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INTRODUCTION: The use of anti-epileptic drugs (AEDs) in degenerative dementia (DD) remains uncertain. We aimed to evaluate the association of early AED administration with subsequent DD occurrence. METHODS: Using a large nationwide database, we enrolled patients newly diagnosed with epilepsy from 2014 to 2019 (n = 104,225), and using propensity score matching, we divided them into treatment (those prescribed AEDs in 2014) and control groups. The primary outcome was subsequent DD occurrence in 2019. RESULTS: Overall, 4489 pairs of patients (2156 women) were matched. The odds ratio (treatment/control) for DD occurrence was 0.533 (95% confidence interval: 0.459-0.617). The DD proportions significantly differed between the treatment (340/4489 = 0.076) and control (577/4489 = 0.129) groups. DISCUSSION: Among patients newly diagnosed with epilepsy, compared to non-use, early AED use was associated with a lower occurrence of subsequent DD. Further investigations into and optimization of early intervention for epilepsy in DD are warranted. HIGHLIGHTS: Anti-epileptic drug (AED) use before epilepsy diagnosis was linked with a lower subsequent degenerative dementia (DD) occurrence.Identifying the epileptic phenotype was crucial for justifying early AED use in DD.AED use with an epilepsy diagnosis did not pose an additional risk of DD.The potential contribution of combination drug therapy to the strategy was noted.

DOI： 10.1002/trc2.70001

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BACKGROUND AND OBJECTIVES: Insulo-opercular surgery can cause ischemic motor complications. A source of this is the arteries around the superior limiting sulcus (SLS), which reach the corona radiata, but the detailed anatomy remains unclear. To characterize arteries around the SLS including the long insular arteries (LIAs) and long medullary arteries, we classified them and examined their distribution in relation to the SLS, which helps reduce the risk of ischemia. METHODS: Twenty adult cadaveric hemispheres were studied. Coronal brain slices were created perpendicular to the SLS representing insular gyri (anterior short, middle short, posterior short, anterior long, and posterior long). The arteries within 10-mm proximity of the SLS that reached the corona radiata were excavated and classified by the entry point. RESULTS: A total of 122 arteries were identified. Sixty-three (52%), 20 (16%), and 39 (32%) arteries penetrated the insula (LIAs), peak of the SLS, and operculum (long medullary arteries), respectively. 100 and six (87%) arteries penetrated within 5 mm of the peak of the SLS. The arteries were distributed in the anterior short gyrus (19%), middle short gyrus (17%), posterior short gyrus (20%), anterior long gyrus (19%), and posterior long gyrus (25%). Seven arteries (5.7%) had anastomoses after they penetrated the parenchyma. CONCLUSION: Approximately 90% of the arteries that entered the parenchyma and reached the corona radiata were within a 5-mm radius of the SLS in both the insula and operculum side. This suggests that using the SLS as a landmark during insulo-opercular surgery can decrease the chance of ischemia.

DOI： 10.1227/ons.0000000000000879

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

DOI： 10.1186/s40478-023-01683-x

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BACKGROUND: Intraosseous clival arteriovenous fistulas (AVFs), in which the shunt drains extracranially from the posterior and anterior condylar veins rather than from the cavernous sinus (CS), are rare. Targeting embolization of an intraosseous clival AVF is challenging because of its complex venous and skull base anatomy; therefore, a therapeutic strategy based on detailed preoperative radiological findings is required to achieve a favorable outcome. Here, the authors report the successful targeted embolization of an intraosseous clival AVF using an ingenious access route. OBSERVATIONS: A 74-year-old woman presented with left-sided visual impairment, oculomotor nerve palsy, and right facial pain. A fusion image of three-dimensional rotational angiography and cone-beam computed tomography revealed a left CS dural AVF and a right intraosseous clival AVF. The shunt flow of the clival AVF drained extracranially from the posterior and anterior condylar veins via the intraosseous venous route. Transvenous embolization was performed by devising suboccipital, posterior condylar, and intraosseous access routes. The symptoms resolved after the bilateral AVFs were treated. LESSONS: Accurate diagnosis and proper transvenous access based on detailed intraosseous and craniocervical venous information obtained from advanced imaging modalities are key to resolving intraosseous clival AVF.

DOI： 10.3171/CASE23492

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PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Since majority of adult malignant brain tumors are gliomas and primary central nervous system lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. Additionally, diffuse gliomas require molecular information on single nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen section (FS) diagnosis through incorporation of a quantitative polymerase chain reaction (qPCR)-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid immunohistochemistry, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined based on the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patientswith glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

DOI： 10.1158/1078-0432.CCR-23-1660

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Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis.

DOI： 10.1186/s43556-023-00141-3

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BACKGROUND AND OBJECTIVES: Insulo-opercular surgery can cause ischemic motor complications. A source of this is the arteries around the superior limiting sulcus (SLS), which reach the corona radiata, but the detailed anatomy remains unclear. To characterize arteries around the SLS including the long insular arteries (LIAs) and long medullary arteries, we classified them and examined their distribution in relation to the SLS, which helps reduce the risk of ischemia. METHODS: Twenty adult cadaveric hemispheres were studied. Coronal brain slices were created perpendicular to the SLS representing insular gyri (anterior short, middle short, posterior short, anterior long, and posterior long). The arteries within 10-mm proximity of the SLS that reached the corona radiata were excavated and classified by the entry point. RESULTS: A total of 122 arteries were identified. Sixty-three (52%), 20 (16%), and 39 (32%) arteries penetrated the insula (LIAs), peak of the SLS, and operculum (long medullary arteries), respectively. 100 and six (87%) arteries penetrated within 5 mm of the peak of the SLS. The arteries were distributed in the anterior short gyrus (19%), middle short gyrus (17%), posterior short gyrus (20%), anterior long gyrus (19%), and posterior long gyrus (25%). Seven arteries (5.7%) had anastomoses after they penetrated the parenchyma. CONCLUSION: Approximately 90% of the arteries that entered the parenchyma and reached the corona radiata were within a 5-mm radius of the SLS in both the insula and operculum side. This suggests that using the SLS as a landmark during insulo-opercular surgery can decrease the chance of ischemia.

DOI： 10.1227/ons.0000000000000879

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Primary central nervous system lymphoma (PCNSL) is a rare and invasive diffuse large B cell lymphoma confined in central nervous system (CNS). The effort to press forward the translational progress has been frustrated by the insufficient understanding of immunophenotype of CNS and tumor genetic alterations of PCNSL, and the lack of validated diagnostic biomarkers. Researchers now have a variety of PCNSL animal models at their disposal that resemble the morphology and immunophenotype of PCNSL, however, a careful and detailed re-examination of these animal models is needed to clarify the differences in genetic alterations, migration capability, and immune status. In this review, we present the knowledge about the phenotypic and genotypic features of PCNSL tumor cells, and compile the preclinical animal models of PCNSL with regard to various injection sites, cell origins, recipient animals, and immune status, and elaborate on the tropism and migration of tumor cells and novel therapeutic strategies for PCNSL. We envisage that the selection of suitable animal models will serve as a well-defined preclinical system to understand the molecular pathogenesis of PCNSL, thereby galvanizing the development of novel and potent therapeutic approaches.

