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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.

In recent years, knowledge transfer studies have produced a great deal of knowledge on technology transfer in MNCs. However, these studies have focused exclusively on the effects on the recipients of knowledge and not on the effects on the suppliers of knowledge. To fill this research gap in previous studies, this study takes the concept of “learning by teaching” proposed in pedagogy as a clue and demonstrates for the first time the effects on the suppliers of technological knowledge. This study (1) sets the international horizontal transfer of production technology systems among overseas subsidiaries as the research object, (2) obtains original data from 391 Japanese multinational manufacturing subsidiaries through a mail questionnaire survey, and (3) analyses the data through multiple regression analysis and Structural Equation Modeling (SEM). The results revealed that overseas subsidiaries of MNCs can make their production technology systems explicit (making them easier to teach) through technical guidance and thereby develop the conceptual skills of their engineers and operators. The results of this study open up the possibility of developing theories on (1) updating the knowledge base at the supplier of knowledge and (2) building the relationship between the supplier and the teaching materials in knowledge transfer.

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.

Objective Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH‐wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre‐ and post‐BEV eras. Methods We analyzed the data of 100 adult patients (over 18 years old) with IDH‐wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients’ OS. Results CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre‐BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post‐BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. Conclusions MGMT and CDKN2A status subdivided our cohort into three race‐specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion., CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status, while, among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion. This difference was more evident in the pre‐BEV era, but has become non‐significant in the post‐BEV era due to OS improvement in patients with CDKN2A homozygous deletion.

High vascularization is a biological characteristic of glioblastoma (GBM); however, an in-vitro experimental model to verify the mechanism and physiological role of vasculogenesis in GBM is not well-established. Recently, we established a self-organizing vasculogenic model using human umbilical vein endothelial cells (HUVECs) co-cultivated with human lung fibroblasts (hLFs). Here, we exploited this system to establish a realistic model of vasculogenesis in GBM. We developed two polydimethylsiloxane (PDMS) devices, a doughnut-hole dish and a 5-lane microfluidic device to observe the contact-independent effects of glioblastoma cells on HUVECs. We tested five patient-derived and five widely used GBM cell lines. Confocal fluorescence microscopy was used to observe the morphological changes in Red Fluorescent Protein (RFP)-HUVECs and fluorescein isothiocyanate (FITC)-dextran perfusion. The genetic and expression properties of GBM cell lines were analyzed. The doughnut-hole dish assay revealed KNS1451 as the only cells to induce HUVEC transformation to vessel-like structures, similar to hLFs. The 5-lane device assay demonstrated that KNS1451 promoted the formation of a vascular network that was fully perfused, revealing the functioning luminal construction. Microarray analysis revealed that KNS1451 is a mesenchymal subtype of GBM. Using a patient-derived mesenchymal GBM cell line, mature de-novo vessel formation could be induced in HUVECs by contact-independent co-culture with GBM in a microfluidic device. These results support the development of a novel in vitro research model and provide novel insights in the neovasculogenic mechanism of GBM and may potentially facilitate the future detection of unknown molecular targets. Supplementary Information The online version of this article (10.1007/s11033-020-06061-7) contains supplementary material, which is available to authorized users.

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.

Diffuse midline glioma, H3 K27M mutant arises from midline structures of the central nervous system and predominately affects pediatric patients. However, this disease entity was only recently established, and the clinical phenotypic spectrum remains largely unclear. We herein report a rare case of diffuse midline glioma, H3 K27M mutant with an unusual distribution in an elderly woman who presented with a diffuse glioma that invaded both sides of the thalami, and left hippocampus and frontoparietal lobes, thus mimicking a hemispheric malignant glioma. A biopsy of the lobular lesion led to a molecular diagnostic confirmation of diffuse midline glioma, H3 K27M mutant. The patient received concurrent bevacizumab and temozolomide therapy with radiation therapy and survived for 30 months. This case highlights the possibility that a glioma with cerebral hemispheric spread in an elderly patient may harbor the H3 K27M mutation.

