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Antonello J, Roy P. Damage-Associated Molecular Patterns (DAMPs) In Vascular Diseases. J Biol Chem 2025:110241. [PMID: 40381697 DOI: 10.1016/j.jbc.2025.110241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025] Open
Abstract
Research into the role of chronic sterile inflammation (i.e. a prolonged inflammatory state not caused by an infectious agent), in vascular disease progression has continued to grow over the last few decades. DAMPs have a critical role in this research due to their ability to link stress-causing cardiovascular risk factors to inflammatory phenotypes seen in vascular disease. In this mini-review, we will briefly summarize the DAMPs and receptor signaling pathways that have been extensively studied in the context of vascular disease, including TLRs, RAGE, cGAS-STING, and the NLRP3 inflammasome. In particular, we will discuss how these pathways can promote the release of pro-inflammatory cytokines and chemokines as well as vascular remodeling. Next, we will summarize the results of studies which have linked the various pro-inflammatory effects of DAMPs with the phenotypes in the context of vascular diseases including atherosclerosis, fibrosis, aneurysm, ischemia, and hypertension. Finally, we will discuss some pre-clinical and clinical trials that have targeted DAMPs, their receptors, or the products of their signaling pathways, and discuss the outlook and future directions for the field at large.
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Affiliation(s)
| | - Partha Roy
- Bioengineering, University of Pittsburgh; Pathology, University of Pittsburgh.
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Singh R, Patel K, Xu H, Adeniyi A, Upshaw JN, Van Buren P, Kaufman PA, Dittus K, Landry KK. Cardio-Oncology and Breast Cancer Therapies. Curr Treat Options Oncol 2025; 26:385-397. [PMID: 40257669 DOI: 10.1007/s11864-025-01311-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/22/2025]
Abstract
OPINION STATEMENT Assessing cardiac risk prior to initiating breast cancer treatment, monitoring cardiac function during treatment, and implementing appropriate follow-up strategies are essential components of managing cardiotoxicity in breast cancer patients. A comprehensive cardiovascular evaluation should be conducted before treatment, including a detailed medical history, physical examination, and baseline cardiac imaging. Risk stratification tools can aid in determining the individual patient's risk profile. Close monitoring of cardiac function, including regular assessment of left ventricular ejection fraction (LVEF) and monitoring for signs and symptoms of cardiac dysfunction, is crucial during treatment. Prompt action should be taken if an adverse cardiovascular event is detected, including considering discontinuing or modifying the treatment regimen. Appropriate follow-up care is essential to monitor for long-term cardiac effects and optimize cardiovascular health in breast cancer survivors. Regular cardiovascular assessments, lifestyle modifications, and collaboration between healthcare professionals are important in managing cardiotoxicity effectively.
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Affiliation(s)
- Rohit Singh
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Krina Patel
- Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Haze Xu
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Aderonke Adeniyi
- Division of Cardiology, Department of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Jenica N Upshaw
- Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Peter Van Buren
- Division of Cardiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Peter A Kaufman
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - Kim Dittus
- Division of Hematology/Oncology, Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Kara K Landry
- Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
- University of Vermont Cancer Center, Burlington, VT, USA.
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Reeves DJ, Leffers K, Rao VU. Immune checkpoint Inhibitor related myocarditis reported through the FDA adverse event reporting system: pharmacovigilance trends in reporting and outcomes. Front Oncol 2025; 15:1498817. [PMID: 40083879 PMCID: PMC11903268 DOI: 10.3389/fonc.2025.1498817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/04/2025] [Indexed: 03/16/2025] Open
Abstract
Introduction As the use of immune checkpoint inhibitors (ICIs) continues to expand, it is important to be mindful of rare but serious side effects such as myocarditis. Multiple analyses of adverse effect databases have demonstrated an association between ICIs and myocarditis; however, given the rapid implementation of therapeutic use, introduction of multiple new ICIs, and expanding indications, it is unclear if trends are evolving in reporting and outcomes. Methods We analyzed the FDA Adverse Event Reporting System to investigate the association between ICIs and myocarditis and trends in myocarditis outcomes among reports submitted between 2012 and the first quarter of 2023. Results After removal of duplicate cases, 1,326 myocarditis cases were reported to the database in patients receiving ICIs. Of these, the majority of reported cases were in males (62%) and the median age was 69 years. Consistent with the increase in utilization, the number of cases reported per year increased with each passing year. The reporting odds ratio (ROR) for all ICI drugs included in the analysis was 30.1 (95% confidence interval: 28.4-32.0). RORs for the individual drugs ranged from 12.3 for durvalumab to 168.5 for nivolumab/ relatlimab. The overall fatality rate of all cases was 37%. A significant difference in fatality rate among reported cases was present when comparing outcomes in 2018 and 2022 (45% vs 33%, respectively, p=0.017). Discussion Myocarditis continues to be associated with immune checkpoint inhibitors, with the number of reported cases increasing consistent with increasing utilization; however, the outcomes may be improving with less cases being reported as fatal.
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Affiliation(s)
- David J. Reeves
- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, United States
- Department of Pharmacy, Franciscan Health Indianapolis, Indianapolis, IN, United States
| | - Kevin Leffers
- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, United States
| | - Vijay U. Rao
- Franciscan Physician Network, Franciscan Health Indianapolis, Indianapolis, IN, United States
- International CardioOncology Society Center of Excellence, Indiana Heart Physicians, Indianapolis, IN, United States
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Ćorović A, Zhao X, Huang Y, Newland SR, Gopalan D, Harrison J, Giakomidi D, Chen S, Yarkoni NS, Wall C, Peverelli M, Sriranjan R, Gallo A, Graves MJ, Sage A, Lyons PA, Sithole N, Bennett MR, Rudd JHF, Mallat Z, Zhao TX, Nus M, Tarkin JM. Coronavirus disease 2019-related myocardial injury is associated with immune dysregulation in symptomatic patients with cardiac magnetic resonance imaging abnormalities. Cardiovasc Res 2024; 120:1752-1767. [PMID: 39073768 PMCID: PMC11587552 DOI: 10.1093/cvr/cvae159] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/01/2024] [Accepted: 05/23/2024] [Indexed: 07/30/2024] Open
Abstract
AIMS While acute cardiovascular complications of coronavirus disease 2019 (COVID-19) are well described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19. METHODS AND RESULTS Twenty-one participants {mean age 47 [standard deviation (SD) 13] years, 71% female} with long COVID-19 (n = 17), raised troponin (n = 2), or unexplained new-onset heart failure (n = 2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment, were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers were performed. Nine of the 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and two had severe left ventricular (LV) impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23, and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T αβ cells showed higher proportions of cytotoxic granzyme B+(GZB+)-secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a least absolute shrinkage and selection operator regression model (composite area under the curve 0.96, 95% confidence interval 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r = 0.47, P = 0.04). CONCLUSION COVID-19-related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection.
