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Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

Background: Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification.Methods: A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated. Results: The tumor cell content was widely distributed from =50%) showed shorter PFS than those with a lower tumor cell content (

BACKGROUND In BIOMARK trial, patients with newly diagnosed glioblastoma were treated with standard chemoradiotherapy combined with first-line bevacizumab; a subset of patients continued bevacizumab beyond progression (BBP). Neurocognitive function (NCF), symptom burden, and health-related quality of life (HRQoL) were examined as secondary endpoints. PATIENTS AND METHODS In the primary protocol, newly diagnosed glioblastoma patients aged 20-75 received standard 6-week radiotherapy combined with temozolomide and bevacizumab followed by 4-week cycles of temozolomide plus bevacizumab, and then 2-3-week cycles of bevacizumab monotherapy. Upon recurrence, patients were subjected to the secondary protocol with 2-3-week cycles of bevacizumab monotherapy with or without other chemotherapeutic agents. NCF tests (Hopkins verbal learning test-revised, trail making test, and controlled oral word association), EORTC QLQ-C30/BN20, and MDASI-BT were completed by the patients. Time to deterioration (TTD) was defined as the time from randomization until a pre-specified change from baseline without further improvement or death. The Kaplan-Meier method and the log-rank test were used to assess TTD for each subscale of the above tests. RESULTS Overall, 94 patients were enrolled in the study. Analyses were based on the full analysis set cohort (N=90), excluding non-glioblastoma diagnosis by central review. The median overall survival (OS) and progression-free survival (PFS) were 25.0 and 14.9 months, respectively. Baseline HRQoL and symptom burden subscales (emotional functioning, symptom severity score, affective factor, and focal factor) were significantly associated with PFS. The median TTD was 8.7, 7.5, 8.1 months for global health status/QoL, symptom severity score, interference score, respectively. Among patients who experienced recurrence, disease progression was apparently preceded by deterioration in terms of symptom burden. CONCLUSIONS Detailed analysis of HRQoL and symptom burden may aid care of glioblastoma patients throughout the disease trajectory.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence., Highlights • Most cases of glioblastoma recur in white matter around the removal cavity after total resection plus chemo-radiotherapy. • miRNAs showing characteristically higher expression in the tumor border were related to oligodendrocyte differentiation. • Increased oligodendrocyte progenitor cells and macrophages enhance stemness and chemo-radioresistance in glioma cells. Glioblastoma (GBM) occurs in adult brain and shows rapid growth and invasion. Despite intensive treatment, the mean 5-year survival rate is still

ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P

Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.

BACKGROUND Intracranial Growing teratoma syndrome(iGTS) is a phenomenon in which a tumor with a teratoma component grows during treatment, and its pathological tissue is often a mature teratoma. Here we report a case of iGTS in which the timing of surgery was determined by tumor markers and changes in tumor size on MRI images. CASE-REPORT: 11-year-old boy with a short stature. He developed a headache and we found a pineal gland tumor on MRI. Due to obstructive hydrocephalus, an endoscopic third ventriculostomy and biopsy were performed. The pathological diagnosis was mature teratoma, but AFP was elevated at 104.2 ng/mL. Considering NGGCT, we started chemoradiation immediately. Despite the declining AFP, it gradually increased, at which point we suspected iGTS. Resection was considered, but at some point tumor growth had stopped, so radiation therapy and a second course of ICE therapy preceded the resection. Thereafter, the tumor was completely removed, and a third course of ICE therapy was performed. DISCUSSION The onset mechanism of iGTS has not been elucidated, and its prediction is difficult. Early resection of the tumor is required, but discontinuation of radiation therapy and side effects of chemotherapy also need to be considered. In our case, resection was performed after normalization of AFP and recovery of myelosuppression. The patient followed an uneventful course, but the timing of resection was controversial. CONCLUSION We experienced a case of iGTS in NGGCT, a mixed tumor with mature teratoma. The optimal timing of the resection was discussed and literature was reviewed.