DOI： 10.1002/jcp.31107

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/noajnl/vdad043

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Primary central nervous system lymphoma (PCNSL) is a malignant neoplasm of the central nervous system that is refractory to treatment and has extremely poor prognosis. One factor hindering the development of therapeutic options for PCNSL is its molecular heterogeneity and the extreme difficulty in establishing in vitro cell lines that permit intensive research on this disease. In the present study, we developed a method to propagate PCNSL cells in vitro using a contacting transwell cell culture system involving brain vascular pericytes. The co-culture system was found to recapitulate the tumor microenvironment that is influenced by the biological activity of adjacent pericytes, and to sustain the survival and proliferation of PCNSL cells in vitro. We further delineated the underlying molecular mechanisms and found that the HGF-c-Met axis may be involved in the long-term in vitro culture of PCNSL cells. Moreover, the peptidylprolyl isomerase Pin1 was found to play a key role in PCNSL cell survival and it sustained proliferation through interactions with key transcription factors related to B-cell lymphomagenesis. These results suggest that our in vitro co-culture system is well suited to analyzing the biological and molecular characteristics of PCNSL, and may contribute to the discovery of new therapeutic interventions.

DOI： 10.3389/fcell.2023.1275519

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BACKGROUND: Brain metastases with hematoma are clinically important as they indicate the potential for rapid neurological deterioration. Non-uterine leiomyosarcoma-derived brain metastases are particularly rare, and their clinical features, including the bleeding rate, are unclear. Herein, we present a rare case of thigh leiomyosarcoma-derived brain metastasis with intratumoral hematoma and review previous case reports. CASE DESCRIPTION: A 68-year-old man with a right thigh leiomyosarcoma presented with multiple brain metastases. The patient received stereotactic radiotherapy; however, he reported sudden right-sided hemiparesis. We found a right frontal irradiated lesion with intratumoral hemorrhage and performed gross total tumor resection. Histopathological examination showed highly atypical cells with prominent necrosis and hemorrhage. Abnormal thin-walled vessels were prominent within the brain tumor, and vascular endothelial growth factor was diffusely expressed immunohistopathologically. To date, 11 cases of brain metastasis from non-uterine leiomyosarcoma, including the present case, have been reported. Of note, six patients had hemorrhage. Three out of six patients presented with hemorrhage before therapeutic intervention, three cases were from residual sites after surgery or radiation. CONCLUSION: More than half the patients with non-uterine leiomyosarcoma-derived brain metastases presented with intracerebral hemorrhage. Furthermore, these patients are at risk of developing rapid neurological deterioration due to intracerebral hemorrhage.

DOI： 10.25259/SNI_113_2023

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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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BACKGROUND: The use of mechanical thrombectomy (MT) for treatment of acute large vessel occlusion has recently increased. Prompt and timely guiding catheter (GC) induction is necessary to improve prognosis of MT and reduce the time for recanalization. However, difficulties in GC induction are encountered in some patients. This GC induction depends mainly on the aortic arch structure. Therefore, this study focused on assessing presence of tracheal shift on chest X-ray images as pre-treatment evaluation method for GC induction due to its wide availability as an indicator for status of the mediastinum. METHODS: We retrospectively examined 33 patients who underwent MT at our facilities between April 2017 and March 2021. The patients were divided into two groups according to presence or absence of tracheal shift on chest X-ray images. Background characteristics and treatment courses in these two groups were compared. RESULTS: Among 33 patients, tracheal shift was observed on the chest X-ray images of 14 patients. Furthermore, tracheal shift was positively correlated with the time of GC induction (32.9 min vs. 11.6 min, [p < 0.05]) and the female sex (p = 0.03). Additionally, tracheal shift exhibited correlations with multiple risk factors of atherosclerosis (p = 0.04). CONCLUSIONS: In patients with tracheal shift, GC induction could be expectedly difficult. Therefore, advanced disinfection of the right upper arm and affected side of the neck during MT in preparation for changing an approach route is required.

DOI： 10.1177/19714009221084237

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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Primary central nervous system lymphoma (PCNSL) is a highly aggressive, extra-nodal non-Hodgkin lymphoma that is confined to the central nervous system (CNS) and the eyes. Most PCNSLs arise in immunocompetent older patients and less frequently in immunocompromised patients with Epstein-Barr virus infection. Although a patient's initial response to chemotherapy and radiation therapy is favorable, the clinical outcome of PCNSL remains poor compared to that of systemic lymphoma. Radiation-induced neurotoxicity is also a critical problem for patients with PCNSL. Therefore, a novel therapeutic strategy is required to overcome these challenges. Recent studies have largely uncovered the genomic landscape and associated histopathological features of PCNSL. Based on this background, novel therapeutic agents, such as Bruton's tyrosine kinase inhibitors and immune checkpoint inhibitors, have been introduced for patients with PCNSL. Here, we provide an overview of the updated histopathological and genomic characterization of PCNSL and summarize the current therapeutic strategies. We also review current preclinical PCNSL models for translational research.

DOI： 10.1007/s10014-021-00408-z

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BACKGROUND: The occipital transtentorial approach (OTA) is a very useful but challenging approach to expose the pineal region because the deep-seated arachnoid membranes usually fold and extend over the great vein of Galen (GVG), leading to dense and poor visibility. In addition, the practical aspects of arachnoid anatomy are not well understood. We aimed to develop a safe surgical procedure for the OTA according to the practical aspects of arachnoid anatomy. METHODS: The procedure is shown through an illustrative video of surgery and cadaver. Five cadavers were analyzed for their arachnoid structures and the surgical procedures via the OTA, in strict compliance with legal and ethical requirements. RESULTS: All cadavers showed a 2-layered arachnoid structure-one belonging to the occipital lobe, and the other to the cerebellum. According to our cadaveric analysis, the arachnoid attachment of the tentorial apex can be peeled bluntly, with an average distance of 10.2 mm. For our clinical presentation, a pineal tumor with hydrocephalus was detected in a 14-year-old boy. While using the OTA and expanding the deep surgical field, we detached the membrane from the tentorial apex and bluntly peeled it to reveal the deep veins. Finally, gross total removal of the tumor was achieved. CONCLUSIONS: A 2-layered arachnoid structure interposes the GVG from above and below the tentorium. The arachnoid membrane below the tentorium can be peeled off bluntly from the GVG to the attachment bundle limited by the penetrating veins. This detachment technique is useful for safe enlargement of the surgical field for the OTA.

DOI： 10.1016/j.wneu.2021.04.041

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

DOI： 10.3390/cancers13061415

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Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N=1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0-617 days. Permanent histopathology confirmed PCNSL in 142/152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% CI: 44.1-70.4% and 87.2-100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2-74.5% and 83.9-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

DOI： 10.1182/blood.2020010137

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.

DOI： 10.1093/jnen/nlaa161

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BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. METHODS: The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. RESULTS: We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. CONCLUSIONS: Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.

DOI： 10.1093/neuonc/noaa180

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

DOI： 10.1093/jnen/nlaa141

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Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

DOI： 10.25259/SNI_868_2021

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Dermatofibrosarcoma protuberans (DFSP) originates from the dermal layer of the skin; the optimum treatment is an extended marginal resection. We describe a case of DFSP of the scalp with a skull invasive defect that was thoroughly examined pathologically to determine the optimum length of surgical margins. The tumor cells infiltrated up to 26 mm into the dermal tissues, whereas no infiltrating tumor cells were present in the skull, indicating the combination of marginal resection of the dermal tissues and lower of the skull can be a clinically relevant strategy for treatment of DFSP cases with skull invasion.

