Ischemic stroke with cancer: Hematologic and embolic biomarkers and clinical outcomes

Navi, Babak B.; Zhang, Cenai; Sherman, Carla; Genova, Richard; LeMoss, Natalie M.; Kamel, Hooman; Tagawa, Scott T.; Saxena, Ashish; Ocean, Allyson J.; Kasner, Scott E.; Cushman, Mary; Elkind, Mitchell S.V.; Peerschke, Ellinor I.B.; DeAngelis, Lisa M.

doi:10.1111/jth.15779

Cited by 18 publications

(19 citation statements)

References 26 publications

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“…14 These biomarkers were all correlated with the outcome measures, but only increased D-dimer levels (hazard ratio: 1.2; 95% CI: 1.0–1.5) were significantly associated with recurrent AIS in the group of AIS patients with cancer. 15 This aligns with previous results supporting the value of D-dimer in predicting recurrent stroke in patients with AIS of undetermined origin, 11 and warrants further investigations for its use as a marker of recurrence in the cancer subpopulation.…”

Section: Oncological Biomarkers In Ais Patientssupporting

confidence: 88%

“…111 A recent prospective study comparing 50 AIS patients with cancer with matched cancer-only and stroke-only groups explored the association of various laboratory biomarkers of coagulation (D-dimer, thrombin–antithrombin), platelet (P-selectin), and endothelial activation (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1]) with recurrent arterial and venous thromboembolism and death. 15 With respect to the reference groups, the levels of D-dimer, P-selectin, and sICAM-1 and sVCAM-1 were significantly higher in AIS patients with cancer. 14 These biomarkers were all correlated with the outcome measures, but only increased D-dimer levels (hazard ratio: 1.2; 95% CI: 1.0–1.5) were significantly associated with recurrent AIS in the group of AIS patients with cancer.…”

Section: Oncological Biomarkers In Ais Patientsmentioning

confidence: 84%

“…Markers of inflammation, coagulation, platelet, and endothelial activation are altered in AIS patients with cancer. 15 Tissue factor produced by cancer cells is increased in cancer patients and contributes to arterial thromboembolism. 107 In addition, 4 to 16% of all patients with cancer have concurrent venous thromboembolism [108][109][110] associated with high plasma D-dimer, which is often used as a biomarker of hypercoagulability, particularly at very high levels.…”

Section: General Markers Of Inflammation Coagulation Platelet and End...mentioning

confidence: 99%

“…39 More recently, another prospective study including 50 patients with AIS and cancer documented microembolic signals in 16 patients, significantly more than in matched patients with stroke- and cancer-only. 15…”

Section: Oncological Biomarkers In Ais Patientsmentioning

confidence: 99%

“…7,[10][11][12][13] In addition, neutrophil extracellular traps (NETs), extracellular vesicles (EVs), and markers of platelet and endothelial activation have been investigated in AIS patients with cancer. 14,15 These biomarkers may help clinicians and researchers better characterize AIS patients with cancer and potentially enable risk stratification for prospective studies, but their current use in routine clinical practice is limited.…”

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confidence: 99%

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Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Costamagna

Navi

Beyeler

et al. 2023

Semin Thromb Hemost

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Ischemic stroke is an important cause of morbidity and mortality in cancer patients. The underlying mechanisms linking cancer and stroke are not completely understood. Long-standing and more recent evidence suggests that cancer-associated prothrombotic states, along with treatment-related vascular toxicity, such as with chemotherapy and immunotherapy, contribute to an increased risk of ischemic stroke in cancer patients. Novel biomarkers, including coagulation, platelet and endothelial markers, cell-free DNA, and extracellular vesicles are being investigated for their potential to improve risk stratification and patient selection for clinical trials and to help guide personalized antithrombotic strategies. Treatment of cancer-related stroke poses unique challenges, including the need to balance the risk of recurrent stroke and other thromboembolic events with that of bleeding associated with antithrombotic therapy. In addition, how and when to restart cancer treatment after stroke remains unclear. In this review, we summarize current knowledge on the mechanisms underlying ischemic stroke in cancer, propose an etiological classification system unique to cancer-related stroke to help guide patient characterization, provide an overview of promising biomarkers and their clinical utility, and discuss the current state of evidence-based management strategies for cancer-related stroke. Ultimately, a personalized approach to stroke prevention and treatment is required in cancer patients, considering both the underlying cancer biology and the individual patient's risk profile.

