from non-TSC patients with epilepsy. Immunoblotting demonstrated a marked reduction of LC3B-I and LC3B-II in tubers relative to the controls. In tubers, strong, diffuse and dot-like immunoreactivity (IR) for LC3B was observed in dysmorphic neurons and balloon cells, but LC3B-IR in other neurons with normal morphology was significantly weaker than that in neurons in the controls. Immunoelectron microscopy revealed diffuse distribution of LC3B-IR within the cytoplasm of balloon cells. The dot-like pattern may correspond to abnormal aggregation bodies involving LC3. In an autopsy patient with TSC, we observed that LC3B-IR in neurons located outside of the tubers was preserved. Thus, autophagy is suppressed in tubers presumably through the mTOR pathway, and possibly a pathological autophagy reaction occurs in the dysmorphic neurons and balloon cells. © 2012 The Authors
Brain Pathology © 2012 International Society of Neuropathology.

DOI： 10.1111/j.1750-3639.2012.00634.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Object. Radiation monotherapy-prophylactic craniospinal or whole-brain irradiation paired with a radiation boost to the primary tumor-is the standard treatment for intracranial germinomas at the authors' institution. The authors assessed long-term outcomes of patients with germinoma who underwent therapy and identified factors affecting them. Methods. The authors retrospectively analyzed data obtained in 46 patients (35 males and 11 females, age 5-43 years at diagnosis) who had been treated for intracranial germinomas between 1990 and 2009 at the authors' institution. Thirty patients had germinomas in localized regions and 16 in multiple regions. Thirty-eight patients (83%) underwent radiotherapy alone (craniospinal irradiation in 32 and whole-brain irradiation in 6). Seven patients underwent radiochemotherapy and 1 underwent chemotherapy alone. The mean radiation doses for the whole brain, spine, and primary tumor site were 26.9, 26.6, and 49.8 Gy, respectively. The median follow-up period was 125 months. Results. The 10-year overall and recurrence-free survival rates were 93.3% and 89.3%, respectively. None of the 38 patients who received radiation monotherapy developed a recurrent lesion, whereas 1 of 7 who underwent radiochemotherapy and the 1 patient who underwent chemotherapy had a recurrent lesion. Of the entire population, 26 patients required hormone replacement therapy, 2 had short stature, and 1 developed a radiation-induced meningioma. Seventeen of the 25 childhood- or adolescent-onset patients were 19 years or older at the latest follow-up visit, 15 of whom graduated from senior high school, and only 2 of whom graduated from college. Of 34 patients who were 19 years or older at the latest visit, 4 were students, 18 worked independently, 4 worked in sheltered workplaces, and 8 were unemployed. Of the 34 patients, 4 got married after the initial treatment, 3 of whom had children. There were 8 patients (17%) with low postoperative Karnofsky Performance Scale (KPS) scores that were significantly associated with impaired neurocognitive functions, severe surgical complications, and neurological impairments. In 10 of the 46 patients, KPS scores at the latest visit were lower than their postoperative KPS scores. These decreases in KPS scores were significantly correlated with a delayed decline in neurocognitive functions in childhood-onset patients and a postoperative impairment of neurocognitive functions in patients with adolescent- or adult-onset germinoma. Conclusions. No tumor recurrence occurred in germinoma patients treated with the authors' radiation monotherapy, which appears to be effective enough to cure the tumor. Brain damage caused by tumors themselves and surgical complications were found to adversely affect functional outcomes in patients regardless of their age. Although radiotherapy rarely caused late adverse effects in patients with adolescent- or adult-onset, in some childhood-onset lesions, the radiation seems to carry the risk of neurocognitive dysfunctions, which are attributable to late adverse effects. Accordingly, treatments for germinoma patients should be selected according to a patient's age and the extent of the tumor and with particular care to avoid surgical complications. Copyright © AANS, 2013.

DOI： 10.3171/2012.12.PEDS12336

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.2176/nmc.oa2013-0195

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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  

Elderly and low Karnofsky performance status (KPS) patients have been excluded from most prospective trials. This retrospective study investigated glioblastoma treatment outcomes, including those of elderly and low KPS patients, and analyzed the prognostic factors using the medical records of 107 consecutive patients, 59 men and 48 women aged from 21 to 85 years (median 65 years), with newly diagnosed glioblastoma treated at our institute. There were 71 high-risk patients with age &gt;70 years and/or KPS &lt;70%. Based on the extent of resection, the patients were classified into 3 groups: more than subtotal resection (subtotal, n = 44), partial resection (partial, n = 29), and biopsy only (biopsy, n = 34). Median overall survival (OS) of all 107 patients was 13.5 months. Median OS was 13.2 months in the high-risk group. Median OSs were 15.8, 12.8, and 12.1 months in the subtotal, partial, and biopsy groups, respectively. Multivariate analysis of 73 patients in the subtotal and partial groups found age &lt;= 65 years (p = 0.047), 60 Gy irradiation (p = 0.009), O-6-methylguanine-deoxyribonucleic acid methyltransferase-negative (p = 0.027), and more than subtotal removal (p = 0.003) were significant prognostic factors. The median postoperative KPS score tended to be better than the preoperative score, even in the high-risk group. We recommend maximal safe resection for glioblastoma patients, even those with advanced age and/or with low KPS scores.