INTRODUCTION Central nervous system germ cell tumor (GCT) is one of the pediatric brain tumors. Although there have been epidemiological studies in the past, long-term prognosis and the late effects remained unclear. In this study, we examined GCT over the past 41 years in Kumamoto prefecture. METHODS Epidemiological features and complications with radiation-induced tumors were searched in patients diagnosed with GCT in the 41-year period from 1977 to 2018. RESULTS There were 93 patients diagnosed with GCT. These cases were divided into 14-year periods before and after incorporation of chemotherapy into the treatment, and the results for germinomas were compared. An improvement in the 10-year survival rate from 12 of 23 cases (52.2%) between 1977 and 1991 to 19 of 28 cases (67.9%) between 1992 and 2006 was observed. The 10-year survival rate for germinoma cases that received medical treatment during a more recent 5-year period between 2004 and 2009 increased to over 90%. However, 10.3% of all long-term survivors of GCT developed radiation-induced glioblastoma. The examination results showed that regardless of the tumor type, patients who received a high dose of radiation during their initial treatment developed the complication of radiation-induced glioblastoma within 10 to 25 years after their initial treatment. CONCLUSION This study suggests that the long-term survival rates for GCT are improving but the rate of radiation-induced glioblastoma in these cases are too high to be ignored. Long-term follow-up of at least 10 years is essential to effectively evaluate the details of treatment for pediatric brain tumors.

Purpose: We aimed to determine whether 3T diffusion-weighted imaging (DWI) has an additive value relative to contrast-enhanced MR imaging for the detection of disseminated lesions in patients with primary malignant brain tumors. Methods: We included consecutive 12 patients with nodular disseminated lesions of primary malignant brain tumors that were confirmed by surgery or follow-up MR imaging. All underwent conventional MR imaging, DWI at b = 1000 and 3000 s/mm2, post-contrast T1-weighted and 3D gradient-echo imaging at 3T. For the largest lesion per person, two radiologists independently evaluated the presence of additional information on DWI compared with postcontrast MR images using a 4-point scoring system. On DW images, one radiologist measured the lesion-to-brain contrast ratio (LBCR). Results: Compared with postcontrast studies, radiologists 1 and 2, respectively, assigned more apparent lesion conspicuity in 2 (17%) and 1 (8%) DWI at b = 1000 s/mm2 and 4 (33%) and 5 (42%) DWI at b = 3000 s/mm2 studies. For one of them, the mean score was significantly higher for b = 3000 s/mm2 than b = 1000 s/mm2 (P < 0.05). Interobserver agreement for DWI at b = 1000 s/mm2 and b = 3000 s/mm2 was very good (κ = 0.85; 95% CI, 0.63–1.00) and excellent (κ = 0.93; 95% CI, 0.78–1.00), respectively. The mean LBCR was significantly higher for DWI at b = 3000 s/mm2 than DWI at b = 1000 s/mm2 (P < 0.01). Conclusion: In the detection of disseminated lesions in patients with primary malignant brain tumors, 3T DWI has an additive value relative to contrast-enhanced MR imaging. DWI at b = 3000 s/mm2 may be more useful than DWI at b = 1000 s/mm2.

Purpose The purpose of the present study was to compare different software algorithms for processing DSC perfusion images of cerebral tumors with respect to i) the relative CBV (rCBV) calculated, ii) the cutoff value for discriminating low- and high-grade gliomas, and iii) the diagnostic performance for differentiating these tumors. Methods Following approval of institutional review board, informed consent was obtained from all patients. Thirty-five patients with primary glioma (grade II, 9; grade III, 8; and grade IV, 18 patients) were included. DSC perfusion imaging was performed with 3-Tesla MRI scanner. CBV maps were generated by using 11 different algorithms of four commercially available software and one academic program. rCBV of each tumor compared to normal white matter was calculated by ROI measurements. Differences in rCBV value were compared between algorithms for each tumor grade. Receiver operator characteristics analysis was conducted for the evaluation of diagnostic performance of different algorithms for differentiating between different grades. Results Several algorithms showed significant differences in rCBV, especially for grade IV tumors. When differentiating between low- (II) and high-grade (III/IV) tumors, the area under the ROC curve (Az) was similar (range 0.85-0.87), and there were no significant differences in Az between any pair of algorithms. In contrast, the optimal cutoff values varied between algorithms (range 4.18-6.53). Conclusions rCBV values of tumor and cutoff values for discriminating low- and high-grade gliomas differed between software packages, suggesting that optimal software-specific cutoff values should be used for diagnosis of high-grade gliomas.