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Section: Oncological Biomarkers In Ais Patientssupporting

confidence: 88%

Section: Oncological Biomarkers In Ais Patientsmentioning

confidence: 84%

Section: General Markers Of Inflammation Coagulation Platelet and End...mentioning

confidence: 99%

Section: Oncological Biomarkers In Ais Patientsmentioning

confidence: 99%

mentioning

confidence: 99%

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Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Costamagna

Navi

Beyeler

et al. 2023

Semin Thromb Hemost

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Apixaban vs Aspirin in Patients With Cancer and Cryptogenic Stroke

Navi,

Zhang,

Miller

et al. 2024

JAMA Neurol

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ImportanceApproximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke.ObjectiveTo compare apixaban vs aspirin for the prevention of adverse clinical outcomes in patients with history of cancer and cryptogenic stroke.Design, Setting, and ParticipantsPost hoc analysis of data from 1015 patients with a recent cryptogenic stroke and biomarker evidence of atrial cardiopathy in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, a multicenter, randomized, double-blind clinical trial conducted from 2018 to 2023 at 185 stroke centers in North America. Data analysis was performed from October 15, 2023, to May 23, 2024.ExposuresOral apixaban, 5 mg (or 2.5 mg if criteria met), twice daily vs oral aspirin, 81 mg, once daily. Subgroups of patients with and without cancer at baseline were examined.Main Outcomes and MeasuresThe primary outcome for this post hoc analysis was a composite of major ischemic or major hemorrhagic events. Major ischemic events were recurrent ischemic stroke, myocardial infarction, systemic embolism, and symptomatic deep vein thrombosis or pulmonary embolism. Major hemorrhagic events included symptomatic intracranial hemorrhage and any major extracranial hemorrhage.ResultsAmong 1015 participants (median [IQR] age, 68 [60-76] years; 551 [54.3%] female), 137 (13.5%) had a history of cancer. The median (IQR) follow-up was 1.5 (0.6-2.5) years for patients with history of cancer and 1.5 (0.6-3.0) years for those without history of cancer. Participants with history of cancer, compared with those without history of cancer, had a higher risk of major ischemic or major hemorrhagic events (hazard ratio [HR], 1.73; 95% CI, 1.10-2.71). Among those with history of cancer, 8 of 61 participants (13.1%) randomized to apixaban and 16 of 76 participants (21.1%) randomized to aspirin had a major ischemic or major hemorrhagic event; however, the risk was not significantly different between groups (HR, 0.61; 95% CI, 0.26-1.43). Comparing participants randomized to apixaban vs aspirin among those with cancer, events included recurrent stroke (5 [8.2%] vs 9 [11.8%]), major ischemic events (7 [11.5%] vs 14 [18.4%]), and major hemorrhagic events (1 [1.6%] vs 2 [2.6%]).Conclusions and RelevanceAmong participants in the ARCADIA trial with history of cancer, the risk of major ischemic and hemorrhagic events did not differ significantly with apixaban compared with aspirin.Trial RegistrationClinicalTrials.gov Identifier: NCT03192215

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Ischemic Stroke with Comorbid Cancer Has Specific miRNA‐mRNA Networks in Blood That Vary by Ischemic Stroke Mechanism

Knepp,

Navi,

Rodriguez

et al. 2024

Annals of Neurology

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ObjectiveApproximately half of ischemic strokes (IS) in cancer patients are cryptogenic, with many presumed cardioembolic. We evaluated whether there were specific miRNA and mRNA transcriptome architectures in peripheral blood of IS patients with and without comorbid cancer, and between cardioembolic versus noncardioembolic IS etiologies in comorbid cancer.MethodsWe studied patients with cancer and IS (CS; n = 42), stroke only (SO; n = 41), and cancer only (n = 28), and vascular risk factor‐matched controls (n = 30). mRNA‐Seq and miRNA‐Seq data, analyzed with linear regression models, identified differentially expressed genes in CS versus SO and in cardioembolic versus noncardioembolic CS, and miRNA‐mRNA regulatory pairs. Network‐level analyses identified stroke etiology‐specific responses in CS.ResultsA total of 2,085 mRNAs and 31 miRNAs were differentially expressed between CS and SO. In CS, 122 and 35 miRNA‐mRNA regulatory pairs, and 5 and 3 coexpressed gene modules, were associated with cardioembolic and noncardioembolic CS, respectively. Complement, growth factor, and immune/inflammatory pathways showed differences between IS etiologies in CS. A 15‐gene biomarker panel assembled from a derivation cohort (n = 50) correctly classified 81% of CS and 71% of SO participants in a validation cohort (n = 33). Another 15‐gene panel correctly identified etiologies for 13 of 13 CS‐cardioembolic and 11 of 11 CS‐noncardioembolic participants upon cross‐validation; 11 of 16 CS‐cryptogenic participants were predicted cardioembolic.InterpretationWe discovered unique mRNA and miRNA transcriptome architecture in CS and SO, and in CS with different IS etiologies. Cardioembolic and noncardioembolic etiologies in CS showed unique coexpression networks and potential master regulators. These may help distinguish CS from SO and identify IS etiology in cryptogenic CS patients. ANN NEUROL 2024

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Ischemic stroke with cancer: Hematologic and embolic biomarkers and clinical outcomes

Cited by 18 publications

References 26 publications

Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Apixaban vs Aspirin in Patients With Cancer and Cryptogenic Stroke

Ischemic Stroke with Comorbid Cancer Has Specific miRNA‐mRNA Networks in Blood That Vary by Ischemic Stroke Mechanism

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