Arterial signal intensities on magnetic resonance angiography (MRA) correlate with the relevant hemisphere’s hemodynamics in patients with cerebrovascular diseases. We evaluated whether superficial temporal artery (STA) signal intensities (SI) on MRA were useful to evaluate the postoperative cerebral hemodynamics of patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease who underwent unilateral STA-MCA anastomosis. Twenty-one consecutive patients undergoing unilateral STA-MCA anastomosis for symptomatic ICA or MCA steno-occlusive disease were enrolled. All patients underwent MRA and superficial temporal artery duplex ultrasonography (STDU) at 3 months and 1 year postoperatively. Bilateral region of interests (ROIs) on time-of-flight (TOF)-MRA source images were placed on the STA just before its bifurcation. The STA-SI ratio, which was the ratio of the SI on the operated STA to that of the contralateral STA, was calculated; the correlation between the ratio and STDU parameters was investigated. The STA diameter and flow velocities (systolic, end-diastolic, and mean) significantly correlated with the STA-SI ratio at 1 year postoperatively (p = .0302, p = .0002, p = .0029, p = .002). The end-diastolic flow velocity ratio was significantly correlated with the STA-SI ratio at 1 year postoperatively (p = .0014, r = 0.6518). The STA-SI ratio can be used to predict the extent of postoperative collateral bypass flow, and it may help predict postoperative cerebrovascular reserve.

Benign brain tumors largely affect the brain and can lead to reversible dementia, which can be resolved following the treatment of the primary etiology. Herein, we report three cases of relatively large frontal meningiomas in patients who presented with cognitive impairment as initial symptoms. The three participants demonstrated notable dementia alongside frontal meningioma. Following resection, all patients showed dramatic cognitive function improvement, and they successfully returned to society. Our cases illustrate the benefit of active surveillance with neuroimaging in selected patients, especially those who present with acute or subacute dementia.

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.

International audience; Buddha statues are a part of human culture, especially of the Asia area, and they have been alongside human civilisation for more than 2,000 years. As history goes by, due to wars, natural disasters, and other reasons, the records that show the built years of Buddha statues went missing, which makes it an immense work for historians to estimate the built years. In this paper, we pursue the idea of building a neural network model that automatically estimates the built years of Buddha statues based only on their face images. Our model uses a loss function that consists of three terms: an MSE loss that provides the basis for built year estimation; a KL divergence-based loss that handles the samples with both an exact built year and a possible range of built years (e.g., dynasty or centuries) estimated by historians; finally a regularisation that utilises both labelled and unlabelled samples based on manifold assumption. By combining those three terms in the training process, we show that our method is able to estimate built years for given images with 37.5 years of a mean absolute error on the test set. CCS CONCEPTS • Computing methodologies → Computer vision; Neural networks; • Applied computing → Fine arts.

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.

Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation is prevalent in bone tumors. In contrast to K27M mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42 for comparison with gliomas harboring K27M and no mutations in H3F3A and with G34W-mutated bone tumors. G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two glioma subgroups. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. They were notably hypermethylated in osteosarcomas with, but not without, G34W mutation. Independent component analysis revealed that G34 mutation-specific components shared a significant similarity between glioma and osteosarcoma, suggesting that G34 mutations exert characteristic methylomic effects regardless of the tumor tissue-of-origin. CRISPR/Cas9-mediated disruption of G34V-allele in KNS-42 cells led to demethylation of a subset of CGIs hypermethylated in G34R-mutated gliomas. These findings will provide a basis for elucidating epigenomic roles of G34 oncohistone in tumorigenesis.

The aim of this study was to examine the utility of surgical management of intracranial meningioma in elderly patients. A total of 138 patients with intracranial meningiomas who underwent surgery from 2008 to 2017 were divided into elderly (≥75 years old, n = 34) and younger (75 years old, n = 104) groups. Clinical and radiological data were retrospectively analyzed. Total tumor removal was achieved in 79% of elderly patients, which was similar to that in young patients (85%, p = .81). The average preoperative Karnofsky performance scale score in elderly patients was significantly lower than that in young patients (70.6 vs. 90.4, respectively; p .0001). However, the average change in the Karnofsky performance scale score after surgery was similar between the two groups (0.3 vs. -0.4, respectively; p = .36). Histopathological grading revealed that the incidence of malignant meningioma (World Health Organization grades II and III) was significantly higher in elderly patients than that in young patients (44% vs. 14%, respectively; p = .004). Among meningiomas showing chronological progression, World Health Organization grade II and III meningiomas accounted for 67% of tumors in elderly patients, but only 23% in younger patients (p = .01). These data suggest that surgical removal of meningiomas may be a safe and useful treatment strategy in elderly patients.

