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

Patent foramen ovale (PFO) concerns nearly a quarter of the general population and incidence may reach up to 50% in patients with cryptogenic stroke. Recent randomized clinical trials confirmed that percutaneous closure of PFO-related stroke reduces the risk of embolic event recurrence. PFO also comes into play in other pathogenic conditions, such as migraine, decompression sickness or platypnea–orthodeoxia syndrome, where the heterogeneity of patients is high and evidence for closure is less well-documented. In this review, we describe the current indications for PFO percutaneous closure and the remaining challenges, and try to provide future directions regarding the technique and its indications.

Definitions used for adjudication and grading of the different evaluated events

Diagnostic work-up for suspected ICI-myocarditis and evaluation of severity criteria

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

Effect of plasmapheresis on ICI circulating levels in the 10 patients receiving plasmapheresis in our cohort.