Santoro, Ciro

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.

Background: The aim of this aortic stenosis registry was to investigate the changes of routine echocardiographic indices and strain in patients with moderate-to-severe aortic stenosis over a 6-month follow-up period. Methods: Our aortic stenosis registry is observational, prospective, multicenter registry of nine countries, with 197 patients with aortic valve area less than 1.5 cm 2 . The enrolment took place from January to August 2017. We excluded patients with uncontrolled atrial arrhythmias, pulmonary hypertension or cardiomyopathies, as well as those with hemodynamically significant valvular disease other than aortic stenosis. We included patients who did not require intervention and who had a complete follow-up study. Results: In patients with preserved ejection fraction, left ventricular mass has significantly increased between baseline and follow-up studies (218 ± 34 grams vs 253 ± 29 grams, p = 0.02). However, when indexed to body surface area, there was no significant difference. Left ventricular global longitudinal strain significantly decreased (-19.7 ± -4.8 vs (-16.4 vs -3.8, p = 0.01). Left atrial volume was significantly higher at follow-up (p = 0.035). Right ventricular basal diameter and mid-cavity diameter were greater at the follow-up (p = 0.04 and p = 0.035, respectively). Patients with low-flow low-gradient aortic stenosis had significantly lower global longitudinal strain (-12.3% ± -3.9% vs -19.7% ± -4.8%, p = 0.01). Conclusion: Left atrial dilatation is one of the first changes to take place in low-flow low-gradient aortic stenosis patients even when left ventricular dimensions and function remains intact. Global longitudinal strain is an important determinant of left ventricular systolic and diastolic dysfunction and right ventricular function is an important parameter of aortic stenosis assessment. Accordingly, our registry has further shed the light on these indices role as multisite follow-up of aortic stenosis.