Background Coronary artery disease (CAD) patients receiving antiplatelet agents occasionally undergo craniotomy. We aimed to clarify clinical outcomes after craniotomy for unruptured intracranial aneurysm (UIA) in patients with CAD. We also aimed to identify the possible predictive factors for morbidity and surgical complications in patients on antiplatelet treatment. Methods We retrospectively analyzed 401 consecutive patients who had undergone craniotomy for UIA at our institution between January 2006 and December 2016. Forty-three patients (10.7%) received antiplatelet agents during the perioperative period. The underlying reasons for antiplatelet treatment were CAD in 12 patients and other diseases in 31 patients. Results Severe morbidity and intracranial hemorrhage occurred more commonly and symptomatic brain infarction occurred less frequently in patients with CAD compared to patients with other underlying diseases (16.7% versus 3.2%, 16.7% versus 9.7%, and 8.3% versus 16.1%, respectively), though differences between the two groups were not significant. Univariate analysis revealed that a low preoperative baseline platelet count was significantly correlated with the occurrence of intracranial hemorrhage (cutoff value, 16.5 × 104/µL; odds ratio (OR), 46.67; 95% confidence interval (CI), 3.88–561.95; p = 0.0005), and a high baseline platelet count tended to correlate with severe morbidity (cutoff value, 29.8 × 104/µL; OR, 11.33; 95% CI, 0.88–145.52; p = 0.0550). Conclusions Our results suggest that surgical complications and clinical outcomes after craniotomy may depend on the underlying reason for antiplatelet treatment. Moreover, a preoperative platelet count can be useful in predicting the occurrence of intracranial hemorrhage and severe morbidity after craniotomy in patients receiving antiplatelet agents.

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.

First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. To elucidate these potential survival benefits, we retrospectively analyzed survival in glioblastoma patients receiving BEV. We analyzed survival in 120 patients with IDH-wild type glioblastoma treated from 2002 to 2018. Overall survival (OS) was assessed in three treatment era subgroups [pre-temozolomide (TMZ), TMZ, and TMZ–BEV], and the correlations of prognostic factors with survival were evaluated. An improvement in survival was observed after BEV approval (median OS in the pre-TMZ, TMZ, and TMZ–BEV eras: 14.6, 14.9, and 22.1 months, respectively). A Cox proportional hazards model identified extent of resection and MGMT methylation status as significant prognostic factors in the TMZ era; however, these factors were not significant in the TMZ–BEV era. In subgroup analyses, patients with MGMT methylation had improved OS after TMZ introduction (pre-TMZ vs. TMZ, 18.5 vs. 28.1 months; P = 0.13), and those without MGMT methylation had significantly increased OS after BEV approval (TMZ vs. TMZ–BEV, 12.2 vs. 16.7 months; P = 0.04). Our findings imply that optional first-line administration of BEV can overcome the impact of conventional risk factors and prolong survival complementary to TMZ. The patient subgroups benefitting from TMZ and BEV did not seem to overlap, and stratification based on risk factors, including MGMT methylation status, might be effective for selecting patients in whom BEV should be preferentially used as a first-line therapy.

While Buddhism has spread along the Silk Roads, many pieces of art have been displaced. Only a few experts may identify these works, subjectively to their experience. The construction of Buddha statues was taught through the definition of canon rules, but the applications of those rules greatly varies across time and space. Automatic art analysis aims at supporting these challenges. We propose to automatically recover the proportions induced by the construction guidelines, in order to use them and compare between different deep learning features for several classification tasks, in a medium size but rich dataset of Buddha statues, collected with experts of Buddhism art history.

