Project description:Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Project description:BackgroundThe advent of comprehensive genomic profiling has markedly advanced the understanding of the biology of pediatric hematological malignancies, however, its application to clinical care is still unclear. We present our experience integrating genomic data into the clinical management of children with high-risk hematologic malignancies and blood disorders and describe the broad impact that genomic profiling has in multiple aspects of patient care.MethodsThe Precision in Pediatric Sequencing Program at Columbia University Medical Center instituted prospective clinical next-generation sequencing (NGS) for high-risk malignancies and blood disorders. Testing included cancer whole exome sequencing (WES) of matched tumor-normal samples or targeted sequencing of 467 cancer-associated genes, when sample adequacy was a concern, and tumor transcriptome (RNA-seq). A multidisciplinary molecular tumor board conducted interpretation of results and final tiered reports were transmitted to the electronic medical record according to patient preferences.ResultsSixty-nine samples from 56 patients with high-risk hematologic malignancies and blood disorders were sequenced. Patients carried diagnoses of myeloid malignancy (n = 25), lymphoid malignancy (n = 25), or histiocytic disorder (n = 6). Six patients had only constitutional WES, performed for a suspicion of an inherited predisposition for their disease. For the remaining 50 patients, tumor was sequenced with matched normal tissue when available. The mean number of somatic variants per sample was low across the different disease categories (2.85 variants/sample). Interestingly, a gene fusion was identified by RNA-seq in 58% of samples who had adequate RNA available for testing. Molecular profiling of tumor tissue led to clinically impactful findings in 90% of patients. Forty patients (80%) had at least one targetable gene variant or fusion identified in their tumor tissue; however, only seven received targeted therapy. Importantly, NGS findings contributed to the refinement of diagnosis and prognosis for 34% of patients. Known or likely pathogenic germline alterations were discovered in 24% of patients involving cancer predisposition genes in 12% of cases.ConclusionIncorporating whole exome and transcriptome profiling of tumor and normal tissue into clinical practice is feasible, and the value that comprehensive testing provides extends beyond the ability to target-specific mutations.

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Columbia University

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