DOI： 10.2176/nmc.52.570

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Purpose: There is no standard therapy for elderly patients with high-grade glioma. We have adopted short course radiotherapy for such patients since 2005. The efficacy of this therapy was assessed retrospectively. Methods: This study reviewed 16 newly diagnosed high-grade glioma patients aged 75 years or older who were treated with short course radiotherapy (focal radiation in daily fraction of 3 Gy given 5 days per week, for a total dose of 39 Gy). Results: All patients received 100% of the planed radiation dose. No patients received prior or concomitant chemotherapy. Thirteen patients had died and median follow-up period was 9 months at the time of analysis. The median age at surgery was 79 years (range 75-86). The estimated median overall survival was 9.6 months. The median Karnofsky Performance Status on admission was 60% (range 40-90) and at discharge was 60% (range 40-80). The median length of hospital stay was 38 days (range19-61 ). There is no severe adverse events related to radiation therapy. The rate of discharge to home was 69%. Conclusion: Short course radiotherapy can reduce the treatment time and adverse events of conventional radiotherapy without decrement in survival. This therapy seems to be a considerable treatment option for elderly patients with high-grade glioma.

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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：SPANDIDOS PUBL LTD  

Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes selected using random survival forests model could be used to define subgroups of gliomas objectively. RNAs from 50 non-treated gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array. We identified 82 genes whose expression was strongly and consistently related to patient survival. For practical purposes, a 15-gene set was also selected. Both the complete 82 gene signature and the 15 gene set subgroup indicated their significant predictivity in the 3 out of 4 independent external dataset. Our method was effective for objectively classifying gliomas, and provided a more accurate predictor of prognosis. We assessed the relationship between gene expressions and survival time by using the random survival forests model and this performance was a better classifier compared to significance analysis of microarrays.

DOI： 10.3892/ijo.2011.1240

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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  

In this report, an extremely rare case of pediatric thyrotropin-secreting pituitary macroadenoma (TSHoma) is described. An 8-year-old boy, complaining of unsteady gait, was suspected of endocrinopathy because of emaciation and muscle weakness of the legs. Endocrinological work-up established a diagnosis of hyperthyroidism due to syndrome of inappropriate secretion of TSH. Magnetic resonance imaging showed a pituitary macroadenoma with suprasellar and sphenoidal extension without cavernous sinus invasion. He underwent an endoscopic endonasal transsphenoidal adenomectory due to the diagnosis of TSHoma. The adenoma was soft and it was totally removed. Histopathological staining confirmed diagnosis of TSHoma. Postoperative evaluation revealed a subnormal level of TSH (from 13-21 to 0.03 micro U/ml), normalization of alpha-subunit (from 10.0 to 0.09 ng/ml), and as a result, hypothyroidism. The boy left the hospital with oral levothyroxine that continued until 12 months of discharge. The present 8-year-old case is the youngest case to the best of our knowledge based on a bibliographical search. Reasons for endocrinological remission following adenomectomy are (1) correct diagnosis without delay: lack of cavernous sinus invasion, (2) soft and non-fibrous adenoma tissue, and (3) endoscopic technique with wide vision and illumination: safe even for a 8-year-old child. Early recognition/detection and pituitary-conserving adenomectomy can cure TSHoma and avoid long-term medical therapy and/or irradiation, which contribute to the best interests of patients with TSHoma.

DOI： 10.1007/s11102-010-0275-y

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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 IRELAND LTD  

Near-infrared spectroscopy (NIRS) has proven to be useful for the evaluation of language lateralization in healthy subjects, infants, and epileptic patients. This study for the first time investigated the expressive and receptive language functions separately, using NIRS in presurgical glioma patients. We also describe a special case with dissociated pattern of language functions. Ten glioma patients were examined. Using NIRS, the hemodynamic changes during a verb generation task or story listening task were measured in the cerebral hemisphere on either side covering the language areas. Following the NIRS study, the Wada test was performed in all the patients. The NIRS study revealed increases of oxyhemoglobin and decreases of deoxyhemoglobin in the language areas elicited by both tasks. In 9 patients, who were all right-handed, the expressive and receptive language functions were lateralized to the left hemisphere. The results of the NIRS study were completely consistent with those of the Wada test. In the remaining 1 patient with a right sided insular glioma, who was right-handed, the NIRS study revealed stronger activation of the right inferior frontal region during the verb generation task, and stronger activation of the left superior temporal region during the story listening task. This dissociated language function was validated by the Wada test and the postoperative neurological course. These results demonstrate that a NIRS study using our technique is extremely valuable for preoperative assessment of the language functions and exemplifies how a preoperative NIRS study can allow detection of unforeseen language lateralization. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2012.01.011

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記述言語：英語  

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Nova Science Publishers, Inc.  

