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Medulloblastoma is the most common pediatric malignant brain tumor composed of four molecular subgroups. Recent intensive genomics has greatly contributed to our understanding of medulloblastoma pathogenesis. Sequencing studies identified novel mutations involved in the cyclic AMP-dependent pathway or RNA processing in SHH subgroup, and core-binding factor subunit alpha (CBFA) complex in group 4 subgroup. Likewise, single-cell sequencing provided detailed insights into the cell of origin associated with brain development. In this review, we will summarize recent findings by sequencing analyses for medulloblastoma.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Controversies exist regarding the aggressive recurrence of glioblastoma after bevacizumab treatment. We analyzed the clinical impact of bevacizumab approval in Japan by evaluating the clinical course and relapse pattern in patients with glioblastoma.We included 100 patients with IDH-wild-type glioblastoma from September 2006 to February 2018 in our institution. The patients were classified into the pre-bevacizumab (n = 51) and post-bevacizumab (n = 49) groups. Overall, progression-free, deterioration-free, and postprogression survivals were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were evaluated.Significant improvement in progression-free (pre-bevacizumab, 7.5 months; post-bevacizumab, 9.9 months; P = 0.0153) and deterioration-free (pre-bevacizumab, 8.5 months; post-bevacizumab, 13.8 months; P = 0.0046) survivals was seen. These survival prolongations were strongly correlated (r: 0.91, P0.0001). The nonenhancing tumor pattern was novel in the post-bevacizumab era (5 of 33). The presence of a nonenhancing tumor did not indicate poor postprogression survival (hazard ratio: 0.82 [0.26-2.62], P = 0.7377). The rate of early focal recurrence was significantly lower (P = 0.0155) in the post-bevacizumab (4 of 33) than in the pre-bevacizumab (18 of 39) era. There was a significant decrease in early focal recurrence after approval of bevacizumab in patients with unresectable tumors (P = 0.0110). The treatment era was significantly correlated with a decreased rate of early focal recurrence (P = 0.0021, univariate analysis; P = 0.0144, multivariate analysis).Approval of first-line bevacizumab in Japan for unresectable tumors may prevent early progression and clinical deterioration of glioblastoma without worsening the clinical course after relapse.

BackgroundCopy number alterations (CNAs) are common in diffuse gliomas and have been shown to have diagnostic significance. While liquid biopsy for diffuse glioma has been widely investigated, techniques for detecting CNAs are currently limited to methods such as next-generation sequencing. Multiplex ligation-dependent probe amplification (MLPA) is an established method for copy number analysis in pre-specified loci. In this study, we investigated whether CNAs could be detected by MLPA using patients’ cerebrospinal fluid (CSF).MethodsTwenty-five cases of adult diffuse glioma with CNAs were selected. Cell-free DNA (cfDNA) was extracted from the CSF, and DNA sizes and concentrations were recorded. Twelve samples, which had appropriate DNA sizes and concentrations, were subsequently used for analysis.ResultsMLPA could be successfully performed in all 12 cases, and the detected CNAs were concordant with those detected using tumor tissues. Cases with epidermal growth factor receptor (EGFR) amplification, combination of gain of chromosome 7 and loss of chromosome 10, platelet-derived growth factor receptor alpha amplification, cyclin-dependent kinase 4 amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion were clearly distinguished from those with normal copy numbers. Moreover, EGFR variant III was accurately detected based on CNA.ConclusionsThus, our results demonstrate that copy number analysis can be successfully performed by MLPA of cfDNA extracted from the CSF of patients with diffuse glioma.

Background In the treatment for glioblastoma (GBM), treatment modalities, such as bevacizumab (BEV) and carmustine wafers implants have been approved in Japan since 2013. However, it is unclear whether such a trend in treatment complexity can accelerate treatment centralization. The aim of this study was to reveal the current trend in the treatment of GBM in Japan. Methods We used diagnostic procedure combination (DPC) database to analyze the data of 1,774 patients from 305 institutions between April 2016 and March 2019. To analyze the situations associated with first-line BEV use during concurrent TMZ (temozolomide)-radiotherapy, we compared TMZ alone and TMZ–BEV groups. Results Of the 1,774 patients with GBM, tumor removal by craniotomy was performed in 1,572 (88.6%) patients, and stereotactic biopsy was performed in 156 (8.8%) patients. A total of 1,229 (69.3%) patients underwent radiotherapy, and 1,287 (72.5%) patients underwent chemotherapy. TMZ alone was administered to 878 (68.2%) and TMZ combined with BEV in 381 (29.6%) patients. In the TMZ–BEV group, as compared to the TMZ-alone group, the rate of discharge to home was significantly lower (P = 0.0044), and the rate of stereotactic biopsy was significantly higher (P P = 0.1240). Conclusion First-line BEV administration seems to be selected properly regardless of the institutional scale. This Japan-wide study of GBM treatment revealed that high level and newly introduced treatments have been steadily generalized in Japanese institutions.

