- In the recently updated World Health Organization (WHO) classification of central nervous system tumors, our concept of infiltrating gliomas as a molecular dichotomy between oligodendroglial and ...astrocytic tumors has been codified. Advances in animal models of glioma and a wealth of sophisticated molecular analyses of human glioma tissue have led to a greater understanding of some of the biologic underpinnings of gliomagenesis.
- To review our understanding of gliomagenesis in the setting of the recently updated WHO classification of central nervous system tumors. Topics addressed include a summary of an updated diagnostic schema for infiltrating gliomas, the crucial importance of isocitrate dehydrogenase mutations, candidate cells of origin for gliomas, environmental and other posited contributing factors to gliomagenesis, and the possible role of chromatin topology in setting the stage for gliomagenesis.
- We conducted a primary literature search using PubMed.
- With multidimensional molecular data sets spanning increasingly larger numbers of patients with infiltrating gliomas, our understanding of the disease at the point of surgical resection has improved dramatically and this understanding is reflected in the updated WHO classification. Animal models have demonstrated a diversity of candidates for glioma cells of origin, but crucial questions remain, including the role of neural stem cells, more differentiated progenitor cells, and glioma stem cells. At this stage the increase in data generated from human samples will hopefully inform the creation of newer animal models that will recapitulate more accurately the diversity of gliomas and provide novel insights into the biologic mechanisms underlying tumor initiation and progression.
During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of ...neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.
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•GABA limits MGE-cIN participation in synchronous network events during development•Synaptic GABA regulates the emergence of interneuron-pyramidal cell assemblies•GABAergic restriction of pyramidal cell activity is required for MGE-cIN apoptosis•GABAAγ2-containing GABAA receptors are essential for interneuron apoptosis
Duan, Che, Chu et al. use genetic tools and in vivo imaging to show that cortical GABAergic signaling restricts functional assemblies and enables developmental apoptosis of MGE interneurons, balancing the number of interneurons integrating into maturing cortical networks.
OBJECTIVE Planum sphenoidale (PS) and tuberculum sellae (TS) meningiomas cause visual symptoms due to compression of the optic chiasm. The treatment of choice is surgical removal with the goal of ...improving vision and achieving complete tumor removal. Two options exist to remove these tumors: the transcranial approach (TCA) and the endonasal endoscopic approach (EEA). Significant controversy exists regarding which approach provides the best results and whether there is a subset of patients for whom an EEA may be more suitable. Comparisons using a similar cohort of patients, namely, those suitable for gross-total resection with EEA, are lacking from the literature. METHODS The authors reviewed all cases of PS and TS meningiomas that were surgically removed at Weill Cornell Medical College between 2000 and 2015 (TCA) and 2008 and 2015 (EEA). All cases were shown to a panel of 3 neurosurgeons to find only those tumors that could be removed equally well either through an EEA or TCA to standardize both groups. Volumetric measurements of preoperative and postoperative tumor size, FLAIR images, and apparent diffusion coefficient maps were assessed by 2 independent reviewers and compared to assess extent of resection and trauma to the surrounding brain. Visual outcome and complications were also compared. RESULTS Thirty-two patients were identified who underwent either EEA (n = 17) or TCA (n = 15). The preoperative tumor size was comparable (mean 5.58 ± 3.42 vs 5.04 ± 3.38 cm
± SD, p = 0.661). The average extent of resection achieved was not significantly different between the 2 groups (98.80% ± 3.32% vs 95.13% ± 11.69%, p = 0.206). Postoperatively, the TCA group demonstrated a significant increase in the FLAIR/edema signal compared with EEA patients (4.15 ± 7.10 vs -0.69 ± 2.73 cm
, p = 0.014). In addition, the postoperative diffusion-weighted imaging signal of cytotoxic ischemic damage was significantly higher in the TCA group than in the EEA group (1.88 ± 1.96 vs 0.40 ± 0.55 cm
, p =0.008). Overall, significantly more EEA patients experienced improved or stable visual outcomes compared with TCA patients (93% vs 56%, p = 0.049). Visual deterioration was greater after TCA than EEA (44% vs 0%, p = 0.012). While more patients experienced postoperative seizures after TCA than after EEA (27% vs 0%, p = 0.038), there was a trend toward more CSF leakage and anosmia after EEA than after TCA (11.8% vs 0%, p = 0.486 and 11.8% vs 0%, p = 0.118, respectively). CONCLUSIONS In this small single-institution study of similarly sized and located PS and TS meningiomas, EEA provided equivalent rates of resection with better visual results, less trauma to the brain, and fewer seizures. These preliminary results merit further investigation in a larger multiinstitutional study and may support EEA resection by experienced surgeons in a subset of carefully selected PS and TS meningiomas.
Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and ...unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
While Machine Learning (ML) models have been increasingly applied to a range of histopathology tasks, there has been little emphasis on characterizing these models and contrasting them with human ...experts. We present a detailed empirical analysis comparing expert neuropathologists and ML models at predicting IDH mutation status in H&E-stained histology slides of infiltrating gliomas, both independently and synergistically. We find that errors made by neuropathologists and ML models trained using the TCGA dataset are distinct, representing modest agreement between predictions (human-vs.-human κ = 0.656; human-vs.-ML model κ = 0.598). While no ML model surpassed human performance on an independent institutional test dataset (human AUC = 0.901, max ML AUC = 0.881), a hybrid model aggregating human and ML predictions demonstrates predictive performance comparable to the consensus of two expert neuropathologists (hybrid classifier AUC = 0.921 vs. two-neuropathologist consensus AUC = 0.920). We also show that models trained at different levels of magnification exhibit different types of errors, supporting the value of aggregation across spatial scales in the ML approach. Finally, we present a detailed interpretation of our multi-scale ML ensemble model which reveals that predictions are driven by human-identifiable features at the patch-level.
Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the ...biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtypespecific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.
The expression of a single odorant receptor (OR) gene from a large gene family in individual sensory neurons is an essential feature of the organization and function of the olfactory system. We have ...used chromosome conformation capture to demonstrate the specific association of an enhancer element,
H, on chromosome 14 with multiple OR gene promoters on different chromosomes. DNA and RNA fluorescence in situ hybridization (FISH) experiments allow us to visualize the colocalization of the
H enhancer with the single OR allele that is transcribed in a sensory neuron. In transgenic mice bearing additional
H elements, sensory neurons that express OR pseudogenes also express a second functional receptor. These data suggest a model of receptor choice in which a single
trans-acting enhancer element may allow the stochastic activation of only one OR allele in an olfactory sensory neuron.
Glioblastoma (GBM), an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of ...current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA sequencing of tumor cells from 5 patients across four patient-specific glioblastoma stem cell (GSC)-derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor-like cell subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models. SIGNIFICANCE: It has been unclear how well different patient-derived GBM models are able to recreate the full heterogeneity of primary tumors. Here, we provide a complete transcriptomic characterization of the major model types. We show that the microenvironment is crucial for recapitulating GSC cellular states, highlighting the importance of tumor-host cell interactions.
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Varicella Zoster Virus (VZV) antigen has been reported to be present in the majority of temporal artery biopsies with implications for antiviral treatment in patients with giant cell arteritis. Using ...immunohistochemistry with VZV antibodies we found reactivity present in diverse myocyte types (smooth, skeletal and cardiac), diverse arteries (including temporal, coronary, and vertebral) and diverse clinical settings. This phenomenon is likely due to shared epitopes between VZV proteins and muscle elements and not due to actual VZV infection. We conclude that VZV immunohistochemistry should be used with caution for screening of VZV infection in the setting of temporal artery biopsies.
The classification of brain tumors is a rapidly evolving field that requires extensive integration of molecular diagnostic findings from an expanding set of platforms and assays. This article ...summarizes the schema presented in the 5th edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors while highlighting diagnostic molecular findings and discussing the strengths and weaknesses of commonly available testing modalities.
Several major changes in practice were introduced with the 5th edition of the CNS WHO classification, including molecular grading of adult diffuse gliomas, the introduction of many new entities within the spectrum of pediatric gliomas and glioneuronal tumors, and the widespread adoption of methylation classes as useful or even necessary diagnostic criteria. Additionally, several revisions to nomenclature (eg, IDH-mutant gliomas) were introduced for simplicity and to disambiguate from other tumor types.
The classification of brain tumors continues to grow in complexity alongside our improved understanding of their nuanced molecular underpinnings.
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