Safety of Immune Checkpoint Inhibitor Rechallenge and Mid-Term Outcomes After Suspected Cardiovascular Immune-Related Adverse Events

Safety of Immune Checkpoint Inhibitor Rechallenge and Mid-Term Outcomes After Suspected Cardiovascular Immune-Related Adverse Events | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety of Immune Checkpoint Inhibitor Rechallenge and Mid-Term Outcomes After Suspected Cardiovascular Immune-Related Adverse Events Francesco Cribari, Imen Hamdi, Soledad Henriquez, Pierre Charles, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8689115/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Background Current European Society of cardiology guidelines recommend systematic troponin screening to detect potential cardiovascular (CV) immune-related adverse events (irAEs) in the increasing numbers of cancer patients receiving immune-checkpoint inhibitors (ICIs), increasing the number of patients referred and broadening the severity spectrum of CV irAEs. Management and outcomes in patients with suspected CV irAEs, are poorly defined. The safety of ICI rechallenge, particularly in patients fulfilling contemporary ICI-myocarditis diagnostic criteria, remains uncertain. Methods Prospective single-centre cohort including consecutive adults referred for suspected CV irAEs. Objectives were to describe outcomes after initial assessment, identify predictors of mid-term CV events, and evaluate outcomes of ICI rechallenge in patients with and without initial CV irAEs. Results Among 175 patients (median age 61 years [IQR 48–72]; 77.1% women), 95 (54.3%) had adjudicated CV irAEs at referral, including 72 (41.1%) fulfilling diagnostic criteria for non-severe ICI-myocarditis. During 234 ± 154 days of follow-up, 15 patients died (12 cancer-related, 1 CV, 2 other). Predictors of CV events included significant coronary stenosis (HR 4.77; 95% CI 1.39–16.40; P = 0.013), hospital admission (HR 13.21; 95% CI 2.51–69.52; P = 0.0023), ICI rechallenge (HR 9.30; 95% CI 1.77–48.77; P = 0.0084), and positive Lake Louise cardiac magnetic resonance (CMR) (HR 18.84; 95% CI 5.13–69.20; P < 0.0001). Eighty-four patients (48.0%) were rechallenged; 3 (3.6%) developed non-severe myocarditis, with no ICU admissions or CV deaths. Ten out of 53 (18.87%) patients without initial CV irAEs who continued ICIs developed CV events. Trial Registration NCT05799898 immune checkpoint inhibitors myocarditis cardiovascular toxicity rechallenge cardio-oncology Figures Figure 1 Figure 2 Figure 3 What is already known on this subject Cardiovascular immune-related adverse events (CV irAEs) are uncommon but clinically significant complications of immune checkpoint inhibitors (ICIs). Diagnostic criteria of ICI-myocarditis may be confounded by cardiovascular toxicities of combined cancer drugs. Decisions about ICI rechallenge after suspected CV irAEs remain inconsistent, largely informed by expert opinion and small case series. Mid-term risk of recurrent CV toxicity or mortality after suspicion of CV irAEs in real-world populations has not been well defined. What this study adds In this prospective cohort of 175 patients with suspected CV irAEs mainly driven by mild troponin raise, cardiovascular mortality rates were low (<1%) at 6 months follow-up. Almost half were rechallenged with ICIs after multidisciplinary evaluation, with low recurrence of ICI-myocarditis (3.6%). Initial clinical presentation, cardiac magnetic resonance features consistent with ICI-myocarditis, coronary artery disease and ICI-rechallenged were associated with increased risk of CV irAEs. How this study might affect clinical practice These findings support structured, multidisciplinary pathways to evaluate ICI rechallenge after suspected CV irAEs. Selected patients can likely resume immunotherapy with low risk of recurrent CV events, avoiding unnecessary permanent discontinuation. The results may inform guideline development and provide real-world evidence for balancing cancer control and cardiovascular safety in ICI-treated patients. Background Cardiovascular immune-related adverse events (CV irAEs) of immune checkpoint inhibitors (ICIs) have emerged as a major concern in cardio-oncology. 1 ICI-myocarditis has attracted particular attention due to initially high mortality rates 2 – 4 and specific pathophysiology 5 linking cardiac and muscular irAEs, leading to the concept of cardio-myotoxicity. Cardiovascular irAEs negatively impact survival, especially in metastatic cancer patients with ICI-cardiomyotoxicity. 6 with mortality driven first by acute complications 7 , and later by cancer progression, especially if ICIs are withheld. Less severe presentations have been however increasingly reported since 2022, broadening the recognised spectrum of CV irAEs. 8 Cancer regimens have also become more complex, with ICIs often combined with other cardiotoxic drugs (e.g., anthracyclines in triple negative breast cancer). 2 , 3 Diagnosing non-severe CV irAEs remains challenging. ICI therapy should not necessarily be withheld, as International Cardio-Oncology Society criteria (IC-OS) 9 diagnostic criteria may be more sensitive than expert opinion. 10 Also, the IC-OS diagnostic criteria may be confounded by other therapies such as vascular endothelial growth factor inhibitors or anthracyclines, now widely used in combination with ICIs. Our group previously showed that patients referred for suspected CV irAEs have favourable short-term outcomes 11 However, longer term data are largely derived from quaternary centres, potentially biased toward the most severe phenotypes. 8 The safety of ICI rechallenge in patients fulfilling ICI-myocarditis diagnostic criteria has been only depicted through clinical cases 12 , 13 and remains to be demonstrated. Earlier expert consensus discouraged rechallenge based on limited data. 14 Broader recognition of smouldering forms and diagnostic uncertainties requires reconsideration of management, particularly regarding rechallenge in non-severe CV irAEs. The FAST TRACK ICI cohort (NCT05799898) is a prospective ongoing project assessing patients’ management when referred for suspected CV irAEs. 11 The aim of this study is to describe mid-long term outcomes in patients referred for suspected CV irAEs; to identify predictors of CV events at follow-up; and to assess the safety of rechallenge in patients after suspected CV irAEs. Methods The FAST TRACK ICIs project is a prospective single-centre cohort study that has been described elsewhere. 11 Briefly, our institution provides CV care for several oncology centres, including Institut Curie , among the largest breast cancer centres in Europe. Patients who are suspected of CV irAEs by the oncology team are referred to the cardio-oncology unit. Our team elaborated clinical CV, ECG, and, extra-CV criteria (e.g., muscular symptoms) for either hospital admission (including intensive care unit) or assessment in the outpatient clinic prior to the publication of a novel risk scoring, 15 or severity algorithm based on an international register 15 . Admission criteria are similar to that of pre-test diagnostic likelihood 16 or severity of ICI-cardio-myotoxicity 15 (e.g., cardiovascular or muscular symptoms, low left ventricular ejection fraction, underlying auto-immune diseases). Patients undergo a standardized multimodal diagnostic workout including repeated serum biomarkers, electrocardiogram, transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging, cardiology and internal medicine clinical evaluations. 11 All cases were discussed during a weekly multidisciplinary meeting. All patients aged ≥ 18 years referred for suspected CV irAEs who provided consent were eligible. The inclusion period was March 1st 2022 – October 31 st, 2023 11 . Objectives and Outcome Measures The objectives of the current work include: (i) to describe outcomes after initial assessment for suspected CV irAEs; (ii) to identify predictors of mid-term CV events; (iii) to describe outcomes after ICI-rechallenge in a population with and without initial CV irAEs after a complete multimodal CV imaging and multidisciplinary assessment. Diagnostic criteria An adjudication committee was deemed necessary due to the discrepancy in diagnostic criteria for ICI-myocarditis published to this date. 9 , 10 , 18 , 19 The committee took into account the IC-OS 9 , definite or probable criteria from the American Heart Association (AHA) 18 , 20 , or significant lymphocyte infiltration based on the Dallas criteria in the subset of patients undergoing EMB. 20 We collected all the data to meet the IC-OS, AHA, or histological diagnosis (i.e., Dallas criteria) criteria. The updated Lake Louise criteria were employed for CMR myocarditis diagnosis 21 . Globally, we followed the diagnostic criteria of the European Society of Cardiology (ESC) 2022 guidelines 22 , 23 . Cardiovascular events at follow-up were defined as either fulfilling new CV event criteria at follow-up or as worsening of the initial CV iRAEs. ICI- rechallenge strategies The decision to re-expose patients to ICIs was made following a thorough evaluation conducted by the multidisciplinary team. This process involved detailed discussions between cardiologists, internal medicine specialists, and oncologists, with careful consideration of the risk-benefit ratio for each individual case, and patient’s will. Patients admitted with overt potentially lethal ICI-myocarditis (cardio-muscular symptoms, elevated troponin > 20 upper limit value, left ventricular dysfunction) were treated with intravenous IV glucosteroids (mostly methylprednisolone 1 gramme intra-venously). Patients fulfilling non-severe ICI-myocarditis diagnostic criteria and expected oncological benefit from ICIs were deemed fit for ICI-rechallenge. If a patient presented with non-severe ICI-myocarditis and was managed as an outpatient, oral steroids (prednisone 1mg/Kg/day with gradual tapering doses within 4 weeks) were initiated when ICI-rechallenge was decided, 24 followed by a 72 hour hospital admission for clinical, electric, biologic and echocardiographic monitoring after the first rechallenge ICI cycle. If no CV IRAEs was diagnosed, then the patient was seen in the outpatient clinic 2–7 days after ICI rechallenge for clinical, ECG, serum cardiac biomarkers, and echocardiography. If the patient was suspected with CV event after rechallenge, the patient was then admitted to cardiology (either ward or intensive care according to the initial FAST TRACK ICI hospital assignment strategy 11 ). Statistical Analysis: Patient characteristics were expressed as mean ± SD, median [IQR], or n (%). Between-group comparisons used t-test or Mann–Whitney U for continuous variables and χ² or Fisher’s exact test for categorical variables. A p value < 0.05 was considered significant. Collinearity was assessed before multivariable analyses. Univariate and competing-risk models (with non-CV death as competing factor) were applied to identify predictors of mid-term CV events. Kaplan–Meier curves described (i) all-cause mortality in the whole cohort and (ii) outcomes in patients with or without CV irAEs at referral. Analyses were performed at Institut Mutualiste Montsouris using SPSS-26 and SAS. The study complied with Good Clinical Practice, French law, and the Declaration of Helsinki, with IRB approval (2022-08) and ClinicalTrials.gov registration (NCT057998). Results Description of the study population From March 1, 2022, to October 31, 2023, 175 patients were enrolled (median age 61 years [IQR 48–72]; 135 women, 77%). Breast cancer was the most frequent malignancy (101, 58%), and 49 (28%) had metastatic disease at baseline. CV irAEs were adjudicated in 95 patients (54%): 72 myocarditis, 10 ACS, 9 pericarditis, 7 non-inflammatory HF, 4 conduction abnormalities/ventricular arrhythmias, and 8 combined cases (5 myocarditis–pericarditis, 3 myocarditis–arrhythmia).Mid-term outcomes The mean follow-up duration was 234 days (SD 154). During this period, 15 deaths were recorded: 12 from cancer, 1 sudden death adjudicated as CV-related, and 2 from non-CV, non-oncological causes (Fig. 1 ). Among the 15 deceased patients, 9 had a prior diagnosis of CV irAEs, but none died from cardiovascular causes. The only CV death occurred in a patient with metastatic lung cancer who experienced an out-of-hospital sudden death 9 months after the initial FAST TRACK ICI referral. No CV irAEs had been diagnosed at baseline, and no symptoms, ECG changes, biomarker elevation, or LVEF decline were noted during follow-up, with the patient remaining clinically stable on ICI therapy until death. Notably, 9 out of the 12 cancer-related deaths in our cohort occurred in patients who had not undergone ICI rechallenge. During follow-up, 49/175 (28.00%) patients developed irAEs (Fig. 2 ). Mid-term CV events were observed in 19/175 (10.87%) patients. Among those with baseline CV irAEs, 6/95 (6.32%) developed new or worsening CV events; whereas 13/80 (16.25%) without CV irAEs at referral, developed CV events during follow-up (Central Illustration). Predictors of mid-term CV events identified by univariate and multivariate competing-risk analyses are reported in Tables 1 and 2 . On multivariate analysis, significant predictors included: coronary artery stenosis at referral (HR 4.77; 95% CI 1.39–16.40; P = 0.013), hospital admission at referral (HR 13.21; 95% CI 2.51–69.52; P = 0.0023), ICI rechallenge (HR 9.30; 95% CI 1.77–48.77; P = 0.0084), and positive Lake Louise criteria on CMR at referral (HR 18.84; 95% CI 5.13–69.20; P < 0.0001). Table 1 Univariate competing analysis of mid-term CV events according to characteristics at referral for all patients referred for suspected CV irAEs. All N = 175 Censor N = 143 CV event at FU N = 20 Non CV death N = 12 Univariate Analysis HR [95% CI] P value Female, N (%) 135 (77.14) 109 (76.22) 17 (85.00) 9 (75.00) 4.497[0.594;34.065] 0.1456 Age, median (IQR) 61 (48.0–72.0) 60.0 (48.0–71.0) 65.0 (29.0–83.0) 75.5 (63.5–78.0) °0.974 [0.305;3.115] 0.4882 Body mass index**, median (IQR) 