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Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027

Although post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, it is associated with toxicities, which might be dose-dependent. We compared the outcomes with PT-Cy at 80 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients undergoing haploidentical hematopoietic cell transplantation (HCT). Inclusion criteria included peripheral blood stem cells, hematological malignancy, and age65 years (or age60 years if cardiac event history). Thirty-eight patients received PT-Cy at 80 mg/kg and 55 100 mg/kg, divided in two doses. The cumulative incidences (CI) of acute grade II-IV, acute grade III-IV, and moderate/severe chronic GVHD were 32%, 16%, and 13% with PT-Cy at 80 mg/kg compared to 33%, 13%, and 16% with 100 mg/kg, respectively. In multivariable analysis, reducing PT-Cy dose had no significant impact on GVHD. Neutrophil and platelet engraftments were significantly improved, and CI of BK virus-associated hemorrhagic cystitis was reduced with 80 mg/kg of PT-Cy compared to 100 mg/kg. At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse-free survival 52% and 36% with 80 mg/kg and 100 mg/kg, respectively. Reducing PT-Cy dose to 80 mg/kg is safe and associated with improved hematological recovery and lower CI of hemorrhagic cystitis in elderly patients undergoing haploidentical HCT.

Treatment modalities and reported adverse events by quartile of period of inclusion.

Example of the first severe ICI-myocarditis case treated with abatacept guided by real-time immune-monitoring assessment of CD86RO (CD86 receptor occupancy) on circulating monocytes.

Methods concerning Immune-checkpoint proteins profiling on peripheral blood mononuclear cells and Circulating immune checkpoint agents drug monitoring

Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation.Significance:Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis.See related commentary by Dougan, p. 1040.This article is highlighted in the In This Issue feature, p. 1027

BackgroundThe immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known.AimThe prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and shigatoxin-producingEscherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study.MethodsUnivariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions.ResultsAmong 73 TMA cases (mean age 46.89 ± 15.99 years (range: 21-87 years) with iTTP (n = 57) or HUS (n= 16), one third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, 3 factors predicted the occurrence of acute ischemic lesions on cerebral MRI: 1) the presence of old infarcts on cerebral MRI, 2) the level of blood pulse pressure, 3) the diagnosis of iTTP.ConclusionCerebral MRI is crucial to detect both symptomatic and covert ischemic lesions at the acute phase of iTTP and HUS and helps identify patients with old infarcts, at the highest risk of neurological worsening. The diagnosis of iTTP further increases the risk of ischemic lesions but also an increased level of blood pressure that may represent a potential target to further improve the therapeutic management of these conditions.Key points-One third of patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) or the hemolytic uremic syndrome (HUS) present with acute ischemic cerebral lesions on magnetic resonance imagery (MRI);-The cerebral manifestations on MRI did not differ between iTTP and HUS;-The presence of old infarcts on cerebral MRI, the level of blood pulse pressure and a diagnosis of iTTP predict the occurrence of acute ischemic lesions on cerebral MRI.

Aims The respective roles of oral anticoagulation or antiplatelet therapy following transcatheter aortic valve implantation (TAVI) remain debated. ATLANTIS is an international, randomized, open-label, superiority trial comparing apixaban to the standard of care. Methods and results After successful TAVI, 1500 patients were randomized (1:1) to receive apixaban 5 mg (2.5 mg if impaired renal function or concomitant antiplatelet therapy) (n = 749) twice daily, or standard of care (n = 751). Randomization was stratified by the need for chronic anticoagulation therapy. Standard-of-care patients received a vitamin K antagonist (VKA) (Stratum 1) or antiplatelet therapy (Stratum 2) if there was an indication for anticoagulation or not, respectively. The primary endpoint was the composite of death, myocardial infarction, stroke or transient ischaemic attack, systemic embolism, intracardiac or bioprosthesis thrombosis, deep vein thrombosis or pulmonary embolism, and life-threatening, disabling, or major bleeding over 1-year follow-up. The primary safety endpoint was major, disabling, or life-threatening bleeding. The primary outcome occurred in 138 (18.4%) and 151 (20.1%) patients receiving apixaban or standard of care, respectively [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.73–1.16] and there was no evidence of interaction between treatment and stratum (Pinteraction = 0.57). The primary safety endpoint was similar in both groups (HR 1.02; 95% CI 0.72–1.44). In Stratum 1 (n = 451), an exploratory analysis showed no difference for all endpoints between apixaban and VKA. In Stratum 2 (n = 1049), the primary outcome and primary safety endpoint did not differ, but obstructive valve thrombosis was reduced with apixaban vs. antiplatelet therapy (HR 0.19; 95% CI 0.08–0.46), while a signal of higher non-cardiovascular mortality was observed with apixaban. Conclusion After TAVI, apixaban was not superior to the standard of care, irrespective of an indication for oral anticoagulation.