Background Primary closure of the surgical wound during neurosurgical procedures is sometimes difficult because of limited ability to expand the scalp, or because the skin defect is large. Hence, our institution recently adopted the technique of intraoperative tissue expansion using a Foley catheter for these cases. We describe this easily accomplished, readily available, effective, economical technique and describe our experience performing the technique. Methods With this procedure, the subcutaneous tissue (usually the subperiosteal layer) surrounding the skin defect is dissected to make a subcutaneous pocket in which to place a 20-French Foley catheter. The standard expander is a 30-mL balloon. The catheter is inserted into the subcutaneous pocket, and the balloon is inflated with 10–30 mL of saline for 5 minutes, after which the balloon is deflated for 3 minutes in a cyclic loading manner. After sufficient expansion, the primary closure of the surgical wound is achieved with minimal tension on the surrounding skin. Results Between November 2018 and February 2020, we performed this technique in 5 patients, each with a large surgical defect in the scalp. Primary closure was achieved, and postoperative wound healing was excellent in all 5 patients. Conclusions Intraoperative skin expansion using a Foley catheter—which is easily performed, readily available, and economical—can be used to achieve surgical wound closure during various neurosurgical procedures.

BACKGROUND AND PURPOSE: Recanalization after coil embolization is widely studied. However, there are limited data on how recanalized aneurysms rupture. Herein, we describe our experience with the rupture of recanalized aneurysms and discuss the type of recanalized aneurysms at greatest rupture risk. MATERIALS AND METHODS: A total of 426 unruptured aneurysms and 169 ruptured aneurysms underwent coil embolization in our institution between January 2009 and December 2017. Recanalization occurred in 38 (8.9%) of 426 unruptured aneurysms (unruptured group) and 37 (21.9%) of 169 ruptured aneurysms (ruptured group). The Modified Raymond-Roy classification on DSA was used to categorize the recanalization type. Follow-up DSA was scheduled until 6 months after treatment, and follow-up MRA was scheduled yearly. If recanalization was suspected on MRA, DSA was performed. RESULTS: In the unruptured group, the median follow-up term was 74.0 months. Retreatment for recanalization was performed in 18 aneurysms. Four of 20 untreated recanalized aneurysms (0.94% of total coiled aneurysms) ruptured. In untreated recanalized aneurysms, class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (P = .025). In the ruptured group, the median follow-up term was 28.0 months. Retreatment for recanalization was performed in 16 aneurysms. Four of 21 untreated recanalized aneurysms (2.37% of total coiled aneurysms) ruptured. Class IIIb aneurysms ruptured significantly more frequently than class II and IIIa (P = .02). CONCLUSIONS: The types of recanalization after coil embolization may be predictors of rupture. Coiled aneurysms with class IIIb recanalization should undergo early retreatment because of an increased rupture risk.

Adult-type diffuse gliomas (Glioblastoma (GBM), Astrocytoma, Oligodendroglioma) are the most common malignant brain tumor in adults with dismal prognoses. Recent large-scale genomic studies have established molecular classification of glioma based on coding mutations and copy number variations. However, whole-genome landscape and multi-omics profiles of gliomas are not well analyzed. To understand the multi-omics genetic landscape of gliomas, we performed deep whole-genome sequencing (≥ ×120 coverage) of 357 cases with adult-type diffuse gliomas (162 GBMs, 96 astrocytomas, 99 oligodendrogliomas) along with EPIC DNA methylation profiling. RNA-seq, whole-genome bisulfate sequencing, and assay for transposase-accessible chromatin with sequencing (ATAC-seq) were performed on 349, 40, and 40 of these tumors, respectively. Deep WGS delineated a fine view of clonal architecture demonstrating mutational order during tumor initiation of each glioma. Mutational signature varies between clonal and subclonal mutations, supporting a model that tumors acquire genetic alterations by distinct mechanisms based on their developmental stage. Structural variants (SVs) are more frequently detected in higher malignant gliomas. While a complex SV is rare in Astrocytoma and Oligodendroglioma (35% of samples), a large proportion of GBM cases (85%) have complex SV with ≥ 10 breakpoints, which involves multiple different chromosomes including driver genes. CDKN2A homozygous deletions and focal CDK4 amplifications are often induced by complex SVs in GBM. These results suggest that complex SVs could play a pivotal role in the initiation and progression of GBM. Integrative analysis of transcriptomic and epigenomic profiles by similarity network fusion (SNF) identifies homogenous clusters in each glioma where those clusters are associated with mutational and SV signatures, suggesting that specific cell states may have distinct sensitivities to mutational processes. In oligodendrogliomas, the SNF classification detected a cluster with poor prognosis which has an enrichment of stem cell-like signature by CIBERSORTx deconvolution analysis. ATAC-seq demonstrated distinct features of genome-wide chromatin accessibility in each glioma which may reflect the difference of cell of the origin. Most of the focally amplified genes have open chromatin status suggesting that tumors take advantage of not only gene duplication but also a transcriptional activity to activate driver genes. Our integrated analysis uncovers molecular mechanisms of gliomas which will help to understand glioma-genesis. Citation Format: Takuma Nakashima, Yusuke Funakoshi, Atsuhito Uneda, Yuriko Sugihara, Shohei Nambu, Manabu Kinoshita, Yoshiki Arakawa, Shota Tanaka, Joji Ishida, Ryuta Saito, Ryosuke Hanaya, Koji Yoshimoto, Yoshitaka Narita, Hiromichi Suzuki. Decoding multi-omics genetic profiling reveals heterogeneity in adult pan-gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1506.