23 (21.0-27.3) 23.5(21.0-27.3) 24.3 (23.5–28.9) 21 (19.1–26.7) **1.105 [0.420;2.909] 0.8396 CV IRAEs at referral 95 (54.29) 82 (57.34) 6 (30.00) 4 (33.33) 0.382 [0.133;1.099] 0.0743 ICI-myocarditis at referral 72 (41.14) 65 (79.27) 2 (33.33) 5 (71.43) 0.187 [0.033;1.046] 0.0563 ICI rechallenge after 1st assessment 84 (48.00) 67 (46.85) 15 (75.00) 2 (16.67) 6.789[1.542;29.87] 0.0113 Referral for asymptomatic troponin elevation, N (%) 112 (64.00) 92 (64.32) 12 (60.00) 8 (66.67) 0.886 [0.322;2.437] 0.8140 Hospital admission, N (%) 29 (16.57) 21 (14.69) 7 (35.00) 2 (16.67) 3.079 [1.066;8.888] 0.0376 History of CV disease, N (%) 41 (23.40) 31 (21.68) 6 (30.00) 4 (33.33) 1.291[0.449;3.709] 0.6351 Smoker (past or present), N (%) 65 (37.14) 50 (34.97) 7 (35.00) 8 (66.67) 0.503 [0.065;3.900] 0.8055 Hypertension, N (%) 52 (29.71) 39 (27.27 8 (40.00) 5 (41.67) 1.632 [0.618;4.312] 0.3230 Diabetes, N (%) 15 (8.57) 11 (7.69) 3 (15.00) 1 (8.33) 1.821[0.413;8.031] 0.4287 Extra cardiovascular toxicity, N (%) 48 (27.43) 36 (25.17) 7 (35.00) 5 (41.26) 1.151 [0.401;3.297] 0.7940 Breast cancer, N (%) 101 (57.7) 87 (60.84) 12 (60.00) 2 (16.67) 1.428 [0.496;4.116] 0.5089 Lung cancer, N (%) 34 (19.43) 27(18.88) 4 (20.00) 3 (25.00) 0.803 [0.226;2.851] 0.7347 MSI, N (%) 9 (5.14) 4 (2.8) 1 (5.00) 5 (41.67) 1.647[0.217;12.50] 0.6293 Urinary tract cancer (Kidney or Bladder), N (%) 11 (6.29) 8 (5.59) 3 (15.00) 0 - - Thymoma, N (%) 3 (1.71) 3 (2.10) 0 0 - - Melanoma, N (%) 3 (1.71) 3 (2.10) 0 0 - - Other, N (%) 15 (8.57) 12 (8.39) 0 2 (16.67) - - Metastatic stage, N (%) 49 (28.00) 35 (24.48) 6 (30.00) 8 (66.67) 1.172[0.408;3.366] 0.7684 PD1/PDL1 + CTLA4, N (%) 16 (9.14) 13 (9.09) 2 (10.00) 1 (8.33) 1.045 [0.222;4.924] 0.9560 ICI lone therapy, N (%) 33 (18.8) 24 (16.78) 6 (30.00) 3 (25.00) 1.307 [0.417;4.100] 0.6462 ICI with chemotherapy and/or radiotherapy, N (%) 130 (74.29) 109 (76.22) 14 (70.00) 7 (58.33) 1.108[0.357;3.439] 0.8592 ICI with VEGF inhibitors, N (%) 12 (6.86) 10 (6.99) 0 2 (16.67) - - Number of doses of ICIs injections ≥ 7, N (%) 96 (54.86) 84 (58.74) 10 (50.00) 2 (16.67) 0.667[0.261;1.755] 0.4217 Doxorubicine dose < 240 mg/m2, N (%) 67 (38.29) 60 (41.96) 6 (30.00 1 (8.33) 0.677 [0.235;1.949] 0.4696 Peak troponin/normal laboratory value, median (IQR) 1.6 (1.2–2.6) 1.5 (1.2–2.6) 1.7 (0.6–2.1) 2.6 (1.3–3.3) 0.703 [0.250;1.978] 0.5049 Cardiovascular or muscle symptoms N (%) 63 (36.00) 47 (32.87) 10 (50.00) 6 (50.00) 1.803 [0.676;4.807] 0.2390 Abnormal ECG N (%) 34 (19.43) 29 (20.28) 3 (15.00) 2 (16.67) 0.427 [0.096;1.895] 0.2629 LVEF on TTE#, median (IQR) 60 (55.0–65.0) 60.0 (55.00–65.00) 60.5 (50.0–65.0) 60.0 (54.5–69.0) 1.104[0.059;20.718] 0.6852 GLS ∞ on TTE, median (IQR) 17.0 (15.0-19.9) 17 (16.0–19.0) 14 (10.0–20.0) 2.529[0.560;11.413] 0.2277 Lake Louise criteria on CMR∞∞, N (%) 55 (32.74) 43 (31.16) 9 (47.37) 3 (27.27) 2.918 [1.085;7.845] 0.0338 °analysis by quartiles; **analysis by groups divided by BMI = 25; ***analysis as peak troponin/normal laboratory value > 1,6 N ; #analysis LVEF ≥ 50% versus < 40%; ∞missing data for 41/175 participants and analysis GLS ≥ 16% versus < 16%; ∞∞CMR performed in 168/175 participants. ACS = Acute coronary syndrome; BMI = Body mass index; CMR = Cardiac magnetic resonance; CV = Cardiovascular; ECG = Electrocardiogram; GLS = Global longitudinal strain; ICI = Immune checkpoint inhibitor; ICU = Intensive care unit; irAE = Immune-related adverse event; LVEF = Left ventricular ejection fraction; MSI = microsatellite instability; TTE = Transthoracic echocardiography Table 2 Multivariate competing-risk analysis for independent predictors of mid-term cardiovascular events. Hazard ratio 95% CI P value Results of coronary artery imaging: significant lesions 4.771 [1.388;16.395] 0.0131 Hospital admission 13.210 [2.510;69.522] 0.0023 ICI rechallenge after initial assessment 9.300 [1.773;48.771] 0.0084 Lake Louise criteria on CMR 18.840 [5.129;69.201] < .0001 Rechallenge population Overall, 84 out of 175 patients (48.00%) underwent ICI rechallenge with re-exposure to the same regimen (Central Illustration). Among these, 32/84 (38.10%) had experienced a CV irAE at referral, including ICI-myocarditis (16 cases), ACS (8 cases), ICI-pericarditis (2 cases), arrhythmias or conduction disease (2 cases), non-inflammatory HF/Takotsubo syndrome (3 cases), and combined CV irAEs (2 cases). Among the 53 patients rechallenged without baseline CV irAEs, 11/53 (20.75%) developed a CV irAE upon rechallenge, including myocarditis (5 cases), ACS (2 cases), isolated conduction abnormalities/arrhythmias (2 cases), and 2 patients with combined conduction abnormalities/arrhythmia and myocarditis. Among patients with ICI-myocarditis at referral, 18/72 (25.0%; 16 lone myocarditis, 1 myocarditis with new conduction abnormality and 1 myo-pericarditis) and 2/72 patients with myocarditis were considered eligible for rechallenge. Two experienced recurrent myocarditis three months after re-exposure, both non-severe and not requiring ICU admission. Furthermore, one patient with baseline ACS developed myocarditis after rechallenge, and one with baseline ICI-pericarditis developed a new conduction abnormalities 3 months after rechallenge. Factors associated with the likelihood of rechallenge are reported in Table 3 . Patients fulfilling FAST TRACK hospital admission criteria 11 were significantly less likely to undergo rechallenge (P = 0.045). On univariate analysis, a reduced probability of re-exposure was observed in patients meeting Lake Louise criteria on CMR (P < 0.001), those undergoing endomyocardial biopsy (P = 0.003), patients diagnosed with myocarditis (P = 0.005), and those with diabetes (P = 0.023) or lung cancer (P = 0.030). Conversely, patients with ACS were significantly more likely to be rechallenged (8/10 cases, P = 0.001). Table 3 Comparison (univariate analysis) of the study population according to the ICI rechallenge status. Characteristics All N = 175 No Rechallenge N = 91 Rechallenge N = 84 P value Female N (%) 135 (77.14) 64 (76.19) 72 (79.12) 0.943 Age, median (IQR) 61 (IQR 48.0–72.0) 61 (IQR 49.0–72.0) 60 (IQR 48.0–72.0) 0.831 Body mass index > 25, N (%) 67 (38.28) 33 (36.26) 34 (41.0) 0.562 CV irAEs at 1st evaluation, N (%) 95 (54.3) 63 (69.23) 32 (38.09) < 0.001 Troponin ratio, median (IQR) 1.62 (I1.17-2.66) 1.74 (1.16–2.95) 1.43 (1.17–2.52) 0.317 Thymoma, N (%) 3 (1.71) 2 (2.19) 1 (1.19) 0.615 LVEF < 50% at referral, N (%) 23 (13.14) 15 (16.48) 8 (9.52) 0.173 Cardio-muscular symptoms, N (%) 62 (35.43) 28 (30.77) 34 (40.48) 0.161 Lake Louise criteria fulfilled, N (%) 49 (28.00) 38 (41.76) 11 (13.09) < 0.001 EMB performed, N (%) 48 (26.86) 34 (37.36) 14 (16.67) 0.003 Abnormal EMB (borderline + definite) in 48 patients, N (%) 42 (87.50) 31 (64.58) 11 (22.92) 0.118 History of CV disease, N (%) 41 (23.43) 21 (23.08) 20 (23.81) 0.909 Hospital admission, N (%) 29 (16.57) 20 (21.98) 9 (10.71) 0.072 Hypertension, N (%) 53 (30.29) 26 (28.57) 26 (30.95) 0.731 Smoker (past or present), N (%) 65 (37.14) 28 (30.77) 37 (44.05) 0.069 Diabetes N (%) 15 (8.57) 12 (13.19) 3 (3.57) 0.046 Breast cancer, N (%) 101 (57.71) 54 (59.34) 47 (55.95) 0.650 Lung cancer, N (%) 34 (19.43)) 12 (13.19) 22 (26.19) 0.047 Other types of cancer N (%) 40 (22.86) 25 (27.47) 15 (17.86) 0.130 Metastasis, N (%) 49 (28.00) 25 (27.47) 24 (28.57) 0.871 Combination PD1/PDL1 + CTLA4, N (%) 15 (8.57) 10 (10.99) 5 (5.95) 0.234 ICI lone therapy, N (%) 33 (18.86) 17 (18.68) 16 (19.05) 0.038 ICI with chemotherapy/radiotherapy, N (%) 130 (74.29) 68 (74.73) 62 (73.81) 0.890 ICI with VEGFi, N (%) 12 (6.86) 6 (6.59) 6 (7.14) 0.886 ICI-myocarditis, N (%) 72 (41.14) 54 (59.34) 18 (21.43) < 0.001 Pericarditis, N (%) 9 (5.14) 6 (6.59) 3 (3.57) 0.574 Acute coronary syndrome, N (%) 10 (5.71) 2 (2.20) 8 (9.52) 0.078 Non Inflammatory Heart Failure/Takotsubo N (%) 8 (4.57) 3 (3.30) 5 (5.95) 0.633 Conduction disease/arrhythmias, N (%) 4 (2.28) 3 (3.30) 1 (1.19) 0.670 Extra cardiovascular irAEs N (%) 41 (23.43) 26 (28.57) 15 (18.86) 0.186 CV, cardiovascular; 95% CI, 95% Confidence Interval; CV irAEs, cardiovascular Immune-related adverse events; IQR, Interquartile range; ICI, Immune-checkpoint Inhibitors; CMR, Cardiac Magnetic Resonance Imaging; VEGFi; vascular endothelial growth factor inhibitor; PD-1, programmed cell death protein 1; PDL-1, programmed death ligand 1; CTLA, cytotoxic T lymphocyte-associated protein 4; EMB, endomyocardial biopsy; LVEF, left ventricular ejection fraction; GLS, global longitudinal strain. Among the 91 patients not rechallenged, 4/95 (42.11%) developed mid-term CV events (two with baseline CV irAEs and two without). In summary, ICI rechallenge was performed in a large subset of patients, with a low rate of recurrent myocarditis, all of which were non-severe. All-cause mortality was lower in rechallenged patients (4/84, 4.76%) compared with those not rechallenged (12/91, 13.18%) in unadjusted analysis (Fig. 3 ). Discussion In this prospective single‑centre cohort of 175 consecutive patients referred for suspected CV irAEs during ICI therapy, we found that CV deaths were rare over a mean follow‑up of 6 months, mortality driven by cancer progression. Half of the cohort received an adjudicated diagnosis of CV irAEs at referral, most fulfilling contemporary diagnostic criteria for ICI-myocarditis albeit potentially confounded by other cancer drug induced cardiotoxicities. Nearly one patient in two was subsequently rechallenged with ICIs after multidisciplinary triage and tailored surveillance. Patients who were deemed fit for ICI rechallenge differed from the restrained population. In patients with non-metastatic breast cancer, ICIs were often discontinued by the oncology team. ICIs were also withheld in patients who fulfilled ICIs-myocarditis diagnosis in spite of non-severe forms and diagnostic confounders such as anthracyclines. Among rechallenged patients, non‑severe myocarditis occurred in only 3.6% (2 recurrences and 1 de‑novo case). Only 1 out-of-hospital sudden death (labelled as CV) occurred after rechallenge in a patient with no clear CV irAE phenotype at referral and no worsening condition after the first ICI rechallenge cycle. By competing‑risk analysis, positive Lake Louise criteria on CMR, hospital admission at referral, significant coronary stenosis, and ICI rechallenge were associated with a higher risk of mid‑term CV events. Our study demonstrates that when patients are channeled through a structured cardio‑oncology pathway for suspected CV irAEs, CV death is uncommon, overall outcomes being primarily conditioned by cancer. This aligns with a maturing literature showing that the initial signal of very high case fatality with ICI‑myocarditis—largely derived from early pharmacovigilance 3 and quaternary centre cohorts 6 —has broadened to include non‑severe presentations with favorable outcomes when recognized early and co‑managed by multidisciplinary teams. 8 Initial reports suggested case‑fatality rates of 25–50% in ICI‑myocarditis, prompting highly conservative guidance and widespread reluctance to re‑expose patients. Subsequent series, including severity‑stratified registries, have delineated a broader spectrum from fulminant to non‑severe ICI-myocarditis, with markedly lower mortality in carefully selected, promptly treated patients. 8 , 15 While previous reports have been largely limited to case reports or anecdotal series, our cohort represents one of the first structured, real-world datasets exploring ICI rechallenge in patients with suspected CV irAEs. In particular, 25% of patients diagnosed with mainly non-severe ICI-myocarditis were considered suitable for rechallenge. Furthermore, the observed recurrence rate was low (11.1%), and all events were non-severe, no ICU admissions being required. This is also the first prospective study to describe rechallenge strategies following non-myocarditis CV irAEs, such as pericarditis, arrhythmias, and troponin elevation without overt myocarditis, thereby expanding the clinical landscape in which rechallenge may be considered. 12,25 An individualised approach — incorporating rigorous risk stratification and structured surveillance, as implemented in the FAST TRACK study 11 — may offer a safe path forward and may allow safe continuation of cancer therapy. Of note, among the twelve cancer-related deaths observed during follow-up, nine occurred in patients who were not considered for ICI rechallenge. As recently underlined by authors such as Itzhaki et al., 8 systematic prospective data on rechallenge have been lacking to date—our study addresses this gap and supports a potential change in clinical practice. Some patients without a clear CV irAEs phenotype at baseline nonetheless experienced subsequent events, including more definitive presentations of ICI-myocarditis during follow-up. This finding supports the concept of “smouldering” or evolving phenotypes that may manifest only over time or with cumulative exposure. Accordingly, even when the initial workup is non-diagnostic, a low threshold for repeat clinical assessment—including biomarkers, ECG, and echocardiography—within the weeks following the index evaluation appears warranted. We therefore advocate programmed re-evaluation within 1 week for patients resuming ICI therapy without a definitive CV irAEs diagnosis after resuming ICI therapy. Moreover, non-cardiovascular irAEs (e.g., dermatologic, endocrine, pulmonary) may emerge after the first assessment, further reinforcing the value of a multidisciplinary approach in managing patients with suspected CV irAEs. The association between Lake Louise–positive CMR and subsequent CV events highlights the potential prognostic value of tissue characterization. Value of T1 and T2 mapping abnormalities in asymptomatic patients appear contradictory. 