DOI： 10.2176/nmccrj.cr.2020-0297

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Background: Nonconvulsive status epilepticus (NCSE) is induced by common neurosurgical conditions, for example, trauma, stroke, tumors, and surgical interventions in the brain. The aggressiveness of the treatment for NCSE depends on its neurological prognosis. Aphasic status epilepticus (ASE) is a subtype of focal NCSE without consciousness impairment. The impact of ASE on neurological prognosis is poorly documented. We describe a case of postoperative ASE resulting in verbal and memory deficits. Case Description: A 54-year-old, right-handed man with focal impaired awareness seizures underwent partial resection for a left temporal lobe tumor. No neurological deficits were observed immediately after surgery. Three days later, however, a focal to bilateral tonic-clonic seizure (FBTCS) occurred, followed by aphasia. Electroencephalography revealed 1.5 Hz left-sided periodic discharges. He was diagnosed with ASE. Multiple anti-seizure drugs were ineffective for the resolution of the patient's verbal disturbance. Nine days after the FBTCS, deep sedation with intravenous anesthetics was performed and the ASE stopped. Thereafter, his symptoms gradually improved. However, the prolonged ASE resulted in verbal and memory deficits. Automated hippocampal volumetry revealed an approximate decrease of 20% on the diseased side on magnetic resonance imaging 3 months after surgery. Conclusion: Prolonged ASE can induce verbal and memory deficits. Early intervention with intravenous anesthetics is required to obtain a favorable neurological prognosis.

DOI： 10.25259/SNI_1120_2021

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation. SIGNIFICANCE: Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit.See related commentary by Pirozzi and Yan, p. 1629.This article is highlighted in the In This Issue feature, p. 1611.

DOI： 10.1158/2159-8290.CD-20-0226

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Thiel's embalming method provides natural coloration, flexibility, and tissue plasticity, and is used widely to prepare specimens for cadaver surgical training. However, this method causes brain softening, thereby restricting the cadaver surgical training of intra-cranial procedures. In this study, three cadavers were embalmed using formalin fixation, Thiel's embalming method, and Thiel's embalming method with additional intra-cerebral ventricular formalin injection, respectively. We also established rat models of the three embalming methods to develop and determine the best method for retaining adequate brain elasticity. The intra-ventricular formalin injection in the cadaver was performed through the Kocher's point, as in the classical external ventricular drain procedure. Both, the cadaver brains and rat models yielded consistent shear wave measurements and brain surface stiffness data. Notably, the Thiel's embalming method with additional intra-cerebral ventricular formalin injection yielded suitable elasticity for brain cadaver surgical training in terms of brain mobilization and surgical field deployment, and also discharged formaldehyde in undetectable quantities. To our knowledge, this is the first report in which a fixed quality, namely, brain elasticity for the performance of head and brain cadaver surgical training, has been evaluated in a cadaver subjected to the Thiel's embalming method with immersion fixation in the cerebrospinal fluid space. We conclude that the Thiel's embalming method with additional intra-cerebral ventricular formalin injection can maintain the brain elasticity, and may therefore improve the quality of head and brain cadaver surgical training safely and easily.

DOI： 10.1007/s12565-020-00545-z

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BACKGROUND: Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects. METHODS: The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively. RESULTS: The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P < 0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds. CONCLUSIONS: Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.

DOI： 10.1016/j.wneu.2020.06.077

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

DOI： 10.1186/s40478-020-01023-3

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OBJECTIVE: This study aimed to clarify the relationship between tumor redox reaction evaluated by Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) PET/computed tomography (CT) and disease-free survival (DFS) in patients with primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS). METHODS: Fifteen consecutive patients with histologically confirmed DLBCL-CNS underwent preoperative Cu-ATSM PET/CT and F-fluorodeoxyglucose (FDG) PET/CT. Statistical features of seven first-order parameters, including the standardized uptake value (SUV); 12 second-order parameters, including gray-level co-occurrence matrices and gray-level zone size matrices; and 5 high-order parameters, including neighborhood gray-tone difference matrices, were calculated from the volume of interest. We compared DFS with parameters, including SUVmax and tumor-to-background (T/B) ratio of FDG, and SUVmax, T/B ratio, and other textural features of Cu-ATSM. RESULTS: The mean follow-up duration after PET/CT was 458 (range, 41-1071) days. The SUVmax of FDG was significantly higher than that of Cu-ATSM (P = 0.001), but the T/B ratio was not significantly different between the scans (3.49 ± 2.29 vs 2.48 ± 1.18; P = 0.244). A Mantel-Cox log-rank test revealed no significant association between SUVmax of FDG and DFS (P = 0.641). A high SUVmax of Cu-ATSM had a tendency of shorter DFS (P = 0.055). Total lesion reduction, reductive tumor volume, and T/B ratio of Cu-ATSM were significantly correlated with poor DFS by univariate analysis (P = 0.049, 0.031, and 0.007, respectively). Neighborhood gray-level co-occurrence matrix dissimilarity was significantly correlated with poor DFS (P = 0.015). CONCLUSIONS: Metabolic and textural features derived from pretreatment Cu-ATSM PET/CT could be used for predicting DFS and establishing a novel treatment strategy in DLBCL-CNS patients.

DOI： 10.1097/MNM.0000000000001197

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The suction decompression (SD) method, which proactively aspirates the blood flowing into the aneurysm and reduces the internal pressure of the aneurysm, is useful for clipping surgery of large and giant cerebral aneurysm. However, there has been little discussion on re-utilization of blood aspirated during SD. This study aimed to examine the safety, convenience, and usefulness of autologous transfusion of aspirated blood using a transfusion bag. At the time of craniotomy, the cervical carotid artery is fully exposed. An angiocatheter sheath was inserted into the carotid artery and placed in the internal carotid artery. In SD, blood was aspirated from the sheath at a constant speed and quickly stored in a blood transfusion storage bag. Blood aspiration was repeated with a new syringe; once the transfusion bag was full, the blood was re-administered to the patient. Changes in vital sign and hemoglobin/hematocrit values before and after SD were examined in five cases performed in this procedure. The aspirated blood volumes of five cases ranged from 130 to 400 mL, and all aspirated blood was successfully re-transfused. There was no critical change in vital sign, and no significant decrease in the hemoglobin/hematocrit value. No findings suggestive of complications of thrombus formation, infection, and hemolysis were noted. Re-transfusion of aspirated blood during SD using a transfusion bag is a simple and safe method, which can minimize potential risk of re-utilizing aspirated blood, and enables the safe and easy execution of SD regardless of aspirated blood volume.

