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Objective The objective of this study was to examine the pathophysiology of ischemic stroke with cancer. Methods We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests. Results Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005). Interpretation Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.

Introduction: Arterial dissections often have no known identifiable risk factor. Whether infection/inflammation may play a role in the development of arterial dissection is uncertain. Hypothesis: Influenza-like illness (ILI) is associated with a heightened risk of arterial dissection. Methods: We performed a case-crossover analysis using administrative claims data on emergency department visits and acute care hospitalizations from 2006 to 2015 in NY and 2005-2015 in FL. We used previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes to identify patients with ILI and arterial dissection. Arterial dissection included the composite of cervical artery dissection (carotid and vertebral), coronary artery dissection, and aortic dissection. We compared the risk of arterial dissection in successive 30-day periods after ILI versus the corresponding 30-day periods one year earlier. We used McNemar test for matched data to calculate the absolute risk increases. Results: We identified 2,838,178 patients with ILI. The absolute increase in arterial dissection was 0.005% (95% CI, 0.004-0.006%) in the thirty days post ILI compared with the same period one year earlier (OR 3.3, 95% CI, 2.5-4.4). The absolute increase in arterial dissection attenuated over successive 30-day periods after ILI and was no longer significant after 120 days post ILI (Figure). Our results were similar in secondary analyses evaluating cervical, coronary, and aortic dissections separately. Conclusions: ILI is associated with a heightened short-term risk of arterial dissection. Further studies are warranted to evaluate mechanisms of how ILI and/or related inflammation leads to a heightened risk of systemic and cerebrovascular dissections.

Introduction: One-tenth of patients with stroke have cancer. We previously identified mRNA profiles differentiating patients with stroke and cancer, stroke only, and cancer only. In this study, we investigated mRNA and microRNA (miRNA) transcriptomes to identify potential miRNA regulators that underlie the observed mRNA changes. Methods: We prospectively enrolled 4 groups of subjects at 3 centers from 2009-2020. This analysis included 41 subjects with ischemic stroke plus cancer, 42 subjects with ischemic stroke only, 28 subjects with cancer only, and 30 vascular risk factor controls. Stroke-only and cancer-only subjects were matched to stroke-plus-cancer subjects by age, sex, and cancer type. We performed miRNA and mRNA sequencing on blood drawn 72-120 hours after stroke. ANCOVA estimated differential expression of miRNA and mRNA between groups (FDR p1.2). Analyses were adjusted for time from stroke onset, sex, age, vascular risk factors and batch. Results: We identified differential expression in 36 miRNA and 264 corresponding mRNA targets between the stroke-plus-cancer and stroke-only groups after accounting for cancer-only expression (Fig 1). Immune and coagulation pathways, including complement, platelet glycoproteins, TGF-β, and mTOR signaling, were overrepresented in stroke-plus-cancer vs stroke-only subjects. T cell, B cell and platelet precursor-specific genes were also overrepresented in stroke-plus-cancer subjects. When compared to other groups, stroke-plus-cancer subjects had 230 unique mRNA encoding for transcriptional regulators, including those involving splicing, epigenetics, and mediator complex genes bridging transcription factors and RNA transcriptional machinery. Conclusion: Patients with stroke and cancer had distinct signatures of miRNA and target mRNA compared to stroke patients without cancer, supporting the hypothesis that cancer-related stroke is a unique subgroup of ischemic stroke.

Introduction: Acute ischemic stroke (AIS) may be the first sign of occult cancer. We aimed to better define the incidence of cancer in the year after AIS and to identify clinical factors associated with new cancer diagnoses. Methods: This was a retrospective cohort study using data from the Cornell Acute Stroke Academic Registry (CAESAR) on patients hospitalized at our center with AIS from 2011-2015. Patients with history of cancer were excluded. Through automated electronic data capture and manual abstraction of inpatient and outpatient medical records, we collected data on patients’ demographics, comorbidities, presentation, radiographic characteristics, stroke subtype, and clinical outcomes. Patients were followed for 1 year after the index AIS for a new diagnosis of pathologically-confirmed cancer. Cox hazards regression adjusting for the competing risk of death was used to evaluate associations between clinical factors and incident cancer. Factors significantly associated in multivariable analysis were entered into a risk stratification score, and this score’s discriminatory ability was evaluated by Harrell’s C-statistic. Results: After excluding 253 patients with history of cancer, this analysis included 963 patients with AIS. During a mean follow-up of 222 days, 16 patients (1.7%; 95% CI, 1.0-2.7%) were diagnosed with cancer. The most common cancers were lung (n=7) and leukemia (n=4) and the median time to cancer diagnosis was 13 days (IQR, 7-194 days). Among patients with cryptogenic stroke, the 1-year cancer incidence rate was 1.7% (95% CI, 0.6-3.7%). Clinical factors associated with incident cancer in multivariable analysis were venous thromboembolism during the AIS hospitalization (HR, 12.5; 95% CI, 3.3-47.0), unexplained weight loss within 6 months (HR 11.7; 95% CI, 3.3-42.0), and three-territory acute infarcts (HR, 4.1, 95% CI, 1.3-13.4). These factors were used to create a clinical score that had a C-statistic of 0.7 (95% CI, 0.5-0.8). Conclusions: In a large urban cohort of AIS, the estimated 1-year incidence of first-ever cancer was 1.7%. Unexplained weight loss, concomitant venous thromboembolism, and three-territory acute infarction pattern may serve as clues to occult cancer with AIS.