26 , 27 Furthermore, the initial retrospective analysis of a multicentric register demonstrated that CMR yielded moderate sensitivity values for the diagnosis of ICI-myocarditis. And others have not included CMR data in the prognostic algorithm for ICI cardiomyotoxicity, based mainly on serum biomarkers that are of more widespread use than CMR. Also, other cancer therapies as anthracyclines may lead to CMR changes 28 that overlap with the Lake Louise criteria for myocarditis diagnosis 21 , complexifying the diagnosis as in breast cancer patients who receive both anthracyclines and ICIs. When considering the role of CMR as a diagnostic or prognostic tool in ICI-myocarditis, there are a number of bias that need consideration: (i) selection bias of patients who are not hemodynamically unstable to undergo a 30–40 minutes long scan 29 ; (ii) the timing of CMR in regard to the initial CV irAE suspicion and potential immunosuppressant therapies; (iii) the completeness of the CMR study beyond late gadolinium enhancement 30 . Regardless the sensitivity and specificity of CMR for the diagnosis of ICI-myocarditis, our results support that active myocardial inflammation and/or fibrosis portends higher risk of CV events. Finally, the apparent association between ICI rechallenge and increased CV events should be interpreted with caution, given the likelihood of confounding by indication and selection bias. In our cohort, approximately half of the patients were rechallenged after suspected CV irAEs, with only one subsequent severe CV event. Notably, this event may not have been CV in origin, as most sudden deaths in patients with cancer are attributable to non-CV causes. 31 Resuming ICI was associated with more CV events but also with better overall survival. These findings support a nuanced, risk-adapted multidisciplinary strategy rather than absolute discontinuation of ICIs, and highlight the need for vigilant follow-up regardless of CV irAEs at referral. The FAST-TRACK ICI data support a pragmatic, risk-adapted strategy: (i) early multidisciplinary triage of suspected cases; (ii) CMR use when feasible; (iii) hospitalisation for predefined severity criteria (hemodynamic or arrhythmic instability, rising biomarkers, high clinical suspicion); (iv) routine evaluation for coronary disease, an independent predictor of long-term events; and (v) structured post-discharge follow-up, including initially non-diagnostic cases where later phenotypes may appear. For rechallenge, our approach—requiring resolution of acute inflammation, shared decision-making, and, in non-severe myocarditis, brief inpatient observation followed by early outpatient reassessment—was associated with low rates of non-severe recurrence.This experience supports considering rechallenge in carefully selected patients, especially when CMR is quiescent and competing cardiotoxic exposures (e.g., anthracyclines, VEGF inhibitors) may be confounders. Recently published diagnostic 16 and prognostic 15 risk tools may assist selection, but prospective validation in rechallenge cohorts remains an unmet need. Strengths and imitations The FAST-TRACK ICI study prospectively enrolled consecutive patients with suspected CV irAEs, largely identified through elevated cardiac biomarkers. CV irAEs were adjudicated using a standardized multidisciplinary, multimodal process, and a prespecified rechallenge pathway was implemented to optimise oncologic care. Limitations include its single-centre design, mid-term follow-up, and potential residual confounding in patients receiving multiple cardiotoxic therapies. Case definitions—particularly for ICI-myocarditis—may also be debated. Nonetheless, the study’s primary aim was to evaluate rechallenge feasibility, and findings indicate that ICI reintroduction is generally safe with structured monitoring. Given the low incidence of severe ICI-related cardiomyotoxicity (~ 1%) 16 , major adverse events were uncommon in our cohort. However, the absolute number of events remained limited, resulting in wide confidence intervals for certain predictors. Multicentre studies enrolling patients referred for suspected CV irAEs—not only those with severe ICI-cardiotoxicity 15 —are warranted to refine our understanding of the full spectrum of CV irAEs. In particular, the role of CMR findings in guiding decisions regarding treatment interruption, initiation of immunosuppression, and post-discharge surveillance requires further validation. Conclusions In a real-world cardio-oncology pathway for suspected CV irAEs, cardiovascular deaths were rare, and outcomes were mainly driven by cancer progression. Lake Louise–positive CMR, hospital admission, significant coronary disease, and ICI rechallenge were associated with higher rates of subsequent CV events. Yet nearly half of patients— including selected non-severe myocarditis cases—were safely rechallenged. These results support moving from categorical avoidance to a risk-adapted, multidisciplinary strategy that balances oncologic benefit with cardiovascular safety and emphasises vigilant follow-up, even in initially non-diagnostic cases. Larger multicentre studies with longer surveillance are needed to refine selection and monitoring for ICI rechallenge. Abbreviations ACS Acute Coronary Syndrome AHA American Heart Association CMR Cardiac Magnetic Resonance CV Cardiovascular EMB Endomyocardial Biopsy GLS Global Longitudinal Strain HF Heart Failure HR Hazard Ratio ICIs Immune Checkpoint Inhibitors IC-OS International Cardio-Oncology Society ICU Intensive Care Unit irAEs Immune-Related Adverse Events IQR Interquartile Range LVEF Left Ventricular Ejection Fraction MDT Multidisciplinary Team TTE Transthoracic Echocardiography Declarations Funding: The FAST TRACK ICI project was funded by the Institut Mutualiste Montsouris, Paris, France. Tweet: In the FAST TRACK ICI cohort, nearly half of patients were safely rechallenged after suspected CV irAEs, with very low recurrence rates. Acknowledgements: We are grateful to our patients for participating in the FAST TRACK study and to all IMM staff for their help and care. We thank the research unit for their support and the radiology team for their prompt assessments. Ethics approval and consent to participate The FAST TRACK ICI project is a prospective, single-centre cohort study conducted in accordance with the Declaration of Helsinki, French regulatory requirements, and Good Clinical Practice guidelines. The study protocol was approved by the institutional review board (IRB) (approval number: 2022-08). All participants provided written informed consent prior to inclusion in the study. Consent for publication Not applicable . Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due to restrictions related to patient confidentiality and French data protection regulations, but are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding The FAST TRACK ICI project was funded by the Institut Mutualiste Montsouris, Paris, France. The funding body had no role in the design of the study; collection, analysis, or interpretation of data; writing of the manuscript; or decision to submit the manuscript for publication. Authors’ contributions MM conceived and designed the study. FC, IH, SH, PC, RC, MLJ, DM, and DL contributed to patient inclusion and data acquisition. FC and MM performed the statistical analyses. FC and MM drafted the manuscript. MM, CC, NG, and ALLL critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgements We are grateful to the patients who participated in the FAST TRACK ICI study and to all staff members of the Institut Mutualiste Montsouris for their support and care. We also thank the research unit and the radiology team for their valuable contributions. Authors’ information Not applicable . References Tocchetti CG, Farmakis D, Koop Y, et al. Cardiovascular toxicities of immune therapies for cancer – a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology. Eur J Heart Fail. 2024;26(10):2055–76. 10.1002/ejhf.3340 . Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016;375(18):1749–55. 10.1056/NEJMoa1609214 . Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579–89. 10.1016/S1470-2045(18)30608-9 . Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. 10.1016/j.jacc.2018.02.037 . Axelrod ML, Meijers WC, Screever EM, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature. 2022;611(7937):818–26. 10.1038/s41586-022-05432-3 . Lehmann LH, Heckmann MB, Bailly G, et al. Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis. Circulation. 2023;148(6):473–86. 10.1161/CIRCULATIONAHA.123.062405 . Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(12):1721. 10.1001/jamaoncol.2018.3923 . Itzhaki Ben Zadok O, Levi A, Divakaran S, Nohria A. Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis. JACC CardioOncology. 2023;5(6):732–44. 10.1016/j.jaccao.2023.09.004 . Herrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022;43(4):280–99. 10.1093/eurheartj/ehab674 . Deharo F, Thuny F, Cadour F, et al. Diagnostic Value of the International Society of Cardio-Oncology Definition for Suspected Immune Checkpoint Inhibitor–Associated Myocarditis. J Am Heart Assoc. 2023;12(8):e029211. 10.1161/JAHA.122.029211 . Cribari F, Hamdi I, Henriquez S et al. Cardiovascular safety of a standardized outpatient triage and diagnostic approach for suspected cardiovascular immune-related adverse events of immune checkpoint inhibitors. Arch Cardiovasc Dis Published online July 2025:S1875213625004024. 10.1016/j.acvd.2025.06.073 Thibault C, Vano Y, Soulat G, Mirabel M. Immune checkpoint inhibitors myocarditis: not all cases are clinically patent. Eur Heart J Published online August. 2018;10. 10.1093/eurheartj/ehy485 . Bailly G, Cohen A, Boccara F, Salem JE. Immune checkpoint inhibitor rechallenge after myocarditis: Time for reappraisal? Arch Cardiovasc Dis Published online July 2025:S1875213625003985. 10.1016/j.acvd.2025.06.069 Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J Published online August. 2022;26:ehac244. 10.1093/eurheartj/ehac244 . Power JR, Dolladille C, Ozbay B, et al. Immune checkpoint inhibitor-associated myocarditis: a novel risk score. Eur Heart J Published online June. 2025;18:ehaf315. 10.1093/eurheartj/ehaf315 . Salem JE, Ajrouche A, Rozes A, Pinto S, De Rycke Y, Tubach F. Incidence and risk factors of immune checkpoint inhibitor myocardial and muscle toxicity: a French nationwide study. Eur Heart J Published online August. 2025;30:ehaf682. 10.1093/eurheartj/ehaf682 . Schulz-Menger J, Collini V, Gröschel J, et al. 2025 ESC Guidelines for the management of myocarditis and pericarditis. Eur Heart J. 2025;46(40):3952–4041. 10.1093/eurheartj/ehaf192 . Bonaca MP, Olenchock BA, Salem JE, et al. Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology. Circulation. 2019;140(1):80–91. 10.1161/CIRCULATIONAHA.118.034497 . Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines. J Am Heart Assoc. 2020;9(18). 10.1161/JAHA.120.018403 . Basso C, Calabrese F, Angelini A, Carturan E, Thiene G. Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease. Heart Fail Rev. 2013;18(6):673–81. 10.1007/s10741-012-9355-6 . Luetkens JA, Faron A, Isaak A, et al. Comparison of Original and 2018 Lake Louise Criteria for Diagnosis of Acute Myocarditis: Results of a Validation Cohort. Radiol Cardiothorac Imaging. 2019;1(3):e190010. 10.1148/ryct.2019190010 . Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J. 2023;44(38):3720–826. 10.1093/eurheartj/ehad191 . McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726. 10.1093/eurheartj/ehab368 . Zhang L, Zlotoff DA, Awadalla M, et al. Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis. Circulation. 2020;141(24):2031–4. 10.1161/CIRCULATIONAHA.119.044703 . Bailly G, Robert-Halabi M, Vion PA, et al. Rechallenge After Severe Immune Checkpoint Inhibitor Myocarditis. JACC CardioOncology. 2025;7(3):300–4. 10.1016/j.jaccao.2025.02.004 . Faron A, Isaak A, Mesropyan N, et al. Cardiac MRI Depicts Immune Checkpoint Inhibitor–induced Myocarditis: A Prospective Study. Radiology. 2021;301(3):602–9. 10.1148/radiol.2021210814 . Mirabel M, Eslami A, Thibault C, et al. Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment. Clin Res Cardiol Published online May. 2024;28. 10.1007/s00392-024-02462-x . Thavendiranathan P, Shalmon T, Fan CPS, et al. Comprehensive Cardiovascular Magnetic Resonance Tissue Characterization and Cardiotoxicity in Women With Breast Cancer. JAMA Cardiol. 2023;8(6):524. 10.1001/jamacardio.2023.0494 . Mirabel M, Luyt CE, Leprince P, et al. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support*. Crit Care Med. 2011;39(5):1029–35. 10.1097/CCM.0b013e31820ead45 . Thavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis. J Am Coll Cardiol. 2021;77(12):1503–16. 10.1016/j.jacc.2021.01.050 . Weizman O, Eslami A, Bougouin W, et al. Sudden cardiac arrest in patients with cancer in the general population: insights from the Paris-SDEC registry. Heart Br Card Soc. 2024;110(16):1022–9. 10.1136/heartjnl-2024-324137 . Additional Declarations No competing interests reported. Supplementary Files Centralillustration.png Central Illustration Flow of ICI Rechallenge and Cardiovascular Outcomes in the FAST-TRACK ICI Cohort Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 18 May, 2026 Reviews received at journal 18 May, 2026 Reviewers agreed at journal 17 May, 2026 Reviews received at journal 13 Mar, 2026 Reviewers agreed at journal 23 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers invited by journal 03 Feb, 2026 Editor assigned by journal 28 Jan, 2026 Submission checks completed at journal 26 Jan, 2026 First submitted to journal 24 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8689115","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585317066,"identity":"28aa6f09-14b5-4bad-aa6e-44494faa0297","order_by":0,"name":"Francesco Cribari","email":"","orcid":"","institution":"Institut Mutualiste Montsouris","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Cribari","suffix":""},{"id":585317069,"identity":"d5607e62-b983-4ebf-ac28-06ae01936923","order_by":1,"name":"Imen Hamdi","email":"","orcid":"","institution":"Institut Mutualiste 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21:23:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8689115/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8689115/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101947199,"identity":"b03e6c70-6bf5-4cb1-916f-0f219a0926c8","added_by":"auto","created_at":"2026-02-05 10:03:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59700,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier survival rates in the entire FAST TRACK ICI cohort (N=175);\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8689115/v1/47332d87beec0bf9ab3b8c4f.png"},{"id":101946998,"identity":"02c0d259-d183-4029-90a1-0a069ae20cff","added_by":"auto","created_at":"2026-02-05 10:03:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":104474,"visible":true,"origin":"","legend":"\u003cp\u003eSwimmer plot on timeline of CV and non-CV events during follow-up.