Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these ...tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a "molecular revolution" in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.
CD8+ T cells outnumber CD4+ cells in multiple sclerosis (MS) lesions associated with disease progression, but the pathogenic role and antigenic targets of these clonally expanded effectors are ...unknown. Based on evidence that demyelination is necessary but not sufficient for disease progression in MS, we previously hypothesized that CNS-infiltrating CD8+ T cells specific for neuronal antigens directly drive the axonal and neuronal injury that leads to cumulative neurologic disability in patients with MS. We now show that demyelination induced expression of MHC class I on neurons and axons and resulted in presentation of a neuron-specific neoantigen (synapsin promoter-driven chicken ovalbumin) to antigen-specific CD8+ T cells (anti-ovalbumin OT-I TCR-transgenic T cells). These neuroantigen-specific effectors surveilled the CNS in the absence of demyelination but were not retained. However, upon induction of demyelination via cuprizone intoxication, neuroantigen-specific CD8+ T cells proliferated, accumulated in the CNS, and damaged neoantigen-expressing neurons and axons. We further report elevated neuronal expression of MHC class I and β2-microglobulin transcripts and protein in gray matter and white matter tracts in tissue from patients with MS. These findings support a pathogenic role for autoreactive anti-axonal and anti-neuronal CD8+ T cells in MS progression.
Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler's murine encephalomyelitis virus ...(TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain-infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear.
Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2.
Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 h postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain.
We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.
Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional ...interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.
Gliosarcoma (GS) is an extraordinarily rare variant of glioblastoma, which is differentiated by its distinct biphasic histopathological morphology consisting of both glial and mesenchymal elements. ...Although GS has a predilection for the cortical hemispheres, rare occurrences of intraventricular gliosarcoma (IVGS) have been documented in the literature. In this report, we present a 68-year-old female patient with a primary IVGS arising from the frontal horn of the left ventricle with corresponding left ventricular entrapment. The clinical course as well as associated tumor features as observed on computed tomography (CT), magnetic resonance imaging (MRI), and immunohistochemical studies are presented along with a relevant review of the current literature.
Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade ...astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.
COVID-19 has been noted to present with neurological symptoms in nearly 30% of patients. While children are more likely to be asymptomatic, neurological involvement has been observed. We present the ...case of a 23-month-old previously healthy female who was brought to the emergency room for a new-onset facial droop. The patient tested positive for COVID-19 but was otherwise asymptomatic. Magnetic resonance imaging of the brain with and without contrast revealed abnormal enhancement along the canalicular segment of the right cranial VII extending to the first genu suggestive of cranial nerve neuritis. Given that our case involves a pediatric patient with no significant comorbidities presenting with facial drop, COVID-19 should be considered on the differential when evaluating causes of new onset peripheral nerve palsies.
Hamartomas are considered a mixture of nonneoplastic tissue, which may be indigenous to a different location in the body. As such, they may be epithelial, mesenchymal, or mixed. In the sinonasal ...region, the following hamartomatous lesions are considered to lie on a spectrum and include respiratory epithelial adenomatoid hamartoma (REAH), chondro-osseous respiratory epithelial adenomatoid hamartoma (COREAH), and nasal chondromesenchymal hamartoma (NCMH). To our knowledge, less than 50 cases of sinonasal hamartomas have been reported in the English literature so far with NCMH being very rare and primarily a tumor in infancy, with only 2 cases reported in individuals older than 16 years of age. We report a highly unusual case of a NCMH in the right maxillary sinus of a 70-year-old female.