Autophagy, rather than apoptosis, is induced in gliomas by various treatments, such as radiation and temozolomide (TMZ). The mechanisms of autophagy are gradually being clarified, however, the role of autophagy in cancer therapy remains controversial. Our goal is to elucidate the role of autophagy for application to clinical treatment. We set out to establish methods of monitoring autophagy in in vitro studies and in glioma samples. There are only a few previous reports discussing the detection of autophagy in tissue samples. In vitro studies employing electron microscopy, analysis of LC31/II conversion by western blotting, and GFP-LC3B immunofluorescence assays were undertaken to detect the induction of autophagy. None of these methods alone are sufficient for monitoring autophagy. Therefore, multiple assays to verify an autophagic response were incorporated. The development of a reliable method to monitor autophagy in surgically obtained tissues is vital in elucidating the role of autophagy in the clinical setting. To achieve this goal, immunohistochemistry was utilized in surgical tissue. Macroautophagy was monitored by immunohistochemistry employing anti-LC3B and anti-lysosome associated membrane protein 1 (LAMP1) antibodies. Likewise, chaperone-mediated autophagy was monitored using anti-LAMP2A antibodies. An increase of autophagy after TMZ treatment was noted. LC3B expression by western blotting in frozen tissue samples showed increases in both LC3-I and LC3-II expression after TMZ treatment. By employing immunohistochemical approaches mentioned, it is possible to monitor autophagy in gliomas, opening the door for monitoring therapeutic effects and/or resistance to treatments in gliomas in the clinical setting. © 2012 by Nova Science Publishers, Inc. All rights reserved.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Autophagy is a dynamic process of protein degradation. Induction of autophagy by temozolomide (TMZ) has been noted in glioma cell lines. Twenty-eight specimens, obtained from 14 patients before and after TMZ treatment, were analyzed to investigate whether induction of autophagy could be detected in surgical specimens by immunohistochemical analysis. Macroautophagy was monitored by immunohistochemical analysis employing anti-light chain 3 isoform B (LC3B) and anti-lysosome-associated membrane protein 1 (LAMP1) antibodies; chaperone-mediated autophagy was monitored by anti-LAMP2A antibody immunostaining. Furthermore, detection of LC3B protein by Western blotting was performed on six specimens obtained from the preserved frozen tissues of three patients. All specimens showed dot-like staining for each immunostain in the cytoplasm of glioma cells, indicating induction of autophagy. LC3B, LAMP1 and LAMP2A immunostains were semiquantitatively scored from 1 to 3 points. Combination of the three scores after TMZ treatment (6.4 +/- 1.2) showed a significant increase (P = 0.020) compared to pre-treatment scores (5.2 +/- 1.5). Western blotting for LC3B showed increased LC3B-I and LC3B-II expression after TMZ treatment. The present study proved that autophagy monitoring by immunohistochemical staining of surgical specimens was feasible. These results suggest that autophagy is induced by TMZ.

DOI： 10.1111/j.1440-1789.2010.01197.x

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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 TOKYO  

Immunohistochemical staining is important for histological diagnosis of brain tumors; however, its intraoperative application has rarely been reported. Herein, we describe our methods and four successfully diagnosed cases. Between January 2008 and April 2010, intraoperative immunohistochemical analysis was performed in 43 patients undergoing brain tumor surgery at our institute. The time for rapid histological diagnosis was 70 min. MIB-1 immunostaining was performed; staining index (SI) was 0.8-76.2% (median, 2.5%) in rapid diagnoses and 0.6-83.9% (median, 7.7%) in permanent diagnoses. There was no discrepancy in low- or high-grade tumors between intraoperative and final pathological diagnosis. The antibodies used for staining were MIB-1 in all cases, L26 in 8 cases, UCHL-1 in 6 cases, GFAP in 4 cases, AFP in 3 cases, and PLAP in 5 cases. The staining patterns were similar between rapid and permanent diagnoses. We think that immunohistochemical examination is indicated under the following conditions: (1) preoperative radiologic differential diagnosis includes both high- and low-grade tumors, (2) intraoperative assessment is necessary to determine the extent of excision, and (3) quick and accurate pathological diagnosis is necessary for early initiation of treatment after surgery.