Glioblastoma (GBM) usually develops in adult brain white matter and shows rapid growth and invasion. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance and survive. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass by miRNA microarray. The top three miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathological oligodendrocyte lineage cells increased in the border, where numbers of macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a novel, promising target for prevention of recurrence.

Unlike in children, brain stem gliomas in adult are rare and still poorly understood. In addition, most adult brain stem gliomas result predominantly in the pons and are less often found in the medulla oblongata. Here, we report a case of an adult glioma in the medulla oblongata and its molecular biological features. A 46-year-old male presented with gait disturbance, paresthesia, and dysphagia. Magnetic resonance imaging (MRI) showed a diffuse hyper-intensive lesion in the medulla oblongata on a T2-weighted image without gadolinium contrast enhancement. We performed an open biopsy and the lesion was pathologically diagnosed as a diffuse astrocytoma. Molecular biological analyses revealed the absence of histone H3.3 mutation (H3F3A K27M), and presence of methylation of O-6-methylguanine-DNA methyltransferase (MGMT) promoter and a mutation in isocitrate dehydrogenase 1 (IDH-1). The patient received local radiotherapy and temozolomide chemotherapy. The patient's symptoms were ameliorated, and MRI showed no tumor growth at 6 months after the initial treatment. Biopsy for brain stem lesions is generally thought to have risk of complications, but if performed minimally, it is useful to diagnose and determine treatment strategy. Obtaining patient characteristics and molecular biological features will provide insight towards therapeutic treatment for adult brain stem gliomas.

Background Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown. Methods Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA). Results In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA. Conclusions Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Stressors contribute to thrombosis and insulin resistance. Since obesity-related adipose inflammation is also involved in these pathological states, we assumed that stress correlates with adipose inflammation. Male mice were subjected to 2-week intermittent restraint stress. Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. To examine effects of MCP-1 blockade, animals were treated with control or neutralizing antibody, or transplanted with control or 7ND (dominant-negative form of MCP-1)-overexpressing adipose-derived stromal cells (ADSCs). Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. Adipose stromal cells highly expressed MCP-1. The stress-induced adipose inflammation increased PAI-1 and TF but did not give rise to thrombus formation. Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. Neutralizing antibody and 7ND-ADSCs reversed stress-induced adipose inflammation, procoagulant state, and insulin resistance. Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1.

In order to develop the interfacial area transport equation for the interfacial transfer terms in the two-fluid model, accurate data sets on axial development of local parameters such as void fraction, interfacial area concentration, interfacial gas velocity and Sauter mean diameter are indispensable to verify the modeled source and sink terms in the interfacial area transport equation. From this point of view, local measurements of both group 1 spherical/distorted bubbles and group 2 cap/slug bubbles in vertical upward air–water two-phase flow in a large diameter pipe with 200 mm in inner diameter and 26 m in height were performed at three axial locations of z / D = 41.5, 82.8 and 113 as well as 11 radial locations from r / R = 0–0.95 by using four-sensor probe method. Here, z , r , D and R are the axial distance from the inlet, radial distance from the pipe center, pipe diameter and pipe radius, respectively. The liquid flow rate and the void fraction ranged from 0.0505 m/s to 0.312 m/s and from 1.98% to 32.6%, respectively in the present experiment. The flow condition covered extensive region of bubbly flow, cap turbulent flow as well as their transition. The extensive analysis on the radial profiles of local flow parameters and their axial developments demonstrate the development of interfacial structures along the flow direction due to the bubble coalescence and breakup and the gas expansion. The significant decrease in void faction and interfacial area concentration and the increase in Sauter mean diameter and interfacial velocity were observed when the gradual flow regime transition occurred. Finally, the net change in the interfacial area concentration due to the bubble coalescence and breakup was quantitatively investigated in the present paper to reflect the true transfer mechanisms in observed two-phase flows.