DOI： 10.2176/nmc.tn.2018-0299

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PURPOSE: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. EXPERIMENTAL DESIGN: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. RESULTS: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo-evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. CONCLUSIONS: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

DOI： 10.1158/1078-0432.CCR-18-4144

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Pediatric low-grade gliomas (PLGGs) have relatively favorable prognosis and some resectable PLGGs, such as cerebellar pilocytic astrocytoma, can be cured by surgery alone. However, many PLGG cases are unresectable and some of them undergo tumor progression. Therefore, a multidisciplinary approach is necessary to treat PLGG patients. Recent genomic analysis revealed a broad genomic landscape underlying PLGG. Notably, the majority of PLGGs present MAPK pathway-associated genomic alterations and MAPK signaling-dependent tumor progression. Following preclinical evidence, many clinical trials based on molecular target therapy have been conducted on PLGG patients, some of whom exhibited durable response to target therapy. Here, we provide an overview of PLGG genetics and the evidence supporting the application of molecular target therapy in these patients.

DOI： 10.1007/s10014-019-00340-3

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In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.

DOI： 10.1111/cas.13903

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

DOI： 10.11477/mf.1436203922

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Publishing type：Research paper (scientific journal)   Publisher：Medknow  

DOI： 10.4103/ajns.ajns_158_19

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OBJECTIVE: Erythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment. METHODS: To develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury. To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO. RESULTS: High-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups. CONCLUSION: EPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.

DOI： 10.1371/journal.pone.0214351

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OBJECTIVE: Postoperative C5 palsy is a well-known complication after cervical decompression with either a posterior or an anterior approach. Its cause has been discussed more regarding the posterior approach. The main hypothesis is that postoperative spinal cord shift causes root traction and palsy. However, the pathogenesis in anterior cases has not been fully described. Therefore, the purpose of this study was to clarify the risk factors for C5 palsy in the anterior approach through our C5 palsy cases. METHODS: A total of 149 surgical patients with an anterior cervical lesion were treated by a specific spinal surgeon under consistent same treatment strategy. Of these patients, 88 who satisfied the evaluation criteria were enrolled. Postoperative C5 palsy was defined as postoperative weakness of the deltoid with or without weakness of the biceps brachii. Risk factors of C5 palsy were extracted from clinical backgrounds, surgical approaches, and radiologic findings from patients with palsy. RESULTS: Four sides of 3 individuals (4.6%) who underwent multiple corpectomy developed C5 palsy. All paralyses became evident several days after the surgery and recovered. Older age, multiple corpectomy, postoperative spinal cord shift, and foraminal stenosis of C4-5 and C5-6 were statistically extracted as causative factor of C5 palsy. In the patients with palsy, distortion of the anterior nerve root as a result of a residual vertebral spur was observed with anterior spinal cord shift after anterior corpectomy. CONCLUSIONS: Multiple corpectomy for patients with longer anterior lesions and locally developed kyphosis is related to a larger postoperative cord shift, which can cause the occurrence of C5 palsy. Moreover, C4-5 or C5-6 foraminal stenosis can accelerate tethering of the C5 or C6 nerve root. Older patients undergoing multiple corpectomy are susceptible to these risks of palsy. Appropriate patient selection and sufficient additional foraminotomy should be considered for extensive anterior lesions and locally developed kyphosis to avoid postoperative C5 palsy.

DOI： 10.1016/j.wneu.2018.08.240

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DOI： 10.1158/1078-0432.CCR-18-2312

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DOI： 10.1016/j.cell.2018.08.038

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Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

DOI： 10.1073/pnas.1805751115

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BACKGROUND: Primary central nervous system lymphoma(PCNSL)is a primary brain tumor, which appears commonly and occupies around 4.6% of all primary brain tumors. The standard therapy for this tumor is high-dose methotrexate chemotherapy(HD-MTX)and whole-brain irradiation. No salvage therapies for HD-MTX therapy-refractory or recurrent PCNSLs have been standardized. In our institution, ESHAP therapy(high-dose cytarabine:2,000mg, cisplatin:25mg/m², etoposide:40mg/m², methylprednisolone:500mg)was administered as a secondary chemotherapy, and the efficiency was examined. METHODS: We administered ESHAP therapy as secondary chemotherapy for patients with refractory/recurrent PCNSL after HD-MTX therapy. Patients with PCNSL who were diagnosed and treated at our institute since 1996 were retrospectively studied. Clinical evaluations were performed based on Karnofsky Performance Status and overall survival, and the effect of ESHAP therapy was evaluated using the Response Assessment in Neuro-Oncology criteria. RESULTS: The number of patients with refractory/recurrent PCNSLs were 18(28-77 years of age, median age of 58.5 years). The response rate(RR)after the first course of salvage ESHAP therapy was 77.8%(14 cases), and complete response(CR)was achieved in 6 cases. The RR after the final course of ESHAP therapy was as high as 61.1%(11 cases), and 4 patients retained CR status. In patients with refractory PCNSL who were treated with HD-MTX, the RR in the final course of salvage ESHAP therapy was as high as 77.8%(7 cases), and 3 patients retained CR status during the periods. The occurrence rate of Grade 3 or higher adverse events, according to the Common Terminology Criteria for Adverse Events version 4.0, was 66.7%(12 cases);all events that were associated with blood and lymphatic system disorders were quickly alleviated, and no fatal adverse events occurred. CONCLUSION: In this study, we retrospectively examined the efficacy of ESHAP therapy as a secondary chemotherapy for patients with refractory/recurrent PCNSL after receiving HD-MTX therapy. Based on our findings, we suggest that ESHAP therapy should be considered as an encouraging secondary chemotherapy for patients with refractory/recurrent PCNSL.

DOI： 10.11477/mf.1436203773

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The utility of surgical simulation with three-dimensional multimodality fusion imaging (3D-MFI) has been demonstrated. However, its potential in deep-seated brain lesions remains unknown. The aim of this study was to investigate the impact of 3D-MFI in deep-seated meningioma operations. MATERIAL AND METHODS: Fourteen patients with deeply located meningiomas were included in this study. We constructed 3D-MFIs by fusing high-resolution magnetic resonance (MR) and computed tomography (CT) images with a rotational digital subtraction angiogram (DSA) in all patients. The surgical procedure was simulated by 3D-MFI prior to operation. To assess the impact on neurosurgical education, the objective values of surgical simulation by 3D-MFIs/virtual reality (VR) video were evaluated. To validate the quality of 3D-MFIs, intraoperative findings were compared. The identification rate (IR) and positive predictive value (PPV) for the tumor feeding arteries and involved perforating arteries and veins were also assessed for quality assessment of 3D-MFI. RESULTS: After surgical simulation by 3D-MFIs, near-total resection was achieved in 13 of 14 (92.9%) patients without neurological complications. 3D-MFIs significantly contributed to the understanding of surgical anatomy and optimal surgical view (p < .0001) and learning how to preserve critical vessels (p < .0001) and resect tumors safety and extensively (p < .0001) by neurosurgical residents/fellows. The IR of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 100% and 92.9%, respectively. The PPV of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 98.8% and 76.5%, respectively. CONCLUSIONS: 3D-MFI contributed to learn skull base meningioma surgery. Also, 3D-MFI provided high quality to identify critical anatomical structures within or adjacent to deep-seated meningiomas. Thus, 3D-MFI is promising educational and surgical planning tool for meningiomas in deep-seated regions.

