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      Characterization of Immune Checkpoint Inhibitor-Related Cardiotoxicity in Lung Cancer Patients From a Rural Setting

      , MD, MSc a , , , MD b , , BSc c , , MD d , , PhD e , , MD f , g , , RN, ANP f , , MD f , , MD a
      JACC: CardioOncology
      immune checkpoint inhibitors, inflammatory markers, myocarditis, neutrophil-to-lymphocyte ratio, CAR T, chimeric antigen receptor T cell, CTCAE, common terminology for clinical adverse events, CTLA-4, cytotoxicity T-cell lymphocyte antigen, ICI, immune checkpoint inhibitor, irAE, immune-related adverse events, iRC, immune checkpoint inhibitor-related cardiotoxicity, MACE, major adverse cardiac events, NLR, neutrophil-to-lymphocyte ratio, NSCLC, non-small cell lung cancer, PD, programmed cell death, PD-L1, programmed cell death-ligand 1

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          Immune checkpoint inhibitor (ICI)-related cardiotoxicity (iRC) is uncommon but can be fatal. There have been few reports of iRC from a rural cancer population and few data for iRC and inflammatory biomarkers.


          The purpose of this study was to characterize major adverse cardiac events (MACE) in ICI-treated lung cancer patients based in a rural setting and to assess the utility of C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) in the diagnosis of iRC.


          Patients with lung cancer treated with ICIs at Vidant Medical Center/East Carolina University (VMC/ECU) between 2015 and 2018 were retrospectively identified. MACE included myocarditis, non-ST-segment elevated myocardial infarction (NSTEMI), supraventricular tachycardia (SVT), and pericardial disorders. Medical history, laboratory values, pre-ICI electrocardiography (ECG), and echocardiography results were compared in patients with and without MACE.


          Among 196 ICI-treated patients, 23 patients (11%) developed MACE at a median of 46 days from the first ICI infusion (interquartile range [IQR]: 17 to 83 days). Patients who developed MACE experienced myocarditis (n = 9), NSTEMI (n = 3), SVT (n = 7), and pericardial disorders (n = 4). Ejection fraction was not significantly different at the time of MACE compared to that at baseline (p = 0.495). Compared to baseline values, NLR (10.9 ± 8.3 vs. 20.7 ± 4.2, respectively; p = 0.032) and CRP (42.1 ± 10.1 mg/l vs. 109.9 ± 15.6 mg/l, respectively; p = 0.010) were significantly elevated at the time of MACE.


          NLR and CRP were significantly elevated at the time of MACE compared to baseline values in ICI-treated patients. Larger datasets are needed to validate these findings and identify predictors of MACE that can be used in the diagnosis and management of ICI-related iRC.

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          Most cited references39

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          Immune-Related Adverse Events Associated with Immune Checkpoint Blockade

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            Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

            Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.
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              Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

              In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.

                Author and article information

                JACC CardioOncol
                JACC CardioOncol
                JACC: CardioOncology
                15 September 2020
                September 2020
                15 September 2020
                : 2
                : 3
                : 491-502
                [a ]Department of Cardiovascular Sciences, Vidant Medical Center, East Carolina University, Greenville, North Carolina, USA
                [b ]Department of Cardiovascular Sciences, Virginia Commonwealth University, Richmond, Virginia, USA
                [c ]Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
                [d ]Department of Internal Medicine, Vidant Medical Center, East Carolina University, Greenville, North Carolina, USA
                [e ]Department of Biostatistics, East Carolina University, Greenville, North Carolina, USA
                [f ]Department of Hematology and Oncology, Vidant Medical Center, East Carolina University, Greenville, North Carolina, USA
                [g ]U.S. National Institutes of Health, Bethesda, Maryland, USA
                Author notes
                [] Address for correspondence: Dr. Melissa Y.Y. Moey, East Carolina Heart Institute, 115 Heart Drive, Greenville, North Carolina 27834. moeym16@ 123456ecu.edu @Melissa_Moey
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 5 January 2020
                : 15 July 2020
                : 15 July 2020
                Original Research

                immune checkpoint inhibitors,inflammatory markers,myocarditis,neutrophil-to-lymphocyte ratio,car t, chimeric antigen receptor t cell,ctcae, common terminology for clinical adverse events,ctla-4, cytotoxicity t-cell lymphocyte antigen,ici, immune checkpoint inhibitor,irae, immune-related adverse events,irc, immune checkpoint inhibitor-related cardiotoxicity,mace, major adverse cardiac events,nlr, neutrophil-to-lymphocyte ratio,nsclc, non-small cell lung cancer,pd, programmed cell death,pd-l1, programmed cell death-ligand 1


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