Object: Brain tumors are the most common solid tumors in children and their prognosis is poor. Epidemiologic data from a population-based cancer registry provide the information necessary to determine the incidence rate of pediatric brain tumors. The aim of this study was to determine the epidemiology of childhood primary intracranial tumors in Kumamoto Prefecture, Japan. Methods: We surveyed 210 patients younger than 15 years who were diagnosed with primary intracranial tumors between 1989 and 2008; 159 (75.7%) of the tumors were confirmed microscopically. Results: The age-adjusted annual incidence rate was 36.1 cases per million children. The boys/girls ratio was 1.31. The age-specific annual incidence rate was 28.5-, 40.9-, and 38.4 cases per million for the 0- to 4-, 5- to 9-, and 10- to 14-year age group, respectively. The incidence was highest in 10- to 14-year-old boys (53.6 per million) and lowest in 10- to 14-year-old girls (22.6 per million). The most common tumor was astrocytoma (35.7%) with an annual incidence rate of 13.2 per million, followed by germ cell tumor (14.3%, 5.0 per million), craniopharyngioma (10.5%, 3.8 per million), medulloblastoma (10.0%, 3.7 per million), and ependymoma (4.8%, 1.5 per million). The distribution of the tumor type varied with the patient age and gender. Although there were no germ cell tumors in 0- to 4-year-old boys, they were the second-most common tumor in 10- to 14-year-old boys. Conversely, while there were no medulloblastomas in 10- to 14-year-old girls, their incidence was high in 0- to 4-year-old girls. Conclusions: In this Kumamoto survey, the incidence rate of primary intracranial tumors in children was similar to that in Western countries. However, the incidence and relative frequency of particular histological types of childhood brain tumors such as germ cell tumors and craniopharyngiomas were different between Japan and Western countries.

It has previously been suggested that the spin trap agent alpha-phenyl-N-tert-butylnitrone (PBN) induces neurite outgrowth through activation of the Ras-ERK pathway in PC12 cells. However, the chemical properties of PBN contributing to its biological function and the detailed mechanism for the activation of Ras by PBN remain unknown. This study demonstrates that the hydrophobic structure of PBN is related to the activation of Ras, by comparing with hydrophilic analogues of PBN. [(14)C]-labelled PBN was found to localize in the lipid fraction and activate Ras indirectly. On the other hand, neurite outgrowth by PBN was inhibited by a nitric oxide (NO) scavenger. Moreover, the neurite outgrowth induced by PBN and the NO donor NOR4 was inhibited by the dominant negative Ras or MAPK/ERK inhibitor. Taken together, these results suggest that PBN is incorporated into the plasma membrane and induces neurite outgrowth in PC12 cells by activating the Ras-ERK pathway through NO release.

An effective coating for a tritium permeation barrier was developed by a chemical densified coating (CDC) method. This will help realize a reasonable design of the Japanese Test Blanket Module (TBM) of the International Thermonuclear Experiment Reactor (ITER). It was confirmed from results of tritium permeation experiments that the permeation reduction factor (PRF) of F82H steel with this coating reached about 300 at 600 °C. Furthermore, it was revealed by diffusion coefficient measurements that with this coating, diffusivity of deuterium is very low. With these measured tritium transport properties, a preliminary tritium permeation analysis was carried out for the Japanese ITER-TBM. It was indicated that tritium permeation through the F82H cooling pipe with the coating will be four orders of magnitude smaller than that without the coating.

BACKGROUND: Lower-grade gliomas (WHO grade II and III gliomas, including astrocytomas, oligodendrogliomas, and oligoastrocytomas) are usually less aggressive but infiltrative neoplasms, and the optimal treatment is still controversial. Studies have confirmed that lower-grade gliomas could be classified into three genetic subtypes based on IDH1/2 mutation and 1p/19q co-deletion: Type-I tumors (IDH1/2 mutated tumor with 1p/19q co-deletion), Type-II tumors (IDH1/2 mutated tumor without 1p/19q co-deletion) and Type-III tumors (IDH1/2 wild-type tumor). We sought to delineate subtype-specific prognostic values of genetic alterations. METHODS: We analyzed genetic alterations detected by exome/targeted sequencing as well as SNP-array karyotyping obtained from clinically well-annotated 700 cases with lower-grade gliomas. We performed univariate and multivariate Cox hazard proportional analyses for overall survival; multivariate models were adjusted for age ≥ 60, sex, histologic subtype, WHO grade, cohorts (Japan or The Cancer Genome Atlas) and extent of resection. RESULTS: In multivariate Cox regression model, we revealed that several genetic alterations had subtype-specific prognostic significance: chromosome 13q deletion and NOTCH1 mutation in Type-I tumors, CDK4 focal amplification, PIK3R1 mutation, chromosome 20p amplification, and chromosome 9p deletion in Type-II tumors, and chromosome 7p amplification and CDKN2A/2B homozygous deletion in Type-III tumors. High risk group which consisted of patients with at least one of these genetic alterations showed poorer prognosis than low risk group which consisted of patients without them in all genetic subtypes; Hazard Ratio (95% Confidence Interval): 2.88(1.60-5.17), 3.01(1.86-4.86) and 2.40(1.40-4.12) in Type I-III tumors respectively. Most of these mutations and focal copy number variations are components of three major signaling pathways frequently affected in glioblastomas, suggesting deregulation of these pathways is a core requirement of tumor malignancy in lower-grade gliomas. CONCLUSIONS: Several genetic alterations had subtype-specific prognostic significance in lower-grade gliomas and classification based on these genetic alteration would improve patient management.