Background Brain tumors are diagnosed based on pathological and genetic features defined by WHO classification. Although targeted gene panels are clinically available, most of them do not cover all the necessary genes for the diagnosis of brain tumors. Moreover, broad copy number analysis, which the current WHO classification requires, usually lacks in the gene panel. Another problem is that those panels demand a high burden of time and cost, which disturbs rapid diagnosis and broad application. To overcome those problems, we developed a rapid and cost-effective workflow of molecular diagnosis for brain tumors. Methods Our panel contains 109 genes of which 68 are necessary for fundamental molecular diagnosis and 41 are other common driver genes. To detect copy number changes and structural variants, which generate a fused gene, additional probes are placed on common SNPs and introns containing common breakpoints. MGMT methylation status is examined at the same time using bisulfite-converted DNA amplification. Sequencing data is analyzed using a supercomputer. Results The analysis time is within 4 days: 2 days for library preparation, 1 day for sequencing, and 12 hours for analysis. Detected driver alterations were validated by whole genome sequencing data. MGMT methylation status was correlated between the results of our workflow and pyrosequencing. Conclusions We have developed a rapid comprehensive molecular analysis workflow that detects genetic alterations and MGMT methylation. Our method allows a cost-effective molecular diagnosis with high accuracy, which would improve molecular diagnosis for brain tumors.

Introduction Medulloblastoma is the most common malignant pediatric brain tumor with a poor prognosis. International collaborative efforts for sequencing the genomes of medulloblastomas have delineated the landscape of coding mutations. However, little is yet known about structural variants (SVs). Here, we analyzed whole-genome sequencing (WGS) data of medulloblastoma to reveal the comprehensive genetic aberrations, including SVs. Methods We collected and analyzed publically available WGS data of 432 cases with medulloblastoma from MAGIC consortium, ICGC, and St Jude cloud. Results The median coverage is 36.4x with no difference among cohorts. The median number of SV per case is 1.0 (WNT), 5.0 (SHH), 6.0 (Group 3), and 5.0 (Group 4), respectively. SHH medulloblastoma with TP53 mutation has significantly a greater number of SVs (77.0/sample), suggesting that genome instability by TP53 mutations gives rise to SVs. At least one SV involved in already known driver genes in 10.9% of the SHH cases, supporting a model where SV could lead to tumor initiation. Since some of those SVs are caused by copy-neutral translocation, detecting those alterations is challenging by other than WGS. Complex SVs involving TERT focal amplification are identified in 11.5% of the SHHα subtype which usually does not have TERT promoter mutation. Although TERT promoter mutation is enriched predominantly in the SHHδ subtype, overexpression of TERT may be necessary for tumor maintenance in some of the SHHα cases. Unbalanced amplifications are commonly observed in known drive genes such as PPM1D, CCND2, and PVT1 where a part of exons are exclusively amplified, implying that functionally important regions are selectively altered by SVs which could promote tumor development. Conclusions SV affects not just copy number changes but also the structure of the genome, where breakpoints exist based on gene function and regulations. SVs along with genetic mutations contribute to medulloblastoma pathogenesis.