Summary Cardio-oncology is an emerging field, that transformed the medical management of patients with cancer. It encompasses the prevention and treatment of cardiovascular toxicities related to cancer treatments, aiming to reduce cardiac adverse events among cancer survivors. Cardiovascular toxicities related to cancer treatments are described through data collected during phase I to phase III therapeutic trials, and post-marketing surveillance (phase IV). Pharmacovigilance analyses, based on datamining from these extensive databases, allowed to understanding and identifying new adverse drug reactions, some recently made available, such as immunotherapy or inhibitor of Bruton tyrosine kinase (IBTK).

Multi-receptor tyrosine kinase inhibitors with anti-angiogenic activity, particularly lenvatinib, have become the standard treatment for radioiodine-refractory metastatic differentiated thyroid cancer but are associated with a high incidence of toxicity. Although patients treated with lenvatinib have been shown to have a significant improvement in progression-free survival, lenvatinib-associated toxicity may result in dose reductions, dose interruptions or even complete lenvatinib withdrawal, compromising anti-tumor efficacy.The article covers the main cardiological and renal toxicities of lenvatinib, including hypertension, prolonged QT interval, heart failure, arterial and venous thromboembolic events, proteinuria and renal failure, and proposes appropriate management of these events during lenvatinib therapy. We performed a literature review of cardiovascular and renal toxicities of Lenvatinib in radioiodine-refractory differentiated thyroid cancer. We discussed prophylactic and therapeutic management for each toxicity based on literature and clinical expertise.Specific pre-therapeutic evaluation and close monitoring of patients treated with lenvatinib is necessary to prevent and detect cardiovascular and/or renal toxicities early, and to propose appropriate management. Oncologists who treat patients with lenvatinib should know how to monitor and treat these adverse events, and when to ask for the advice of a specialist (cardiologist or nephrologist).

International audience; Background: The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%. Objective: To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy. Methods: From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to

Resume Le traitement du melanome metastatique a connu recemment des innovations therapeutiques majeures grâce au developpement des therapies ciblees anti-BRAF et anti-MEK chez les patients porteurs d’une mutation BRAF V600. Les associations vemurafenib + cobimetinib, dabrafenib + trametinib, et encorafenib + binimetinib, evaluees respectivement dans les etudes de phase III coBRIM, COMBI-d/COMBI-v et COLUMBUS, sont actuellement approuvees dans cette indication. Les toxicites associees aux combinaisons sont differentes de celles deja connues avec les monotherapies, en termes de frequence et de severite. Les medecins qui prennent en charge les patients atteints de melanome sont donc confrontes a de nouvelles problematiques concernant la prevention, la detection et le traitement de ces effets indesirables. Cet article fait le point sur les donnees de tolerance issues des trois etudes pivotales (coBRIM, COMBI-v et COLUMBUS) et propose des recommandations de prise en charge specifiques basees sur des avis d’experts. Les toxicites dermatologiques, ophtalmologiques, cardiovasculaires, digestives, musculosquelettiques, renales et generales sont discutees et un calendrier de realisation des examens complementaires avant l’instauration et pendant le traitement anticancereux est propose.