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Affiliation(s)
- Andrej Ćorović
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Xiaohui Zhao
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Yuan Huang
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Stephen R Newland
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Deepa Gopalan
- Department of Radiology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - James Harrison
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Despina Giakomidi
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Shanna Chen
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Natalia S Yarkoni
- Cell Phenotyping Hub, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Christopher Wall
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Marta Peverelli
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Rouchelle Sriranjan
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Arianna Gallo
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Martin J Graves
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Andrew Sage
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Paul A Lyons
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Nyarie Sithole
- Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Martin R Bennett
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - James H F Rudd
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Ziad Mallat
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Tian X Zhao
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Meritxell Nus
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jason M Tarkin
- Section of Cardiorespiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
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Gradone AL, Ma VT, Vasbinder A, Fecher LA, Yentz S, Hayek SS, Lao CD. Increased myositis and possible myocarditis in melanoma patients treated with immune checkpoint inhibitors in the COVID-19 era. Cancer Immunol Immunother 2024; 73:259. [PMID: 39369180 PMCID: PMC11456101 DOI: 10.1007/s00262-024-03803-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 08/08/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy. METHODS A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis. RESULTS 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%-7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis. CONCLUSION Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.
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Affiliation(s)
- Allison L Gradone
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
| | - Vincent T Ma
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Internal Medicine, University of Wisconsin, Madison, WI, USA
- Department of Dermatology, University of Wisconsin, Madison, WI, USA
| | - Alexi Vasbinder
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Leslie A Fecher
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Sarah Yentz
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Salim S Hayek
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Christopher D Lao
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
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Domínguez F, Uribarri A, Larrañaga-Moreira JM, Ruiz-Guerrero L, Pastor-Pueyo P, Gayán-Ordás J, Fernández-González B, Esteban-Fernández A, Barreiro M, López-Fernández S, Gutiérrez-Larraya Aguado F, Pascual-Figal D. Diagnosis and treatment of myocarditis and inflammatory cardiomyopathy. Consensus document of the SEC-Working Group on Myocarditis. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2024; 77:667-679. [PMID: 38763214 DOI: 10.1016/j.rec.2024.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 02/21/2024] [Indexed: 05/21/2024]
Abstract
Myocarditis is defined as myocardial inflammation and its etiology is highly diverse, including infectious agents, drugs, and autoimmune diseases. The clinical presentation also varies widely, extending beyond the classic clinical picture of acute chest pain, and includes cases of cardiomyopathy of unknown cause whose etiology may be inflammatory. Because certain patients may benefit from targeted treatments, the search for the etiology should begin when myocarditis is first suspected. There remain several areas of uncertainty in the diagnosis and treatment of this disease. Consequently, this consensus document aims to provide clear recommendations for its diagnosis and treatment. Hence, a diagnostic algorithm is proposed, specifying when non-invasive diagnosis with cardiac MR is appropriate vs a noninvasive approach with endomyocardial biopsy. In addition, more novel aspects are discussed, such as when to suspect an underlying genetic etiology. The recommendations cover the management of myocarditis and inflammatory cardiomyopathy, both for general complications and specific clinical entities.
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Affiliation(s)
- Fernando Domínguez
- Servicio de Cardiología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain.
| | - Aitor Uribarri
- Servicio de Cardiología, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | | | - Luis Ruiz-Guerrero
- Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
| | - Pablo Pastor-Pueyo
- Servicio de Cardiología, Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | - Jara Gayán-Ordás
- Servicio de Cardiología, Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | | | | | - Manuel Barreiro
- Servicio de Cardiología, Hospital Álvaro Cunqueiro, Vigo, Pontevedra, Spain
| | | | | | - Domingo Pascual-Figal
- Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, El Palmar, Murcia, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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7
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Racine JJ, Bachman JF, Zhang JG, Misherghi A, Khadour R, Kaisar S, Bedard O, Jenkins C, Abbott A, Forte E, Rainer P, Rosenthal N, Sattler S, Serreze DV. Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1287-1306. [PMID: 38426910 PMCID: PMC10984778 DOI: 10.4049/jimmunol.2300841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/08/2024] [Indexed: 03/02/2024]
Abstract
Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.
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Affiliation(s)
| | | | | | - Adel Misherghi
- The Jackson Laboratory, Bar Harbor, Maine, USA
- College of the Atlantic, Bar Harbor, Maine, USA
| | - Raheem Khadour
- The Jackson Laboratory, Bar Harbor, Maine, USA
- College of the Atlantic, Bar Harbor, Maine, USA
| | | | | | | | | | | | - Peter Rainer
- Medical University of Graz, Graz, 8053 Austria
- BioTechMed Graz, Graz, Austria
- BKH St. Johann in Tirol, 6380 St. Johann in Tirol, Austria
| | - Nadia Rosenthal
- The Jackson Laboratory, Bar Harbor, Maine, USA
- Imperial College London, London SW7 2AZ, UK
| | - Susanne Sattler
- Imperial College London, London SW7 2AZ, UK
- Medical University of Graz, Graz, 8053 Austria
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Saad R, Ghaddar A, Zeenny RM. Pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient: a case report and review of the literature. J Med Case Rep 2024; 18:107. [PMID: 38383436 PMCID: PMC10882824 DOI: 10.1186/s13256-024-04397-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 01/19/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND The cardiovascular system is among the least systems affected by immune-related adverse events. We report a rare life-threatening case of pembrolizumab-induced myocarditis with complete atrioventricular block and concomitant myositis in a metastatic bladder cancer patient. CASE PRESENTATION An 82-year-old Caucasian female with invasive urothelial carcinoma, started on first-line pembrolizumab, was admitted four days after receiving her second dose for severe asthenia, diffuse muscle aches, neck pain, and lethargy. In the emergency department, she had several episodes of bradycardia reaching 40 beats per minute associated with general discomfort and fatigue. Electrocardiography showed a third-degree atrioventricular heart block, while the patient remained normotensive. Cardiac damage parameters were altered with elevated levels of creatine phosphokinase of 8930 U/L, suggestive of immune checkpoint inhibitor-induced myositis, and troponin T of 1.060 ng/mL. Transthoracic echocardiography showed a preserved ejection fraction. Pembrolizumab-induced myocarditis was suspected. Therefore, treatment was initiated with high-dose glucocorticoids for 5 days, followed by a long oral steroid taper. A pacemaker was also implanted. Treatment resulted in the resolution of heart block and a decrease in creatine phosphokinase to the normal range. CONCLUSION Life-threatening cardiac adverse events in the form of myocarditis may occur with pembrolizumab use, warranting vigilant cardiac monitoring. Troponin monitoring in high-risk patients, along with baseline echocardiography may help identify this complication promptly to prevent life-threatening consequences.