Introduction: Glioblastoma, IDH-wild type (GBM) is the most common malignant brain tumor with a dismal prognosis. Although its coding region is well-analyzed, little is yet known about the landscape of whole-genome in GBM. Here, we analyzed whole-genome sequencing data from large cohorts to completely uncover the genetic aberrations in GBM. Methods: We analyzed 281 whole-genome sequencing data of patients with GBM, of which 152 cases are from our cohort with deep coverage (×120) and 129 cases are from a public database. Results: The median numbers of somatic mutations and structural variants (SVs) per case are 3.0/Mb and 62.5, respectively. While a complex SV is rare in other malignant brain tumors such as IDH-mutant glioma (35% of samples), a large proportion of GBM cases (85%) have complex SV with ≥10 breakpoints. CDKN2A/B homozygous deletions (HDs) are usually comprised of a simple deletion in IDH-mutant glioma whereas about a quarter of CDKN2A/B HDs in GBM are induced by complex SVs. In addition, 30.5% of extrachromosomal DNA (ecDNA) involves multiple chromosomes. Taken together, complex SVs could play a key role in the initiation and progression of GBM. Our deep WGS enables us to delineate a fine view of clonal architecture, where mutational signature varies between clonal and subclonal mutations. The majority of clonal mutations consist of the clock-like signature, whereas subclonal mutations have a relatively low proportion of the clock-like signature. Instead, several other signatures including the APOBEC signature significantly increase in subclones, presuming that various mutational processes along with the clock-like signature contribute to the GBM pathogenesis in its progression phase. Conclusions: GBM evolves through exploiting complex structural variants involving multiple driver genes and the accumulation of genetic mutations caused by distinct mechanisms depending on its developmental stage.

Introduction Recent large-scale sequencing projects for IDH-mutant adult-type diffuse glioma (Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant and 1p/19q-codeleted) have revealed the genetic landscape of coding mutations. However, little is yet known about the non-coding regions and structural variants (SVs). We analyzed deep (> x120) whole-genome sequencing (WGS) to delineate the comprehensive genetic lesions of IDH-mutant gliomas. Methods We investigated WGS of 228 cases with IDH-mutant glioma (204 cases in our cohort along with 24 publically available cases). Results The median tumor mutational burden in astrocytoma and oligodendroglioma was 2.0/Mb and 1.7/Mb, respectively. The median number of SV per case was 15.0 and 4.5, respectively. SV was involved in known driver genes in 7.7% of cases, supporting a model in which accumulation of SV as well as mutation drives tumor initiation and/or progression. The distribution of SV is biased on each chromosome, suggesting that each chromosome has a distinct susceptibility for SV. In IDH-mutant astrocytoma, complex SVs are significantly enriched on chromosome 12 which frequently involves CDK4, suggesting that SVs could lead to tumor evolution. The numbers of SVs and single nucleotide variants (SNVs) per case are correlated, presuming that IDH-mutant glioma can progress by acquiring both SNV and SV in a time-dependent manner. Conclusion SV could contribute to the development of IDH-mutant gliomas as well as mutations. Since WGS has a great resolution for genetic alterations, further analysis would enable us to uncover glioma pathogenesis.

Intracranial subdural abscess is a rare condition. Although brain abscess is often reported in relation to dental infection, reports of intracranial subdural abscess are few. Actinomyces spp. forms part of the normal flora of the oral, gastrointestinal, and genital tract, and is rarely the cause of intracranial infection; moreover, the pathogen Actinomyces meyeri is very rare. We report an exceptional case of intracranial subdural abscess caused by A. meyeri and related to dental treatment. A 57-year-old woman initially presented with a 5-day history of headache. Because left arm numbness and weakness became apparent, she was admitted to our department. She had a history of hypertension and dental problems requiring tooth extractions. Diffusion-weighted imaging (DWI) showed a 1-cm right convexity hyperintense mass above the postcentral gyrus. A post-gadolinium T1-weighted image showed a thin hypointense area with peripheral rim enhancement in the right subdural space that appeared to partially thicken in the same location as the DWI-positive mass. She underwent emergent navigation-guided drainage and 4 mL of pus was obtained. Postoperatively, left arm numbness and weakness disappeared. Cultures showed growth of A. meyeri and Fusobacterium nucleatum. She was started on intravenous penicillin G and metronidazole. After a 4-week course of the intravenous antibiotics, her headache gradually improved and the abscess in the subdural space subsided. To our best knowledge this is the first case report of intracranial subdural abscess caused by A. meyeri associated with dental treatment.

IntroductionIn our institute, most cases of carotid artery stenosis are treated by carotid artery stenting (CAS) with an open-cell stent and double-balloon protection, even if plaques are unstable. This study was performed to examine the outcome of CAS with an open-cell stent and double-balloon protection for unstable plaques.MethodsA total of 184 CAS procedures in our institute between October 2010 and February 2018 were assessed. Ultrasonography findings of low-echo plaques, plaque ulceration, or both were defined as unstable plaques. A plaque-to-muscle ratio (PMR) of >1.8 on T1-weighted black blood imaging using spin-echo was also defined as an unstable plaque. Seventy-four unstable plaques on ultrasonography and 86 unstable plaques evaluated by PMR were included. Open-cell stents and double-balloon protection (proximal balloon protection during lesion crossing and distal balloon protection after lesion crossing) were used in all cases.ResultsOn ultrasonography, perioperative asymptomatic thromboembolization was significantly more frequent in the unstable plaque group (39/74, 52.7%) than in the stable plaque group (41/110, 37.3%, p=0.0384). Asymptomatic thromboembolization was also significantly more frequent in the PMR >1.8 group (44/86, 51.2%) than in the PMR ConclusionsThe outcomes of CAS with an open-cell stent and double-balloon protection are acceptable. This method is effective and safe, even if carotid artery stenosis comprises unstable plaques.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2019-08-26, 資料番号: PA2010049000

