Immune-related adverse events in a nationwide cohort of real-world melanoma patients treated with adjuvant anti-PD1 - Seasonal variation and association with outcome.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) carry the risk of immune-related adverse events (irAEs), a significant concern as therapy has transitioned to the adjuvant setting. Balancing therapeutic benefits against potential risks is crucial, necessitating real-world data from an unselected patient population in addition to clinical trial data to ensure optimal clinical decision-making. METHODS: This nationwide real-world study assessed irAEs in patients receiving adjuvant anti-PD1 therapy, primarily nivolumab, for resected stage III-IV melanoma between 2018-2022. Data were retrieved from two national databases: the IMMUNOTOX database and the Danish Metastatic Melanoma Database (DAMMED). IrAEs were sub-grouped according to organ systems graded using CTCAE ver. 5.0 ranging from mild toxicities (grade 1-2) to severe (grade 3-4) and fatal (grade 5). RESULTS: Among 792 included patients, (55 % male, median age 62 years (range 16-88)), 697 patients (88 %) experienced an irAE. Severe irAEs occurred in 116 patients (15 %) and five (0.6 %) died due to toxicity. A landmark analysis showed that patients who experienced at least one irAE before the 1st evaluation at 90 days had an increased progression free survival (PFS) (p = 0.032) and overall survival (OS) (p = 0.0071). Additionally, a seasonal pattern was noted with higher incidence of irAEs during summer. CONCLUSION: The prevalence of irAEs in real-world patients is comparable to the observed risk in clinical trials. Patients experiencing irAEs demonstrate a lower risk of melanoma relapse. Further, gender, age and seasonal variation may impact the incidence of irAEs.

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma.

BACKGROUND: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. METHODS: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). RESULTS: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. CONCLUSION: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up.

BACKGROUND: According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease. OBJECTIVES: The purpose of this study was to investigate the prevalence and incidence, and to identify predictors of developing familial dilated cardiomyopathy (FDC) in relatives participating in family screening. METHODS: The study was a retrospective, longitudinal cohort study of families screened and followed from 2006 to 2020 at a regional assembly of clinics for inherited cardiomyopathies. RESULTS: In total, 211 families (563 relatives, 50% women) were included. At baseline, 124 relatives (22%) were diagnosed with FDC. Genetic sequencing identified the etiology in 37% of screened families and classified 101 (18%) relatives as unaffected carriers (n = 43) or noncarriers (ie, not at risk of FDC [n = 58]). The combined clinical and genetic baseline yield was 30%. During follow-up (2,313 person-years, median 5.0 years), 45 developed FDC (incidence rate of 2.0% per person-year; 95% CI: 1.4%-2.8%), increasing the overall yield to 34%. The incidence rate of FDC was high in relatives with baseline abnormalities on electrocardiogram or echocardiography compared with relatives with normal findings (4.7% vs 0.4% per person-year; HR: 12.9; P < 0.001). In total, baseline screening identified 326 (58%) relatives to be at low risk of FDC. CONCLUSIONS: Family screening identified a genetic predisposition to or overt FDC in 1 of 3 relatives at baseline. Genetic and clinical screening was normal in more than half of relatives, and these relatives had a low risk of developing FDC during follow-up. Thus, baseline screening identified a large proportion, in whom follow-up may safely be reduced, allowing focused follow-up of relatives at risk.

Prevention of sudden cardiac death in hypertrophic cardiomyopathy: Risk assessment using left atrial diameter predicted from left atrial volume.

BACKGROUND: Left atrial diameter (LAd) is included in the European Society for Cardiology's (ESC) risk model for assessment of sudden cardiac death (SCD) risk in hypertrophic cardiomyopathy (HCM), but the recommended measure of LA size is left atrial volume (LAv). HYPOTHESIS: We hypothesized that LAv could be used instead of LAd in the HCM risk-SCD model. We aimed to determine the relation between LAd and LAv and to assess the impact of using LAv instead of LAd. METHODS: Echocardiographic measurements of anteroposterior LAd in the parasternal long-axis window and LAv from Simpson's biplane method of disks were used. The 5-year risk of SCD by measured LAd and by LAd predicted from LAv were estimated using the ESC risk-SCD model. RESULTS: In 205 HCM patients (age 56 ± 14 years, 62% male), the relation between LAd and LAv was linear. Median 5-year risk of SCD was 2.4% (interquartile range [IQR]: 1.6; 3.8) using measured LAd and 2.4% (IQR: 1.6; 3.7) using predicted LAd. The correlation between the SCD risk assessed by measured vs predicted LAd was excellent (r2 = 0.96). Use of predicted LAd resulted in four patients (2%) being recategorized between the moderate and high-risk categories. CONCLUSIONS: The relation between LAd and LAv was linear with good agreement. On a population level, the correlation between the risk of SCD using measured LAd or LAd predicted from LAv was excellent. On a patient level, using LAd predicted from LAv resulted in the vast majority remaining in the same risk category; however, for a minority of patients, it changed the recommendation.

Screening relatives in arrhythmogenic right ventricular cardiomyopathy: yield of imaging and electrical investigations.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease and presymptomatic screening of relatives is recommended. In 2010, the Task Force Criteria (TFC2010) introduced specific diagnostic imaging parameters. The aim of the study was to evaluate the diagnostic yield of family screening and the value of different diagnostic modalities. METHODS AND RESULTS: Family evaluation, including cardiac magnetic resonance (CMR), is routinely offered to ARVC relatives at our institution. We retrospectively registered baseline characteristics, symptomatology, and results of non-invasive examinations from 2010 to 2016 and assessed the findings according to TFC2010. A total of 286 relatives (150 females; age 12-76 years; 251 first-degree) were included. A total of 103 (36%) individuals reported cardiovascular symptoms. The non-invasive workup showed that 101 (35%) relatives had ≥1 positive parameter on signal-averaged electrocardiogram (ECG), 40 (14%) had abnormal findings on Holter monitoring, 36 (13%) fulfilled an ECG criterion, six (2%) fulfilled CMR criteria, and echocardiographic abnormalities was seen in one (0.3%) relative. In total, 21 (7% overall; 13% among gene-positive subgroup) relatives were diagnosed with ARVC and 78 (27% overall; 49% among gene-positive subgroup) with borderline ARVC based on the combined non-invasive evaluations. Family history and electrical investigations alone diagnosed 20 out of 21 (95%) ARVC cases and 73 out of 78 (94%) borderline cases. CONCLUSION: Consecutive evaluation of ARVC relatives diagnosed 7% with definite and 27% with borderline ARVC according to the TFC2010. Screening relatives for electrical abnormalities with 12 lead ECG, signal-averaged ECG, and Holter monitoring was more sensitive than imaging modalities.