Simple Summary Recent research has enhanced our understanding of the diverse biological processes that occur in pediatric gliomas; and molecular genetic analysis has become essential to diagnose and treat these conditions. Because targetable molecular aberrations can be detected in pediatric gliomas, identifying these aberrations is very important. This review provides an overview of pediatric gliomas, and describes recent developments made in strategies for their diagnosis and treatment. Additionally, it presents a current picture of pediatric gliomas in light of advances in molecular genetics, and describes the current scientific progress in gliomas’ treatment using information from recently completed and ongoing clinical trials. The era of incorporating molecular genetic analysis into clinical practice is emerging. Abstract Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment.

BACKGROUND Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation was prevalent in bone tumors. In contrast to K27 mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42. Similarly, we analyzed seven and three gliomas harboring K27M and no mutations in H3F3A, respectively. These data were compared with those on bone tumors. RESULTS G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs compared with those bearing K27M and no mutations. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. These CGIs were hypermethylated in osteosarcomas with, but not without, the G34W mutation. In KNS-42 cells, CGIs with G34V-mutated histone H3.3 exhibited higher methylation levels than those with wild-type histone H3.3. This effect was also observed in the G34R-mutated glioma samples. CONCLUSIONS Gliomas bearing G34R/V mutations display characteristic methylomic alterations, some of which are shared by osteosarcomas with the G34W mutation. Deposition of G34 variants may lead to elevated methylation of otherwise hypomethylated, histone H3.3-bearing CGIs.

Kyushu University Hospital was designated a Cancer Genome Core Hospital in April 2018, and the multi-gene panel test has been introduced since August 2019. The expert panel has been held for 21 cases of the central nervous system (11 adult glioma, 5 pediatric brain tumors, 5 extramedullary tumors). Actionable gene abnormalities were newly detected in two cases. First case is epithelioid glioblastoma with BRAF V600E mutation, and second is embryonal tumor with VCL-ALK fusion. For the first case, BRAF/MEK inhibitor can be used by the prospective trial of patient-proposed healthcare services with multiple targeted agent based on the result of gene profiling by multigene panel test (NCCH1901). For the second case, we are planning to introduce ALK inhibitor by indicator-initiated clinical trial while continuing ICE therapy. The current approved agents for tumor-agnostic treatment are immune checkpoint inhibitors for mismatch repair deficient (dMMR) cases and TRK inhibitors for NTRK fusion gene-positive cases. We selected microsatellite instability (MSI) test and immunostaining of MMR gene for the indication of immune checkpoint inhibitor for recurrent glioma and Lynch syndrome that require dMMR evaluation, but FoundationOne CDx (F1CDx) allows simultaneous evaluation of MSI and MMR gene abnormalities. Regarding the indication of TRK inhibitors, F1CDx assay is selected as a companion diagnosis for ALK, NTRK1/2/3 fusion gene analysis for pediatric cases. At present, the actionable gene abnormalities are detected by multi-gene panel tests in about 10% of brain tumors. Development of tumor-agnostic treatment will expand the molecular target therapy for brain tumor in the future. Based on the experience of different schemes for molecular targeted therapy, it became clear that it is necessary to establish a cancer genome medical system for prompt introduction of precision medicine for highly malignant brain tumors.

Background Brain tumor are a major etiology of secondary intracranial hemorrhage (ICH) because ICH in patients with cancer often occurs from an intratumoral hemorrhage. However, it is sometimes difficult to detect a tumor when it is tiny and buried, especially during initial examination. Case description A 65-year-old woman who was diagnosed with pulmonary small cell carcinoma 6 months previously developed sudden-onset consciousness disturbance and left hemiparesis. Head computed tomography (CT) showed a round, high-density lesion with a diameter of 31 mm in the right thalamus. There was no enhancement with administration of contrast agent. Five days later, CT revealed significant progression of the hematoma in the thalamus with perifocal edema. She underwent total removal of the hematoma. Histopathological examination revealed a tiny cluster of metastatic cancer tissue within the hematoma. Conclusions When cerebral hemorrhage occurs in a cancer patient, we must consider the possibility of hemorrhage due to a brain metastasis.

Objectives The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. Patients and methods We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. Results A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as “molecular GBM.” IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. Conclusion GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting “molecular GBM” by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.