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Affiliation(s)
- R Saad
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon
| | - A Ghaddar
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon
| | - R M Zeenny
- Department of Pharmacy, American University of Beirut Medical Center, Riad El-Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon.
- INSPECT-LB (Institut National de Santé Publique, d'Épidémiologie Clinique et de Toxicologie-Liban), Beirut, Lebanon.
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Shalata W, Steckbeck R, Abu Salman A, Abu Saleh O, Abu Jama A, Attal ZG, Shalata S, Alnsasra H, Yakobson A. Perimyocarditis Associated with Immune Checkpoint Inhibitors: A Case Report and Review of the Literature. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:224. [PMID: 38399513 PMCID: PMC10890382 DOI: 10.3390/medicina60020224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/22/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024]
Abstract
Patient prognoses have been significantly enhanced by immune checkpoint inhibitors (ICIs), altering the standard of care in cancer treatment. These novel antibodies have become a mainstay of care for metastatic non-small-cell lung cancer (mNSCLC) patients. Several types of adverse events related to ICIs have been identified and documented as a result of the launch of these innovative medicines. We present here a 74-year-old female patient with a stage IV lung adenocarcinoma, treated with nivolumab plus ipilimumab, who developed perimyocarditis two weeks after receiving the third cycle of immune checkpoint inhibitor therapy. The patient was diagnosed using troponin levels, computed tomography (CT) angiography, and echocardiography. After hospitalization, her cardiac condition was successfully resolved with corticosteroids, colchicine, and symptomatic treatment. To the best of our knowledge, this is one of the rarest cases to be reported of perimyocarditis as a toxicity of immunotherapy in a patient treated for adenocarcinoma of the lung.
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Affiliation(s)
- Walid Shalata
- The Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Rachel Steckbeck
- Medical School for International Health and Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Amjad Abu Salman
- Cardiology Department, Soroka Medical Center & Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Omar Abu Saleh
- Department of Dermatology and Venereology, Emek Medical Centre, Afula 18341, Israel
| | - Ashraf Abu Jama
- The Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Zoé Gabrielle Attal
- Medical School for International Health and Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Sondos Shalata
- Nutrition Unit, Galilee Medical Center, Nahariya 22000, Israel
| | - Hilmi Alnsasra
- Cardiology Department, Soroka Medical Center & Ben-Gurion University, Beer-Sheva 84105, Israel
| | - Alexander Yakobson
- The Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka Medical Center & Ben-Gurion University, Beer-Sheva 84105, Israel
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Gul R, Shehryar M, Mahboob A, Kareem HK, Inayat A, Safi D, Kamran A. Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review. Cureus 2024; 16:e52952. [PMID: 38406102 PMCID: PMC10894055 DOI: 10.7759/cureus.52952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2024] [Indexed: 02/27/2024] Open
Abstract
Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use. Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.
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Affiliation(s)
- Rohail Gul
- Internal Medicine, Shifa Tameer-E-Millat University Shifa College of Medicine, Islamabad, PAK
| | | | - Anber Mahboob
- Internal Medicine, Sharif Medical and Dental College, Lahore, PAK
| | - Hira K Kareem
- Internal Medicine, King Edward Medical University, Lahore, PAK
| | - Arslan Inayat
- Internal Medicine, HSHS St. Marys Hospital, Decatur, USA
| | - Danish Safi
- Hematology and Medical Oncology, West Virginia University School of Medicine, Morgantown, USA
| | - Amir Kamran
- Hematology and Medical Oncology, Charleston Area Medical Center, Charleston, USA
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Fateh ST, Fateh ST, Salehi-Najafabadi A, Aref AR. Commercial and regulatory challenges in cancer nanomedicine. FUNCTIONALIZED NANOMATERIALS FOR CANCER RESEARCH 2024:579-601. [DOI: 10.1016/b978-0-443-15518-5.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Salloum FN, Tocchetti CG, Ameri P, Ardehali H, Asnani A, de Boer RA, Burridge P, Cabrera JÁ, de Castro J, Córdoba R, Costa A, Dent S, Engelbertsen D, Fernández-Velasco M, Fradley M, Fuster JJ, Galán-Arriola C, García-Lunar I, Ghigo A, González-Neira A, Hirsch E, Ibáñez B, Kitsis RN, Konety S, Lyon AR, Martin P, Mauro AG, Mazo Vega MM, Meijers WC, Neilan TG, Rassaf T, Ricke-Hoch M, Sepulveda P, Thavendiranathan P, van der Meer P, Fuster V, Ky B, López-Fernández T, International Cardio-Oncology Society. Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2023; 5:715-731. [PMID: 38205010 PMCID: PMC10774781 DOI: 10.1016/j.jaccao.2023.08.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 01/12/2024] Open
Abstract
Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.
