Objective:To determine the prevalence and associated mortality of well-defined neurologic diagnoses among COVID-19 patients, we prospectively followed hospitalized SARS-Cov-2 positive patients and recorded new neurologic disorders and hospital outcomes.Methods:We conducted a prospective, multi-center, observational study of consecutive hospitalized adults in the NYC metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between COVID-19 patients with and without neurologic disorders.Results:Of 4,491 COVID-19 patients hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were: toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis, or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were RT-PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all P<0.05). After adjusting for age, sex, SOFA-scores, intubation, past history, medical complications, medications and comfort-care-status, COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (Hazard Ratio[HR] 1.38, 95% CI 1.17-1.62, P<0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, P<0.001).Conclusions:Neurologic disorders were detected in 13.5% of COVID-19 patients and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.

Background and Purpose: We conducted this study to investigate the prevalence and distribution of cerebral microbleeds and leukoencephalopathy in hospitalized patients with coronavirus disease 2019 (COVID-19) and correlate with clinical, laboratory, and functional outcomes. Methods: We performed a retrospective chart review of 4131 COVID-19 positive adult patients who were admitted to 3 tertiary care hospitals of an academic medical center at the epicenter of the COVID-19 pandemic in New York City from March 1, 2020, to May 10, 2020, to identify patients who had magnetic resonance imaging (MRI) of the brain. We evaluated the MRIs in detail, and identified a subset of patients with leukoencephalopathy and/or cerebral microbleeds. We compared clinical, laboratory, and functional outcomes for these patients to patients who had a brain MRI that did not show these findings. Results: Of 115 patients who had an MRI of the brain performed, 35 (30.4%) patients had leukoencephalopathy and/or cerebral microbleeds. Patients with leukoencephalopathy and/or cerebral microbleeds had neuroimaging performed later during the hospitalization course (27 versus 10.6 days; P <0.001), were clinically sicker at the time of brain MRI (median GCS 6 versus 14; P <0.001), and had higher peak D-dimer levels (8018±6677 versus 3183±3482; P <0.001), lower nadir platelet count (116.9±62.2 versus 158.3±76.2; P =0.03), higher peak international normalized ratio (2.2 versus 1.57; P <0.001) values when compared with patients who had a brain MRI that did not show these findings. They required longer ventilator support (34.6 versus 9.1 days; P <0.001) and were more likely to have moderate and severe acute respiratory distress syndrome score (88.6% versus 23.8%, P <0.001). These patients had longer hospitalizations (42.1 versus 20.9 days; P <0.001), overall worse functional status on discharge (mRS 5 versus 4; P =0.001), and higher mortality (20% versus 9%; P =0.144). Conclusions: The presence of leukoencephalopathy and/or cerebral microbleeds is associated with a critical illness, increased mortality, and worse functional outcome in patients with COVID-19.

Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. Experimental Design: Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. Results: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P &lt; 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. Conclusions: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.

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