INTRODUCTION First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma (GBM) patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. As we have emphasized the combined effect of BEV and radiation therapy, the strategies; 1) first-line add-on BEV to TMZ-radiation for unresectable GBMs and 2) re-irradiation using IMRT under BEV administration for recurrent GBMs, have been positively applied. To elucidate these potential survival benefits, we retrospectively analyzed survival in GBM patients. METHODS We analyzed survival in 101 patients with IDH-wild type GBM treated from 2006 to 2018. PFS and OS were assessed in two subgroups (TMZ and TMZ-BEV eras), and the correlations of prognostic factors with survival were evaluated. RESULTS After BEV approval, OS prolongation tendency (median OS: 14.9 vs. 22.1 months; P = 0.52) was observed, and this tendency was clearer in unresectable cases (10.1 vs 16.1 m P = 0.38). Subanalysis showed a significant prolongation of prognosis in the MGMT unmethylated group (12.2 vs 16.7 m; P = 0.04). In 10 patients of recurrent GBMs receiving BEV combined re-irradiation, adverse events of Grade 3 or higher did not occur. All patients showed PR (N=5) or CR (N=5) after treatment. The mPFS and mOS from the recurrence were 4.3 and 9.4 months, however, no local relapse was observed at their second recurrences. CONCLUSIONS Our treatment strategy has improved the outcome of high-risk cases after BEV approval. These results implied that hypofractionated radiotherapy under BEV administration might be an efficient treatment protocol as a first-line for high-risk cases, such as after partial excision and MGMT unmethylation.

Objective Patients receiving antithrombotic treatment occasionally undergo craniotomy. We aimed to explore the impact of perioperative use of antithrombotic agents on the occurrence of surgical complications and clinical outcomes in patients with unruptured intracranial aneurysm (UIA). Patients and methods We retrospectively analyzed 401 consecutive patients who had undergone craniotomy for UIA at our institution between January 2006 and December 2016. Patients were divided into two groups: those who received oral antiplatelet and/or anticoagulant agents during the perioperative period (antithrombotic treatment group, n = 45); and those who did not (no antithrombotic treatment group, n = 356). In the antithrombotic treatment group, 40 patients received antiplatelet alone, 2 received anticoagulant alone, and 3 received antiplatelet plus anticoagulant. Results The two groups showed no significant differences in mortality, morbidity, or occurrence of symptomatic brain infarction, but intracranial hemorrhage was more frequent in the antithrombotic treatment group than in the no antithrombotic treatment group (p = 0.0187). Multivariate analysis revealed posterior location of the aneurysm (odds ratio (OR), 8.10; 95% confidence interval (CI), 2.77-23.68; p = 0.0001) and surgical procedure (OR, 5.48; 95%CI, 1.68-17.86; p = 0.0048) as significantly correlated with severe morbidity, and intracranial hemorrhage as correlated significantly with antithrombotic treatment (OR, 3.83; 95%CI, 1.36-10.76; p = 0.0110). Conclusions This study provides important information about the occurrence of intracranial hemorrhage and clinical outcomes in patients undergoing antithrombotic treatment during the perioperative period of craniotomy for UIA.

The 2007 World Health Organization classification defined a new variant of glioblastoma (GBM) containing oligodendroglioma foci as GBM with an oligodendroglioma component (GBMO), which shows a favorable clinical outcome compared with "classic" GBM. However, all of the reported cases of GBMO have been adult cases, with no previous reports of pediatric cases. In this report, we demonstrated molecular characteristics of a pediatric GBMO case, showing aggressive clinical behavior with 8-month overall survival. The case showed neither isocitrate dehydrogenase 1/2 genes (IDH1/2) mutation nor 1p/19q co-deletion, a hallmark of oligodendroglioal tumors. In addition, microsatellite instability, leading to the putative mechanism of temozolomide (TMZ) resistance, was frequently detected. Molecular genetic analysis may provide critical prognostic and therapeutic insights, especially for the pediatric glioma containing oligodendroglioma components.