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Affiliation(s)
- Fadi N. Salloum
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Carlo G. Tocchetti
- Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, Interdepartmental Center of Clinical and Translational Sciences, Interdepartmental Hypertension Research Center, Federico II University, Naples, Italy
| | - Pietro Ameri
- Cardiac, Thoracic and Vascular Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Hossein Ardehali
- Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, Illinois, USA
| | - Aarti Asnani
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Rudolf A. de Boer
- Cardiovascular Institute, Thorax Center, Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Paul Burridge
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - José-Ángel Cabrera
- Cardiology Department, Hospital Universitario Quirónsalud Madrid, European University of Madrid, Madrid, Spain
| | - Javier de Castro
- Medical Oncology Department, Hospital La Paz Institute for Health Research, La Paz University Hospital, Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
| | - Raúl Córdoba
- Health Research Institute, Instituto de Investigación Sanitaria Fundación Jimenez Diaz, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | - Ambra Costa
- Cardiac, Thoracic and Vascular Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Susan Dent
- Duke Cancer Institute, Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Daniel Engelbertsen
- Cardiovascular Research - Immune Regulation, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - María Fernández-Velasco
- Hospital La Paz Institute for Health Research, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Mike Fradley
- Thalheimer Center for Cardio-Oncology, Abramson Cancer Center and Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - José J. Fuster
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Carlos Galán-Arriola
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Inés García-Lunar
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Alessandra Ghigo
- Molecular Biotechnology Center Guido Tarone, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Anna González-Neira
- Human Genotyping Unit, Spanish National Genotyping Centre, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain
| | - Emilio Hirsch
- Molecular Biotechnology Center Guido Tarone, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Borja Ibáñez
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Richard N. Kitsis
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Montefiore Einstein Comprehensive Cancer Center, Bronx, New York, New York USA
| | - Suma Konety
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Alexander R. Lyon
- Cardio-Oncology Service, Royal Brompton Hospital, London, United Kingdom
| | - Pilar Martin
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
| | - Adolfo G. Mauro
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Manuel M. Mazo Vega
- Division of Advanced Technologies, Cima Universidad de Navarra, Pamplona, Spain
| | - Wouter C. Meijers
- Cardiovascular Institute, Thorax Center, Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Tomas G. Neilan
- Cardio-Oncology Program, Massachusetts General Hospital, Harvard Medical School. Boston, Massachusetts, USA
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
| | - Melanie Ricke-Hoch
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Pilar Sepulveda
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
| | - Paaladinesh Thavendiranathan
- Division of Cardiology, Department of Medicine, Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Peter van der Meer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Valentin Fuster
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York
| | - Bonnie Ky
- Thalheimer Center for Cardio-Oncology, Abramson Cancer Center and Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Teresa López-Fernández
- Cardiology Department, Hospital La Paz Institute for Health Research, La Paz University Hospital, Madrid, Spain
| | - International Cardio-Oncology Society
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
- Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, Interdepartmental Center of Clinical and Translational Sciences, Interdepartmental Hypertension Research Center, Federico II University, Naples, Italy
- Cardiac, Thoracic and Vascular Department, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Department of Internal Medicine, University of Genova, Genova, Italy
- Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, Illinois, USA
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
- Cardiovascular Institute, Thorax Center, Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
- Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
- Cardiology Department, Hospital Universitario Quirónsalud Madrid, European University of Madrid, Madrid, Spain
- Medical Oncology Department, Hospital La Paz Institute for Health Research, La Paz University Hospital, Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain
- Health Research Institute, Instituto de Investigación Sanitaria Fundación Jimenez Diaz, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- Duke Cancer Institute, Department of Medicine, Duke University, Durham, North Carolina, USA
- Cardiovascular Research - Immune Regulation, Department of Clinical Sciences, Lund University, Malmö, Sweden
- Hospital La Paz Institute for Health Research, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
- Thalheimer Center for Cardio-Oncology, Abramson Cancer Center and Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Centro Nacional de Investigaciones Cardiovasculares, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Madrid, Spain
- Molecular Biotechnology Center Guido Tarone, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Human Genotyping Unit, Spanish National Genotyping Centre, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, New York, USA
- Montefiore Einstein Comprehensive Cancer Center, Bronx, New York, New York USA
- Cardio-Oncology Service, Royal Brompton Hospital, London, United Kingdom
- Division of Advanced Technologies, Cima Universidad de Navarra, Pamplona, Spain
- Cardio-Oncology Program, Massachusetts General Hospital, Harvard Medical School. Boston, Massachusetts, USA
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe, Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Carlos III Institute of Health, Madrid, Spain
- Division of Cardiology, Department of Medicine, Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York
- Cardiology Department, Hospital La Paz Institute for Health Research, La Paz University Hospital, Madrid, Spain
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Banerjee A, Narasimhulu CA, Singla DK. Immune interactions in pembrolizumab (PD-1 inhibitor) cancer therapy and cardiovascular complications. Am J Physiol Heart Circ Physiol 2023; 325:H751-H767. [PMID: 37594487 PMCID: PMC10659324 DOI: 10.1152/ajpheart.00378.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 08/19/2023]
Abstract
The use of immunotherapies like pembrolizumab (PEM) is increasingly common for the management of numerous cancer types. The use of PEM to bolster T-cell response against tumor growth is well documented. However, the interactions PEM has on other immune cells to facilitate tumor regression and clearance is unknown and warrants further investigation. In this review, we present literature findings that have reported the interactions of PEM in stimulating innate and adaptive immune cells, which enhance cytotoxic phenotypes. This triggers secretion of cytokines and chemokines, which have both beneficial and detrimental effects. We also describe how this leads to the development of rare but underreported occurrence of PEM-induced immune-related cardiovascular complications that arise suddenly and progress rapidly to debilitating and fatal consequences. This review encourages further research and investigation of PEM-induced cardiovascular complications and other immune cell interactions in patients with cancer. As PEM therapy in treating cancer types is expanding, we expect that this review will inform health care professionals of diverse specializations of medicine like dermatology (melanoma skin cancers), ophthalmology (eye cancers), and pathology (hematological malignancies) about PEM-induced cardiac complications.
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Affiliation(s)
- Abha Banerjee
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Chandrakala Aluganti Narasimhulu
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States
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14
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Dülgar Ö, Saha A, Elleson KM, Markowitz J. Successful treatment with carboplatin and paclitaxel in melanoma progression after immune-related adverse events. Immunotherapy 2023; 15:993-999. [PMID: 37525573 PMCID: PMC10565538 DOI: 10.2217/imt-2022-0213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 06/09/2023] [Indexed: 08/02/2023] Open
Abstract
The overall survival of melanoma patients has improved using antibodies targeting immune checkpoints (anti-PD-1, anti-CTLA-4 and anti-LAG-3). Systemic chemotherapy was administered in melanoma for many years with limited effectiveness. Here we report a case of a patient who experienced immune-mediated adverse effects from checkpoint blockade therapy and subsequently responded to chemotherapy. The patient presented with melanoma and paraneoplastic digital ischemia. She received a combination of ipilimumab/nivolumab and experienced G3 myocarditis, followed by melanoma progression after a steroid taper. This patient achieved a partial and durable response with platinum and taxane-based chemotherapy. This report suggests the possibility of a subset of patients who experience progression after immune-based side effects where chemotherapy may be effective in the modern age of melanoma treatment.