Background Stent-assisted coil embolization (SAC) for treating anterior communicating artery (AcomA) aneurysms is safe and effective. Straightening of parent vessels by stent placement can lead to progressive thrombosis. We describe our experience with SAC for AcomA aneurysms and demonstrate the effect of straightening the parent vessels. Methods A total of 26 patients with AcomA aneurysms were treated using SAC in our institute between July 2010 and December 2017. Follow-up digital subtraction angiography was performed 6 months after treatment, magnetic resonance angiography was performed every year, and outcomes were analyzed. Results From all aneurysms (n = 24), 12 (50.0%) were neck remnant, and 12 (50.0%) were dome-filling types immediately after the procedure. At the 6-month digital subtraction angiography follow-up (n = 22), 13 (59.1%) aneurysms were complete obliteration, 8 (36.4%) were neck remnant, and 1 (4.5%) was dome filling. The median parent vessel angle was measured preoperatively at 98.1°, increased to 124.8° immediately after stent deployment, and further increased to 149.6° at the 6-month follow-up. Progressive thrombosis was observed in 13 of 22 (59.1%) aneurysms. The parent vessel angle change immediately after stent deployment in the progressive thrombosis group tended to be larger than that observed in the no thrombosis group; this change was significant at the 6-month follow-up. The median follow-up term was 18 months. No patients required retreatment. Conclusions Good SAC outcomes were achieved for AcomA aneurysms, and hemodynamic changes related to straightening of the parent vessels is a consideration in SAC.

Background Ventral lesions of upper thoracic spinal cord due to degenerative diseases are rare and often have poor operative outcomes. Anterior decompression of the lesion is difficult because of the local anatomy. This retrospective study aimed to evaluate reproducible anatomic measurements for selecting the best surgical approach for anterior decompression of ventral lesions of upper thoracic spinal cord. Methods Cases of anterior decompression of ventral lesions of upper thoracic spinal cord due to degenerative diseases at our institution from 2004 to 2015 were assessed. Several lines were drawn on magnetic resonance imaging and computed tomography scans of midsagittal sections of the upper thoracic spine to evaluate the most optimal approach for treating upper thoracic lesions. A line from the suprasternal notch to the vertebral body (suprasternal notch to vertebral body [SV] line) was accepted as baseline. Results The caudal edge of the lesion was above the SV line in 10 cases, each of which was treated via an anterior approach without sternotomy. The caudal edge was below the SV line in 7 cases, 5 of which underwent surgery with the sternum-splitting or transthoracic approach. The other 2 lesions were approached via an obliquely deviated route without sternotomy. The SV line sometimes changed with patients' posture alterations. Conclusions The SV line, a useful landmark for upper thoracic lesions, is not sufficiently reliable because it changes according to the patient's posture. By leaning in the direction of the surgical microscope, more caudal upper thoracic lesions can be reached than when using the SV line as a surgical landmark.

IntroductionWe have observed that aneurysms treated by insufficient coil embolization and filled with contrast agent immediately after the procedure are often completely occluded at follow-up. However, there are limited studies showing progressive thrombosis of aneurysms after coil embolization. Herein, we describe our experience with coil embolization for aneurysms, and discuss the factors involved in progressive thrombosis.MethodsA total of 255 aneurysms treated by coil embolization in our institute between January 2011 and June 2017 and observed >6 months were included. ‘Progressive thrombosis’ indicated that aneurysms that were neck remnant (NR) or dome filling (DF) immediately after coil embolization changed to complete obliteration (CO) at the 6-month follow-up digital subtraction angiography. The factors involved in progressive thrombosis were assessed.ResultsIn all aneurysms (n=255), 24 (9.4%) were CO, 82 (32.2%) were NR, and 149 (58.4%) were DF immediately after the procedure. At 6-month digital subtraction angiography, 123 (48.2%) were CO, 95 (37.3%) were NR, and 37 (14.5%) were DF. Retreatment for major recanalization was performed in eight cases (3.1%). One hundred and three aneurysms showed progressive thrombosis. There were significant differences in aneurysm location (P=0.0002), aneurysm dome diameter (P=0.0015), aneurysm neck diameter (P=0.0068), volume embolization ratio (P=0.0054), and endovascular procedure with stent (P=0.0264) between the progressive thrombosis and no thrombosis groups.ConclusionsProgressive thrombosis can occur in aneurysms after coil embolization depending on aneurysm location and size, and stent use. Thus, the degree of coil embolization and combination with a stent should be adjusted depending on aneurysm type.