A 34-year-old man presented with fever, palpitations, maculopapular rash, pharyngitis, left cheilitis, and bilateral gonalgia. High-sensitivity troponin I concentration was 4,900 ng/l. Transthoracic echocardiogram revealed reduced global longitudinal strain. Cardiac magnetic resonance imaging showed acute myocarditis. Adult-onset Still’s disease was diagnosed, and treatment with intravenous corticosteroids and tocilizumab was initiated. (Level of Difficulty: Beginner.), Central Illustration

International audience; An increasing number of studies of left ventricular myocardial deformation have been published. Layer-specific strain using speckle tracking echocardiography to evaluate left ventricular function is not recommended in clinical practice. However, evaluation of myocardial mechanics using longitudinal and circumferential layer-specific strain enables the detection of subclinical impairment of myocardial deformation in various diseases. Unfortunately, normal values for longitudinal and circumferential strain have not been clearly defined. In normal subjects, layer-specific strain decreases from the endocardial to the epicardial layer, and from the apex to the base of the left ventricle. Although various studies have tried to define normal values for each layer in healthy subjects, studies with more subjects are needed. This tool has good reproducibility in terms of intraobserver and interobserver variability, but, as with monolayer strain, it has poor intervendor variability. Efforts that aim for standardization between vendors will be required before widespread use of this technique can be advocated.

Identifying which patients with acute myocardial infarction (AMI) during sepsis are at risk of poor outcome is a clinical challenge.To evaluate Global Registry of Acute Coronary Events (GRACE) and Thrombolysis In Myocardial Infarction (TIMI) risk scores to predict in-hospital mortality and severe ischaemic events in this setting.In this single-centre retrospective study conducted from 2012 to 2016, all consecutive adults hospitalized in the intensive care unit for sepsis who had a concomitant AMI (within 72hours of admission) were enrolled. AMI was defined by an elevated cardiac troponin I value associated with at least one sign (clinical, electrocardiographic or echocardiographic) suggestive of myocardial ischaemia. The primary outcome was in-hospital mortality from any cause. Secondary outcomes were in-hospital occurrence of severe ischaemic events (cardiac arrest with resuscitation, ischaemic stroke and myocardial reinfarction) and major bleeding events.Among 856 patients hospitalized for sepsis, 120 (14.5%) had a concomitant AMI (37.5% women; median age 65 years; median Sequential Organ Failure Assessment [SOFA] score 8). Severe ischaemic events occurred in 15 patients (12.5%), and 39 (33%) died in hospital. Neither the GRACE score (median 192, interquartile range 154-223) nor the TIMI score (median 3, interquartile range 2-4) was associated with occurrence of severe ischaemic events. Only the GRACE score was associated with in-hospital mortality (odds ratio 1.01, 95% confidence interval 1.00-1.02 per 1 point increase). Multivariable analysis identified previous aspirin use and SOFA score as independent factors associated with in-hospital mortality.GRACE and TIMI scores did not predict in-hospital severe ischaemic events and mortality in patients with AMI during sepsis. Among individual components of both scores, previous aspirin use was associated with poor prognosis. However, because of lack of statistical power, we cannot formally rule out the usefulness of these scores in this setting.

Immune-checkpoint inhibitors (ICI) have profoundly improved the prognosis of cancer patients but are associated with life-threatening myocarditis (incidence≤1%).The diagnosis of ICI-myocarditis remains challenging necessitating the need for novel diagnostic strategies.This single center cohort included 61 consecutive patients referred to our cardio-oncology unit for a suspicion of ICI-myocarditis with a positive troponin, between March 2019 and March 2021. In the 31 patients with suspected ICI-myocarditis with available FDG-PET, the median delay between admission and the first available FDG-PET performed was 12 days [interquartile-range:9-30]. Patients received ICI (ICI-monotherapy: 24/31, 77% and ICI-combination therapy: 7/31, 23%), mainly for lung cancer (n=10), melanoma (n=5), and kidney cancer (n=3). FDG-PET was performed using a standardized protocol involving dietary measures prior to PET, including fasting of at least 6h and a fat enriched diet without carbohydrates for 24h. FDG-PET platforms included Biograph-mCT-Flow Siemens (n=9/34, 26%) or Discovery-MI-5-Ring General Electric (n=25/34, 74%) devices and analysed using Singo.via Workstation (Siemens) by a nuclear medicine physician blinded to patients’ medical records. Interpretation of FDG-PET was based on the following classification: 1/No FDG uptake, 2/Diffuse FDG uptake, 3/Focal FDG uptake, 4/Focal on diffuse FDG uptake.An abnormal cardiac fixation on FDG-PET suggestive of myocarditis was observed in only 2/21 (9.5%) patients with otherwise definite ICI-myocarditis (1 diffuse, 1 focal), not different in proportion versus 1/7 (14.3%, 1 focal) patient without ICI-myocarditis (p>0.99). The sensitivity, specificity, positive predictive and negative predictive values (with their 95% confidence-interval) of FDG-PET for ICI-myocarditis was 9.5% (1.2-30.4%), 85.7% (42.1-99.6%), 66% (17.5-95%), 24% (18.5-30.6%), respectively. Only 2/14(14.2%) FDG-PET were positive despite being performed at a time in which ICI-myocarditis was fully active with troponin levels over ten-times the normal values versus 0/6(0%,p>0.99) for FDG-PET performed when troponin levels were abnormal but below ten-times the upper limit. Similarly, there was no difference in FDG-PET positivity rate for exams performed within 14 days (1/7, 14.3%; plus 3 inconclusive exams) versus those performed after 14 days (1/14, 7.2%; no inconclusive exams; p>0.99) of hospital admission.Altogether, our study suggests that FDG-PET has a limited diagnostic value for the diagnosis of ICI-Myocarditis.