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8689115/v1/719e21e32741a7df842ac06b.png"},{"id":101946997,"identity":"54f69440-df74-48bb-bd4b-ea943336ac83","added_by":"auto","created_at":"2026-02-05 10:03:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":68544,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier: Overall survival according to ICI rechallenge.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8689115/v1/26a93f3363f6cd888b100ae5.png"},{"id":101947544,"identity":"8bd18fcf-2b1e-4c65-a23d-81e884c7f90e","added_by":"auto","created_at":"2026-02-05 10:04:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1670305,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8689115/v1/24cd9746-e96a-4023-b5e1-6f02d3b269d2.pdf"},{"id":101946993,"identity":"94d42d55-7bb5-4347-b344-2d719aef7f24","added_by":"auto","created_at":"2026-02-05 10:03:13","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":309592,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCentral Illustration\u003c/strong\u003e Flow of ICI Rechallenge and Cardiovascular Outcomes in the FAST-TRACK ICI Cohort\u003c/p\u003e","description":"","filename":"Centralillustration.png","url":"https://assets-eu.researchsquare.com/files/rs-8689115/v1/784f9c7c0eb83c115c8b3914.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety of Immune Checkpoint Inhibitor Rechallenge and Mid-Term Outcomes After Suspected Cardiovascular Immune-Related Adverse Events","fulltext":[{"header":"What is already known on this subject","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eCardiovascular immune-related adverse events (CV irAEs) are uncommon but clinically significant complications of immune checkpoint inhibitors (ICIs).\u003c/li\u003e\n \u003cli\u003eDiagnostic criteria of ICI-myocarditis may be confounded by cardiovascular toxicities of combined cancer drugs.\u003c/li\u003e\n \u003cli\u003eDecisions about ICI rechallenge after suspected CV irAEs remain inconsistent, largely informed by expert opinion and small case series.\u003c/li\u003e\n \u003cli\u003eMid-term risk of recurrent CV toxicity or mortality after suspicion of CV irAEs in real-world populations has not been well defined.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat this study adds\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eIn this prospective cohort of 175 patients with suspected CV irAEs mainly driven by mild troponin raise, cardiovascular mortality rates were low (\u0026lt;1%) at 6 months follow-up.\u003c/li\u003e\n \u003cli\u003eAlmost half were rechallenged with ICIs after multidisciplinary evaluation, with low recurrence of ICI-myocarditis (3.6%).\u003c/li\u003e\n \u003cli\u003eInitial clinical presentation, cardiac magnetic resonance features consistent with ICI-myocarditis, coronary artery disease and ICI-rechallenged were associated with increased risk of CV irAEs.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eHow this study might affect clinical practice\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eThese findings support structured, multidisciplinary pathways to evaluate ICI rechallenge after suspected CV irAEs.\u003c/li\u003e\n \u003cli\u003eSelected patients can likely resume immunotherapy with low risk of recurrent CV events, avoiding unnecessary permanent discontinuation.\u003c/li\u003e\n \u003cli\u003eThe results may inform guideline development and provide real-world evidence for balancing cancer control and cardiovascular safety in ICI-treated patients.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Background","content":"\u003cp\u003eCardiovascular immune-related adverse events (CV irAEs) of immune checkpoint inhibitors (ICIs) have emerged as a major concern in cardio-oncology.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e ICI-myocarditis has attracted particular attention due to initially high mortality rates\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and specific pathophysiology\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e linking cardiac and muscular irAEs, leading to the concept of cardio-myotoxicity. Cardiovascular irAEs negatively impact survival, especially in metastatic cancer patients with ICI-cardiomyotoxicity.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e with mortality driven first by acute complications\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, and later by cancer progression, especially if ICIs are withheld. Less severe presentations have been however increasingly reported since 2022, broadening the recognised spectrum of CV irAEs.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Cancer regimens have also become more complex, with ICIs often combined with other cardiotoxic drugs (e.g., anthracyclines in triple negative breast cancer).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDiagnosing non-severe CV irAEs remains challenging. ICI therapy should not necessarily be withheld, as International Cardio-Oncology Society criteria (IC-OS)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e diagnostic criteria may be more sensitive than expert opinion.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Also, the IC-OS diagnostic criteria may be confounded by other therapies such as vascular endothelial growth factor inhibitors or anthracyclines, now widely used in combination with ICIs. Our group previously showed that patients referred for suspected CV irAEs have favourable short-term outcomes\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, longer term data are largely derived from quaternary centres, potentially biased toward the most severe phenotypes.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The safety of ICI rechallenge in patients fulfilling ICI-myocarditis diagnostic criteria has been only depicted through clinical cases\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and remains to be demonstrated. Earlier expert consensus discouraged rechallenge based on limited data.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Broader recognition of smouldering forms and diagnostic uncertainties requires reconsideration of management, particularly regarding rechallenge in non-severe CV irAEs.\u003c/p\u003e \u003cp\u003eThe FAST TRACK ICI cohort (NCT05799898) is a prospective ongoing project assessing patients\u0026rsquo; management when referred for suspected CV irAEs.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The aim of this study is to describe mid-long term outcomes in patients referred for suspected CV irAEs; to identify predictors of CV events at follow-up; and to assess the safety of rechallenge in patients after suspected CV irAEs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe FAST TRACK ICIs project is a prospective single-centre cohort study that has been described elsewhere.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Briefly, our institution provides CV care for several oncology centres, including \u003cem\u003eInstitut Curie\u003c/em\u003e, among the largest breast cancer centres in Europe. Patients who are suspected of CV irAEs by the oncology team are referred to the cardio-oncology unit. Our team elaborated clinical CV, ECG, and, extra-CV criteria (e.g., muscular symptoms) for either hospital admission (including intensive care unit) or assessment in the outpatient clinic prior to the publication of a novel risk scoring,\u003csup\u003e15\u003c/sup\u003e or severity algorithm based on an international register\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Admission criteria are similar to that of pre-test diagnostic likelihood\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e or severity of ICI-cardio-myotoxicity\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e (e.g., cardiovascular or muscular symptoms, low left ventricular ejection fraction, underlying auto-immune diseases). Patients undergo a standardized multimodal diagnostic workout including repeated serum biomarkers, electrocardiogram, transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging, cardiology and internal medicine clinical evaluations.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e All cases were discussed during a weekly multidisciplinary meeting. All patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years referred for suspected CV irAEs who provided consent were eligible. The inclusion period was March 1st 2022 \u0026ndash; October 31\u003csup\u003est,\u003c/sup\u003e 2023\u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eObjectives and Outcome Measures\u003c/h2\u003e \u003cp\u003eThe objectives of the current work include: (i) to describe outcomes after initial assessment for suspected CV irAEs; (ii) to identify predictors of mid-term CV events; (iii) to describe outcomes after ICI-rechallenge in a population with and without initial CV irAEs after a complete multimodal CV imaging and multidisciplinary assessment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic criteria\u003c/h3\u003e\n\u003cp\u003eAn adjudication committee was deemed necessary due to the discrepancy in diagnostic criteria for ICI-myocarditis published to this date.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The committee took into account the IC-OS\u003csup\u003e9\u003c/sup\u003e, definite or probable criteria from the American Heart Association (AHA)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, or significant lymphocyte infiltration based on the Dallas criteria in the subset of patients undergoing EMB.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e We collected all the data to meet the IC-OS, AHA, or histological diagnosis (i.e., Dallas criteria) criteria. The updated Lake Louise criteria were employed for CMR myocarditis diagnosis\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Globally, we followed the diagnostic criteria of the European Society of Cardiology (ESC) 2022 guidelines\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Cardiovascular events at follow-up were defined as either fulfilling new CV event criteria at follow-up or as worsening of the initial CV iRAEs.\u003c/p\u003e\n\u003ch3\u003eICI- rechallenge strategies\u003c/h3\u003e\n\u003cp\u003eThe decision to re-expose patients to ICIs was made following a thorough evaluation conducted by the multidisciplinary team. This process involved detailed discussions between cardiologists, internal medicine specialists, and oncologists, with careful consideration of the risk-benefit ratio for each individual case, and patient\u0026rsquo;s will. Patients admitted with overt potentially lethal ICI-myocarditis (cardio-muscular symptoms, elevated troponin\u0026thinsp;\u0026gt;\u0026thinsp;20 upper limit value, left ventricular dysfunction) were treated with intravenous IV glucosteroids (mostly methylprednisolone 1 gramme intra-venously). Patients fulfilling non-severe ICI-myocarditis diagnostic criteria and expected oncological benefit from ICIs were deemed fit for ICI-rechallenge. If a patient presented with non-severe ICI-myocarditis and was managed as an outpatient, oral steroids (prednisone 1mg/Kg/day with gradual tapering doses within 4 weeks) were initiated when ICI-rechallenge was decided,\u003csup\u003e24\u003c/sup\u003e followed by a 72 hour hospital admission for clinical, electric, biologic and echocardiographic monitoring after the first rechallenge ICI cycle. If no CV IRAEs was diagnosed, then the patient was seen in the outpatient clinic 2\u0026ndash;7 days after ICI rechallenge for clinical, ECG, serum cardiac biomarkers, and echocardiography. If the patient was suspected with CV event after rechallenge, the patient was then admitted to cardiology (either ward or intensive care according to the initial FAST TRACK ICI hospital assignment strategy\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003ePatient characteristics were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, median [IQR], or n (%). Between-group comparisons used t-test or Mann\u0026ndash;Whitney U for continuous variables and χ\u0026sup2; or Fisher\u0026rsquo;s exact test for categorical variables. A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. Collinearity was assessed before multivariable analyses. Univariate and competing-risk models (with non-CV death as competing factor) were applied to identify predictors of mid-term CV events. Kaplan\u0026ndash;Meier curves described (i) all-cause mortality in the whole cohort and (ii) outcomes in patients with or without CV irAEs at referral. Analyses were performed at \u003cem\u003eInstitut Mutualiste Montsouris\u003c/em\u003e using SPSS-26 and SAS. The study complied with Good Clinical Practice, French law, and the Declaration of Helsinki, with IRB approval (2022-08) and ClinicalTrials.gov registration (NCT057998).