The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis.

Purpose Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBM), the relationship between early radiographic response and survival outcome remains unclear. We performed a volumetric study of early radiographic responses in nd-GBM treated with BEV. Methods Twenty-two patients with unresectable nd-GBM treated with BEV during concurrent temozolomide radiotherapy were analyzed. An experienced neuroradiologist interpreted early responses on fluid-attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1-weighted images (GdT1WI). Volumetric changes were evaluated using diffusion-weighted imaging (DWI) and GdT1WI according to the Response Assessment in Neuro-Oncology (RANO) criteria. The results were categorized into improved (complete response [CR] or partial response [PR]) or non-improved (stable disease [SD] or progressive disease [PD]) groups; outcomes were compared using Kaplan–Meier analysis. Results The volumetric GdT1WI improvement was a significant predictive factor for overall survival (OS) prolongation (p = 0.0093, median OS: 24.7 vs. 13.6 months); however, FLAIR and DWI images were not predictive. The threshold for the neuroradiologist’s interpretation of improvement in GdT1WI was nearly 20% of volume reduction, which was lesser than 50%, the definition of PR applied in the RANO criteria. However, even less stringent neuroradiologist interpretation could successfully predict OS prolongation (improved vs. non-improved: p = 0.0067, median OS: 17.6 vs. 8.3 months). Significant impact of OS on the early response in volumetric GdT1WI was observed within the cut-off range of 20–50% (20%, p = 0.0315; 30%, p = 0.087; 40%, p = 0.0456). Conclusions Early response during BEV-containing chemoradiation can be a predictive indicator of patient outcome in unresectable nd-GBM.

Background: Osteosarcoma (OS) is a malignant tumor of the bone, which rarely occurs in the head-and-neck regions as a primary or a secondary malignancy. Adequate surgical resection is currently the mainstay of treatment for head-and-neck OS; however, en bloc resection and reconstruction can be difficult because the anatomies of these regions are complex. We present a case of an OS arising from the temporal bone 40 years after radiation therapy, which was successfully treated with en bloc resection and a one-stage reconstruction using intraoperative tissue expansion technique. Case Description: A 62-year-old woman who underwent surgery and radiotherapy for a left temporal lesion 40 years before presentation was hospitalized for aphasia and a right hemiparesis. She had a 4 × 3 cm subcutaneous mass in the left temporal area of the head. Computed tomography imaging showed destruction of the left temporal bone and a partially calcified mass. Magnetic resonance imaging showed an enhancing mass with intracranial and extracranial cystic components (5 cm and 3 cm in diameter, respectively). Due to rapid growth of the lesion, a semi-urgent surgery was performed. In this operation, a continuous narrow craniectomy was performed around the tumor using a ruler. Then, en bloc resection of the tumor, with adjacent skin, temporal muscle, skull, dura mater, and cerebral cortex, was achieved. Subsequently, a one-stage reconstruction of the dura mater, skull, and skin of the head was performed using fascia lata, artificial bone, and a local skin flap combined with intraoperative tissue expansion using a 20-French Foley catheter. Postoperative histological examinations revealed the tumor to be an OS. Conclusion: We have presented a rare case of an OS occurring from the temporal bone 40 years after radiation therapy. We describe our experience and the surgical methods in this case to provide options for surgical strategies in patients with head-and-neck OS.

Objective Periprocedural thromboembolic events are a serious complication associated with coil embolization of unruptured intracranial aneurysms. However, no established clinical rule for predicting thromboembolic events exists. This study aimed to clarify the significance of adding preoperative clopidogrel response value to clinical factors when predicting the occurrence of thromboembolic events during/after coil embolization and to develop a nomogram for thromboembolic event prediction. Methods In this prospective, single-center, cohort study, we included 345 patients undergoing elective coil embolization for unruptured intracranial aneurysm. Thromboembolic event was defined as the occurrence of intra-procedural thrombus formation and postprocedural symptomatic cerebral infarction within 7 days. We evaluated preoperative clopidogrel response and patients’ clinical information. We developed a patient-clinical-information model for thromboembolic event using multivariate analysis and compared its efficiency with that of patient-clinical-information plus preoperative clopidogrel response model. The predictive performances of the two models were assessed using area under the receiver-operating characteristic curve (AUC-ROC) with bootstrap method and compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results Twenty-eight patients experienced thromboembolic events. The clinical model included age, aneurysm location, aneurysm dome and neck size, and treatment technique. AUC-ROC for the clinical model improved from 0.707 to 0.779 after adding the clopidogrel response value. Significant intergroup differences were noted in NRI (0.617, 95% CI: 0.247–0.987, p < .001) and IDI (0.068, 95% CI: 0.021–0.116, p = .005). Conclusions Evaluation of preoperative clopidogrel response in addition to clinical variables improves the prediction accuracy of thromboembolic event occurrence during/after coil embolization of unruptured intracranial aneurysm.

