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ABSTRACT: The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell‐based immune therapies including chimeric antigen receptor T lymphocyte (CAR‐T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune‐related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune‐related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI‐related myocarditis with cardiogenic shock to more common complications including less severe ICI‐related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non‐inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR‐T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Resumen: La capacitación toxicológica cursa con disparidad en relación con otras áreas del conocimiento médico, lo que favorece vacíos cognitivos en los profesionales de la salud. Este documento presenta una propuesta educativa para el abordaje de «toxíndromes mayores» a través de un esquema que integra su identificación y tratamiento mediante escenarios de simulación clínica con empleo de pacientes simulados/estandarizados para el pregrado médico en el Centro Universitario del Sur de la Universidad de Guadalajara, desarrollado durante el año 2023. Abstract: Toxicological training has disparities in relation to other areas of medical knowledge, which favors cognitive gaps in health professionals. This document presents an educational proposal for the approach of “major toxidromes” through a scheme that integrates their identification and treatment through clinical simulation scenarios with the use of simulated/standardized patients for the medical undergraduate degree at the Centro Universitario del Sur of the Universidad de Guadalajara, developed during the year 2023.

Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction

Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year.

The burdens of cardiovascular (CV) diseases and cardiotoxic side effects of cancer treatment in oncology patients are increasing in parallel. The European Society of Cardiology (ESC) 2022 Cardio-Oncology guidelines recommend the use of standardized risk stratification tools to determine the risk of cardiotoxicity associated with different anticancer treatment modalities and the severity of their complications. The use of the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) is essential for assessing risk prior to starting cancer treatment, and validation of these methods has been performed in patients receiving anthracyclines, human epidermal receptor 2 (HER2)-targeted therapies and breakpoint cluster region-abelson oncogene locus (BCR-ABL) inhibitors. The benefits of performing baseline CV risk assessment and stratification include early recognition of cardiotoxicities, personalisation of cancer treatment and monitoring strategies, and allocation of cardioprotection to those at the highest risk. This review summarizes the key points of risk stratification in these patients. The steps include identifying the target population, assessing nonmodifiable and modifiable CV risk factors, reviewing previous oncologic therapies and CV histories, and performing baseline investigations. In summary, this review aims to provide general physicians with a simple 7-step guide that will help steer and navigate them through cardiac risk evaluation of potentially cardiotoxic oncologic treatment strategies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs. METHODS: Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death. RESULTS: The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002). CONCLUSION: The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

This study used rhetorical and relational goal theory to examine the different ways college instructors respond to disruptive behaviors by students in the classroom. Student participants provided and described a critical incident involving a disruptive classmate that either was or was not handled effectively by the instructor. Results identified differences between effective and ineffective instructors' responses. Although teachers responded to similar types of incidents, there were thematic differences between what students named as effective and ineffective responses, with effective teachers managing both rhetorical goals and relational goals successfully. These teachers facilitated an open discussion, provided explanations to students' questions, remained composed and respectful, and managed cumbersome issues outside of the classroom. In contrast, ineffective teachers insisted on their own view and/or dismissed students' voices, ignored and/or avoided students' concerns, escalated conflicts, or indulged students or issues for too long. They showed little attention to relational goals and did not pursue highly effective rhetorical goals. Furthermore, participants often had strong, negative lasting impressions when instructors handled issues poorly.

BACKGROUND: Hypertension is commonly reported in multiple myeloma (MM) patients and may be associated with older age, disease-related complications and consequences of MM treatments. This study evaluated the incidence rates of and risk factors for hypertension and malignant hypertension in newly-treated MM patients in the United States. METHODS: Newly-treated adult MM patients were identified from Truven MarketScan claims database from 1/1/05 to 3/31/14. Inclusion criteria were new diagnosis of MM with start of MM treatment, ≥12 months continuous enrollment prior to diagnosis, ≥30 days of continuous enrollment following initial diagnosis, and prescription drug coverage. Non-MM patients were matched for age (within +/- 5 years), sex and distribution of index dates to MM patients. Baseline cardiovascular (CV) comorbidities, incidence rate of hypertension and malignant hypertension in the follow-up period, and risk of hypertension and malignant hypertension based on existing baseline CV comorbidities were evaluated. RESULTS: A total of 7895 MM patients (38% with hypertension history) and 23,685 non-MM patients (24% with hypertension history) were included in the study. Twenty-two percent of MM patients versus 3% of non-MM patients had baseline renal failure. A higher percentage of MM versus non-MM patients had baseline hypertension in combination with renal failure, congestive heart failure or both. The incidence rate of hypertension in MM and non-MM patients was 260 and 178 per 1000 person-years, respectively. There was a 30% increase in the risk of hypertension for MM versus non-MM patients: hazard ratio (HR) 1.30 (95% confidence interval [CI] 1.22, 1.37). In MM patients with a history of hypertension, the risk of malignant hypertension was significantly increased with the following comorbid conditions: cardiomyopathy, HR 2.79 (95% CI 1.20, 6.48); renal failure, HR 2.13 (95% CI 1.36, 3.34); and diabetes mellitus, HR 1.59 (95% CI 1.05, 2.39). CONCLUSIONS: This study confirms that the incidence of hypertension and malignant hypertension is significantly higher in newly-treated MM versus non-MM patients. Hypertension is a risk factor for MM patients developing malignant hypertension. Management of CV comorbidities in MM patients is important based on the increased risk of hypertension and malignant hypertension among patients with these comorbidities.