Aims With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). Methods and results We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P Conclusion This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements. Clinical trial registration NCT03530215.

International audience

International audience; Background: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI.Methods: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290.Findings: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070).Interpretation: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI.Funding: ACTION Study Group and AstraZeneca.

Importance In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor–associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed. Observations Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte–associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis. Conclusion and Relevance This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.

"Targeted therapies and hypertension The recent advent of molecular targeted agents represents an important improvement in the management of cancer patients. The administration of therapies targeting the vascular endothelial growth factor or its receptor could be associated with side effects including cardiovascular complications (hypertension, heart Failure, QT interval prolongation). Hypertension due to molecular targeted agents is considered as a class effect, which can affect nearly 90% of treated patients; its management is most often based on the introduction of anti-hypertensive treatment and more rarely on dose drug reduction.""Thérapies ciblées et hypertension artérielle La mise à disposition des thérapies ciblées et notamment des thérapies moléculaires ciblées antiangiogéniques constitue une avancée importante dans la prise en charge des patients atteints de cancers. L’administration des thérapies ciblées ciblant le vascular endothelial growth factor ou son récepteur peut s’accompagner d’effets indésirables, dont des complications cardiovasculaires (hypertension artérielle, insuffisance cardiaque, allongement de l’intervalle QT). L’hypertension secondaire à l’administration des thérapies ciblées est un effet de classe, pouvant affecter près de 90 % des patients traités ; sa prise en charge repose le plus souvent sur l’introduction d’un traitement antihypertenseur et plus rarement sur la modulation de la posologie de la thérapie ciblée."

Background Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce. Objectives This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy. Methods The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring. Results The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no–PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival. Conclusions PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy., Central Illustration

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.

Aim Despite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. Methods In this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD–(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. Results Overall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. Conclusion Most patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

International audience; BACKGROUND 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.OBJECTIVES This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.METHODS 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.RESULTS 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

International audience; No abstract available

BackgroundMyocarditis 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.MethodsFrom 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.ResultsBoth 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, pConclusionsThe QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Depuis la révolution de l’immunothérapie utilisant les inhibiteurs de points de contrôle immunitaire dans la prise en charge de nombreux cancers, les oncologues font face à de nouveaux types de toxicités dites immuno-induites. La compréhension de leurs mécanismes et la mise en place de recommandations claires sont les clés de leur prise en charge. La gravité potentielle de ces toxicités et la très nette amélioration du pronostic apportée par ces traitements pour les patients porteurs de cancers métastatiques rend le rôle du réanimateur primordial. Le but de cette mise au point est d’effectuer une synthèse des toxicités immuno-induites pouvant conduire les patients en cours de traitement par inhibiteur de points de contrôle immunitaireen réanimation et ainsi de proposer des recommandations dans leur prise en charge afin d’aider le réanimateur dans sa démarche diagnostique et thérapeutique. L’imbrication de toxicités immuno-induites pouvant toucher plusieurs organes de façon concomitante, impose une prise en charge pluridisciplinaire regroupant oncologue, spécialiste d’organes et réanimateur. La mise en place de réunion de concertation pluridisciplinaire dédiée à ce type de toxicités permet ce regroupement, de même que le développement d’une expertise commune au sein d’un centre, la création de protocoles de soins et de recherche dédiés à la compréhension et la prise en charge de ces toxicités, et ce afin d’optimiser la gestion de ces patients.