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Affiliation(s)
- Özgecan Dülgar
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Aditi Saha
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Kelly M Elleson
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, Morsani School of Medicine University of South Florida, Tampa, FL 33612, USA
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15
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Yousif LI, Screever EM, Versluis D, Aboumsallem JP, Nierkens S, Manintveld OC, de Boer RA, Meijers WC. Risk Factors for Immune Checkpoint Inhibitor-Mediated Cardiovascular Toxicities. Curr Oncol Rep 2023; 25:753-763. [PMID: 37079251 PMCID: PMC10256640 DOI: 10.1007/s11912-023-01414-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2023] [Indexed: 04/21/2023]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have improved the field of cancer, especially in patients with advanced malignancies. Nevertheless, cardiovascular immune-related adverse events (irAEs) with high mortality and morbidity have been observed, including myocarditis, pericarditis, and vasculitis. To date, only a few clinical risk factors have been described and are currently being investigated. RECENT FINDINGS In this review, we address the four most prevailing risk factors for cardiovascular irAEs. ICI combination therapy is a predominant risk factor for developing ICI-mediated myocarditis. Additionally, ICI combined with other anti-cancer treatments (e.g., tyrosine kinase inhibitors, radiation, chemotherapy) seems to increase the risk of developing cardiovascular irAEs. Other risk factors include female sex, pre-existing cardiovascular disease, and specific tumors, on which we will further elaborate in this review. An a priori risk strategy to determine who is at risk to develop these cardiovascular irAEs is needed. Insights into the impact of risk factors are therefore warranted to help clinicians improve care and disease management in these patients.
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Affiliation(s)
- Laura I. Yousif
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
| | - Elles M. Screever
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
| | - Daniëlle Versluis
- Graduate School of Life Science, Utrecht University, P.O. Box 80125, 3508 TC Utrecht, The Netherlands
| | - Joseph Pierre Aboumsallem
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
| | - Stefan Nierkens
- Center for Translational Immunology, Utrecht University, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, The Netherlands
| | - Olivier C. Manintveld
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
| | - Rudolf A. de Boer
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
| | - Wouter C. Meijers
- Department of Cardiology, Thorax Center, Erasmus University Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands
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Ciccone V, Ziche M, Spini A, Donnini S. Uncovering Knowledge Gaps in the Safety Profile of Antiangiogenic Drugs in Cancer Patients: Insights from Spontaneous Reporting Systems Studies. Pharmaceuticals (Basel) 2023; 16:867. [PMID: 37375814 DOI: 10.3390/ph16060867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despite the exclusion of pharmacoepidemiological studies, we believe that this scoping review, which focuses on an entire class of drugs, could be considered as a novel approach to highlight possible safety concerns of drugs and as a guide for the conduction of a target postmarketing surveillance on AADs.
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Affiliation(s)
- Valerio Ciccone
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Marina Ziche
- Department of Medicine Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Andrea Spini
- Department of Medicine Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
- Azienda Ospedaliera Universitaria Senese, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Sandra Donnini
- Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
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Dora D, Bokhari SMZ, Aloss K, Takacs P, Desnoix JZ, Szklenárik G, Hurley PD, Lohinai Z. Implication of the Gut Microbiome and Microbial-Derived Metabolites in Immune-Related Adverse Events: Emergence of Novel Biomarkers for Cancer Immunotherapy. Int J Mol Sci 2023; 24:ijms24032769. [PMID: 36769093 PMCID: PMC9916922 DOI: 10.3390/ijms24032769] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have changed how we think about tumor management. Combinations of anti-programmed death ligand-1 (PD-L1) immunotherapy have become the standard of care in many advanced-stage cancers, including as a first-line therapy. Aside from improved anti-tumor immunity, the mechanism of action of immune checkpoint inhibitors (ICIs) exposes a new toxicity profile known as immune-related adverse effects (irAEs). This novel toxicity can damage any organ, but the skin, digestive and endocrine systems are the most frequently afflicted. Most ICI-attributed toxicity symptoms are mild, but some are severe and necessitate multidisciplinary side effect management. Obtaining knowledge on the various forms of immune-related toxicities and swiftly changing treatment techniques to lower the probability of experiencing severe irAEs has become a priority in oncological care. In recent years, there has been a growing understanding of an intriguing link between the gut microbiome and ICI outcomes. Multiple studies have demonstrated a connection between microbial metagenomic and metatranscriptomic patterns and ICI efficacy in malignant melanoma, lung and colorectal cancer. The immunomodulatory effect of the gut microbiome can have a real effect on the biological background of irAEs as well. Furthermore, specific microbial signatures and metabolites might be associated with the onset and severity of toxicity symptoms. By identifying these biological factors, novel biomarkers can be used in clinical practice to predict and manage potential irAEs. This comprehensive review aims to summarize the clinical aspects and biological background of ICI-related irAEs and their potential association with the gut microbiome and metabolome. We aim to explore the current state of knowledge on the most important and reliable irAE-related biomarkers of microbial origin and discuss the intriguing connection between ICI efficacy and toxicity.
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Affiliation(s)
- David Dora
- Department of Anatomy, Histology, and Embryology, Semmelweis University, Tuzolto St. 58, 1094 Budapest, Hungary
- Correspondence: (D.D.); (Z.L.)
| | | | - Kenan Aloss
- Translational Medicine Institute, Semmelweis University, 1094 Budapest, Hungary
| | - Peter Takacs
- Department of Anatomy, Histology, and Embryology, Semmelweis University, Tuzolto St. 58, 1094 Budapest, Hungary
| | - Juliane Zsuzsanna Desnoix
- Department of Anatomy, Histology, and Embryology, Semmelweis University, Tuzolto St. 58, 1094 Budapest, Hungary
| | - György Szklenárik
- Translational Medicine Institute, Semmelweis University, 1094 Budapest, Hungary
| | | | - Zoltan Lohinai
- Translational Medicine Institute, Semmelweis University, 1094 Budapest, Hungary
- National Korányi Institute of Pulmonology, Pihenő út 1-3, 1121 Budapest, Hungary
- Correspondence: (D.D.); (Z.L.)
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Guo JC, Chiu CC. Immune-related giant cell myocarditis after immune checkpoint inhibitor therapy in a patient with urothelial carcinoma and myasthenia gravis. JOURNAL OF CANCER RESEARCH AND PRACTICE 2023. [DOI: 10.4103/2311-3006.371526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023] Open
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19
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Vasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, Shadid H, Anderson E, Catalan T, Blakely P, Nelapudi N, Fardous M, Bretagne MC, Adie SK, Pogue KT, Leja M, Yentz S, Schneider B, Fecher LA, Lao CD, Salem JE, Hayek SS. Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis. JACC CardioOncol 2022; 4:689-700. [PMID: 36636441 PMCID: PMC9830199 DOI: 10.1016/j.jaccao.2022.11.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 12/24/2022] Open
Abstract
Background Myocarditis is a dreaded and unpredictable complication of immune checkpoint inhibitors (ICI). We sought to determine whether routinely measured biomarkers could be helpful in monitoring for ICI myocarditis. Objectives The authors examined biomarker trends of patients on ICI and their association with the incidence of ICI myocarditis and outcomes. Methods We conducted an observational cohort study of adults who received at least one dose of ICI at Michigan Medicine between June 2014 and December 2021 and underwent systematic serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy. Results Among 2,606 patients (mean age 64 ± 13 years; 60.7% men), 27 (1.0%) were diagnosed with ICI myocarditis. At diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR: 1.83; 95% CI: 1.59-2.10) and all-cause mortality (HR: 1.10; 95% CI: 1.01-1.20) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis. Conclusions ICI myocarditis is associated with changes in AST, ALT, and CPK. An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis.
