The Phenotypical Characterization of Dual-Nature Hybrid Cells in Uveal Melanoma.

BACKGROUND: Metastasis, occurring years after primary diagnosis, represents a poor prognosis in uveal melanoma (UM)-affected individuals. The nature of cells involved in this process is under debate. Circulating hybrid cells that have combined tumor and immune cell features found in blood were predictive of metastasis and may correspond to dual-nature cells (DNC) in the primary tumor. Herein, we sought to determine the presence of DNCs in primary UM tumors, the cell types involved in their genesis, and their ability to be formed in vitro. METHODS: UM lesions (n = 38) were immunolabeled with HMB45 in combination with immune-cell-specific antibodies. In parallel, we co-cultured UM cells and peripheral blood mononuclear cells (PBMCs) to analyze DNC formation. RESULTS: HMB45+/CD45+ DNCs were present in 90% (26/29) of the tumors, HMB45+/CD8+ DNCs were present in 93% (26/28), and HMB45+/CD68+ DNCs were present in 71% (17/24). DNCs formed with CD8+ and CD68+ cells were positively correlated to the infiltration of their respective immune cells. Notably, UM cells were prone to hybridize with PBMCs in vitro. CONCLUSIONS: This phenotypical characterization of DNCs in UM demonstrates that CD8+ T-cells and macrophages are capable of DNC formation, and they are important for better understanding metastatic dissemination, thus paving the path towards novel therapeutic avenues.

Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives.

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Recent advances highlight the role of tumor-derived extracellular vesicles (TEV) and circulating hybrid cells (CHC) in UM tumorigenesis. Bridged with liquid biopsies, a novel technology that has shown incredible performance in detecting cancer cells or products derived from tumors in bodily fluids, it can significantly impact disease management and outcome. The aim of this comprehensive literature review is to provide a summary of current knowledge and ongoing advances in posterior UM pathophysiology, diagnosis, and treatment. The first section of the manuscript discusses the complex and intricate role of TEVs and CHCs. The second part of this review delves into the epidemiology, etiology and risk factors, clinical presentation, and prognosis of UM. Third, current diagnostic methods, ensued by novel diagnostic tools for the early detection of UM, such as liquid biopsies and artificial intelligence-based technologies, are of paramount importance in this review. The fundamental principles, limits, and challenges associated with these diagnostic tools, as well as their potential as a tracker for disease progression, are discussed. Finally, a summary of current treatment modalities is provided, followed by an overview of ongoing preclinical and clinical research studies to provide further insights on potential biomolecular pathway alterations and therapeutic targets for the management of UM. This review is thus an important resource for all healthcare professionals, clinicians, and researchers working in the field of ocular oncology.

Comprehensive clinical imaging, histopathological analysis and liquid biopsy-based surveillance of human uveal melanoma in a prolonged rabbit xenograft model.

Uveal melanoma is the most common intraocular tumor in adults. Our group has previously developed a human uveal melanoma animal model; however, adverse effects caused by the immunosuppressive agent, cyclosporine A, prevented animals from surviving more than 12 weeks. In this study, we tested multiple cyclosporine A doses over an extended disease course up to 20 weeks, providing complete clinical imaging of intraocular tumors, histopathological analysis and liquid biopsy biomarker analysis. Twenty albino rabbits were divided into four groups with different daily cyclosporine A schedules (0-10 mg/kg) and inoculated with human uveal melanoma cell lines, 92.1 or MP41, into the suprachoroidal space. Rabbits were monitored with fundoscopy, ultrasound and optical coherence tomography. Intraocular tumors (macroscopic or microscopic) were detected in all study animals. Tumor size and growth were correlated to cyclosporine A dose, with tumors regressing when cyclosporine A was arrested. All tumors expressed HMB-45 and MelanA; however, tumor size, pigmentation and cell morphology differed in 92.1 vs. MP41 tumors. Finally, across all groups, circulating tumor DNA from plasma and aqueous humor was detected earlier than tumor detection by imaging and correlated to tumor growth. In conclusion, using three clinically relevant imaging modalities (fundoscopy, ultrasonography and optical coherence tomography) and liquid biopsy, we were successfully able to monitor tumor progression in our rabbit xenograft model of human uveal melanoma.

The impact of music, play, and pet therapies in managing pain and anxiety in paediatric patients in hospital: a rapid systematic review.

Background: Hospitalized children face pain and anxiety associated with the environment and procedures. Objective: This review aimed to assess the impact of music, play, pet and art therapies on pain and anxiety in hospitalized paediatric patients. RCTs assessing the impact of music, play, pet, and/or art therapies on pain and/or anxiety in hospitalized paediatric patients were eligible. Methods: Database searching and citation screening was completed to identify studies. A narrative synthesis was used to summarize study findings and certainty of evidence was assessed using GRADE. Of the 761 documents identified, 29 were included spanning music (n = 15), play (n = 12), and pet (n = 3) therapies. Results: A high certainty of evidence supported play in reducing pain and moderate certainty for music and pet. A moderate certainty of evidence supported music and play in reducing anxiety. Conclusion: Complementary therapies utilized alongside conventional medical treatment may mitigate pain and anxiety in hospitalized paediatric patients.