Targeting the unique glioma immune microenvironment is a promising approach in developing breakthrough immunotherapy treatments. However, recent advances in immunotherapy, including the development of immune checkpoint inhibitors, have not improved the outcomes of patients with glioma. A way of monitoring biological activity of immune cells in neural tissues affected by glioma should be developed to address this lack of sensitivity to immunotherapy. Thus, in this study, we sought to examine the feasibility of non-invasive monitoring of glioma-associated microglia/macrophages (GAM) by utilizing our previously developed induced microglia-like (iMG) cells. Primary microglia (pMG) were isolated from surgically obtained brain tissues of 22 patients with neurological diseases. iMG cells were produced from monocytes extracted from the patients’ peripheral blood. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed a significant correlation of the expression levels of representative markers for M1 and M2 microglia phenotypes between pMG and the corresponding iMG cells in each patient (Spearman’s correlation coefficient = 0.5225, P <0.0001). Synchronous upregulation of CD206 expression levels was observed in most patients with glioma (6/9, 66.7%) and almost all patients with glioblastoma (4/5, 80%). Therefore, iMG cells can be used as a minimally invasive tool for monitoring the disease-related immunological state of GAM in various brain diseases, including glioma. CD206 upregulation detected in iMG cells can be used as a surrogate biomarker of glioma.

Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two randomized clinical trials, AVAglio and RTOG 0825, were performed. Bevacizumab was found to improve progression-free survival (PFS) and was reported to be beneficial for maintaining patient performance status as an initial treatment. These outcomes led to bevacizumab approval in Japan in 2013 as an insurance-covered first-line drug for glioblastoma concurrently with its second-line application. However, prolongation of overall survival was not evinced in these clinical trials; hence, the clinical benefit of bevacizumab for newly diagnosed glioblastomas remains controversial. A recent meta-analysis of randomized controlled trials of bevacizumab combined with temozolomide in recurrent glioblastoma also showed an effect only on PFS, and the benefit of bevacizumab even for recurrent glioblastoma is controversial. Here, we discuss the clinical impact of bevacizumab for glioblastoma treatment by reviewing previous clinical trials and real-world evidence by focusing on Japanese experiences. Moreover, the efficacy and safety of bevacizumab are summarized, and we provide suggestions for updating the approaches and management of bevacizumab.

Purpose Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). Methods CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. Results We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. Conclusion We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.

Accepted: 2020-06-11, 資料番号: PA2110038000

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2019-01-26, 資料番号: PA1910027000

Background We experienced two cases of ischemic stroke resulting from carotid artery occlusion associated with acute type A aortic dissection (ATAAD), in which carotid artery stenting before the surgery for ATAAD resulted in good clinical outcomes. Case 1 description: A 63-year-old woman was hospitalized for conscious disturbance, right hemiparesis, and total aphasia. Computed tomography of the head showed no abnormal findings. Computed tomography angiography showed ATAAD and bilateral common carotid artery occlusion. Surgery was not indicated for ATAAD because of a poor prognosis of ischemic stroke. However, carotid artery stenting of the left common carotid artery occlusion was successfully performed, and her neurological findings improved. The patient underwent hemiarch replacement for ATAAD on the day after carotid artery stenting. Her final modified Rankin Scale was 1. Case 2 Description: A 57-year-old woman was hospitalized for mild left hemiparesis. Magnetic resonance imaging showed right watershed infarction and right common carotid artery occlusion. Computed tomography angiography showed ATAAD. After hospitalization, conscious disturbance appeared and left hemiparesis worsened. Ischemic stroke indicated a poor prognosis for revascularization by surgery for ATAAD. Thus, carotid artery stenting of the right common carotid artery occlusion was performed. The patient’s neurological findings improved and she underwent hemiarch replacement for ATAAD at 19 days after carotid artery stenting. Her final modified Rankin Scale was 1. Conclusions In the present cases, although ischemic stroke was serious and precluded surgical indication for ATAAD, carotid artery stenting before surgery for ATAAD resulted in good clinical outcomes. Performing carotid artery stenting before surgery for ATAAD is challenging but achievable, and is a valid treatment option depending on the individual cases.