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Affiliation(s)
- Alexi Vasbinder
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - YeeAnn Chen
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Adrien Procureur
- Department of Pharmacology and Clinical Investigation Centre, Pitié-Salpêtrière Hospital, Sorbonne Universite, Paris, France
| | - Allison Gradone
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Tariq U. Azam
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Daniel Perry
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Husam Shadid
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Elizabeth Anderson
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Tonimarie Catalan
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Pennelope Blakely
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Namratha Nelapudi
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Mohamad Fardous
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Marie C. Bretagne
- Department of Pharmacology and Clinical Investigation Centre, Pitié-Salpêtrière Hospital, Sorbonne Universite, Paris, France
| | - Sarah K. Adie
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Kristen T. Pogue
- Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Monika Leja
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Sarah Yentz
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Bryan Schneider
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Leslie A. Fecher
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Christopher D. Lao
- Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Joe-Elie Salem
- Department of Pharmacology and Clinical Investigation Centre, Pitié-Salpêtrière Hospital, Sorbonne Universite, Paris, France
| | - Salim S. Hayek
- Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA,Address for correspondence: Dr Salim Hayek, Department of Medicine, Division of Cardiology, University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, CVC #2709, Ann Arbor, Michigan 48109, USA. @salimhayek
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20
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Hicks KA, Fashoyin-Aje LA, Amiri-Kordestani L. To Adjudicate or Not Adjudicate: That Is the Question. JACC CardioOncol 2022; 4:657-659. [PMID: 36636434 PMCID: PMC9830205 DOI: 10.1016/j.jaccao.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Karen A. Hicks
- Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Lola A. Fashoyin-Aje
- Division of Oncology III, Office of Oncologic Drugs, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Laleh Amiri-Kordestani
- Division of Oncology I, Office of Oncologic Drugs, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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21
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Yoon BK, Oh TG, Bu S, Seo KJ, Kwon SH, Lee JY, Kim Y, Kim JW, Ahn HS, Fang S. The Peripheral Immune Landscape in a Patient with Myocarditis after the Administration of BNT162b2 mRNA Vaccine. Mol Cells 2022; 45:738-748. [PMID: 35904026 PMCID: PMC9589374 DOI: 10.14348/molcells.2022.0031] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/27/2022] [Accepted: 06/09/2022] [Indexed: 12/02/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed a serious threat to global public health. A novel vaccine made from messenger RNA (mRNA) has been developed and approved for use at an unprecedented pace. However, an increased risk of myocarditis has been reported after BNT162b2 mRNA vaccination due to unknown causes. In this study, we used single-cell RNA sequencing and single-cell T cell receptor sequencing analyses of peripheral blood mononuclear cells (PBMCs) to describe, for the first time, changes in the peripheral immune landscape of a patient who underwent myocarditis after BNT162b2 vaccination. The greatest changes were observed in the transcriptomic profile of monocytes in terms of the number of differentially expressed genes. When compared to the transcriptome of PBMCs from vaccinated individuals without complications, increased expression levels of IL7R were detected in multiple cell clusters. Overall, results from this study can help advance research into the pathogenesis of BNT162b2-induced myocarditis.
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Affiliation(s)
- Bo Kyung Yoon
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Tae Gyu Oh
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Seonghyeon Bu
- Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Seoul 06591, Korea
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Kyung Jin Seo
- Department of Pathology, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Seoul 06591, Korea
| | - Se Hwan Kwon
- Department of Radiology, Kyung Hee University Medical Center, Seoul 02447, Korea
| | | | | | - Jae-woo Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Hyo-Suk Ahn
- Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Seoul 06591, Korea
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sungsoon Fang
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
- KYNOGEN Co., Suwon 16229, Korea
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea
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22
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Hwang N, Huh Y, Bu S, Seo KJ, Kwon SH, Kim JW, Yoon BK, Ahn HS, Fang S. Single-cell sequencing of PBMC characterizes the altered transcriptomic landscape of classical monocytes in BNT162b2-induced myocarditis. Front Immunol 2022; 13:979188. [PMID: 36225942 PMCID: PMC9549039 DOI: 10.3389/fimmu.2022.979188] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the most dangerous threat to public health worldwide for the last few years, which led to the development of the novel mRNA vaccine (BNT162b2). However, BNT162b2 vaccination is known to be associated with myocarditis. Here, as an attempt to determine the pathogenesis of the disease and to develop biomarkers to determine whether subjects likely proceed to myocarditis after vaccination, we conducted a time series analysis of peripheral blood mononuclear cells of a patient with BNT162b2-induced myocarditis. Single-cell RNA sequence analysis identified monocytes as the cell clusters with the most dynamic changes. To identify distinct gene expression signatures, we compared monocytes of BNT162b2-induced myocarditis with monocytes under various conditions, including SARS-CoV-2 infection, BNT162b2 vaccination, and Kawasaki disease, a disease similar to myocarditis. Representative changes in the transcriptomic profile of classical monocytes include the upregulation of genes related to fatty acid metabolism and downregulation of transcription factor AP-1 activity. This study provides, for the first time, the importance of classical monocytes in the pathogenesis of myocarditis following BNT162b2 vaccination and presents the possibility that vaccination affects monocytes, further inducing their differentiation and infiltration into the heart.