DOI： 10.1007/s10014-011-0026-4

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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  

Angiocentric glioma (AG) is an epileptogenic benign cerebral tumor primarily affecting children and young adults, and characterized histopathologically by an angiocentric pattern of growth of monomorphous bipolar cells with features of ependymal differentiation (WHO grade I). We report an unusual cerebral glial tumor in a 66-year-old woman with generalized tonic-clonic seizure; the patient also had a 6-year history of headache. On MRI, the tumor appeared as a large T2-hyperintense lesion involving the right insular gyri-anterior temporal lobe, with post-contrast enhancement in the insula region. Histopathologically, the tumor involving the insular cortex-subcortical white matter was composed of GFAP-positive glial cells showing two different morphologies: one type had monomorphous bipolar cytoplasm and was angiocentric with circumferential alignment to the blood vessels, with dot-like structures positive for epithelial membrane antigen and a Ki-67 labeling index of &lt; 1%, and the other was apparently astrocytic, being diffusely and more widely distributed in the parenchyma, showing mitoses and a Ki-67 labeling index of &gt; 5%. In the anterior temporal lobe, a diffuse increase in the number of astrocytic cells was evident in part of the cortex and subcortical white matter. On the basis of these findings, we considered whether the present tumor may represent an unusual example of AG with infiltrating astrocytic cells showing primary anaplastic features (AG with anaplastic features), or anaplastic astrocytoma showing primary vascular-associated ependymal differentiation (anaplastic astrocytoma with angiocentric ependymal differentiation). At present, the latter appears to be the more appropriate interpretation.

DOI： 10.1111/j.1440-1789.2010.01161.x

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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. The authors retrospectively analyzed various clinicopatholouical factors to determine which are related to regrowth during a long-term follow-up period in patients who underwent incomplete vestibular schwannoma (VS) resection.
Methods. This study involved 74 patients (25 men and 49 women) in whom a VS was treated surgically via the lateral suboccipital approach, and who had postoperative follow-up periods exceeding 5 years. The mean follow-up was 104.1 months (range 60-241 months), and the mean patient age at surgery was 48.1 years (range 19-75 years). The tumors ranged in size from 0 mm (localized within the internal auditory canal) to 56 mm (28.3 +/- 12.2 mm [mean S 13]).
Results. Gross-total resection (GTR) was performed in 41 (55%) of the 74 patients; subtotal resection GSTR]; 90-99%) in 25 (34%); and partial resection ([PR]; &lt; 90%) in 8 (11%). Regrowth rates in the GTR, STR, and PR groups were 2.4% (1 of 41 cases), 52% (13 of 25), and 62.5% (5 of 8), respectively, and the times to regrowth ranged from 6 to 76 months (median 31.9 months). The regrowth-free survival curves differed significantly between the complete (GTR) and incomplete (STR and PR) resection groups. Eighteen (54.5%) of the 33 patients who underwent incomplete resection showed evidence of regrowth during follow-up. Univariate and multivariate analyses of various factors revealed that both the thickness of the residual tumor, based on MR imaging after surgery, and the MIB-1 index were positively related to residual tumor regrowth. The receiver operating characteristic curves, plotted for both the thickness of the residual tumor and the MIB-1 index, identified the optimal cutoff points for these values as 7.4 mm (sensitivity 83.3%, specificity 86.7%) and 1.6 (sensitivity 83.3%, specificity 66.7%), respectively.
Conclusions. Greater residual tumor thickness, based on MR imaging after the initial surgery, and a higher MIB-1 index are both important factors related to postoperative tumor regrowth in patients who have undergone incomplete VS resection. These patients require frequent neuroimaging investigation during follow-up to assure early detection of tumor regrowth. (DO!: 10.3171/2010.11.JNS101041)

DOI： 10.3171/2010.11.JNS101041

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction. Examples of the spontaneous regression of primary intracranial germinomas can be found in the literature. We present the case of a patient with disseminated lesions of primary intracranial germinoma which synchronously shrunk following diagnostic irradiation. We will discuss whether this regression was spontaneous or radiation-induced. Case presentation. A 43-year-old Japanese woman presented to our hospital complaining of memory problems over a period of one year and blurred vision over a period of three months. Following magnetic resonance imaging, she was found to have a massive lesion in the third ventricle and small lesions in the pineal region, fourth ventricle, and in the anterior horn of the left lateral ventricle. Prior to an open biopsy to confirm the pathology of the lesions, she underwent a single cranial computed tomography scan and a single cranial digital subtraction angiography for a transcranial biopsy. Fourteen days after the first magnetic resonance image - 12 and eight days after the computed tomography scan and digital subtraction angiography, respectively - a pre-operative magnetic resonance image was taken, which showed a notable synchronous shrinkage of the third ventricle tumor, as well as shrinkage of the lesions in the pineal region and in the fourth ventricle. She did not undergo steroid administration until after a biopsy that confirmed the pathological diagnosis of pure germinoma. She then underwent whole craniospinal irradiation and went into a complete remission. Conclusions. In our case report, we state that diagnostic radiation can induce the regression of germinomas
this is the most reasonable explanation for the synchronous multiple regression observed in this case of germinoma. Clinicians should keep this non-spontaneous regression in mind and monitor germinoma lesions with minimal exposure to diagnostic radiation before diagnostic confirmation, and also before radiation treatment with or without chemotherapy begins. © 2011 Yoneoka et al
licensee BioMed Central Ltd.