Introduction Le traitement du cancer a ete profondement modifie ces dernieres annees avec l’introduction des inhibiteurs du checkpoint immunologiques (ICI). Le pronostic de certains cancers, tels le melanome ou le cancer pulmonaire non a petites cellules s’en est trouve largement ameliore [1] , [2] . Ces traitements sont cependant a l’origine d’effets secondaires appeles effets indesirables lies a l’immunotherapie (EILI), dont les atteintes les plus frequentes (digestives, cutanees, endocriniennes) sont maintenant bien decrites, et relativement simples a diagnostiquer et traiter [3] . A contrario, certaines atteintes plus rares comme la myocardite sont peu decrites, alors que le taux de mortalite est eleve (jusqu’a 40 %) et de prise en charge plus delicate. Patients et methodes Nous avons conduit une etude transversale retrospective multicentrique sur une periode allant de juillet 2019 a novembre 2020. Les criteres d’inclusion etaient : traitement par un inhibiteur du checkpoint immunologique, survenue d’une suspicion de myocardite en s’appuyant sur les criteres de la societe europeenne de cardiologie, donnees de suivi disponibles pour chaque patient. Les myocardites etaient classees en possible/probable/definies selon des criteres internationaux, la severite a ete cotee en utilisant la classification CTCAE v5.0. Resultats Vingt-neuf patients ont ete inclus, de 6 centres differents, avec un âge median de 69 (32-83) ans. Les cancers traites etaient majoritairement pulmonaires (10 patients), des melanomes (8 patients), ou urotheliaux (4 patients). La myocardite survenait dans un delai median de 39 (2-181) jours, principalement avec des anti-PD1 (16 patients, 55 %). La plupart des patients (83 %) etaient symptomatiques, la dyspnee etant le symptome le plus frequent (17 patients, 59 %). Tous avaient une troponine HS elevee, avec une mediane de 5,35 fois la normale superieure, l’ECG montrait des anomalies chez 19 patients (68 %), alors que l’ETT etait disponible chez 27 patients et montrait une FEVG alteree chez 10 d’entre eux (37 %). Une IRM cardiaque a ete realisee chez 24 patients, montrant une prise de contraste tardive chez 9 d’entre eux (37 %). Quatorze patients (48 %) ont subi une coronarographie, et 6 ont beneficie d’une biopsie endomyocardique. Ces dernieres montraient chez 5 patients une infiltration lymphocytaire, majoritairement CD8+. Parmi les toxicites associees, la myosite etait la plus frequente (13 patients, 45 %), suivie du syndrome sec (11 patients, 38 %). Les patients les plus severes (CTCAE grade 4 et 5, n = 11) avaient un taux plus important de maladies auto-immunes systemiques preexistantes (5 patients contre 1, p = 0,018), une frequence cardiaque plus elevee a l’admission (113 contre 79,5, p = 0,001), une troponinemie d’entree plus elevee (42 fois la norme superieure contre 3,55, p = 0,001), et presentaient plus souvent des anticorps anti-recepteur de l’acetylcholine (5 contre 0, p = 0,001). L’analyse en courbe ROC nous a permis de selectionner une valeur seuil de troponinemie a 4,89 fois la norme superieur (sensibilite = 90,9 %, specificite 66,7 %) pour predire l’evolution vers une forme grave. Concernant le traitement, la plupart des patients (28) ont recu des corticoides, le plus souvent apres des bolus initiaux (19 patients, 68 %). Les autres modalites de traitement concernaient les plasmaphereses (10 patients), les immunoglobulines polyvalentes (8 patients), et d’autres immunosuppresseurs (5 patients). 7 patients (24 %) sont morts lors de la prise en charge initiale. Nous disposions d’une evaluation de la reponse carcinologique chez 21 patients, dont seulement 1 presentait une progression de la maladie. Au cours du suivi (d’une mediane de 4 mois), 7 patients supplementaires sont decedes. 6 patients ont recu a nouveau un traitement par ICI, seulement 1 ayant presente une rechute de myocardite. Conclusion Certains facteurs de mauvais pronostic ont ete mis en evidence, comme un taux eleve de troponine a l’admission, ce qui pourrait aider a la decision therapeutique. La mortalite est moindre dans notre serie, possiblement par le depistage de formes subintrantes en dosant la troponine de facon systematique. Cependant, la contre-indication definitive de l’immunotherapie sera peut etre a rediscuter selon la balance benefice/risque.