DOI： 10.1080/02688697.2018.1485877

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BACKGROUND: Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%-20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy-d-glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. CASE DESCRIPTION: A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. CONCLUSION: In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

DOI： 10.1016/j.wneu.2018.02.147

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

Objective: The potential of positron emission tomography/computed tomography using 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of 62Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG). Method: 56 patients with glioma of World Health Organization grade 2–4 were enrolled. All participants had undergone both 62Cu-ATSM PET/CT and 18F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox’s proportional hazards model. Results: Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using 62Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using 62Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p &lt
0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using 62Cu-ATSM PET/CT showed significant difference of progression-free survival (p &lt
0.05). Conclusions: 62Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to 18F-FDG PET/CT.

DOI： 10.1007/s12149-018-1241-4

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Background: Bow hunter's syndrome (BHS) is rare and typically induced by mechanical compression of the dominant vertebral artery (VA) during head rotation. We report a case of BHS induced by nondominant VA compression in which contralateral VA patency was preserved. Definite diagnosis of BHS is not often feasible because of transient symptoms and nonspecific clinical features, such as vertigo or dizziness, especially in nondominant VA compression. We discuss the diagnostic clues of BHS and clinical features of BHS caused by nondominant VA compression through a literature review. Case Description: A 65-year-old man suffered repeated bouts of dizziness whenever his head was rotated to the left. This dizziness was consistently accompanied by downbeat nystagmus (DBN). Radiography revealed left VA compression by a lateral osteophyte at the C3-C4 level only during left head rotation. In contrast, patency of the right VA, which was almost equivalent in size to the left VA, was preserved during head rotation. The distinctive clinical finding of head rotation-induced DBN, which is usually associated with lesions involving the caudal midline cerebellum, was observed. Symptoms disappeared immediately after left VA decompression with osteophytectomy and C3-C4 fusion. Conclusions: Despite excellent flow through the contralateral VA, occlusion of the nondominant VA occasionally induces BHS. According to a review of the literature, BHS cases do not always depend on the VA on one side for blood supply. Head rotation–induced DBN can be useful for diagnosis of BHS, even in cases of nondominant VA compression.

DOI： 10.1016/j.wneu.2017.12.167

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BACKGROUND: Intracranial mycotic aneurysm (IMA) is a rare neurovascular disease and a well-known complication after infective endocarditis. IMAs potentially carry a high mortality risk resulting from intracranial hemorrhage. Therefore, initial treatment is crucial for IMA patients, but an optimal treatment strategy remains unknown. Herein, we report 1 cases of IMA patients treated with the current usual modalities, and we provide a comprehensive literature review to propose an optimal initial treatment strategy for IMAs.
CASE DESCRIPTIONS: Case 1: An 80-year-old man received a diagnosis of ruptured IMA. He immediately underwent trapping surgery and was discharged without neurologic deficit. Case 2: A 36-year-old man with previous aortic root replacement received a diagnosis of ruptured IMA. His general condition was considered too unstable to allow him to undergo direct surgery, and the angiographic access route was limited because of the previous aortic replacement surgery. Therefore, we selected conservative therapy; however, the patient subsequently died after complications from a huge intracerebral hemorrhage during medical treatment.
CONCLUSIONS: On the basis of 129 IMA cases across 54 reports published from 2006 to 2016, we propose initial surgical intervention as an optimal treatment for patients with ruptured, and even unruptured, IMAs. Regarding surgical intervention, there was no significant difference in postoperative modified Rankin scale scores between direct surgery and endovascular treatment. By contrast, because antibiotic treatment significantly decreased IMA size in unruptured IMAs, antibiotic treatment might be a reasonable alternative for patients with unruptured IMAs, depending on the patient's situation.

DOI： 10.1016/j.wneu.2017.07.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Ependymomas are primary neuroepithelial malignancies that mainly occur during childhood, and arise from ependymal cells along the ventricular systems of the CNS. Recently, it was elucidated that two-thirds of supratentorial (ST) ependymomas harbor oncogenic fusions of RELA, whose protein product is the principal effector of canonical NF-kappa B signaling. RELA fusion proteins activate signaling for tumor proliferation and malignant progression, resulting in poorer prognoses in these patients compared to those in patients with other ST ependymomas. In this study, we encountered a case of C11orf-RelA fusion-positive ST anaplastic ependymoma that was diagnosed in first tumor resection surgery of multi-staged gross total resection with molecular evidence. In ependymomas, regardless of tumor location or pathological grade, subtotal resection is associated with higher rates of mortality compared with GTR. Molecular analysis based on the application of recent molecular knowledge for ST ependymomas performs a role in appropriate and individualized treatment strategies.

DOI： 10.1007/s10014-017-0297-5

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Authorship：Lead author   Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Oxford University Press  

DOI： 10.1093/neuros/nyx247

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

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

DOI： 10.1158/0008-5472.CAN-16-2263

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DOI： 10.1007/s00401-016-1664-8

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Clinical and radiological features or characteristics of posterior clinoid process (PCP) meningiomas have rarely been described because of their extreme scarcity and terminological confusion. Therefore, the strategies in the surgical intervention for PCP meningiomas have not been well established. Moreover, the presence of deep and critical neuroanatomical structures and relatively high morbidity, which can be difficult to predict preoperatively, make their surgical excision more challenging. We report two surgical cases of PCP meningioma and discuss the appropriate assessment of preoperative features and surgical strategies with review of the literature. Our study suggests that PCP meningioma may be characterized by the anterior displacement of internal carotid artery, and infero-laterally shifted posterior communicating arteries, and homonymous hemianopsia, a distinctive clinical feature. One of the key issues in PCP meningioma surgery is preservation of the optic nerve. Unlocking the optic nerve by anterior clinoidectomy and dissection, the falciform ligament is the important step to preserve vision for larger tumors. Complication with the perforators is also hazardous of these challenging surgeries than anterior clinoid meningiomas for their specific neuroanatomical structures and might not be feasible to avoid even with additional techniques and critical monitoring. A combination and multi-staged-surgical approach can be options of tailor-made surgical strategy in cases with tumor adhesion to the perforators.

DOI： 10.1007/s10143-016-0774-z

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DOI： 10.1093/neuonc/now090

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Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.
Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using C-13 metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.
Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.
Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically

DOI： 10.1158/1078-0432.CCR-15-2274

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

AimsPrimary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-B (NF-B) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-B pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.
MethodsWe conducted the systematic sequencing of 21 genes relevant to the NF-B signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.
ResultsThe results showed that 68 out of 71 PCNSLs had mutations in the NF-B gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.
ConclusionsThe prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.