DOI： 10.1186/1752-1947-5-39

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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  

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor that usually occurs in the superficial cerebral hemispheres of children and young adults and has a relatively favorable prognosis. We report an unusual case of supratentorial, intraventricular tumor in a 52-year-old man. The tumor was composed of pleomorphic cells, including giant cells, most of which were multinucleated, and small cells. In addition, frequent xanthic changes in the cytoplasm of the tumor cells, and widespread reticulin deposits and lymphocytic infiltrates in the stroma were characteristic features. Large areas of necrosis were also evident. However, mitotic figures were rare (1-2 mitoses per 10 high-power fields). Many tumor cells were positive for GFAP, and a number were positive for neurofilament protein and synaptophysin, indicating their neuronal differentiation. In addition, occasional tumor cells were positive for CD34. p53 protein was entirely negative in the tumor cells. In diagnosing this tumor histopathologically, differentiation between PXA and giant cell glioblastoma (GCG), a rare variant of glioblastoma, was problematic. However, considering the overall histopathological picture, a final diagnosis of PXA with anaplastic features was made. The present case indicates that PXA can occur as an intraventricular tumor, and suggests that in some instances, it would be very difficult to differentiate PXA and GCG histopathologically.

DOI： 10.1111/j.1440-1789.2009.01080.x

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IGAKU-SHOIN LTD  

Relationships between hypothalamic arteries and anterior communicating artery aneurysms were examined in 34 cases treated by clipping operations, using the anterior interhemispheric approach. The directions of the aneurysmal domes and hypothalamic arteries were analyzed and divided into 2 groups. The different direction(D.D.) group involved cases in which a hypothalamic artery ran in a different direction to that of the dome of the aneurysm. The same direction (S.D.) group involved cases in which a hypothalamic artery ran parallel to the dome of the aneurysm. The D.D. group consisted of 15 cases, and the S.D. group consisted of 13 cases. In the remaining 6 cases, the hypothalamic artery was not found during the operation. In many cases of the D.D. group, the aneurysm was located anterior to the A2 portions of the bilateral anterior cerebral arteries, whereas, in all cases of the S,D. group, the aneurysm was located between or posterior to the bilateral A2 portions. We also investigated the flow direction of the anterior communicating artery in the S.D. group, The dominant At was defined as the side of internal carotid angiography in which the aneurysm was depicted on preoperative angiography. The flow direction of the anterior communicating artery was assumed to flow from the dominant A1 side to the recessive A1 side. Considering the flow direction of the anterior communicating artery, the hypothalamic artery was located downstream from the aneurysm in 9 cases and upstream in 3 cases. These results suggested that it is important to pay more attention to the downstream of the aneurysm to avoid injury of the hypothalamic artery in the S.D. group. For cases in which the hypothalamic artery was located upstream to the aneurysm, these aneurysms seemed to arise from the bifurcation of the anterior communicating artery and hypothalamic artery, and might be named hypothalamic artery aneurisms.

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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

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

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

免疫チェックポイント阻害剤は、非小細胞肺がんや悪性黒色腫など様々ながんの治療に革命的な進歩をもたらした。悪性神経膠腫領域でも、その有効性が期待されたが、残念ながら単剤投与での効果は限られているようである。悪性神経膠腫に対する免疫チェックポイント阻害剤の現状を報告し、その可能性について探る。(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=2022&ichushi_jid=J03120&link_issn=&doc_id=20220310290017&doc_link_id=issn%3D0917-1495%26volume%3D32%26issue%3D2%26spage%3D284&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0917-1495%26volume%3D32%26issue%3D2%26spage%3D284&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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記述言語：日本語   出版者・発行元：(NPO)日本レーザー医学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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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：日本語   出版者・発行元：(株)医学書院  

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

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

記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞Point ・レルミット・ダクロス病は,小脳回が腫大し変形する比較的境界明瞭な小脳半球の稀な良性腫瘍,あるいは過誤腫性病変である.・虎縞様層構造(tiger-striped striation)が特徴的MRI所見で,拡散制限はない.・カウデン症候群の主要な中枢神経系の病変で,小児〜高齢者の広い年齢層で認められる.・カウデン症候群の診断がついていない場合,カウデン症候群に伴う全身の過誤腫性・腫瘍性病変の検索を行う.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01228&link_issn=&doc_id=20210406190026&doc_link_id=10.11477%2Fmf.1436204404&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436204404&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 ・単純CTで高吸収,T1WIで高信号を認める場合,出血・石灰化に加えメラニン含有性病変を考える.・頭蓋内にメラニン含有性病変を認めた場合,皮膚病変(母斑)の有無を確認する.・無症状でも大きな,あるいは多発する先天性母斑を認める場合,神経皮膚黒色症を疑う.・神経皮膚黒色症の40〜60%に悪性黒色腫が発生し,予後不良である.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01228&link_issn=&doc_id=20210406190025&doc_link_id=10.11477%2Fmf.1436204403&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436204403&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 ・大脳多結節空胞状神経細胞腫瘍(MVNT)は,痙攣,頭痛あるいは偶然発見される大脳半球の脳回に沿う皮質深部〜皮質下神経系腫瘍性病変(WHO 2016 gradeI相当)である.・MRIで1〜5mmの結節が3〜10個以上集合する7〜57mmの大きさで,mass effectは乏しくGd増強効果を示さない.・増大せず,痙攣を来す一部の例を除き生検や病変摘出などの外科的処置を必要としない"leave-me-alone" lesionと考えらえる.