The structure of the mouse prion (moPrP) was studied using site-directed spin-labeling electron spin resonance (SDSL-ESR). Since a previous NMR study by Hornemanna et al., [Hornemanna, Korthb, Oeschb, Rieka, Widera, Wüthricha, Glockshubera, Recombinant full-length murine prion protein, mPrP (23-231): purification and spectroscopic characterization, FEBS Lett. 413 (1997) 277-281] has indicated that N96, D143, and T189 in moPrP are localized in a Cu(2+) binding region, Helix1 and Helix2, respectively, three recombinant moPrP mutations (N96C, D143C, and T189C) were expressed in an Escherichia coli system, and then refolded by dialysis under low pH and purified by reverse-phase HPLC. By using the preparation, we succeeded in preserving a target cystein residue without alteration of the alpha-helix structure of moPrP and were able to apply SDSL-ESR with a methane thiosulfonate spin label to the full-length prion protein. The rotational correlation times (tau) of 1.1, 3.3, and 4.8ns were evaluated from the X-band ESR spectra at pH 7.4 and 20 degrees C for N96R1, D143R1, and T189R1, respectively. tau reflects the fact that the Cu(2+) binding region is more flexible than Helix1 or Helix2. ESR spectra recorded at various temperatures revealed two phases together with a transition point at around 20 degrees C in D143R1 and T189R1, but not in N96R1. With the variation of pH from 4.0 to 7.8, ESR spectra of T189R1 at 20 degrees C showed a gradual increase of tau from 2.9 to 4.8ns. On the other hand, the pH-dependent conformational changes in N96R1 and D143R1 were negligible. These results indicated that T189 located in Helix2 possessed a structure sensitive to physiological pH changes; simultaneously, N96 in the Cu(2+) binding region and D143 in Helix1 were conserved.

Background: Esophageal carcinoma (EC) is a major malignancy with a poor prognosis. Although esophageal cancers rarely metastasize to the brain, the number of patients diagnosed with brain metastases (BM) from EC is steadily increasing. Therefore, the risk factors for BM from EC should be known. Here we reviewed our experiences and the previous literature regarding BM from EC. Methods: Between 2000 and 2013, we retrospectively reviewed the clinical features and neurological findings of 19 patients diagnosed with and treated for BM from EC to determine the clinical risk factors and features. Results: In all patients, the lesions were partially or completed located in the thoracic esophagus, and the average size of the EC lesion at diagnosis was 5.8 ± 2.9 cm, which was smaller than the previously reported size of EC lesions accompanied by BM. Patients without lung metastases were more common than those with lung metastases. The lesions in the 13 patients included squamous cell carcinoma (SqCC) in 9 (69.2%) and small cell carcinoma (SmCC) in 3 (23.0%). Six patients were not examined. Although there was no trend toward a higher incidence of BM in patients with adenocarcinoma and SqCC, this trend was observed in patients with SmCC. Excluding a single patient with SmCC, all patients had beyond stage III disease at EC diagnosis. Conclusions: Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children

Ceramic coatings on structural material are expected as a barrier for tritium permeation in fusion devices. A Cr2O3–SiO2–CrPO4 coating on stainless steel by use of a chemical densified coating (CDC) method was experimentally studied. The sample disk was exposed to a deuterium plasma and an analyzing beam of 3He ions irradiated the sample to observe deuterium concentration profiles. It was found that a very long time, typically 10 ks at 563 K, was needed for deuterium to diffuse from the surface to a few μm in depth. The profiles were analyzed with a diffusion model to obtain the diffusion coefficient of deuterium, which was expressed by 1.1 × 10−10exp(−0.71 eV/kT) [m2 s−1] between 470 and 723 K. The diffusion coefficient was about 5 orders of magnitude smaller than that in type 304 stainless steel at 563 K. The CDC coating is expected to significantly delay tritium permeation.