Tension-compression fatigue tests were performed on two types of Ni-based superalloy 718 with different microstructures, to which small artificial defects of various shapes and sizes were introduced. Similar tests were also conducted on hydrogen-charged specimens with defects, with a solute hydrogen content ranging from 26.3 to 91.0 mass ppm. In the non-charged specimens in particular, the fatigue strength susceptibility to defects varied significantly according to the type of microstructural morphology, i.e., a smaller grain size made the alloy more vulnerable to defects. The fatigue limit as a small-crack threshold was successfully predicted using the √area parameter model. Depending on the size of defects, the fatigue limit was calculated in relation to three phases: (i) harmless-defect regime, (ii) small-crack regime and (iii) large-crack regime. Such a classification enabled comprehensive fatigue limit evaluation in a wide array of defects, taking into consideration (a) the defect size over a range of small crack and large crack and (b) the characteristics of the matrix represented by grain size and hardness. In addition, the effect of defects and hydrogen on fatigue strength will be comprehensively discussed, based on a series of experimental results.

The transventricular endoscopic approach is an effective less invasive method for the management of symptomatic intrasellar arachnoid cysts in adults. The open area of the brain tissue defect in the infundibular recess caused by the upward compression of the cyst is a common target site for fenestration from the third ventricle. This report highlighted an alternative approach through the tuber cinereum (denoted as "trans-tuberal"), which enabled the treatment of symptomatic cases with a small opening for cyst fenestration in the infundibular recess.

Background Dural arteriovenous fistulas (AVFs) in the middle cranial fossa are rare. Pial AVFs are similarly rare but differ from dural AVFs in that they derive their arterial supply from pial or cortical arterial vessels and do not lie within the intradural region. We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. Case Description In a 58-year-old man with a subcortical hemorrhage in the right temporal lobe, digital subtraction angiography showed a dural AVF in the middle cranial fossa fed by the middle meningeal artery (MMA) and draining into the sphenopetrosal vein. A combination with a small pial AVF connected to the same sphenopetrosal vein was suspected. Open surgery was performed to directly observe the shunt points. Transarterial indocyanine green (ICG) angiography using the MMA via the superficial temporal artery on a skin flap was performed to repeatedly and distinctly evaluate the dural shunt points and to prevent cerebral thromboembolism. Although the dural supply was completely disconnected, the sphenopetrosal vein remained arterialized. ICG angiography revealed pial AVF, which was fed by the cortical arteries draining into the same drainer. The pial supply was completely disconnected, and disappearance of the dural and pial AVF was confirmed. Conclusions We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. To our knowledge, this is the first such case report described in the literature.

Introduction: There exist controversies on recurrence and aggressiveness after use of first-line bevacizumab (BEV) which has been approved in Japan and proven to be beneficial. Therefore, we analyzed the clinical impact of BEV approval by investigating the overall clinical course and glioblastoma (GBM) relapse pattern. Methods: We included 100 patients with IDH-wildtype GBM between September 2006 and February 2018 from our institution. They were subdivided into pre-BEV (n=51) and post-BEV (n=49) groups. Overall, progression-free, deterioration-free, and post-progression survivals (OS, PFS, DFS, and PPS, respectively) were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were confirmed. Results: Significant improvements in DFS (median DFS in the pre-BEV and post-BEV eras: 8.5 and 13.8 months, P=0.0046), and PFS (7.5 and 9.9 months, P=0.0153) after BEV approval were observed. These survival prolongations were strongly correlated (r: 0.91, P Conclusions: We found that, first-line BEV in Japan for unresectable tumors has a positive impact on the prevention of early progression and clinical deterioration of GBM without accelerating the clinical course after recurrence.

Unruptured aneurysms are often discovered incidentally on MRI. In some patients, multiple aneurysms cannot be treated with only craniotomy or endovascular surgery. When both craniotomy and endovascular surgery are deemed necessary, craniotomy is generally performed first because of the use of antiplatelet agents involved, followed by endovascular surgery several months later. However, no clear criteria for this treatment policy have been elicited. We investigated therapeutic outcomes in patients with aneurysms treated by craniotomy followed by endovascular surgery at our hospital.This was a retrospective study including patients undergoing craniotomy clipping of one or more unruptured aneurysms at one site and endovascular surgery for those at a different site, between January 2012 and May 2018 in our hospital. The types of treatment, interval between treatments, complications, and other factors were analyzed.This study included 22 patients who underwent a total of 25 craniotomies and 23 endovascular surgeries. The mean time from final craniotomy to initial endovascular surgery was 118 days. Although treatment-related complications occurred in three patients, they were not associated with the time interval between craniotomy and endovascular surgery or the timing of the start of the antiplatelet therapy.The treatment was successful and was carried out safely and appropriately by first performing the craniotomy, followed by a set interval of time before starting the antiplatelet therapy, and then performing the endovascular surgery. Further studies analyzing more cases are required to establish the criteria better, such as the appropriate interval time between treatments.