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Affiliation(s)
- Nahee Hwang
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Yune Huh
- Department of Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Seonghyeon Bu
- Divison of Cardiology, Department of Internal medicine, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Seoul, South Korea
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Kyung Jin Seo
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Se Hwan Kwon
- Department of Radiology, Kyung Hee University Medical Center, Seoul, South Korea
| | - Jae-woo Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Bo Kyung Yoon
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Bo Kyung Yoon, ; Hyo-Suk Ahn, ; Sungsoon Fang,
| | - Hyo-Suk Ahn
- Divison of Cardiology, Department of Internal medicine, The Catholic University of Korea, Uijeongbu St. Mary’s Hospital, Seoul, South Korea
- Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, Seoul, South Korea
- *Correspondence: Bo Kyung Yoon, ; Hyo-Suk Ahn, ; Sungsoon Fang,
| | - Sungsoon Fang
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Bo Kyung Yoon, ; Hyo-Suk Ahn, ; Sungsoon Fang,
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23
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Deharo F, Carvelli J, Cautela J, Garcia M, Sarles C, Maues de Paula A, Bourenne J, Gainnier M, Bichon A. Immune Checkpoint Inhibitor-Induced Myositis/Myocarditis with Myasthenia Gravis-like Misleading Presentation: A Case Series in Intensive Care Unit. J Clin Med 2022; 11:jcm11195611. [PMID: 36233479 PMCID: PMC9573481 DOI: 10.3390/jcm11195611] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 11/21/2022] Open
Abstract
Introduction: Immune checkpoint inhibitors (ICIs) are a major breakthrough in cancer treatment. Their increasingly frequent use leads to an uprising incidence of immune-related adverse events (irAEs). Among those, myocarditis is the most reported fatal cardiovascular irAE, frequently associated with ICI-related myositis. Case series: Here, we report three cases of ICI-induced myocarditis/myositis with an extremely severe myasthenia gravis-like (MG-like) presentation, highlighting the main challenges in irAEs management. These patients were over 60 years old and presented an ongoing melanoma, either locally advanced or metastatic, treated with ICI combinations. Shortly after the first or second ICI infusion, they were admitted in an intensive care unit (ICU) for grade 3 ICI-induced MG-like symptoms leading to acute respiratory failure (ARF) requiring invasive mechanical ventilation (IMV). The initial misdiagnosis was later corrected to severe ICI-induced seronegative myocarditis/myositis upon biological results and histopathology from muscular/endomyocardial biopsies. All of them received urgent high-dose corticosteroids pulses. The oldest patient died prematurely, but the two others received targeted therapies leading to complete recovery for one of them. Discussion: These cases highlight the four main challenges of irAEs, encompassing the lack of knowledge among physicians, the risk of misdiagnosis due to numerous and non-specific symptoms, the frequent overlapping forms of irAEs, and the extremely rare MG-like misleading presentation of myocarditis/myositis. The exact pathophysiology of irAEs remains unclear, although a major involvement of the lymphoid compartment (specifically T lymphocytes) was evidenced. Therapeutic management is based on urgent high-dose corticosteroids. For the severest forms of irAEs, case-by-case targeted immunosuppressive therapies should be urgently administered upon multidisciplinary meetings. Conclusion: These cases highlight the lack of knowledge of irAEs among physicians, aggravated by misleading overlapping forms, requiring specific management in trained units and multidisciplinary care. Severe MG-like presentation of irAEs constitutes an absolute therapeutic emergency with high-dose corticosteroids and targeted immunosuppressive therapy.
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24
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Jiménez-Alejandre R, Ruiz-Fernández I, Martín P. Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis. Cancers (Basel) 2022; 14:4494. [PMID: 36139654 PMCID: PMC9497311 DOI: 10.3390/cancers14184494] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have recently emerged as strong therapies for a broad spectrum of cancers being the first-line treatment for many of them, even improving the prognosis of malignancies that were considered untreatable. This therapy is based on the administration of monoclonal antibodies targeting inhibitory T-cell receptors, which boost the immune system and prevent immune evasion. However, non-specific T-cell de-repression can result in a wide variety of immune-related adverse events (irAEs), including gastrointestinal, endocrine, and dermatologic, with a smaller proportion of these having the potential for fatal outcomes such as neurotoxicity, pulmonary toxicity, and cardiotoxicity. In recent years, alarm has been raised about cardiotoxicity as it has the highest mortality rate when myocarditis develops. However, due to the difficulty in diagnosing this cardiac condition and the lack of clinical guidelines for the management of cardiovascular disease in patients on therapy with ICIs, early detection of myocarditis has become a challenge in these patients. In this review we outline the mechanisms of tolerance by which this fatal cardiomyopathy may develop in selected cancer patients treated with ICIs, summarize preclinical models of the disease that will allow the development of more accurate strategies for its detection and treatment, and discuss the challenges in the future to decrease the risks of its development with better decision making in susceptible patients.
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Affiliation(s)
| | | | - Pilar Martín
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBER-CV), 28029 Madrid, Spain
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25
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Curtiaud A, Delmas C, Gantzer J, Zafrani L, Siegemund M, Meziani F, Merdji H. Cardiogenic shock among cancer patients. Front Cardiovasc Med 2022; 9:932400. [PMID: 36072868 PMCID: PMC9441759 DOI: 10.3389/fcvm.2022.932400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Sophisticated cancer treatments, cardiovascular risk factors, and aging trigger acute cardiovascular diseases in an increasing number of cancer patients. Among acute cardiovascular diseases, cancer treatment, as well as the cancer disease itself, may induce a cardiogenic shock. Although increasing, these cardiogenic shocks are still relatively limited, and their management is a matter of debate in cancer patients. Etiologies that cause cardiogenic shock are slightly different from those of non-cancer patients, and management has some specific features always requiring a multidisciplinary approach. Recent guidelines and extensive data from the scientific literature can provide useful guidance for the management of these critical patients. Even if no etiologic therapy is available, maximal intensive supportive measures can often be justified, as most of these cardiogenic shocks are potentially reversible. In this review, we address the major etiologies that can lead to cardiogenic shock in cancer patients and discuss issues related to its management.