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDescription of the study population\u003c/h2\u003e \u003cp\u003eFrom March 1, 2022, to October 31, 2023, 175 patients were enrolled (median age 61 years [IQR 48\u0026ndash;72]; 135 women, 77%). Breast cancer was the most frequent malignancy (101, 58%), and 49 (28%) had metastatic disease at baseline. CV irAEs were adjudicated in 95 patients (54%): 72 myocarditis, 10 ACS, 9 pericarditis, 7 non-inflammatory HF, 4 conduction abnormalities/ventricular arrhythmias, and 8 combined cases (5 myocarditis\u0026ndash;pericarditis, 3 myocarditis\u0026ndash;arrhythmia).Mid-term outcomes\u003c/p\u003e \u003cp\u003eThe mean follow-up duration was 234 days (SD 154). During this period, 15 deaths were recorded: 12 from cancer, 1 sudden death adjudicated as CV-related, and 2 from non-CV, non-oncological causes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the 15 deceased patients, 9 had a prior diagnosis of CV irAEs, but none died from cardiovascular causes. The only CV death occurred in a patient with metastatic lung cancer who experienced an out-of-hospital sudden death 9 months after the initial FAST TRACK ICI referral. No CV irAEs had been diagnosed at baseline, and no symptoms, ECG changes, biomarker elevation, or LVEF decline were noted during follow-up, with the patient remaining clinically stable on ICI therapy until death. Notably, 9 out of the 12 cancer-related deaths in our cohort occurred in patients who had not undergone ICI rechallenge.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDuring follow-up, 49/175 (28.00%) patients developed irAEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Mid-term CV events were observed in 19/175 (10.87%) patients. Among those with baseline CV irAEs, 6/95 (6.32%) developed new or worsening CV events; whereas 13/80 (16.25%) without CV irAEs at referral, developed CV events during follow-up (Central Illustration).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePredictors of mid-term CV events identified by univariate and multivariate competing-risk analyses are reported in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. On multivariate analysis, significant predictors included: coronary artery stenosis at referral (HR 4.77; 95% CI 1.39\u0026ndash;16.40; P\u0026thinsp;=\u0026thinsp;0.013), hospital admission at referral (HR 13.21; 95% CI 2.51\u0026ndash;69.52; P\u0026thinsp;=\u0026thinsp;0.0023), ICI rechallenge (HR 9.30; 95% CI 1.77\u0026ndash;48.77; P\u0026thinsp;=\u0026thinsp;0.0084), and positive Lake Louise criteria on CMR at referral (HR 18.84; 95% CI 5.13\u0026ndash;69.20; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate competing analysis of mid-term CV events according to characteristics at referral for all patients referred for suspected CV irAEs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;175\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCensor\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;143\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCV event at FU\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon CV death\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnivariate Analysis\u003c/p\u003e \u003cp\u003eHR [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e135 (77.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e109 (76.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (85.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (75.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.497[0.594;34.065]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.1456\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61 (48.0\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.0 (48.0\u0026ndash;71.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.0 (29.0\u0026ndash;83.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e75.5 (63.5\u0026ndash;78.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026deg;0.974 [0.305;3.115]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4882\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index**, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (21.0-27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23.5(21.0-27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.3 (23.5\u0026ndash;28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (19.1\u0026ndash;26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e**1.105 [0.420;2.909]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8396\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCV IRAEs at referral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95 (54.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e82 (57.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.382 [0.133;1.099]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0743\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI-myocarditis at referral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72 (41.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65 (79.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (71.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.187 [0.033;1.046]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0563\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI rechallenge after 1st assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84 (48.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e67 (46.85)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e15 (75.00)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e2 (16.67)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e6.789[1.542;29.87]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0113\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReferral for asymptomatic troponin elevation, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e112 (64.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e92 (64.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (60.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.886 [0.322;2.437]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8140\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital admission, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (16.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e21 (14.69)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e7 (35.00)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e2 (16.67)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e3.079 [1.066;8.888]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0376\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of CV disease, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (23.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (21.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.291[0.449;3.709]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6351\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker (past or present), N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65 (37.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50 (34.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (35.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.503 [0.065;3.900]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52 (29.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (27.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (40.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (41.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.632 [0.618;4.312]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.3230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (8.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (7.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (15.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.821[0.413;8.031]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtra cardiovascular toxicity, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48 (27.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (25.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (35.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (41.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.151 [0.401;3.297]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7940\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101 (57.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87 (60.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (60.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.428 [0.496;4.116]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung cancer, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34 (19.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27(18.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (25.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.803 [0.226;2.851]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7347\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSI, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (5.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (41.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.647[0.217;12.50]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract cancer (Kidney or Bladder), N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (6.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (5.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (15.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThymoma, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMelanoma, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (8.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (8.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic stage, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (28.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (24.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.172[0.408;3.366]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD1/PDL1\u0026thinsp;+\u0026thinsp;CTLA4, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (9.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (10.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.045 [0.222;4.924]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.9560\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI lone therapy, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (16.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (30.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (25.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.307 [0.417;4.100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6462\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI with\u0026nbsp;chemotherapy and/or radiotherapy, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e130 (74.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e109 (76.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (70.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (58.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.108[0.357;3.439]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI with VEGF inhibitors, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (6.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (6.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of doses of ICIs injections\u0026thinsp;\u0026ge;\u0026thinsp;7, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96 (54.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84 (58.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (50.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.667[0.261;1.755]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4217\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDoxorubicine dose\u0026thinsp;\u0026lt;\u0026thinsp;240 mg/m2, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67 (38.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60 (41.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (30.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.677 [0.235;1.949]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4696\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak troponin/normal laboratory value, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.6 (1.2\u0026ndash;2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.5 (1.2\u0026ndash;2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7 (0.6\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.6 (1.3\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.703 [0.250;1.978]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular or muscle symptoms N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63 (36.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47 (32.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (50.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (50.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.803 [0.676;4.807]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2390\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal ECG N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34 (19.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (20.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (15.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.427 [0.096;1.895]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2629\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLVEF on TTE#, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60 (55.0\u0026ndash;65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.0 (55.00\u0026ndash;65.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.5 (50.0\u0026ndash;65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60.0 (54.5\u0026ndash;69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.104[0.059;20.718]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6852\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLS\u0026thinsp;\u0026infin;\u0026thinsp;on TTE, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.0 (15.0-19.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (16.0\u0026ndash;19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (10.0\u0026ndash;20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.529[0.560;11.413]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2277\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLake Louise criteria on CMR\u0026infin;\u0026infin;, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e55 (32.74)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e43 (31.16)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e9 (47.37)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e3 (27.27)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e2.918 [1.085;7.845]\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0338\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u0026deg;analysis by quartiles; **analysis by groups divided by BMI\u0026thinsp;=\u0026thinsp;25; ***analysis as peak\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003etroponin/normal laboratory value\u0026thinsp;\u0026gt;\u0026thinsp;1,6 N ; #analysis LVEF\u0026thinsp;\u0026ge;\u0026thinsp;50% versus \u0026lt;\u0026thinsp;40%; \u0026infin;missing data for 41/175 participants and analysis GLS\u0026thinsp;\u0026ge;\u0026thinsp;16% versus \u0026lt;\u0026thinsp;16%; \u0026infin;\u0026infin;CMR performed in 168/175 participants.