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記述言語：日本語   出版者・発行元：(一社)日本皮膚悪性腫瘍学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本作業療法士協会  

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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：日本語   出版者・発行元：(株)医学書院  

46歳男。主訴は左片麻痺で、発症から63分後に救急搬送され、CTでは右中大脳動脈近位部にhyperdense signを認めた。3D-CT angiographyでは右頸部内頸動脈起始部の高度狭窄と頭蓋内内頸動脈以遠の閉塞を認めた。前日に剣道で右前頸部へ直接突きを受けており、鈍的外傷による右頸部内頸動脈解離と同部由来の塞栓による頭蓋内内頸動脈閉塞、急性期脳梗塞と診断した。到着から109分後に血管内再開通療法を開始し、内頸動脈起始部の狭窄部にステント留置を先行させ、その後総頸動脈遮断下に閉塞した内頸動脈終末部を直接吸引して血栓を回収した。再開通までは発症から245分であった。術後頭部MRIでは、右被殻、尾状核頭、島皮質、前頭葉弁蓋部、側頭葉内側に梗塞巣を認めたが、症状は劇的に改善し、23病日には軽度の注意障害を残し、modified Rankin Scale 1で退院した。

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記述言語：日本語   出版者・発行元：(株)メジカルビュー社  

＜文献概要＞成人の代表的な脳実質内腫瘍は神経膠腫,転移性脳腫瘍,中枢神経原発性リンパ腫(PCNSL)である。それぞれ治療方針が異なるため,術前画像診断はきわめて重要である。頭部CT,MRIなどでの鑑別が難しい場合は,MRSが診断の一助となる。本稿では脳実質内腫瘍におけるプロトンMRSの特徴および診断のピットフォールについてまとめた。

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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：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語  

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記述言語：日本語  

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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）  

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記述言語：日本語   出版者・発行元：(株)北隆館  

近年の遺伝子発現解析技術の飛躍的な進歩により髄膜腫の分子生物学的な背景の理解が深まった。基本的に良性腫瘍である髄膜腫にあって悪性髄膜腫は、手術や放射線治療に抵抗性の症例では、次の有効な治療手段が確立されていない。我々の施設では、がん医療で先行して利用され始めた遺伝子パネルを利用することで悪性髄膜腫固有のドライバー変異が同定可能であるという仮説を立て、現在研究を行っている。本研究について本コーナーで概説する。(著者抄録)

CiNii Article

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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：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：新潟県医師会  

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記述言語：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：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01883&link_issn=&doc_id=20170323050019&doc_link_id=%2Fao7brnui%2F2017%2F003304%2F021%2F0374-0376%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fao7brnui%2F2017%2F003304%2F021%2F0374-0376%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：英語   掲載種別：書評論文，書評，文献紹介等   出版者・発行元：Wiley-Liss Inc.  

Cancer stem-like cells (CSCs) are thought to be the main cause of tumor occurrence, progression and therapeutic resistance. Strong research efforts in the last decade have led to the development of several tailored approaches to target CSCs with some very promising clinical trials underway
however, until now no anti-CSC therapy has been approved for clinical use. Given the recent improvement in our understanding of how onco-proteins can manipulate cellular metabolic networks to promote tumorigenesis, cancer metabolism research may well lead to innovative strategies to identify novel regulators and downstream mediators of CSC maintenance. Interfering with distinct stages of CSC-associated metabolics may elucidate novel, more efficient strategies to target this highly malignant cell population. Here recent discoveries regarding the metabolic properties attributed to CSCs in glioblastoma (GBM) and malignant colorectal cancer (CRC) were summarized. The association between stem cell markers, the response to hypoxia and other environmental stresses including therapeutic insults as well as developmentally conserved signaling pathways with alterations in cellular bioenergetic networks were also discussed. The recent developments in metabolic imaging to identify CSCs were also summarized. This summary should comprehensively update basic and clinical scientists on the metabolic traits of CSCs in GBM and malignant CRC.

DOI： 10.1002/ijc.30259

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PubMed

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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：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  

Web of Science

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳神経CI学会  

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

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：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/nou244.2

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(株)インナービジョン  

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

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟県医師会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