DOI： 10.1111/nan.12259

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

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

DOI： 10.1016/j.ccell.2015.11.006

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DOI： 10.1093/neuonc/nou265.31

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RADIOLOGICAL SOC NORTH AMERICA  

Purpose: To compare the diagnostic performance of fluorine 18 (F-18) fluoride positron emission tomography (PET)/computed tomography (CT) with that of conventional imaging (CT and magnetic resonance [MR] imaging) in evaluating the osseous involvement in meningioma.
Materials and Methods: The study was approved by the ethics committee and institutional review board and was conducted according to the Declarations of Helsinki and Tokyo. Written informed consent was obtained from all patients. A retrospective comparative study between F-18-fluoride PET/CT and conventional imaging was conducted to detect osseous involvement in patients with a verified diagnosis of meningioma. Osseous involvement was verified by using definitive surgery (including drilling or careful sampling of the skull in all patients). The diagnostic performance, determined by calculating the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, was assessed.
Results: Data sets from a total of 78 patients with proven meningioma were compared. Osseous involvement was histopathologically confirmed in 25 patients (32%). The sensitivity, specificity, PPV, NPV, and accuracy were 92.0%, 86.8%, 76.7%, 95.8%, and 88.5% for F-18-fluoride PET/CT and 64.0%, 83.0%, 64.0%, 83.0%, and 76.9% for conventional imaging, respectively. The receiver operating characteristic (ROC) analysis revealed that the area under the ROC curve (A(z)) value of F-18-fluoride PET/CT was significantly greater than that of conventional imaging (0.965 +/- 0.02 [standard error] vs 0.703 +/- 0.066 [standard error], P &lt; .0001).
Conclusion: An approach using F-18-fluoride PET/CT improves preoperative detection of osseous involvement. In those without abnormal F-18-fluoride uptake within the skull, the patient may proceed directly to conventional surgery. However, a positive finding of osseous involvement at F-18-fluoride PET/CT should prompt confirmation by drilling or sampling of bone. (C) RSNA, 2014

DOI： 10.1148/radiol.14132118

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Objectives The aim of this study was to clarify the relationship between tumor hypoxia and microscopic diffusion capacity in primary brain tumors using Cu-62-Diacetyl-Bis (N4-Methylthiosemicarbazone) (Cu-62-ATSM) PET/CT and diffusion-weighted MR imaging (DWI).
Methods This study was approved by the institutional human research committee and was HIPAA compliant, and informed consent was obtained from all patients. Cu-62-ATSM PET/CT and DWI were performed in a total of 40 primary brain tumors of 34 patients with low grade glioma (LGG, n = 13), glioblastoma (GBM, n = 20), and primary central nervous system lymphoma (PCNSL, n = 7). Cu-62-ATSM PET/CT parameters and apparent diffusion coefficient (ADC) obtained by DWI were compared.
Results High intensity signals by Cu-62-ATSM PET/CT and DWI in patients with GBM and PCNSL, and low intensity signals in LGG patients were observed. An inverse correlation was found between maximum SUV (SUVmax) and minimum ADC (ADC(min)) (r = -0.583, p &lt; 0.0001), and between tumor/brain ratio (T/B-ratio) and ADC(min) for all tumors (r = -0.532, p &lt; 0.0001). Both SUVmax and T/B-ratio in GBM were higher than LGG (p &lt; 0.0001 and p &lt; 0.0001), and those in PCNSL were also higher than GBM (p = 0.033 and p = 0.044). The ADC(min) was lower in GBM (p = 0.011) and PCNSL (p = 0.01) than in LGG, while no significant difference was found between GBM and PCNSL (p = 0.90).
Conclusion Tumor hypoxia assessed by Cu-62-ATSM PET/CT correlated with microscopic diffusion capacity obtained by DWI in brain tumors. Both Cu-62-ATSM PET/CT and DWI were considered feasible imaging methods for grading glioma. However, Cu-62-ATSM PET/CT provided additional diagnostic information to differentiate between GBM and PCNSL.

DOI： 10.1007/s00259-014-2714-x

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A 65-year-old woman presented with basilar invagination manifesting as neck pain, dysesthesia around the lips, and truncal ataxia. The radiological findings demonstrated invagination of the odontoid process into the medulla oblongata and vertical atlantoaxial subluxation with C1 assimilation. The clivo-axial angle was 88A degrees and the cervicomedullary angle was 115A degrees, indicating severe basilar invagination. We planned occipitocervical fusion with atlantoaxial distraction using a cylindrical titanium cage. C2 pedicle screws were inserted, and the atlantoaxial joint was opened to translocate the odontoid process downward. A cylindrical titanium cage packed with local bone graft was inserted into the opened facet joint space. Occipital-C2 fusion was completed by fastening the occipital bone plates with pedicle screws using titanium rods. Postoperatively, the apex of the odontoid process descended by 7 mm, and the clivo-axial and cervicomedullary angles opened to 112A degrees and 125A degrees, respectively. Invagination of the odontoid process into the medulla oblongata was relieved. The preoperative symptoms improved, and she remained symptom-free without requiring anterior decompression over 2 years. Bone fusion of the atlantoaxial joints was completed with sustained facet distraction 12 months after the surgery, and adequate relief of the basilar invagination was maintained. The atlantoaxial distraction method using a cylindrical titanium cage can be a useful option in posterior fusion surgery for basilar invagination.

DOI： 10.1007/s10143-014-0531-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

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

DOI： 10.1158/1078-0432.CCR-13-3052

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND AND PURPOSE: Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone) was developed as a hypoxic radiotracer in PET. We compared imaging features among MR imaging and Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone)-PET, FDG-PET, and L-methyl-[C-11]methionine)-PET in gliomas.
MATERIALS AND METHODS: We enrolled 23 patients who underwent Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone)-PET and FDG-PET and 19 (82.6%) who underwent L-methyl-[C-11]methionine)-PET, with all 23 patients undergoing surgery and their diagnosis being then confirmed by histologic examination as a glioma. Semiquantitative and volumetric analysis were used for the comparison.
RESULTS: There were 10 newly diagnosed glioblastoma multiforme and 13 nonglioblastoma multiforme (grades II and III), including 4 recurrences without any adjuvant treatment. The maximum standardized uptake value and tumor/background ratios of Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone), as well as L-methyl-[C-11]methionine, were significantly higher in glioblastoma multiforme than in nonglioblastoma multiforme (P = .03 and P = .03, respectively); no significant differences were observed on FDG. At a tumor/background ratio cutoff threshold of 1.9, Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone) was most predictive of glioblastoma multiforme, with 90.0% sensitivity and 76.9% specificity. The positive and negative predictive values, respectively, for glioblastoma multiforme were 75.0% and 85.7% on Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone), 83.3% and 60.0% on L-methyl-[C-11]methionine, and 72.7% and 75.0% on MR imaging. In glioblastoma multiforme, volumetric analysis demonstrated that Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone) uptake had significant correlations with FDG (r = 0.68, P = .03) and L-methyl-[C-11]methionine (r = 0.87, P = .03). However, the Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone)-active region was heterogeneously distributed in 50.0% (5/10) of FDG-active and 0% (0/6) of L-methyl-[C-11]methionine)-active regions.
CONCLUSIONS: Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone) may be a practical radiotracer in the prediction of glioblastoma multiforme. In addition to FDG-PET, L-methyl-[C-11]methionine)-PET, and MR imaging, Cu-62-diacetyl-bis(N-4-methylthiosemicarbazone)-PET may provide intratumoral hypoxic information useful in establishing targeted therapeutic strategies for patients with glioblastoma multiforme.

