3 research outputs found
Neuropathology of COVID-19 (neuro-COVID): clinicopathological update
Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21st century. Its causative agent, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is an enveloped single-stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved. In Western clinical studies, relatively mild neurological dysfunction such as anosmia and dysgeusia is frequent (~70-84%) while severe neurologic disorders such as stroke (~1-6%) and meningoencephalitis are less common. It is unclear how much SARS-CoV-2 infection contributes to the incidence of stroke given co-morbidities in the affected patient population. Rarely, clinically-defined cases of acute disseminated encephalomyelitis, Guillain-Barré syndrome and acute necrotizing encephalopathy have been reported in COVID-19 patients. Common neuropathological findings in the 184 patients reviewed include microglial activation (42.9%) with microglial nodules in a subset (33.3%), lymphoid inflammation (37.5%), acute hypoxic-ischemic changes (29.9%), astrogliosis (27.7%), acute/subacute brain infarcts (21.2%), spontaneous hemorrhage (15.8%), and microthrombi (15.2%). In our institutional cases, we also note occasional anterior pituitary infarcts. COVID-19 coagulopathy, sepsis, and acute respiratory distress likely contribute to a number of these findings. When present, central nervous system lymphoid inflammation is often minimal to mild, is detected best by immunohistochemistry and, in one study, indistinguishable from control sepsis cases. Some cases evince microglial nodules or neuronophagy, strongly supporting viral meningoencephalitis, with a proclivity for involvement of the medulla oblongata. The virus is detectable by reverse transcriptase polymerase chain reaction, immunohistochemistry, or electron microscopy in human cerebrum, cerebellum, cranial nerves, olfactory bulb, as well as in the olfactory epithelium; neurons and endothelium can also be infected. Review of the extant cases has limitations including selection bias and limited clinical information in some cases. Much remains to be learned about the effects of direct viral infection of brain cells and whether SARS-CoV-2 persists long-term contributing to chronic symptomatology
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Increased epithelial membrane protein 2 expression in glioblastoma after treatment with bevacizumab.
BackgroundAntiangiogenic therapy with bevacizumab has failed to provide substantial gains in overall survival. Epithelial membrane protein 2 (EMP2) is a cell surface protein that has been previously shown to be expressed in glioblastoma, correlate with poor survival, and regulate neoangiogenesis in cell lines. Thus, the relationship between bevacizumab and EMP2 was investigated.MethodsTumor samples were obtained from 12 patients with newly diagnosed glioblastoma at 2 time points: (1) during the initial surgery and (2) during a subsequent surgery following disease recurrence post-bevacizumab treatment. Clinical characteristics and survival data from these patients were collected, and tumor samples were stained for EMP2 expression. The IVY Glioblastoma Atlas Project database was used to evaluate EMP2 expression levels in 270 samples by differing histological areas of the tumor.ResultsPatients with high EMP2 staining at initial diagnosis had decreased progression-free and overall survival after bevacizumab (median progression-free survival 4.6 months vs 5.9 months; log-rank P = .076 and overall survival 7.7 months vs 14.4 months; log-rank P = .011). There was increased EMP2 staining in samples obtained after bevacizumab treatment in both unpaired (mean H-score 2.31 vs 1.76; P = .006) and paired analyses (mean difference 0.571; P = .019). This expression increase correlated with length of bevacizumab therapy (R 2 Â = 0.449; Pearson P = .024).ConclusionsBevacizumab treatment increased EMP2 protein expression. This increase in EMP2 correlated with reduced mean survival time post-bevacizumab therapy. We hypothesize a role of EMP2 in clinical bevacizumab resistance and as a potential antiangiogenic therapeutic target in glioblastoma
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Identification of epithelial membrane protein 2 (EMP2) as a molecular marker and correlate for angiogenesis in meningioma
PurposeAlthough intracranial meningiomas are the most common primary brain tumor in adults, treatment options are few and have traditionally been limited to surgical resection and radiotherapy. Additional targeted therapies and biomarkers are needed, especially as complete surgical resection is frequently not feasible in many patients.MethodsNon-pathologic brain tissue from 3 patients undergoing routine autopsies and tumor specimens from 16 patients requiring surgical resection for meningioma were collected. EMP2 protein expression was evaluated by immunohistochemistry and western blot analysis. EMP2 mRNA expression was also investigated using surgical specimens and validated by analysis of several independent NCBI GEO databases.ResultsEMP2 mRNA expression levels were found to be higher in meningioma relative to non-pathologic meninges (P = 0.0013) and brain (P = 0.0011). Concordantly, strong EMP2 protein expression was demonstrated in 100% of meningioma specimens from all 16 patients, with no observable protein expression in normal brain tissue samples from 3 subjects (P < 0.001). EMP2 expression was confirmed by western blot analysis in five samples, with EMP2 protein intensity positively correlating with histologic staining score (R2 = 0.780; P = 0.047). No association was found between EMP2 mRNA or protein levels and WHO grade or markers of proliferation. However, EMP2 expression was positively associated with an angiomatous pattern on histologic evaluation (P = 0.0597), VEGF-A mRNA expression (P < 0.001), and clinical markers of tumor vascularity such as operative blood loss (P = 0.037).ConclusionsEMP2 is not found in normal brain tissue, yet has shown consistently high mRNA and protein expression in meningiomas, and may serve as a useful molecular marker for these tumors