In situ optical observations were performed for suspensions composed of carbon nanoparticles under the sinusoidal electric field with an amplitude around 20 kV/mm (volt per micrometer) and various frequencies. For extremely diluted suspensions of mixed fullerenes or multiwalled carbon nanotubes (MWNTs) in a silicone oil, the dark-field optical microscopy was effective for the in situ observation of the particle behavior under the electric field. The nanoparticles in a fullerene suspension under the sinusoidal electric field with a frequency of 100 Hz (in short, 100 Hz electric field) were aggregated to form a rigid spherical microstructure around the halfway between the electrodes. On the other hand, the nanoparticles in an MWNT suspension under 100 Hz electric field were also aggregated but aligned to form a chain-like microstructure which spans the electrodes. Both of the aggregated particles were stable even after the removal of the electric field, and they were redispersed by application of 10 Hz electric field.

40歳から83歳の1, 769名 (男1, 184名, 女585名) の一般中高年者について, 保有する危険因子の数と, 最大酸素摂取量 (VO2max) , および無酸素性作業閾値 (Anaerobic Threshold, AT) における酸素摂取量 (VO2AT) , 心拍数 (AT時HR) , 収縮期血圧 (AT時SBP) との関連を調査した。危険因子としてはSyndrome XとDeadly Quartetの指標を参考に, 空腹時血糖, 血圧, LDLコレステロール, HDLコレステロール, トリグリセライド, 体格指数 (Body Mass Index, BMI) の各項目について検討した。運動負荷は, 自転車エルゴメーターによるRamp負荷を行った。男女別に保有する危険因子の数 (N) によりN=0群 (n=343) ～N=5群 (n=18) (N=6該当者なし) に分類したところ, 男女とも抱えている危険因子の多い群ほど, VO2max, VO2ATともに低い値を示した。また個々の危険因子の程度も, 危険因子数が多い者ほど高い (HDLについては低い) 傾向が認められた。これに対し, AT時HRの予測最大HRに対する割合は男女ともほぼ一定で, 63.8%～68.9%であった。VO2max, VO2ATともに保有危険因子の数とおおむね逆相関を呈し, 体力レベルの低い者ほど多くの危険因子を抱えていた。AT時HRの予測最大HRに対する割合はその保有危険因子数の多寡にも影響を受けず, 運動処方の目安として合理性の高いものであると考えられた。

Background: We report a rare case of metastatic tumor in the perfusion territory of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Case Description: A 63-year-old man, who had undergone left STA-MCA anastomosis in the treatment of occlusion of internal carotid artery 4 years ago, presented with a hyperintense lesion on T2-weighted image in the left frontal lobe, the perfusion territory of the prior bypass. Follow-up magnetic resonance imaging 1 month later showed enhanced tumor within the T2 hyperintense lesion. A total removal of the tumor through another craniotomy was performed. The pathologic diagnosis was metastatic carcinoma. Conclusion: This is the first report of the metastatic carcinoma by seeding of tumor cells through STA-MCA bypass flow.

It is well known that physical exercise can reduce coronary risk factors. But how an aerobic exercise modifies coronary risk factors in relation to severity and physical fitness is still controversial. Fifty-four middle-aged women (mean age, 55 years) completed a 6-month on-site and home-based anaerobic threshold-level exercise program. The changes in coronary risk factor profiles were observed during the pre-intervention and intervention periods. Before the intervention (during control period), most coronary risk factors showed a rather unfavorable trend. After the program, their mean body weight decreased from 56.7 to 55.7 kg (p>0.05) and the proportion of body fat from 30.9 to 27.9% (p>0.05) without any reduction in lean body mass. Systolic blood pressure (SBP) decreased from 129.0 to 125.0 mm Hg (p>0.05) and diastolic blood pressure from 79.5 to 76.6 mm Hg (p>0.05). Fasting plasma glucose (FPG) declined from 109.6 to 103.4 mg/dl (p>0.05). Changes in SBP and FPG were most remarkable in their respective worst tertile. Serum lipids improved only modestly. Maximum oxygen uptake increased from 23.6 to 26.1 ml/kg/min (p>0.01). However, no significant correlations were found between changes in coronary risk factors and those in physical fitness. We conclude that the 6-month aerobic exercise program would modify women’s coronary risk factors depending on their initial values, probably independently of the changes in physical fitness.