Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3CD8 cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68 macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68HLA-DR) macrophages than nonactivated (CD68HLA-DR) macrophages ( < 0.0001). CTLs were further in proximity from proliferating SOX10 melanoma cells than nonproliferating ones ( < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma ( = 0.0038 and = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor ( = 0.0147 and = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR CTLs ( = 0.0005). CTL distance to HLA-DR macrophages associated with poor DSS ( = 0.0016), whereas distance to Ki67 tumor cells associated inversely with DSS ( = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis ( = 0.009) and merits further development as a biomarker for clinical application. .
Atopic dermatitis (AD) is a common disease of childhood, and some patients experience a prolonged clinical course into adolescence and adulthood. Systemic management is required when AD is not adequately controlled with topical medications. Our aim is to provide a comprehensive review of commonly used systemic immunomodulating agents in childhood and adult AD, including cyclosporine A (CsA), azathioprine (AZA), methotrexate (MTX) and mycophenolate mofetil (MMF), which are prescribed off-label in the United States, as well as dupilumab, an FDA-approved biologic. We will also provide a brief overview of emerging systemic therapies currently under investigation.
Atopic dermatitis (AD) is a common disease of childhood, and infantile AD may manifest from birth to 2 years. Guidelines for the management of infantile AD are lacking, and our aim is to provide a comprehensive review of best practices and possible interventions. We will focus on topical therapy, since the use of systemic immunomodulating agents in infantile AD is rarely advised. Topical agents include emollients, topical corticosteroids (TCS), topical calcineurin inhibitors (TCIs), and phosphodiesterase 4 (PDE-4) inhibitors. We will also provide a brief overview of promising emerging therapies currently under investigation in the pediatric population.
Disclosure of Potential Conflicts of Interest: K Busam has received minor royalties from editing a textbook with Elsevier. SB Gruber is the Co-Founder of Brogent International LLC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.