Background: Atypical teratoid/rhabdoid tumor in adults is a relatively rare malignant neoplasm. It is characterized by the presence of rhabdoid cells in combination with loss of either the INI1 or BRG1protein from the tumor cells.Methods: A systematic review was conducted using MEDLINE using the terms “atypical teratoid rhabdoid tumor” AND “adult.” The systematic review was supplemented with relevant articles from the references. Cases were included if the pathology was confirmed by loss of INI1 or BRG1. We included a case from our institution. The dataset was analyzed using descriptive statistics and log-rank test.Results: A total of 50 cases from 29 articles were included in this study. The average age at diagnosis was 36.7 years. The most common locations reported are the sellar region and cerebral hemispheres (without deep gray matter involvement). Of the 50 cases, 14 were reported to show evidence of dissemination. The average overall survival was 20 months. There was a significant difference in survival between the adjuvant therapy groups (p = < 0.0001).Conclusion: Atypical teratoid rhabdoid tumor of the central nervous system in adults is a rare neoplasm associated with a poor prognosis in a majority of patients. The treatment and clinical course are highly variable, and it remains unclear which factors impact prognosis.
Background: Pyroptosis is a type of proinflammatory regulated cell death (RCD) in which caspase-1 proteolytically cleaves gasdermin D (GSDMD) to yield a cytotoxic pore-forming protein. Recent studies have suggested that additional cell death pathways may interact with GSDMD under certain circumstances to execute pyroptosis. Microglia/macrophages in the central nervous system (CNS) undergo GSDMD-associated pyroptosis in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) but the contribution of other cell death pathways to this phenomenon is unknown. Herein, we tested the hypothesis that multiple RCD pathways underlie microglial pyroptosis in the context of neuroinflammation. Methods: A siRNA screen of genes with known RCD functions was performed in primary human microglia to evaluate their role in nigericin-induced pyroptosis using supernatant lactate dehydrogenase activity as a read-out of cell lysis. Activation of apoptotic executioner proteins and their contribution to pyroptosis was assessed using semiquantitative confocal microscopy, high-sensitivity ELISA, immunoblot, cell lysis assays, and activity-based fluorescent probes. Quantification of pyroptosis-related protein expression was performed in CNS lesions from patients with progressive MS and mice with MOG 35-55-induced EAE, and in matched controls. Results: Among progressive MS patients, activated caspase-3 was detected in GSDMD immunopositive pyroptotic microglia/macrophages within demyelinating lesions. In the siRNA screen, suppression of caspase-3/7, caspase-1, or GSDMD expression prevented plasma membrane rupture during pyroptosis. Upon exposure to pyroptotic stimuli (ATP or nigericin), human microglia displayed caspase-3/7 activation and cleavage of caspase-3/7-specific substrates (e.g., DFF45, ROCK1, and PARP), with accompanying features of pyroptosis including GSDMD immunopositive pyroptotic bodies, IL-1β release, and membrane rupture. Pyroptosis-associated nuclear condensation and pyroptotic body formation were suppressed by caspase-3/7 inhibition. Pharmacological and siRNA-mediated inhibition of caspase-1 diminished caspase-3/7 activation during pyroptosis. In mice with EAE-associated neurological deficits, activated caspase-3 colocalized with GSDMD immunopositivity in lesion-associated macrophages/microglia.
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