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eACS\u0026thinsp;=\u0026thinsp;Acute coronary syndrome; BMI\u0026thinsp;=\u0026thinsp;Body mass index; CMR\u0026thinsp;=\u0026thinsp;Cardiac magnetic resonance; CV\u0026thinsp;=\u0026thinsp;Cardiovascular; ECG\u0026thinsp;=\u0026thinsp;Electrocardiogram; GLS\u0026thinsp;=\u0026thinsp;Global longitudinal strain; ICI\u0026thinsp;=\u0026thinsp;Immune checkpoint inhibitor; ICU\u0026thinsp;=\u0026thinsp;Intensive care unit; irAE\u0026thinsp;=\u0026thinsp;Immune-related adverse event; LVEF\u0026thinsp;=\u0026thinsp;Left ventricular ejection fraction; MSI\u0026thinsp;=\u0026thinsp;microsatellite instability; TTE\u0026thinsp;=\u0026thinsp;Transthoracic echocardiography\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate competing-risk analysis for independent predictors of mid-term cardiovascular events.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResults of coronary artery imaging: significant lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.771\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e[1.388;16.395]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e[2.510;69.522]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI rechallenge after initial assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e[1.773;48.771]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0084\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLake Louise criteria on CMR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.840\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e[5.129;69.201]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRechallenge population\u003c/h3\u003e\n\u003cp\u003eOverall, 84 out of 175 patients (48.00%) underwent ICI rechallenge with re-exposure to the same regimen (Central Illustration). Among these, 32/84 (38.10%) had experienced a CV irAE at referral, including ICI-myocarditis (16 cases), ACS (8 cases), ICI-pericarditis (2 cases), arrhythmias or conduction disease (2 cases), non-inflammatory HF/Takotsubo syndrome (3 cases), and combined CV irAEs (2 cases).\u003c/p\u003e \u003cp\u003eAmong the 53 patients rechallenged without baseline CV irAEs, 11/53 (20.75%) developed a CV irAE upon rechallenge, including myocarditis (5 cases), ACS (2 cases), isolated conduction abnormalities/arrhythmias (2 cases), and 2 patients with combined conduction abnormalities/arrhythmia and myocarditis.\u003c/p\u003e \u003cp\u003eAmong patients with ICI-myocarditis at referral, 18/72 (25.0%; 16 lone myocarditis, 1 myocarditis with new conduction abnormality and 1 myo-pericarditis) and 2/72 patients with myocarditis were considered eligible for rechallenge. Two experienced recurrent myocarditis three months after re-exposure, both non-severe and not requiring ICU admission. Furthermore, one patient with baseline ACS developed myocarditis after rechallenge, and one with baseline ICI-pericarditis developed a new conduction abnormalities 3 months after rechallenge.\u003c/p\u003e \u003cp\u003eFactors associated with the likelihood of rechallenge are reported in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Patients fulfilling FAST TRACK hospital admission criteria\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e were significantly less likely to undergo rechallenge (P\u0026thinsp;=\u0026thinsp;0.045). On univariate analysis, a reduced probability of re-exposure was observed in patients meeting Lake Louise criteria on CMR (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), those undergoing endomyocardial biopsy (P\u0026thinsp;=\u0026thinsp;0.003), patients diagnosed with myocarditis (P\u0026thinsp;=\u0026thinsp;0.005), and those with diabetes (P\u0026thinsp;=\u0026thinsp;0.023) or lung cancer (P\u0026thinsp;=\u0026thinsp;0.030). Conversely, patients with ACS were significantly more likely to be rechallenged (8/10 cases, P\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison (univariate analysis) of the study population according to the ICI rechallenge status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll N\u0026thinsp;=\u0026thinsp;175\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo Rechallenge N\u0026thinsp;=\u0026thinsp;91\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRechallenge N\u0026thinsp;=\u0026thinsp;84\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (77.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (76.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72 (79.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (IQR 48.0\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (IQR 49.0\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (IQR 48.0\u0026ndash;72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.831\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody mass index\u0026thinsp;\u0026gt;\u0026thinsp;25, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (38.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (36.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.562\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCV irAEs at 1st evaluation, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (54.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (69.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (38.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTroponin ratio, median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.62 (I1.17-2.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.74 (1.16\u0026ndash;2.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.43 (1.17\u0026ndash;2.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThymoma, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.615\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVEF\u0026thinsp;\u0026lt;\u0026thinsp;50% at referral, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (13.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (16.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardio-muscular symptoms, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (35.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (30.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (40.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLake Louise criteria fulfilled, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (28.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (41.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (13.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEMB performed, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (26.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (37.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbnormal EMB (borderline\u0026thinsp;+\u0026thinsp;definite) in 48 patients, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (87.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (64.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (22.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of CV disease, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (23.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (23.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (23.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospital admission, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (16.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (21.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (10.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (30.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (30.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoker (past or present), N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (37.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (30.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (44.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (8.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (13.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast cancer, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (57.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (59.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (55.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung cancer, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (19.43))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (13.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (26.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther types of cancer N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (22.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (27.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (17.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastasis, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (28.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (27.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCombination PD1/PDL1\u0026thinsp;+\u0026thinsp;CTLA4, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (8.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (10.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (5.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICI lone therapy, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (18.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (18.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (19.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICI with\u0026nbsp;chemotherapy/radiotherapy, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 (74.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (74.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (73.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICI with VEGFi, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (6.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (6.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (7.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.886\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICI-myocarditis, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (41.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (59.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (21.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePericarditis, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (5.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (6.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAcute coronary syndrome, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (5.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNon Inflammatory Heart Failure/Takotsubo N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (5.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eConduction disease/arrhythmias, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.670\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtra cardiovascular irAEs N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (23.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (18.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.186\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCV, cardiovascular; 95% CI, 95% Confidence Interval; CV irAEs, cardiovascular Immune-related adverse events; IQR, Interquartile range; ICI, Immune-checkpoint Inhibitors; CMR, Cardiac Magnetic Resonance Imaging; VEGFi; vascular endothelial growth factor inhibitor; PD-1, programmed cell death protein 1; PDL-1, programmed death ligand 1; CTLA, cytotoxic T lymphocyte-associated protein 4; EMB, endomyocardial biopsy; LVEF, left ventricular ejection fraction; GLS, global longitudinal strain.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 91 patients not rechallenged, 4/95 (42.11%) developed mid-term CV events (two with baseline CV irAEs and two without).\u003c/p\u003e \u003cp\u003eIn summary, ICI rechallenge was performed in a large subset of patients, with a low rate of recurrent myocarditis, all of which were non-severe. All-cause mortality was lower in rechallenged patients (4/84, 4.76%) compared with those not rechallenged (12/91, 13.18%) in unadjusted analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospective single‑centre cohort of 175 consecutive patients referred for suspected CV irAEs during ICI therapy, we found that CV deaths were rare over a mean follow‑up of 6 months, mortality driven by cancer progression. Half of the cohort received an adjudicated diagnosis of CV irAEs at referral, most fulfilling contemporary diagnostic criteria for ICI-myocarditis albeit potentially confounded by other cancer drug induced cardiotoxicities. Nearly one patient in two was subsequently rechallenged with ICIs after multidisciplinary triage and tailored surveillance. Patients who were deemed fit for ICI rechallenge differed from the restrained population. In patients with non-metastatic breast cancer, ICIs were often discontinued by the oncology team. ICIs were also withheld in patients who fulfilled ICIs-myocarditis diagnosis in spite of non-severe forms and diagnostic confounders such as anthracyclines. Among rechallenged patients, non‑severe myocarditis occurred in only 3.6% (2 recurrences and 1 de‑novo case). Only 1 out-of-hospital sudden death (labelled as CV) occurred after rechallenge in a patient with no clear CV irAE phenotype at referral and no worsening condition after the first ICI rechallenge cycle. By competing‑risk analysis, positive Lake Louise criteria on CMR, hospital admission at referral, significant coronary stenosis, and ICI rechallenge were associated with a higher risk of mid‑term CV events.