28歳男。12歳時、急性リンパ性白血病にて化学療法と予防的全脳全脊髄照射で完解したが、化学療法により拡張型心筋症となり、27歳時に透析導入、直腸癌と肝細胞癌の治療、大腸癌の手術を施行された。今回、頭痛、嘔気、嘔吐から歩行困難となり、左小脳半球と後頭部の皮下腫瘍が認められた。頭部CTで左小脳に径5cm、左後頭部に皮下腫瘍を認めたが、間に介在する後頭骨破壊はなかった。MRIでは、CT同様の腫瘍病変を認め、間に介在する後頭骨に明らかな信号変化はなく腫瘍は独立しており、放射線誘発髄膜腫が疑われた。小脳腫瘍と皮下腫瘍を介在する後頭骨と共に摘出し、大孔部で椎骨動脈に癒着した部分を一部残存して亜摘出した。病理所見では、皮下・小脳腫瘍ともに類骨形成を伴う骨肉腫の腫瘍細胞が密に増生し、介在する後頭骨にも浸潤していた。術後1ヵ月で頭蓋内に局所再発を認めた。その後、胸髄への播種病変による対麻痺が出現したため胸髄腫瘍を摘出したが、頭蓋内・脊髄の残存病変は急速に進行し11ヵ月後に死亡した。白血球DNA検査でTP53遺伝子に点突然変異が認められた。剖検では、肺・腎など頭蓋外転移も認め、腫瘍細胞はp53免疫染色に強陽性を示し、Li-Fraumeni類縁症候群に発症した頭蓋内骨肉腫と診断した。

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

1995年1月〜2004年12月に標準的放射線療法を施行した75歳以上の初発膠芽腫10例、2005年1月〜2011年4月に少分割照射を施行した75歳以上の初発膠芽腫16例を対象に、2005年以降の患者の負担を軽減するために採用した少分割照射の有用性を標準的放射線療法と比較検討した。標準的放射線療法は10例中8例(80%)において放射線治療を完遂し得た。3例は温熱療法を併用し、1例でラニムスチンを用いた化学療法を併用した。フォローアップ期間は3〜20ヵ月、中央値10ヵ月で全例死亡した。入院期間は44〜96日、中央値68日、生存期間は3〜20ヵ月、中央値10ヵ月であった。少分割照射は16例中14例において総照射線量を39Gyに設定し、残り2例において30Gyに設定した。フォローアップ期間は2〜45ヵ月、中央値9.6ヵ月で2011年12月迄に13例(81%)が死亡した。入院期間は19〜61日、中央値38日、生存期間は2〜45ヵ月、中央値9.6ヵ月であった。入院時との比較では改善5例、悪化5例、不変6例であった。両群間において退院時のKarnofsky Performance Status(KPS)はほぼ同様の数値を示し、有意差を認めていない。少分割照射の治療効果として全生存期間が同等で、利点とし治療期間(入院期間)の短縮(30日間)、合併症の軽減(有害事象0%)、ステロイド減少、高い治療完遂率、自宅退院割合の増加、医療費削減、放射線部の負担軽減が挙げられる。欠点として白質脳症、認知機能低下、放射線壊死の増加、長期生存の割合の低下の潜在的可能性がある。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01228&link_issn=&doc_id=20120705070006&doc_link_id=10.11477%2Fmf.1436101766&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436101766&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：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

当施設における小児期発症の頭蓋内胚腫の治療成績と長期予後を検討した。対象は、1990年から2009年に初期治療を行った15歳以下の胚腫23名で、88%に照射単独治療(全脳脊髄照射15名、全脳照射5名)を、残り3名に化学療法単独もしくは併用治療を行った。照射単独治療群では、再発を認めなかった。10歳以下で同治療を行った3名で高次脳機能低下を認めた。胚腫における照射単独治療は、治癒が望める有効な治療法ではあるが、低年齢時の放射線治療は、高次脳機能低下を来す可能性があり、年齢や病変の広がりに応じた治療法の検討が必要である。(著者抄録)

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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   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)日本脳神経外傷学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：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：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経外科学会  

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記述言語：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)日本内分泌学会  

頭蓋咽頭腫60例を対象に、治療経過の分析、治療方法と内分泌機能・視機能・ADL・高次脳機能・有害事象との関連を検討した。観察期間は平均100.9ヵ月であった。その結果、59例に初回手術が行われ、到達法はpterional/subfrontal approachが27例、anterior/basal interhemispheric approachが23例と多用されていた。手術後放射線治療群は、手術単独群に比べ無増悪生存期間が有意に長かったが、全生存期間に有意差はなかった。全摘・亜全摘群と部分摘出・生検群の間でも、全生存期間に有意差は認めなかった。視機能は治療後44例中32例が改善した。下垂体前葉機能は52例中2例が改善したが、14例で悪化し、41例にホルモン補充療法を要した。尿崩症は11例中1例が改善したが、治療後に25例が新たに尿崩症を呈し、35例でDDAVP投与を要した。腫瘍摘出度・到達法・照射療法の有無と下垂体前葉機能ならびに後葉機能・視機能・KPS・高次脳機能の転帰の間に関連性は認めなかった。

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：信州医学会  

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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：信州医学会  

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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：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：DUKE UNIV PRESS  

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：日本語   出版者・発行元：新潟県厚生農業協同組合連合会  

