Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes. MRI scans from the TCGA/TCIA lower grade glioma database ( = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2-FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort ( = 82) was analyzed to validate the T2-FLAIR mismatch sign. Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ = 0.234 (0.111-0.358)], T2-FLAIR mismatch sign [ = 0.728 (0.538-0.918)], lesion margins [ = 0.292 (0.135-0.449)], and peritumoral edema [ = 0.173 (0.096-0.250)]. All 15 cases that were positive for the T2-FLAIR mismatch sign were -mutant, 1p/19q non-codeleted tumors ( < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2-FLAIR mismatch sign [ = 0.747 (0.536-0.958)]; all 10 cases positive for the T2-FLAIR mismatch sign were -mutant, 1p/19q non-codeleted tumors ( < 0.00001; PPV = 100%, NPV = 76%). Among lower-grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the -mutant, 1p/19q non-codeleted molecular subtype..

Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation. Recent advances in molecular profiling technology, including comprehensive DNA sequencing and methylation analysis, have enabled the application of more precise and biologically relevant classification schemes to these tumors. In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnormalities involving either B-Raf proto-oncogene (BRAF) or fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3). These findings suggest that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1639-9) contains supplementary material, which is available to authorized users.

The D2HG product of IDH1 may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1 gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1 inhibitors may improve antiepileptic therapy in patients with IDH1 gliomas.

Following a discussion of recent policies for the city centre in Britain, the paper explores the contribution of residential development to aspects of sustainability, drawing on a range of survey evidence in Bristol and Swansea. The residents are frequent shoppers, helping to sustain the local daytime economy. Sustainability goals are also supported because large proportions of residents walk to city centre attractions, and many also to their places of work, showing reduced reliance on the private car. Support for the expanding nighttime economy reflects the age, gender and social class composition of the resident population, with different attractions receiving different levels of support from different social groups, but with younger adults as the mainstay. Sustainability in the city centre context appears best served by a majority of young adult residents, ameliorated by a sizeable proportion of older adults, and an absence of households with children. Grandiose government sustainability aims of creating the truly balanced community which includes many children, should be modified in this local context.

No abstract

No abstract

Over the past 30 years the pre-eminent commercial status of the city centre in the retail system of British cities has been challenged by the competitive impact of retail decentralisation. A contemporaneous decentralisation of of ce and leisure activities has exacerbated the situation. At the same time, early redevelopment strategies have created signi cant degrees of spatial fragmentation between functions and the loss of a substantial residential population. In the contemporary social climate, these changes have resulted in negative implications for the perception of safety and the generation of fear and anxiety amongst all users of the city centre. Consequently, safety issues have accentuated the emerging problems of the city centres, particularly for evening and night-time activities. City-centre revitalisation strategies have increasingly aimed to extend 'vitality and viability' beyond the temporal divide associated with the '5pm ight'. This has involved the incorporation of the '24-hour city' concept. However, this strategy has proved problematic due to the negative perceptions of safety, which are associated with the emergence of an 'exclusionary' youth culture in many major cities in recent years. This paper seeks to examine the nature and scale of the obstacles to the revitalisation of the evening and night-time economy and culture of Swansea and Cardiff in order the better to inform strategies which aim to instigate the 24-hour city concept. The study reveals substantial obstacles to the realisation of a vibrant 24-hour city, the scale of which suggests the need for considerable and concerted planning and development efforts if they are to be overcome. Many opportunities exist but the impediments suggest that progress in the direction of a 'liveable' 24-hour city is likely, at best, to be slow and incremental in the British situation.

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for Tissue Factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26–30% of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0%). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85–90% in wild-type versus 2–6% in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.