Immune checkpoint inhibitors (ICI) have modified the management of patients with cancer. Their administration is associated with an increased risk of toxicities that can affect every organ. Cardiovascular toxicities, particularly myocarditis, can occur with a low incidence (

Introduction: The natural history of tricuspid regurgitation (TR) and right heart chambers remodeling in patients with atrial fibrillation (AF) according to the cardiac rhythm at mid-term follow-up has been poorly assessed. Hypothesis: Restoration of sinus rhythm in AF patients is beneficial to the remodeling of right heart chambers and decrease in TR severity. Methods: We prospectively and serially evaluated 24 consecutive patients hospitalized for AF using three dimensional (3D) transthoracic echocardiography (TTE) at admission (M0) and every 6 months during a 2 years-follow-up (FU, M6, M12, M18, M24) (120 TTE exams). Patients were divided into two groups according to their cardiac rhythm at M24: restoration to SR (SR group, n=14) and persistence of AF (AF group, n=10). TR grade severity was divided into 4 grades using an integrated approach (0: none or trace; 1: mild; 2: moderate; 3: severe TR). 3D indexed volumes (3D Vi) of the right atrium (RA) and right ventricle (RV) as well as 3D tricuspid annulus (TA) area were analyzed in end systole (ES) and end diastole (ED). Results: Beyond 6 months of FU, the SR group had overall significantly lower 3D ES RA Vi, 3D ED RA Vi, 3D TA ES area and TR severity in comparison with AF group (Figure). There were no significant differences between the 2 groups with regard to 3D RV Volumes and 3D ED TA area. Conclusions: According to our results on both TR evolution and right heart cavities reverse remodeling, strategies aiming at SR restoration in patients with AF and TR should be broadly discussed.

Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.

Background The severity of tricuspid regurgitation (TR) in patients with restored normal sinus rhythm (SR) after atrial fibrillation (AF) has been poorly assessed. Purpose Our study aimed to assess (1) right chamber remodelling and (2) TR severity in patients with AF who have had their rhythms restored to normal sinus. Methods We prospectively evaluated 94 consecutive patients hospitalized for AF who received either ablation, direct current cardioversion, or pharmacological therapy. Patients were divided into two groups according to their cardiac rhythm at 6 months follow up (6M): restoration to SR (SR group, n=54), persistence of AF (AF group, n=40). TR vena contracta (VC), TR grade severity was divided into 4 grades using an integrated approach (0: none or trace; 1: mild; 2: moderate; 3: severe TR). Two dimensional (2D) end diastolic (ED) tricuspid annulus (TA) diameter in the apical 4 chambers view, three-dimensional (3D) indexed volumes (3D Vi) of the right atrium (RA) and right ventricle (RV) in end systole (ES) and ED were acquired using transthoracic echocardiography at admission and at 6M. Results At 6M, in the SR group a significant improvement in TR VC (Figure A) and TR grade (Figure B) were noted, whereas there was no differences in the AF group (0.41 vs. 0.42cm, p=0.24 for TR VC; 1.70 vs. 1.76, p=0.16 for mean TR grade). In the SR group a significant reduction in 3D ES RV Vi, 2D ED TA diameter, 3D ES and ED Vi of the RA (Table) were observed. Regression of TR VC was correlated with regression of right cavities parameters (ρ=0.47, p Conclusion Restoration of normal SR in patients with AF results in beneficial remodelling of right cavities at 6M of follow-up which were associated with a significant decrease in TR severity. Strategies for normal SR restoration in patients with AF and TR should be vigorously attempted. TR Evolution Funding Acknowledgement Type of funding source: None