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Affiliation(s)
- Anais Curtiaud
- Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Strasbourg, France
| | - Clement Delmas
- Intensive Cardiac Care Unit, Cardiology Department, University Hospital of Rangueil, Toulouse, France
| | - Justine Gantzer
- Department of Medical Oncology, Strasbourg-Europe Cancer Institute (ICANS), Strasbourg, France
| | - Lara Zafrani
- Medical Intensive Care Unit, Saint-Louis Hospital, Assistance Publique des Hôpitaux de Paris, University of Paris, Paris, France
| | - Martin Siegemund
- Intensive Care Unit, Department of Acute Medicine, University Hospital, Basel, Switzerland
- Department of Clinical Research, University of Basel, Basel, Switzerland
| | - Ferhat Meziani
- Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - Hamid Merdji
- Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
- *Correspondence: Hamid Merdji
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26
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Randomized Versus Real-World Evidence on the Efficacy and Toxicity of Checkpoint Inhibitors in Cancer in Patients with Advanced Non-small Cell Lung Cancer or Melanoma: A Meta-analysis. Target Oncol 2022; 17:507-515. [PMID: 35913645 PMCID: PMC9512877 DOI: 10.1007/s11523-022-00901-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 11/22/2022]
Abstract
Background Both randomized controlled trials (RCTs) and real-world evidence (RWE) studies provide results regarding the efficacy and toxicity of checkpoint inhibitors in cancer patients. The results from these two sources are considered complementary but whether they are comparable remains unknown. Objective The aim of this study was to compare the efficacy and toxicity of checkpoint inhibitors between RCTs and RWE studies in patients with advanced non-small cell lung cancer (NSCLC) or melanoma. Patients and Methods Two electronic databases were searched to identify eligible studies, either RCTs or RWE studies, investigating the efficacy or toxicity of checkpoint inhibitors given for indications that were approved by the European Medicines Agency (EMA) at the date of the last search. A meta-analysis was performed and the pooled estimates of objective response rates (ORR), progression-free survival (PFS), overall survival (OS), and toxicity and treatment discontinuation between RCTs and RWE studies were compared. Results In total, 43 RWE studies and 15 RCTs were eligible, with adequate data for pooled estimates for immunotherapy indications regarding NSCLC and melanoma. No statistically significant or clinically meaningful differences in terms of pooled PFS, OS, or rates of treatment discontinuation due to toxicity between RCTs and RWE studies were observed. In some indications, a higher rate of response rates and lower rate of toxicity in favor of RWE was observed. Conclusion In patients with melanoma or NSCLC, the clinical value of checkpoint inhibitors is evident in both RCTs and real-world settings. Some differences in response or toxicity rates in favor of RWE mainly reflects the inherent difficulties in evaluating these outcomes in RWE studies. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-022-00901-1.
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27
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Kwan JM, Oikonomou EK, Henry ML, Sinusas AJ. Multimodality Advanced Cardiovascular and Molecular Imaging for Early Detection and Monitoring of Cancer Therapy-Associated Cardiotoxicity and the Role of Artificial Intelligence and Big Data. Front Cardiovasc Med 2022; 9:829553. [PMID: 35369354 PMCID: PMC8964995 DOI: 10.3389/fcvm.2022.829553] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer mortality has improved due to earlier detection via screening, as well as due to novel cancer therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitions. However, similarly to older cancer therapies such as anthracyclines, these therapies have also been documented to cause cardiotoxic events including cardiomyopathy, myocardial infarction, myocarditis, arrhythmia, hypertension, and thrombosis. Imaging modalities such as echocardiography and magnetic resonance imaging (MRI) are critical in monitoring and evaluating for cardiotoxicity from these treatments, as well as in providing information for the assessment of function and wall motion abnormalities. MRI also allows for additional tissue characterization using T1, T2, extracellular volume (ECV), and delayed gadolinium enhancement (DGE) assessment. Furthermore, emerging technologies may be able to assist with these efforts. Nuclear imaging using targeted radiotracers, some of which are already clinically used, may have more specificity and help provide information on the mechanisms of cardiotoxicity, including in anthracycline mediated cardiomyopathy and checkpoint inhibitor myocarditis. Hyperpolarized MRI may be used to evaluate the effects of oncologic therapy on cardiac metabolism. Lastly, artificial intelligence and big data of imaging modalities may help predict and detect early signs of cardiotoxicity and response to cardioprotective medications as well as provide insights on the added value of molecular imaging and correlations with cardiovascular outcomes. In this review, the current imaging modalities used to assess for cardiotoxicity from cancer treatments are discussed, in addition to ongoing research on targeted molecular radiotracers, hyperpolarized MRI, as well as the role of artificial intelligence (AI) and big data in imaging that would help improve the detection and prognostication of cancer-treatment cardiotoxicity.
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Affiliation(s)
- Jennifer M. Kwan
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Evangelos K. Oikonomou
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Mariana L. Henry
- Geisel School of Medicine at Dartmouth, Hanover, NH, United States
| | - Albert J. Sinusas
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
- Department of Biomedical Engineering, Yale University, New Haven, CT, United States
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28
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Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, Watkinson P, Khunti K, Harnden A, Coupland CAC, Channon KM, Mills NL, Sheikh A, Hippisley-Cox J. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med 2022; 28:410-422. [PMID: 34907393 PMCID: PMC8863574 DOI: 10.1038/s41591-021-01630-0] [Citation(s) in RCA: 399] [Impact Index Per Article: 133.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020 and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the 1-28 days following adenovirus (ChAdOx1, n = 20,615,911) or messenger RNA-based (BNT162b2, n = 16,993,389; mRNA-1273, n = 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n = 3,028,867). We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1-28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines was present only in those younger than 40.
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Affiliation(s)
- Martina Patone
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK
| | - Xue W Mei
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK
| | | | - Sharon Dixon
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK
| | - Francesco Zaccardi
- Leicester Real World Evidence Unit, Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Manu Shankar-Hari
- Usher Institute, University of Edinburgh, Edinburgh, UK
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Peter Watkinson
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Kamlesh Khunti
- Leicester Real World Evidence Unit, Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Anthony Harnden
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK
| | - Carol A C Coupland
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK
- Division of Primary Care, School of Medicine, University of Nottingham, Nottingham, UK
| | - Keith M Channon
- British Heart Foundation Centre of Research Excellence, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Nicholas L Mills
- Usher Institute, University of Edinburgh, Edinburgh, UK
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Aziz Sheikh
- Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Julia Hippisley-Cox
- Nuffield Department of Primary Health Care Sciences, University of Oxford, Oxford, UK.
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29
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Makunts T, Jerome L, Abagyan R, de Boer A. Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database. Front Psychiatry 2021; 12:824288. [PMID: 35140642 PMCID: PMC8820588 DOI: 10.3389/fpsyt.2021.824288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/28/2021] [Indexed: 11/13/2022] Open
Abstract
3,4-Methylenedioxymethamphetamine (MDMA), is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions in multiple placebo-controlled and open label studies. MDMA-assisted therapy is projected for approval by the United States Food and Drug Administration (FDA) and other regulatory agencies worldwide within the next few years. MDMA is a monoamine releaser and uptake inhibitor affecting serotonin, potentially increasing the risk of serotonin syndrome (SS). No instances of SS have occurred in clinical trials. The relatively small number of patients in controlled trials warranted a survey of FDA Adverse Event Reporting System data for the occurrence of SS in a larger database. We found 20 SS cases in people exposed to MDMA, all of which had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants, and opioids. There were no cases of SS associated with MDMA where MDMA was the sole reported compound taken.
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Affiliation(s)
- Tigran Makunts
- MAPS Public Benefit Corporation, San Jose, CA, United States.,Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, United States
| | - Lisa Jerome
- MAPS Public Benefit Corporation, San Jose, CA, United States
| | - Ruben Abagyan
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, United States
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