Glioma initiating cells (GICs) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC maintenance/differentiation, we established GIC clones having the potential to differentiate into malignant gliomas, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart. Gene Ontology analysis revealed that the expression of cell adhesion molecules, including integrin subfamilies, such as α2 and αV, and extracellular matrices (ECMs), such as collagen IV (COL4), laminin α2 (LAMA2), and fibronectin 1 (FN), was significantly upregulated during serum-induced GIC differentiation. This differentiation process, accompanied by the upregulation of MAPK as well as glioma specific proteins in GICs, was dramatically accelerated in these ECM (especially FN)-coated dishes. Integrin αV blocking antibody and RGD peptide significantly suppressed early events in GIC differentiation, suggesting that the coupling of ECMs to integrin αV is necessary for GIC differentiation. In addition, the expression of integrin αV and its strong ligand FN was prominently increased in glioblastomas developed from mouse intracranial GIC xenografts. Interestingly, during the initial phase of GIC differentiation, the RGD treatment significantly inhibited GIC proliferation and raised their sensitivity against anti-cancer drug temozolomide (TMZ). We also found that combination treatments of TMZ and RGD inhibit glioma progression and lead the longer survival of mouse intracranial GIC xenograft model. These results indicate that GICs induce/secrete ECMs to develop microenvironments with serum factors, namely differentiation niches that further stimulate GIC differentiation and proliferation via the integrin recognition motif RGD. A combination of RGD treatment with TMZ could have the higher inhibitory potential against the glioma recurrence that may be regulated by the GICs in the differentiation niche. This study provides a new perspective for developing therapeutic strategies against the early onset of GIC-associated glioma.

We previously showed tumor-associated macrophages/microglia (TAMs) polarized to the M2 phenotype were significantly involved in tumor cell proliferation and poor clinical prognosis in patients with high grade gliomas. However, the detailed molecular mechanisms involved in the interaction between TAMs and tumor cells have been unclear. Current results reveal that, in coculture with human macrophages, BrdU incorporation was significantly elevated in glioma cells, and signal transducer and activator of transcription-3 (Stat3) activation was found in both cell types. Direct mixed coculture led to stronger Stat3 activation in tumor cells than did indirect separate coculture in Transwell chamber dishes. Screening with an array kit for phospho-receptor tyrosine kinases revealed that phosphorylation of macrophage-colony stimulating factor receptor (M-CSFR, CD115, or c-fms) is possibly involved in this cell-cell interaction; M-CSFR activation was detected in both cell types. Coculture-induced tumor cell activation was suppressed by siRNA-mediated downregulation of the M-CSFR in macrophages and by an inhibitor of M-CSFR (GW2580). Immunohistochemical analysis of phosphorylated (p)M-CSFR, pStat3, M-CSF, M2 ratio, and MIB-1(%) in high grade gliomas revealed that higher staining of pM-CSFR in tumor cells was significantly associated with higher M-CSF expression and higher MIB-1(%). Higher staining of pStat3 was associated with higher MIB-1(%). High M2 ratios were closely correlated with high MIB-1(%) and poor clinical prognosis. Targeting these molecules or deactivating M2 macrophages might be useful therapeutic strategies for high grade glioma patients.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

A ROSA/LSTF experiment was conducted for OECD/NEA ROSA Project simulating a PWR loss-of-feedwater (LOFW) transient with specific assumptions of failure of scram that may cause natural circulation with high core power and total failure of high pressure injection system. Auxiliary feedwater (AFW) was provided to well observe the long-term high-power natural circulation. The core power curve was obtained from a RELAP5 code analysis of PWR LOFW transient without scram. The primary and steam generator (SG) secondary-side pressures were maintained, respectively, at around 16 and 8 MPa by cycle opening of pressurizer (PZR) power-operated relief valve and SG relief valves for a long time. Large-amplitude level oscillation occurred in SG U-tubes for a long time in a form of slow fill and dump while the two-phase natural circulation flow rate gradually decreased with some oscillation. RELAP5 post-test analyses were performed to well understand the observed phenomena by employing a fine-mesh multiple parallel flow channel representation of SG U-tubes with a Wallis counter-current flow limiting correlation at the inlet of U-tubes. The code, however, has remaining problems in proper predictions of the oscillative primary loop flow rate and SG U-tube liquid level as well as PZR liquid level.