Background Few studies have assessed the evolution of cardiac chambers deformation imaging in patients with atrial fibrillation (AF) according to cardiac rhythm outcome. Purpose To evaluate cardiac chamber deformation imaging in patients admitted for AF and the evolution at 6-month follow-up (M6). Methods In forty-one consecutive patients hospitalised for AF two-dimensional transthoracic echocardiography was performed at admission (M0) and after six months (M6) of follow up. In addition to the usual parameters of chamber size and function, chamber deformation imaging was obtained including global left atrium (LA) and right atrium (RA) reservoir strain, global left ventricular (LV) and right ventricular (RV) free wall longitudinal strain. Patients were divided into three groups according to their cardiac rhythm at M0 and M6: AF at M0 and sinus rhythm (SR) at M6 (AF-SR) (n=23), AF at M0 and AF at M6 (AF-AF) (n=11), SR at M0 (spontaneous conversion before the first echocardiography exam) and SR in M6 (SR-SR) (n=7) Results In comparison with SR patients (n=7), at M0, AF patients (n=34)) had lower global LA reservoir strain (+5.2 (+0.4 to 12.8) versus +33.2 (+27.0 to +51.5)%; p Conclusion Initial atrial and ventricular deformations were not associated with rhythm outcome at six-month follow up in AF. The improvement in strain in all four chambers strain suggests global reverse remodelling all cardiac cavities with the restoration of sinus rhythm. Evolution of strain between M0 and M6 Funding Acknowledgement Type of funding source: None

Background Acute kidney injury (AKI) frequently occurs after diuretic treatment initiation during acute heart failure (AHF). Treatment-induced hemoconcentration seems associated with improved prognosis. Transient AKI, with or without hemoconcentration, is of unsettled prognosis. Purpose We aimed to determine the independent prognostic values of transient AKI, persistent AKI and hemoconcentration in the context of hospitalized AHF. Methods Data were obtained from our institution's Clinical Data Warehouse. Patients that visited our unit at least once were screened. All hospitalizations in our institution were examined (>30 hospitals). Inclusion criteria were: ≥1 hospitalization with ≥1 recorded furosemide administration and ≥1 AHF ICD-10 code. Only the first hospitalization fulfilling these criteria was considered. AKI during 1–13 days following first furosemide administration was defined based on Kidney Disease Improving Global Outcome guidelines. Hemoconcentration was defined as an increase in serum proteins ≥5 g/l during the same period. We performed multivariate logistic regression to determine which characteristics were predictive of AKI. We used Cox regression of 100-days all-cause mortality using several confounders to determine the prognostic values of transient AKI (lasting Results We included 579 patients in the study. Median follow-up was 114 days. AKI following furosemide initiation occurred in 234 patients (40.4%). Patients that experienced AKI more frequently suffered from chronic kidney disease (43.6% vs. 33%, p=0.01) or presented with right ventricular dilatation (12% vs. 6.7%, p=0.04). Independent predictors of AKI were arterial hypertension (adjusted OR: 1.86 [1.08–3.22]), elevated serum creatinine at baseline (adjusted OR: 1.07 [1.01–1.14] per 10 μmol/l increase) and initial intravenous furosemide (adjusted OR: 2.42 [1.39–4.29]). Death during follow-up occurred in 35% of patients in the AKI group compared to 21% in the non-AKI group (p Conclusion In the context of hospitalized AHF, AKI that developed 1–13 days after furosemide initiation and that lasted ≥14 days was independently associated with decreased 100 days survival. Hemoconcentration, using a clinically relevant definition, was independently associated with improved survival. These findings show that serum creatinine and proteins, routinely used and with limited cost, accurately stratify mortality risk during AHF. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

Major therapeutic advances have been made recently in the treatment of metastatic melanoma, due to the development of targeted therapies, namely BRAF and MEK inhibitors, in patients with BRAF V600 mutation. Combinations of vemurafenib+cobimetinib, dabrafenib+trametinib, et encorafenib+binimetinib, evaluated in coBRIM, COMBI-d/COMBI-v and COLUMBUS trials respectively have been approved in this indication. Toxicities induced by combination therapies are different from those reported with monotherapies, in terms of frequency and intensity. Physicians who treat melanoma patients thus face news issues relating to prevention, detection and treatment of these adverse events. This paper summarizes tolerance data from the three pivotal trials (coBRIM, COMBI-v and COLUMBUS) and issues recommendations for the specific management of main toxicities, based on experts' opinion. We discuss dermatological, ophthalmological, cardiovascular, digestive, musculoskeletal, renal and general toxicities and propose a timetable for examinations to be performed before and during treatment.