Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival.

INTRODUCTION: Sarcoid-like reactions (SLRs) to immune checkpoint inhibitors (ICIs) are a rare but increasingly recognized immune-related adverse event of which the clinical significance is unclear. METHODS: We conducted a retrospective cohort study at a tertiary academic center of consecutive patients who received at least one dose of ICI from 2013 to 2020. Patient characteristics, risk factors, and outcomes were compared between patients with and without SLR following ICI treatment. RESULTS: A total of 2963 cancer patients received at least 1 dose of ICI between 2013 and 2020, and 7 patients (0.24 %) developed SLR. There were no significant demographic differences between patients with and without SLR following ICI. SLRs occurred in 5 of 451 (1.07 %) melanoma patients and 2 of 840 (0.24 %) non-small cell lung cancer patients. Two of the 7 patients had multi-organ SLR, and both were symptomatic requiring systemic corticosteroids and permanent ICI discontinuation, while single organ SLR patients did not require immune suppression. Development of SLR did not appear to have negative impact on cancer progression or overall survival; in fact, a trend towards improved progression-free and overall survival was observed (median time: 1363 days vs 127 days, p = 0.091; 1387 days vs 428.5 days, p = 0.19, respectively). CONCLUSIONS: SLRs are a known but understudied complication associated with ICI therapy. Multisystem SLR patients were more symptomatic and required ICI discontinuation and immune suppression. Larger studies are needed to fully evaluate the impact of SLR on cancer outcomes.

Mitochondrial mechanisms of sepsis-induced organ failure.

Sepsis is the leading cause of death in medical intensive care units. Though progress has been made in the early treatment of sepsis associated with hemodynamic collapse (septic shock), little is known about the pathogenesis of delayed organ dysfunction during sepsis. A growing body of data indicates that sepsis is associated with acute changes in cell metabolism, and that mitochondria are particularly susceptible. The severity of mitochondrial pathology varies according to host and pathogen factors, and appears to correlate with loss of organ dysfunction. In this regard, low levels of cell apoptosis and mitochondrial turnover are normally observed in all metabolically active tissues; however, these homeostatic mechanisms are frequently overwhelmed during sepsis and contribute to cell and tissue pathology. Thus, a better understanding of the mechanisms regulating mitochondrial damage and repair during severe sepsis may provide new treatment options and better outcomes for this deadly disease (30-60% mortality). Herein, we present compelling evidence linking mitochondrial apoptosis pathways to sepsis-induced cell and organ failure and discuss the implications in terms of future sepsis research.

New advances in the development of sarcoidosis models: a synopsis of a symposium sponsored by the Foundation for Sarcoidosis Research.

Sarcoidosis is a complex disease with variable phenotypes that will require a multisystem approach to understand pathophysiology. One of the most challenging problems in sarcoidosis research is the absence of valid and widely accepted experimental models that accurately simulate human disease. The Foundation of Sarcoidosis Research (FSR) has funded five projects for the development of novel experimental models for sarcoidosis, presented and discussed in a workshop organized during the European Respiratory Society Congress held in Milan from September 9th to 13th. The experimental, in vivo or in sillico models presented may be quite helpful for investigating specific pathogenic and therapeutic questions, addressing especially severe forms of sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 2-4).

Transformation of pulmonary histoplasmosis to sarcoidosis: a case report.

Histoplasmosis, a dimorphic fungus, and sarcoidosis, a disease of unknown etiology, share many clinical features, including typical manifestations of granulomatous inflammation involving the lungs and mediastinal lymphatics in association with constitutional symptoms. As such, they are often difficult to distinguish based upon clinical presentation. Recent studies suggest that sarcoidosis may be triggered by infectious agents. Here we present a case of documented pulmonary histoplasmosis that evolved into sarcoidosis. This case supports the notion that infections promote sarcoidosis in predisposed hosts.

Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis.

BACKGROUND: Sepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways are associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. This study was designed to develop a new model to investigate the early events of cardiac damage during sepsis progression. METHODS AND RESULTS: Francisella tularensis subspecies novicida (Ft.n) is a Gram-negative intracellular pathogen causing severe sepsis syndrome in mice. BALB/c mice (N=12) were sham treated or infected with Ft.n through the intranasal route. Serial electrocardiograms were recorded at multiple time points until 96 hours. Hearts were then harvested for histology and gene expression studies. Similar to septic patients, we illustrate both cardiac electrical and structural phenotypes in our murine Ft.n infection model, including prominent R' wave formation, prolonged QRS intervals, and significant left ventricular dysfunction. Notably, in infected animals, we detected numerous microlesions in the myocardium, previously observed following nosocomial Streptococcus infection and in sepsis patients. We show that Ft.n-mediated microlesions are attributed to cardiomyocyte apoptosis, increased immune cell infiltration, and expression of inflammatory mediators (tumor necrosis factor, interleukin [IL]-1ß, IL-8, and superoxide dismutase 2). Finally, we identify increased expression of microRNA-155 and rapid degradation of heat shock factor 1 following cardiac Ft.n infection as a primary cause of myocardial inflammation and apoptosis. CONCLUSIONS: We have developed and characterized an Ft.n infection model to understand the pathogenesis of cardiac dysregulation in sepsis. Our findings illustrate novel in vivo phenotypes underlying cardiac dysfunction during Ft.n infection with significant translational impact on our understanding of sepsis pathophysiology.