DOI： 10.3174/ajnr.A3679

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Language：English   Publisher：OXFORD UNIV PRESS INC  

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Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

DOI： 10.1007/s00401-013-1141-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Purpose: The present study was conducted to assess the diagnostic performance of F-18-fluoride PET/CT in evaluating hyperostosis and osseous involvement in patients with meningioma.
Patients and Methods: Thirty-four patients with meningioma (mean age, 61 years) underwent F-18-fluoride PET/CT before surgery. In 24 patients (71%), F-18-FDG PET/CT was also given before surgery, and the results were compared. The images were reviewed by 2 board-certified nuclear medicine specialists who were unaware of any clinical information and a consensus was reached. Uptake patterns and measurements of tracers were compared with pathological findings from resected specimens, with hyperostosis and osseous involvement as the reference standard.
Results: There were 27 grade I tumors (79%) and 7 grade II tumors (21%). The primary tumor focus was identified in each patient using both F-18-fluoroide PET/CT and F-18-FDG PET/CT, but there were no significant correlations in the degree of uptake between the 2 tracers. The SUVmax, SUVmax corrected for lean body mass (SULmax), and tumor metabolic volume (TMV) for F-18-fluoride and F-18-FDG were greater in grade II tumors than in grade I tumors. Hyperostosis and osseous involvement was identified in 12 tumors (38%). The SUVmax, SULmax, and TMV of tumors visualized with F-18-fluoride PET/CT were greater in tumors with hyperostosis and osseous involvement than in those without (P = 0.005, P = 0.003, and P = 0.006, respectively). In contrast, the SUVmax, SULmax, and TMV of tumors visualized with F-18-FDG PET/CT were similar regardless of hyperostosis or osseous involvement.
Conclusions: F-18-fluoride PET/CT may improve detection of hyperostosis and osseous involvement in patients with meningioma.

DOI： 10.1097/RLU.0b013e318279fd79

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

BACKGROUND AND PURPOSE: Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, Cu-62-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia.
MATERIALS AND METHODS: 6(2)Cu-ATSM PET was performed in 22 patients with glioma, and the Cu-62-ATSM SUVmax and T/B ratio were semiquantitatively evaluated. Cu-62-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1 alpha expression, a hypoxia marker, was compared with Cu-62-ATSM uptake values.
RESULTS: The Cu-62-ATSM SUVmax and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, Cu-62-ATSM uptake was predictive of HIF-1 alpha expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1 alpha-positive glioma tissue than in HIF-1 alpha-negative tissue (P = .001). Using this optimal threshold of T/B ratio, Cu-62-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002).
CONCLUSIONS: Our results demonstrated that Cu-62-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the Cu-62-ATSM T/B ratio showed significant correlation with HIF-1 alpha expression. Thus, Cu-62-ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma.

DOI： 10.3174/ajnr.A3159

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：THIEME MEDICAL PUBL INC  

We used the combined subtemporal presigmoid and suboccpital retro-sigmoid multidirectional approach with the aid of a rotatable head frame (periauricular three-quarter twist-rotation approach) in 20 cases of petroclival meningiomas. Patients were placed in the lateral decubitus (park-bench) position. The head is twisted, rotated, and positioned 30 degrees face down in the Sugita rotatable head frame. By rotating this head frame, a 30- to 60-degree face-down position can be obtained when the suboccipital retrosigmoid route is used. Alternatively, the straight lateral or slightly brow-up position is obtained when the subtemporal presiginoid route is used. This twist-rotation approach provides multiple trajectories through the petroclival region with minimal drilling of the petrous bone, fatigue of the surgeon, and retraction of the brain.

DOI： 10.1055/s-2004-860952

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＜文献概要＞Point ・WHO脳腫瘍分類第5版では,新たに限局性星細胞系膠腫が加わった.・限局性星細胞系膠腫には,毛様細胞性星細胞腫,多形黄色星細胞腫をはじめとする6つの腫瘍型が含まれる.・限局性星細胞系膠腫の多くでMAPK経路の遺伝子異常が認められる.

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In this review, I summarized the biology of gliomas. Through past clinical and basic studies, I reviewed the evidence of the cell of origin of gliomas and the presence of brain tumor-initiating cells in gliomas, which are driven by multiple genomic alterations. In addition, the complicated tumor heterogeneity and neuronal-glioma network were studied. These mechanisms may underlie the treatment resistance and poor prognosis and support the identification of novel therapeutic targets for gliomas.

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Radiation therapy to the head occasionally leads to radiation-induced brain tumors, but synchronous or metachronous radiation-induced brain tumors are very rare. Herein, we present a case of radiation-induced glioblastoma and meningioma that were synchronously diagnosed 41 years after radiation therapy. The patient was a 49-year-old man who was diagnosed with anaplastic ependymoma at the age of 8 years. He underwent tumor resection from the right frontal lobe, followed by extended focal radiation therapy. Pathological findings were consistent with anaplastic ependymoma. Forty-one years later, the patient was transferred to the hospital due to a seizure attack. Magnetic resonance imaging revealed an irregular contrast-enhanced tumor in the right frontal white matter and a well-enhanced mass attached to the dura of the right frontal convexity. He underwent tumor resection in distinct regions. The tumors were histopathologically diagnosed as glioblastoma and meningioma, respectively. The present case reveals the risk of radiation-induced benign and malignant brain tumors even after long period, which highlights the necessity of persistent follow-up.

DOI： 10.7887/jcns.30.305

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Language：Japanese   Publisher：The Japanese Congress of Neurological Surgeons  

Medical science, including neurosurgical science, has been advanced by basic and clinical research. Unfortunately, the number of Japanese medical doctors choosing a research career has decreased in the past decade. However, the perspectives and experiences gained through basic and clinical research are expected to enhance clinical abilities. In addition, there are numerous things to learn through research experience. Herein, we discuss how research careers are important for clinical physicians. In addition, we present a brain tumor study as an example to show how basic research can contribute to clinical practice.

DOI： 10.7887/jcns.30.280

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Language：Japanese   Publisher：(一社)日本病理学会  

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脊髄硬膜動静脈瘻(SPDAVF)5例を対象に、MRI(3T MRI 3D T2 Cube画像)と3D-CTAによる画像診断の有用性について検討した。その結果、両者の再構築画像を組み合わせることで、診断と病変部位同定に大きく貢献し、その後の選択的脊髄DSAの効率化と手術シミュレーションとしての活用が可能であった。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02079&link_issn=&doc_id=20200527200008&doc_link_id=%2Fcp4strok%2F2020%2F004801%2F008%2F0042-0048%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp4strok%2F2020%2F004801%2F008%2F0042-0048%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publisher：The Japanese Society on Surgery for Cerebral Stroke  

<p>Introduction: Magnetic resonance imaging (MRI) and spinal digital subtraction angiography (DSA) are considered the gold standard for the screening and diagnosis of spinal dural arteriovenous fistula (SPDAVF). However, the flow-void signals of abnormal vessels are not always reported, even when spinal cord edema is detected with the MRI, rendering the diagnosis in such cases difficult. Similarly, although selective spinal DSA is useful for the definite diagnosis of SPDAVF, it can be a lengthy procedure requiring technical proficiency. Here, we introduce an effective diagnostic procedure with MRI (3T MRI 3D T2 Cube), followed by reconstruction of the 3D-CTA (64 row multistring detector CT).</p><p>Material and Methods: A total of 15 consecutive cases of SPDAVF present in the departmental database from April 2006 to June 2017 were reviewed in this study. Of these, we enrolled 5 patients who conducted the 3T MRI 3D T2 Cube and/or 3D-CTA with the analysis application VINCENT®.</p><p>Result: Of the 5 SPDAVF cases analyzed, 4 showed flow-void signals around the spinal cord in the 1.5T MRI T2WI. In contrast, all cases showed engorged vessels around the spinal cord with the 3D-CTA reconstructed VINCENT® image. The entry point of the influx vessels can be easily identified, resulting in simple and efficient selective spinal DSA. Furthermore, the 3D-CTA reconstructed image was helpful as a surgical simulation tool.</p><p>Conclusion: The diagnostic procedure of the 3T MRI 3D T2 Cube followed by the reconstructed 3D-CTA image markedly contributes to the diagnosis of SPDAVF and the identification of the entry point of the influx vessels and is helpful for both efficient spinal DSA and surgical simulation.</p>