背景:中枢神経系障害でみられる環境適応障害とは、柏木によれば「空間に対して自己の位置関係を認知できないため、体の安定を喪失している状態である」と定義され、その特徴的な症状として「外部環境との接触抵抗に固執して、なるべく強く変化しない抵抗を求めようと体の一部を強く支持面に押し付ける。」「体の各部位を強く連結しておこうとする」の2点をあげている。これらの症状に対して、タオルによる接触刺激を加えることにより改善が得られたとする報告がみられる。症例内容:今回の症例は、脳出血再発により昭和60年の脳出血後遺症による右片麻痺と失語に新たに環境適応障害が加わったものである。これに対してタオルによる接触刺激を加えたところ環境適応障害の改善がみられ、予想以上に早期の運動機能の再獲得が得られた。結論:タオルによる接触刺激を加えることは、環境適応障害の症状を改善するのに有効である。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本農村医学会  

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記述言語：日本語   出版者・発行元：(一社)日本農村医学会  

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記述言語：日本語   出版者・発行元：(一社)日本脳神経外科学会  

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記述言語：日本語   出版者・発行元：(株)自然科学社  

重症肺炎のうちで、急性呼吸窮迫症候群(ARDS)の定義に当てはまるものは4例存在した。4例とも、ARDSの確定診断を待たずに気管内挿管、人工呼吸器管理を開始し、ARDSと診断後は速やかにシベレスタットナトリウムを使用したことが奏効し、早期に呼吸器から離脱し、抜管できた。4例中3例では気管内挿管、SIMV管理下でARDSの条件を満たし、ただちにシベレスタットナトリウムの使用を開始した。1例は気管内挿管後数時間は人工呼吸器管理が不要であったが、呼吸障害が進行するにつれ、ただちに人工呼吸器管理とし、ARDSの基準を満たしたためシベレスタットナトリウムの使用を開始した。躊躇することなく挿管し、シベレスタットナトリウムの適応を速やかに評価し、可及的早期に使用することが好成績につながったと思われた。

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記述言語：日本語   出版者・発行元：(株)医学書院  

前交通動脈瘤に対しanterior interhemispheric approachによるクリッピング手術を行った34例(男性15例、女性19例、35〜84歳)を対象として視床下部動脈と脳動脈瘤との位置関係を検索した。術中、視床下部動脈と脳動脈瘤が別の方向を向いていたD.D.群は15例、両者が同方向を向いていたS.D.群は13例、残りの6例は視床下部動脈が不明であった。D.D群では安井らの分類におけるtype 1が13例、type 2が2例であり、S.D.群ではtype 2が6例、type 3が7例であった。S.D.群のうち前交通動脈の血流が右から左に向いている4症例のち視床下部動脈が脳動脈瘤の左に認めたのは3例であり、前交通動脈の血流が左から右に向いている8症例のうち視床下部動脈が右に認めたのは6例であったことから、視床下部動脈は脳動脈瘤の下流に存在する可能性が高いことが示唆された。

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟大学  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：日本脳死・脳蘇生学会  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：長野赤十字病院  

69歳男.呂律不良,右半身麻痺で発症し,頭部CTで2.0×1.5×2.5cmの左視床血腫を認めた.グリセオール200ml×2/dayで保存的に治療し,呼吸苦を訴えたため心エコーを施行したところびまん性の心筋肥厚を認め,高血圧性心筋症と診断した.体重80kg(推定)であったため摂食制限で体重減少を図り,リハビリテーションを開始し下肢麻痺はMMT4/5レベルとなり,上肢も動くようになった.頻尿のため自ら飲水を控えていたところ,上肢の軽度脱力,構音障害を来たし,MRIで右頭頂葉および左脳室周囲にlacunar infarctを認めた.飲水の徹底のみで症状は改善したが,40℃の熱発,嘔吐,背腹部痛が出現し,腎機能異常より腎盂腎炎と診断した.その後血圧が低下し,尿・血液培養でE.coli陽性,エンドトキシン陽性を認め,吸着療法,持続透析を開始した.呼吸性,代謝性アシドーシスが改善せず,DIC傾向,四肢不全麻痺,pAfなどを認め,頭部CTを行なったが脳出血や塞栓症の所見はなかった.CT施行後心肺停止となり,心臓マッサージ,気管内挿管,投薬にも反応がなく,発症2日後に死亡した

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   出版者・発行元：長野赤十字病院  

29歳妊婦.患者は分娩直後より,頭痛および軽度血圧上昇を認め,産褥第3日目に痙攣発作が生じ,産褥子癇と診断された.頭部MRI T2強調画像,ならびにFLAIRでは特徴的な高信号域を呈し,MRAでは主幹動脈の血管攣縮を認めた.そこで,抗痙攣剤,オザグレルナトリウムで加療を開始したところ,痙攣発作は消失したものの,意識障害と頭痛は遷延し,発症から10日目のMRI上,血管攣縮と浮腫の悪化が認められた.以上の経過より,プレドニンの経口投与を開始した結果,意識障害,頭痛は改善となり,画像所見も26日目には改善,51日目には消失が確認された

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：信州医学会  

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記述言語：日本語   出版者・発行元：日本赤十字社医学会  

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