Importance It is uncertain whether coronavirus disease 2019 (COVID-19) is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection. Objective To compare the rate of ischemic stroke between patients with COVID-19 and patients with influenza, a respiratory viral illness previously associated with stroke. Design, Setting, and Participants This retrospective cohort study was conducted at 2 academic hospitals in New York City, New York, and included adult patients with emergency department visits or hospitalizations with COVID-19 from March 4, 2020, through May 2, 2020. The comparison cohort included adults with emergency department visits or hospitalizations with influenza A/B from January 1, 2016, through May 31, 2018 (spanning moderate and severe influenza seasons). Exposures COVID-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 in the nasopharynx by polymerase chain reaction and laboratory-confirmed influenza A/B. Main Outcomes and Measures A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, mechanisms, and outcomes. We used logistic regression to compare the proportion of patients with COVID-19 with ischemic stroke vs the proportion among patients with influenza. Results Among 1916 patients with emergency department visits or hospitalizations with COVID-19, 31 (1.6%; 95% CI, 1.1%-2.3%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78 years); 18 (58%) were men. Stroke was the reason for hospital presentation in 8 cases (26%). In comparison, 3 of 1486 patients with influenza (0.2%; 95% CI, 0.0%-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was higher with COVID-19 infection than with influenza infection (odds ratio, 7.6; 95% CI, 2.3-25.2). The association persisted across sensitivity analyses adjusting for vascular risk factors, viral symptomatology, and intensive care unit admission. Conclusions and Relevance In this retrospective cohort study from 2 New York City academic hospitals, approximately 1.6% of adults with COVID-19 who visited the emergency department or were hospitalized experienced ischemic stroke, a higher rate of stroke compared with a cohort of patients with influenza. Additional studies are needed to confirm these findings and to investigate possible thrombotic mechanisms associated with COVID-19.

Key Points Question How does the risk of acute ischemic stroke compare between patients with Covid-19 and patients with influenza (a respiratory virus previously linked to stroke)? Findings In this large retrospective cohort study conducted at two academic hospitals in New York City, patients with emergency department visits and hospitalizations with Covid-19 were approximately seven times as likely to have an acute ischemic stroke as compared to patients with emergency department visits or hospitalizations with influenza. Meaning Patients with Covid-19 are at heightened risk for acute ischemic stroke as compared to patients with influenza. Importance Case series without control groups suggest that Covid-19 may cause ischemic stroke, but whether Covid-19 is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection is uncertain. Objective To compare the rate of ischemic stroke between patients with Covid-19 and patients with influenza, a respiratory viral illness previously linked to stroke. Design A retrospective cohort study. Setting Two academic hospitals in New York City. Participants We included adult patients with emergency department visits or hospitalizations with Covid-19 from March 4, 2020 through May 2, 2020. Our comparison cohort included adult patients with emergency department visits or hospitalizations with influenza A or B from January 1, 2016 through May 31, 2018 (calendar years spanning moderate and severe influenza seasons). Exposures Covid-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharynx by polymerase chain reaction, and laboratory-confirmed influenza A or B. Main Outcomes and Measures A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, etiological mechanisms, and outcomes. We used logistic regression to compare the proportion of Covid-19 patients with ischemic stroke versus the proportion among patients with influenza. Results Among 2,132 patients with emergency department visits or hospitalizations with Covid-19, 31 patients (1.5%; 95% confidence interval [CI], 1.0%-2.1%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78) and 58% were men. Stroke was the reason for hospital presentation in 8 (26%) cases. For our comparison cohort, we identified 1,516 patients with influenza, of whom 0.2% (95% CI, 0.0-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was significantly higher with Covid-19 than with influenza infection (odds ratio, 7.5; 95% CI, 2.3-24.9). Conclusions and Relevance Approximately 1.5% of patients with emergency department visits or hospitalizations with Covid-19 experienced ischemic stroke, a rate 7.5-fold higher than in patients with influenza. Future studies should investigate the thrombotic mechanisms in Covid-19 in order to determine optimal strategies to prevent disabling complications like ischemic stroke.