\u003c/p\u003e \u003cp\u003eOur study demonstrates that when patients are channeled through a structured cardio‑oncology pathway for suspected CV irAEs, CV death is uncommon, overall outcomes being primarily conditioned by cancer. This aligns with a maturing literature showing that the initial signal of very high case fatality with ICI‑myocarditis\u0026mdash;largely derived from early pharmacovigilance\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and quaternary centre cohorts\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u0026mdash;has broadened to include non‑severe presentations with favorable outcomes when recognized early and co‑managed by multidisciplinary teams.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Initial reports suggested case‑fatality rates of 25\u0026ndash;50% in ICI‑myocarditis, prompting highly conservative guidance and widespread reluctance to re‑expose patients. Subsequent series, including severity‑stratified registries, have delineated a broader spectrum from fulminant to non‑severe ICI-myocarditis, with markedly lower mortality in carefully selected, promptly treated patients.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhile previous reports have been largely limited to case reports or anecdotal series, our cohort represents one of the first structured, real-world datasets exploring ICI rechallenge in patients with suspected CV irAEs. In particular, 25% of patients diagnosed with mainly non-severe ICI-myocarditis were considered suitable for rechallenge. Furthermore, the observed recurrence rate was low (11.1%), and all events were non-severe, no ICU admissions being required. This is also the first prospective study to describe rechallenge strategies following non-myocarditis CV irAEs, such as pericarditis, arrhythmias, and troponin elevation without overt myocarditis, thereby expanding the clinical landscape in which rechallenge may be considered. \u003csup\u003e12,25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAn individualised approach \u0026mdash; incorporating rigorous risk stratification and structured surveillance, as implemented in the FAST TRACK study\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e \u0026mdash; may offer a safe path forward and may allow safe continuation of cancer therapy. Of note, among the twelve cancer-related deaths observed during follow-up, nine occurred in patients who were not considered for ICI rechallenge. As recently underlined by authors such as Itzhaki et al.,\u003csup\u003e8\u003c/sup\u003e systematic prospective data on rechallenge have been lacking to date\u0026mdash;our study addresses this gap and supports a potential change in clinical practice.\u003c/p\u003e \u003cp\u003eSome patients without a clear CV irAEs phenotype at baseline nonetheless experienced subsequent events, including more definitive presentations of ICI-myocarditis during follow-up. This finding supports the concept of \u0026ldquo;smouldering\u0026rdquo; or evolving phenotypes that may manifest only over time or with cumulative exposure. Accordingly, even when the initial workup is non-diagnostic, a low threshold for repeat clinical assessment\u0026mdash;including biomarkers, ECG, and echocardiography\u0026mdash;within the weeks following the index evaluation appears warranted. We therefore advocate programmed re-evaluation within 1 week for patients resuming ICI therapy without a definitive CV irAEs diagnosis after resuming ICI therapy. Moreover, non-cardiovascular irAEs (e.g., dermatologic, endocrine, pulmonary) may emerge after the first assessment, further reinforcing the value of a multidisciplinary approach in managing patients with suspected CV irAEs.\u003c/p\u003e \u003cp\u003eThe association between Lake Louise\u0026ndash;positive CMR and subsequent CV events highlights the potential prognostic value of tissue characterization. Value of T1 and T2 mapping abnormalities in asymptomatic patients appear contradictory.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Furthermore, the initial retrospective analysis of a multicentric register demonstrated that CMR yielded moderate sensitivity values for the diagnosis of ICI-myocarditis. And others have not included CMR data in the prognostic algorithm for ICI cardiomyotoxicity, based mainly on serum biomarkers that are of more widespread use than CMR. Also, other cancer therapies as anthracyclines may lead to CMR changes\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e that overlap with the Lake Louise criteria for myocarditis diagnosis\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, complexifying the diagnosis as in breast cancer patients who receive both anthracyclines and ICIs. When considering the role of CMR as a diagnostic or prognostic tool in ICI-myocarditis, there are a number of bias that need consideration: (i) selection bias of patients who are not hemodynamically unstable to undergo a 30\u0026ndash;40 minutes long scan\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e; (ii) the timing of CMR in regard to the initial CV irAE suspicion and potential immunosuppressant therapies; (iii) the completeness of the CMR study beyond late gadolinium enhancement \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Regardless the sensitivity and specificity of CMR for the diagnosis of ICI-myocarditis, our results support that active myocardial inflammation and/or fibrosis portends higher risk of CV events.\u003c/p\u003e \u003cp\u003eFinally, the apparent association between ICI rechallenge and increased CV events should be interpreted with caution, given the likelihood of confounding by indication and selection bias. In our cohort, approximately half of the patients were rechallenged after suspected CV irAEs, with only one subsequent severe CV event. Notably, this event may not have been CV in origin, as most sudden deaths in patients with cancer are attributable to non-CV causes.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Resuming ICI was associated with more CV events but also with better overall survival. These findings support a nuanced, risk-adapted multidisciplinary strategy rather than absolute discontinuation of ICIs, and highlight the need for vigilant follow-up regardless of CV irAEs at referral.\u003c/p\u003e \u003cp\u003eThe FAST-TRACK ICI data support a pragmatic, risk-adapted strategy: (i) early multidisciplinary triage of suspected cases; (ii) CMR use when feasible; (iii) hospitalisation for predefined severity criteria (hemodynamic or arrhythmic instability, rising biomarkers, high clinical suspicion); (iv) routine evaluation for coronary disease, an independent predictor of long-term events; and (v) structured post-discharge follow-up, including initially non-diagnostic cases where later phenotypes may appear.\u003c/p\u003e \u003cp\u003eFor rechallenge, our approach\u0026mdash;requiring resolution of acute inflammation, shared decision-making, and, in non-severe myocarditis, brief inpatient observation followed by early outpatient reassessment\u0026mdash;was associated with low rates of non-severe recurrence.This experience supports considering rechallenge in carefully selected patients, especially when CMR is quiescent and competing cardiotoxic exposures (e.g., anthracyclines, VEGF inhibitors) may be confounders. Recently published diagnostic\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e and prognostic\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e risk tools may assist selection, but prospective validation in rechallenge cohorts remains an unmet need.\u003c/p\u003e \u003cp\u003eStrengths and imitations\u003c/p\u003e \u003cp\u003eThe FAST-TRACK ICI study prospectively enrolled consecutive patients with suspected CV irAEs, largely identified through elevated cardiac biomarkers. CV irAEs were adjudicated using a standardized multidisciplinary, multimodal process, and a prespecified rechallenge pathway was implemented to optimise oncologic care. Limitations include its single-centre design, mid-term follow-up, and potential residual confounding in patients receiving multiple cardiotoxic therapies. Case definitions\u0026mdash;particularly for ICI-myocarditis\u0026mdash;may also be debated. Nonetheless, the study\u0026rsquo;s primary aim was to evaluate rechallenge feasibility, and findings indicate that ICI reintroduction is generally safe with structured monitoring. Given the low incidence of severe ICI-related cardiomyotoxicity (~\u0026thinsp;1%)\u003csup\u003e16\u003c/sup\u003e, major adverse events were uncommon in our cohort. However, the absolute number of events remained limited, resulting in wide confidence intervals for certain predictors. Multicentre studies enrolling patients referred for suspected CV irAEs\u0026mdash;not only those with severe ICI-cardiotoxicity\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u0026mdash;are warranted to refine our understanding of the full spectrum of CV irAEs. In particular, the role of CMR findings in guiding decisions regarding treatment interruption, initiation of immunosuppression, and post-discharge surveillance requires further validation.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn a real-world cardio-oncology pathway for suspected CV irAEs, cardiovascular deaths were rare, and outcomes were mainly driven by cancer progression. Lake Louise\u0026ndash;positive CMR, hospital admission, significant coronary disease, and ICI rechallenge were associated with higher rates of subsequent CV events. Yet nearly half of patients\u0026mdash; including selected non-severe myocarditis cases\u0026mdash;were safely rechallenged. These results support moving from categorical avoidance to a risk-adapted, multidisciplinary strategy that balances oncologic benefit with cardiovascular safety and emphasises vigilant follow-up, even in initially non-diagnostic cases. Larger multicentre studies with longer surveillance are needed to refine selection and monitoring for ICI rechallenge.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute Coronary Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAHA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Heart Association\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCardiac Magnetic Resonance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCardiovascular\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEndomyocardial Biopsy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGLS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlobal Longitudinal Strain\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHeart Failure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune Checkpoint Inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIC-OS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Cardio-Oncology Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eirAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune-Related Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterquartile Range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVEF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeft Ventricular Ejection Fraction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultidisciplinary Team\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTTE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTransthoracic Echocardiography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003cbr\u003e\u003c/strong\u003eThe FAST TRACK ICI project was funded by the Institut Mutualiste Montsouris, Paris, France.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTweet:\u0026nbsp;\u003c/strong\u003eIn the FAST TRACK ICI cohort, nearly half of patients were safely rechallenged after suspected CV irAEs, with very low recurrence rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003cbr\u003e\u003c/strong\u003eWe are grateful to our patients for participating in the FAST TRACK study and to all IMM staff for their help and care. We thank the research unit for their support and the radiology team for their prompt assessments.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe FAST TRACK ICI project is a prospective, single-centre cohort study conducted in accordance with the Declaration of Helsinki, French regulatory requirements, and Good Clinical Practice guidelines. The study protocol was approved by the institutional review board (IRB) (approval number: 2022-08). All participants provided written informed consent prior to inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to restrictions related to patient confidentiality and French data protection regulations, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FAST TRACK ICI project was funded by the Institut Mutualiste Montsouris, Paris, France. The funding body had no role in the design of the study; collection, analysis, or interpretation of data; writing of the manuscript; or decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM conceived and designed the study.\u003c/p\u003e\n\u003cp\u003eFC, IH, SH, PC, RC, MLJ, DM, and DL contributed to patient inclusion and data acquisition.\u003c/p\u003e\n\u003cp\u003eFC and MM performed the statistical analyses.\u003c/p\u003e\n\u003cp\u003eFC and MM drafted the manuscript.\u003c/p\u003e\n\u003cp\u003eMM, CC, NG, and ALLL critically revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eWe are grateful to the patients who participated in the FAST TRACK ICI study and to all staff members of the Institut Mutualiste Montsouris for their support and care. We also thank the research unit and the radiology team for their valuable contributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTocchetti CG, Farmakis D, Koop Y, et al. Cardiovascular toxicities of immune therapies for cancer \u0026ndash; a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology. Eur J Heart Fail. 2024;26(10):2055\u0026ndash;76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ejhf.3340\u003c/span\u003e\u003cspan address=\"10.1002/ejhf.3340\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016;375(18):1749\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1609214\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1609214\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579\u0026ndash;89. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(18)30608-9\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(18)30608-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2018.02.037\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2018.02.037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAxelrod ML, Meijers WC, Screever EM, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis. Nature. 2022;611(7937):818\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41586-022-05432-3\u003c/span\u003e\u003cspan address=\"10.1038/s41586-022-05432-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLehmann LH, Heckmann MB, Bailly G, et al. Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis. Circulation. 2023;148(6):473\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.123.062405\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.123.062405\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(12):1721. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaoncol.2018.3923\u003c/span\u003e\u003cspan address=\"10.1001/jamaoncol.2018.3923\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eItzhaki Ben Zadok O, Levi A, Divakaran S, Nohria A. Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis. JACC CardioOncology. 2023;5(6):732\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaccao.2023.09.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jaccao.2023.09.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022;43(4):280\u0026ndash;99. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehab674\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehab674\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeharo F, Thuny F, Cadour F, et al. Diagnostic Value of the International Society of Cardio-Oncology Definition for Suspected Immune Checkpoint Inhibitor\u0026ndash;Associated Myocarditis. J Am Heart Assoc. 2023;12(8):e029211. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/JAHA.122.029211\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.122.029211\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCribari F, Hamdi I, Henriquez S et al. Cardiovascular safety of a standardized outpatient triage and diagnostic approach for suspected cardiovascular immune-related adverse events of immune checkpoint inhibitors. Arch Cardiovasc Dis Published online July 2025:S1875213625004024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.acvd.2025.06.073\u003c/span\u003e\u003cspan address=\"10.1016/j.acvd.2025.06.073\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThibault C, Vano Y, Soulat G, Mirabel M. Immune checkpoint inhibitors myocarditis: not all cases are clinically patent. Eur Heart J Published online August. 2018;10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehy485\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehy485\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBailly G, Cohen A, Boccara F, Salem JE. Immune checkpoint inhibitor rechallenge after myocarditis: Time for reappraisal? Arch Cardiovasc Dis Published online July 2025:S1875213625003985. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.acvd.2025.06.069\u003c/span\u003e\u003cspan address=\"10.1016/j.acvd.2025.06.069\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyon AR, L\u0026oacute;pez-Fern\u0026aacute;ndez T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J Published online August. 2022;26:ehac244. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehac244\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehac244\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePower JR, Dolladille C, Ozbay B, et al. Immune checkpoint inhibitor-associated myocarditis: a novel risk score. Eur Heart J Published online June. 2025;18:ehaf315. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehaf315\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehaf315\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalem JE, Ajrouche A, Rozes A, Pinto S, De Rycke Y, Tubach F. Incidence and risk factors of immune checkpoint inhibitor myocardial and muscle toxicity: a French nationwide study. Eur Heart J Published online August. 2025;30:ehaf682. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehaf682\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehaf682\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz-Menger J, Collini V, Gr\u0026ouml;schel J, et al. 2025 ESC Guidelines for the management of myocarditis and pericarditis. Eur Heart J. 2025;46(40):3952\u0026ndash;4041. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehaf192\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehaf192\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonaca MP, Olenchock BA, Salem JE, et al. Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology. Circulation. 2019;140(1):80\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.118.034497\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.118.034497\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexandre J, Cautela J, Ederhy S, et al. Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines. J Am Heart Assoc. 2020;9(18). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/JAHA.120.018403\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.120.018403\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasso C, Calabrese F, Angelini A, Carturan E, Thiene G. Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease. Heart Fail Rev. 2013;18(6):673\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10741-012-9355-6\u003c/span\u003e\u003cspan address=\"10.1007/s10741-012-9355-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuetkens JA, Faron A, Isaak A, et al. Comparison of Original and 2018 Lake Louise Criteria for Diagnosis of Acute Myocarditis: Results of a Validation Cohort. Radiol Cardiothorac Imaging. 2019;1(3):e190010. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1148/ryct.2019190010\u003c/span\u003e\u003cspan address=\"10.1148/ryct.2019190010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eByrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J. 2023;44(38):3720\u0026ndash;826. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehad191\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehad191\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599\u0026ndash;726. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehab368\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehab368\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Zlotoff DA, Awadalla M, et al. Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor\u0026ndash;Associated Myocarditis. Circulation. 2020;141(24):2031\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.119.044703\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.119.044703\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBailly G, Robert-Halabi M, Vion PA, et al. Rechallenge After Severe Immune Checkpoint Inhibitor Myocarditis. JACC CardioOncology. 2025;7(3):300\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaccao.2025.02.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jaccao.2025.02.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaron A, Isaak A, Mesropyan N, et al. Cardiac MRI Depicts Immune Checkpoint Inhibitor\u0026ndash;induced Myocarditis: A Prospective Study. Radiology. 2021;301(3):602\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1148/radiol.2021210814\u003c/span\u003e\u003cspan address=\"10.1148/radiol.2021210814\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMirabel M, Eslami A, Thibault C, et al. Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment. Clin Res Cardiol Published online May. 2024;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00392-024-02462-x\u003c/span\u003e\u003cspan address=\"10.1007/s00392-024-02462-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThavendiranathan P, Shalmon T, Fan CPS, et al. Comprehensive Cardiovascular Magnetic Resonance Tissue Characterization and Cardiotoxicity in Women With Breast Cancer. JAMA Cardiol. 2023;8(6):524. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamacardio.2023.0494\u003c/span\u003e\u003cspan address=\"10.1001/jamacardio.2023.0494\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMirabel M, Luyt CE, Leprince P, et al. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support*. Crit Care Med. 2011;39(5):1029\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CCM.0b013e31820ead45\u003c/span\u003e\u003cspan address=\"10.1097/CCM.0b013e31820ead45\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor\u0026ndash;Associated Myocarditis. J Am Coll Cardiol. 2021;77(12):1503\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2021.01.050\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2021.01.050\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeizman O, Eslami A, Bougouin W, et al. Sudden cardiac arrest in patients with cancer in the general population: insights from the Paris-SDEC registry. Heart Br Card Soc. 2024;110(16):1022\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/heartjnl-2024-324137\u003c/span\u003e\u003cspan address=\"10.1136/heartjnl-2024-324137\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardio-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"caon","sideBox":"Learn more about [Cardio-Oncology](http://cardiooncologyjournal.biomedcentral.com)","snPcode":"40959","submissionUrl":"https://submission.nature.com/new-submission/40959/3","title":"Cardio-Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"immune checkpoint inhibitors, myocarditis, cardiovascular toxicity, rechallenge, cardio-oncology","lastPublishedDoi":"10.21203/rs.3.rs-8689115/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8689115/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e Current European Society of cardiology guidelines recommend systematic troponin screening to detect potential cardiovascular (CV) immune-related adverse events (irAEs) in the increasing numbers of cancer patients receiving immune-checkpoint inhibitors (ICIs), increasing the number of patients referred and broadening the severity spectrum of CV irAEs. Management and outcomes in patients with suspected CV irAEs, are poorly defined. The safety of ICI rechallenge, particularly in patients fulfilling contemporary ICI-myocarditis diagnostic criteria, remains uncertain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eProspective single-centre cohort including consecutive adults referred for suspected CV irAEs. Objectives were to describe outcomes after initial assessment, identify predictors of mid-term CV events, and evaluate outcomes of ICI rechallenge in patients with and without initial CV irAEs.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 175 patients (median age 61 years [IQR 48\u0026ndash;72]; 77.1% women), 95 (54.3%) had adjudicated CV irAEs at referral, including 72 (41.1%) fulfilling diagnostic criteria for non-severe ICI-myocarditis. During 234\u0026thinsp;\u0026plusmn;\u0026thinsp;154 days of follow-up, 15 patients died (12 cancer-related, 1 CV, 2 other). Predictors of CV events included significant coronary stenosis (HR 4.77; 95% CI 1.39\u0026ndash;16.40; P\u0026thinsp;=\u0026thinsp;0.013), hospital admission (HR 13.21; 95% CI 2.51\u0026ndash;69.52; P\u0026thinsp;=\u0026thinsp;0.0023), ICI rechallenge (HR 9.30; 95% CI 1.77\u0026ndash;48.77; P\u0026thinsp;=\u0026thinsp;0.0084), and positive Lake Louise cardiac magnetic resonance (CMR) (HR 18.84; 95% CI 5.13\u0026ndash;69.20; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Eighty-four patients (48.0%) were rechallenged; 3 (3.6%) developed non-severe myocarditis, with no ICU admissions or CV deaths. Ten out of 53 (18.87%) patients without initial CV irAEs who continued ICIs developed CV events.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e \u003cp\u003eNCT05799898\u003c/p\u003e","manuscriptTitle":"Safety of Immune Checkpoint Inhibitor Rechallenge and Mid-Term Outcomes After Suspected Cardiovascular Immune-Related Adverse Events","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 09:56:51","doi":"10.21203/rs.3.rs-8689115/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-18T17:34:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-18T09:25:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209456177816449571453815178759164664537","date":"2026-05-18T01:58:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-13T11:24:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86278478253083409359815200758470613652","date":"2026-02-23T16:25:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279413437088195932290796984621564959156","date":"2026-02-18T19:39:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294099704164220997081525984989764155843","date":"2026-02-17T10:13:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-03T13:02:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-28T17:38:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-26T11:35:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardio-Oncology","date":"2026-01-24T21:02:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardio-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"caon","sideBox":"Learn more about [Cardio-Oncology](http://cardiooncologyjournal.biomedcentral.com)","snPcode":"40959","submissionUrl":"https://submission.nature.com/new-submission/40959/3","title":"Cardio-Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c4413ef6-30c7-4185-9b35-147868616834","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-18T17:34:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-18T09:25:34+00:00","index":49,"fulltext":""},{"type":"reviewerAgreed","content":"209456177816449571453815178759164664537","date":"2026-05-18T01:58:56+00:00","index":48,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T17:38:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 09:56:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8689115","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8689115","identity":"rs-8689115","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}