DOI： 10.2335/scs.48.42

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS INC  

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Language：Japanese   Publisher：The Japanese Society for Neuroendovascular Therapy  

<p><b>Objective:</b> We report a case of the basilar artery occlusion treated with the mechanical thrombectomy through transradial approach.</p><p><b>Case presentation:</b> A 73-year-old man caused the loss of consciousness and was taken to the hospital in an ambulance. The hyperdense sign was recognized at the top of the basilar artery (BA) on head CT. The angiogram showed occlusion of the right vertebral artery (VA) and severe stenosis of the left VA at the origin. In addition, left VA was markedly tortuous. We decided to perform the mechanical thrombectomy for BA embolism, following the angioplasty of the left VA via the left radial artery. Eventually, complete recanalization was achieved after the thrombectomy.</p><p><b>Conclusion:</b> In mechanical thrombectomy, the time to reperfusion should be as short as possible. Transradial approach sometimes facilitates access to the posterior circulation.</p>

DOI： 10.20626/nkc.cr.2018-0097jnet

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J06751&link_issn=&doc_id=20190513310006&doc_link_id=%2Fcf5nokec%2F2019%2F000402%2F006%2F0090-0094%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf5nokec%2F2019%2F000402%2F006%2F0090-0094%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1436203922

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Language：Japanese   Publisher：SGH財団  

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

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03120&link_issn=&doc_id=20180730200002&doc_link_id=issn%3D0917-1495%26volume%3D28%26issue%3D8%26spage%3D764&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0917-1495%26volume%3D28%26issue%3D8%26spage%3D764&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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診断・治療を行った中枢神経系原発悪性リンパ腫(PCNSL)は78例で、大量シタラビン、シスプラチン、エトポシド、メチルプレドニゾロンを用いた化学療法(ESHAP療法)を施行したものは35例であった。そのなかで大量メトトレキサート(HD-MTX)療法を行ったが進行・再発し、二次化学療法としてESHAP療法を施行した18例(28〜77歳)を対象とした。全生存期間は3.9〜124.9ヵ月、PCNSL発症時のKarnofsky Performance Statusは30〜100に対して、ESHAP療法施行時は50〜100であった。ESHAP療法1クール目終了時のRRは77.8%で、CRを6例に認めた。ESHAP療法は1〜8クール施行し、最終クール後のRRは61.1%で、CRを4例に認めた。HD-MTX療法においてPDであった早期進行症例についても、ESHAP療法の最終クールにおけるRRは77.8%で、CRを3例に認めた。ESHAP療法における、Grade 3以上の副作用は66.7%に認め、全症例が骨髄抑制による好中球減少、あるいは血小板減少であった。

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DOI： 10.11477/mf.1436203773

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DOI： 10.2335/scs.46.58

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J02079&link_issn=&doc_id=20180205260007&doc_link_id=%2Fcp4strok%2F2018%2F004601%2F007%2F0058-0064%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp4strok%2F2018%2F004601%2F007%2F0058-0064%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：The Japanese Society on Surgery for Cerebral Stroke  

We report herein five cases of symptomatic brainstem cavernous malformations (CM). Specific surgical approaches were designed to directly access each lesion. Neuronavigation and intraoperative monitoring were used. Four lesions underwent gross total resection, and one was subtotally partially removed. None of the patients developed new neurological deficits and all cases showed an improvement based on the modified Rankin Scale and the Karnofsky Performance Status. Although brainstem CM have a relatively high rate of re-bleeding, thus adversely affecting the neurological status of the patient, recent reports have demonstrated favorable outcomes after their resection. Hence, surgical removal can be recommended for cases of symptomatic brainstem CM, particularly those with re-bleeding. An optimal surgical approach, providing direct access to the lesion, is critical for successfully resecting brainstem CM.

DOI： 10.2335/scs.46.58

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＜POINT 1＞グリオーマの発生に、IDH変異がどのようにかかわっているのかを理解しよう。＜POINT 2＞IDHを含めた遺伝子変異に基づくWHO分類(2016 CNS WHO)とIDH変異の予後因子としての位置付けを確認しよう。＜POINT 3＞IDH変異が手術を含めたグリオーマ治療に及ぼす影響と今後の治療法の展望について、最新の研究成果を知ろう。(著者抄録)

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DOI： 10.11477/mf.5002200673

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DOI： 10.11477/mf.5002200673

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60歳女性。左顔面痙攣を主訴とした。頭部単純MRI/MRAにて左後下小脳動脈(左PICA)による左顔面神経の圧迫所見を認めたため、治療目的に入院となった。左顔面痙攣に対し、異常筋反応モニタリング(AMR)併用下に動脈刺激筋反応モニタリング(AWS-EMG)を行い、術中に異常波形を確認し、微小血管減圧術を施行した。術後AMR、AWS-EMGの異常波形は消失し、顔面痙攣も改善が得られた。

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Language：Japanese   Publisher：(NPO)日本小児血液・がん学会・(NPO)日本小児がん看護学会・(公財)がんの子供を守る会  

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当科では脊髄髄内腫瘍・病変の手術において、「腫瘍にアクセスしやすい進入経路選択」「摘出に必要十分なmyelotomy」「腫瘍側の可動化と鋭的な剥離」「脊髄実質への直接的操作の回避」を心がけている。また、全例に経頭蓋MEPを行い、最近では術前のdiffusion tensor imagingによる錐体外路描出と術中の脊髄内MEPによるmappingも行っている。今回、これらのコンセプトのもと最近3年間に手術を施行した25例のアプローチ選択や手術手技、治療成績などについて報告した。疾患の内訳は、上衣腫9例、血管芽腫6例、嚢胞性病変2例、脊髄炎2例、星細胞腫、転移性腫瘍、海綿状血管奇形、孤立性線維性腫瘍、原発性悪性黒色腫、サルコイドーシスが各1例であった。手術の内容は、腫瘤性病変(20例)のうち黒色腫に対しては亜全摘、他の19例には全摘を行い、非腫瘤性病変(5例)には部分摘出または生検を行った。術後経過中に再発・再増大したものはなかった。

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We report a case of malignant tumor of nasal cavity that was invading the orbit and anterior cranial base treated by craniofacial resection. The cranial procedure was performed by reflection of dismasking facial skin flap and a facial approach for the maxillectomy performed by a sublabial superior gingival incision were combined. En block excision with a safety margin was successfully achieved due to the wide exposure of the tumor made possible with this procedure. The en block specimen included bilateral cribliform plates, the ipsilateral orbit and its contents, the upper side of the sphenoid body and maxilla, and the nasal septum. After the resection, the anterior cranial base was reconstructed using a titanium mesh plate, and the orbito-facial reconstruction was accomplished using a free abdominal fatty graft. The patient's cosmetic results were acceptable due to the orbital reconstruction and the preservation of facial nerve function.

DOI： 10.7887/jcns.15.773

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DOI： 10.7887/jcns.13.278_2

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