Background To determine the prognostic value of isocitrate dehydrogenase 1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion in Japanese patients with malignant gliomas. Methods We studied 267 malignant gliomas, which included 171 glioblastomas (GBMs), 40 anaplastic astrocytomas (AAs), 30 anaplastic oligodendrogliomas (AOs), and 26 anaplastic oligoastrocytomas (AOAs). These malignant gliomas were divided into 2 groups (Group 1: GBM + AA, Group 2: AO + AOA) according to the presence of the oligodendroglioma component. We examined IDH1 mutation and MGMT promoter methylation in each group by direct sequencing and methylation-specific PCR, respectively. We further examined 1p/19q co-deletion in Group 2 by fluorescence in situ hybridization. Survival between groups was compared by Kaplan–Meier analysis. Results In Group 1, patients with IDH1 mutations exhibited a significantly longer survival time than patients with wild-type IDH1. However, no significant difference was observed in Group 2, although patients with IDH1 mutations tended to show prolonged survival. For both Group 1 and Group 2, patients with MGMT methylation survived longer than those without this methylation. Further, patients with 1p/19q co-deletion showed significantly better outcome in Group 2. Conclusions Our study confirms the utility of IDH1 mutations and MGMT methylation in predicting the prognosis of Group 1 patients (GBM + AA) and demonstrated that IDH1 mutations may serve as a more reliable prognostic factor for such patients. We also showed that MGMT methylation and 1p/19q co-deletion rather than IDH1 mutations were prognostic factors for Group 2 patients (AOA + AO). Our study suggests that patients survive longer if they have IDH1 mutations and undergo total resection. Further, irrespective of MGMT promoter methylation status, the prognosis of glioma patients can be improved if total resection is performed. Moreover, our study includes the largest number of Japanese patients with malignant gliomas that has been analyzed for these three markers. We believe that our findings will increase the awareness of oncologists in Japan of the value of these markers for predicting prognosis and designing appropriate therapeutic strategies for treating this highly fatal disease.

Phospholipase A2 (PLA2) activities in cytosolic, mitochondrial, and microsomal fractions of rat kidneys were characterized under control conditions, after ischemia, and subsequent to ischemia and reperfusion. Two forms of PLA2 activity were present in the cytosolic fraction: a high molecular weight form, active against phosphatidylcholine (PC), and phosphatidylethanolamine (PE), which upon purification has a molecular mass of 110 kD; and smaller form (Mr approximately 14 kD), active against PE. In mitochondrial and microsomal fractions a single form (Mr approximately 14 kD), active against both PC and PE, was dominant. Activities in each fraction were optimal at pH 8.5-9.5. Cytosolic PLA2 activity was enhanced when Ca2+ concentration [( Ca2+]) was increased over the range of 10(-7) to 10(-6) M. Mitochondrial PLA2 activity required higher [Ca2+] for activation (greater than 10(-6) M). After 45 min of ischemia cytosolic PLA2 activity was decreased, whereas mitochondrial and microsomal activities were increased. When ischemia was followed by 1 h of reperfusion, cytosolic, mitochondrial, and microsomal activities were enhanced. Ischemia alone did not change the gel filtration chromatography patterns of PLA2 activity, but ischemia and reperfusion resulted in the appearance of a new peak of activity in cytosolic and mitochondrial fractions (Mr approximately 2-3 kD). Thus, the rat kidney has multiple forms of PLA2 activity, likely representing distinct enzymes, with Ca2+ dependencies suggesting regulation by Ca2+ in vivo. Ischemia and reperfusion result in stable increases of PLA2 activity in each subcellular fraction, perhaps related to covalent modifications of PLA2's, which likely account for membrane phospholipid degradation, and increased tissue levels of unsaturated free fatty acids.