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Uveal melanomas (UMs) comprise the most common primary intraocular malignancies in adults, with the eye representing the second most common site for melanoma, following the skin. Prognosis remains poor, with approximately half of the cases presenting with metastatic disease at the time of diagnosis. Erythropoietin-producing human hepatocellular receptors (EPHs) comprise the largest known family of tyrosine receptors, in which, along with their ligands, ephrins, play an important role in a plethora of processes in human physiology, and are implicated in key steps of carcinogenesis. In the present study, EPHA2, EPHA4, and EPHA6 immunohistochemical expressions were investigated in UM tissues and further correlated to a multitude of clinicopathological parameters, including disease stage and patients' overall survival (OS). High levels of EPHA2 expression were significantly associated with increased tumor vertical thickness (p = 0.03) and the presence of intrascleral involvement (p = 0.05), whereas high EPHA6 nuclear expression was associated with older age at diagnosis (p = 0.03) and absence of retinal detachment (p = 0.05). In a multivariate survival analysis, increased EPHA4 expression was associated with shortened OS along with the presence of metastasis (p < 0.001) and monosomy 3 (p = 0.02). In a separate model, the concurrent overexpression of at least two of the investigated EPHs (HR = 14.7, p = 0.03) also proved to be an independent poor prognostic factor. In conclusion, our results implicate these specific members of the EPHA group as potential biomarkers for disease prognosis as well as possible targets for the development of novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Histone Deacetylases (HDACs) have been reportedly associated with tumor development and progression in several types of human malignancy, being currently investigated as potential targets of anti-cancer therapy. The aim of this study is to assess the clinical significance and prognostic role of the of HDAC-1, -2, -4, and -6 immunohistochemical expression, in 75 uveal melanoma (UM) cases. HDACs are differentially expressed in UMs, HDAC-2 being the most frequently expressed isoform, whereas cytoplasmic expression of class I HDAC isoforms is also observed. Additionally, HDAC-1 was associated with increased tumor size, HDAC-6 with mitotic index, and HDAC-2 with epithelioid cell morphology and presence of tumor-infiltrating lymphocytes, both parameters of adverse prognosis. Moreover, our data support a significant association of HDAC-2 with patients' improved OS. These findings suggest that HDACs, and especially HDAC-2, may be implicated in the formation and progression of UM. Background: Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults, exerting high metastatic potential and poor prognosis. Histone deacetylases (HDACs) play a key role in carcinogenesis, and HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical settings. The aim of this study was to evaluate the clinical significance of HDAC-1, -2, -4, and -6 expression in UM. Methods: HDAC-1, -2, -4, and -6 expression was examined immunohistochemically in 75 UM tissue specimens and was correlated with tumors' clinicopathological characteristics, the presence of tumor-infiltrating lymphocytes (TILS), as well as with our patients' overall survival (OS). Results: HDAC-2 was the most frequently expressed isoform (66%), whereas we confirmed in addition to the expected nuclear expression the presence of cytoplasmic expression of class I HDAC isoforms, namely HDAC-1 (33%) and HDAC-2 (9.5%). HDAC-4 and -6 expression was cytoplasmic. HDAC-1 nuclear expression was associated with increased tumor size (p = 0.03), HDAC-6 with higher mitotic index (p = 0.03), and nuclear HDAC-2 with epithelioid cell morphology (p = 0.03) and presence of tumor-infiltrating lymphocytes (p = 0.04). The association with the remaining parameters including Monosomy 3 was not significant. Moreover, the presence as well as the nuclear expression pattern of HDAC-2 were correlated with patients' improved OS and remained significant in multivariate survival analysis. Conclusions: These findings provide evidence for a potential role of HDACs and especially HDAC-2 in the biological mechanisms governing UM evolution and progression. [ABSTRACT FROM AUTHOR]

Simple Summary: The following study provides an overview of the English-language literature on the search for new prognostic factors for uveal melanoma. Uveal melanoma is the most common primary intraocular tumor in adults, and although it is a relatively rare disease, it poses a significant health problem. About half of the patients develop distant metastases, and unfortunately there are currently no effective treatments for the disease at such an advanced stage. The search for new prognostic factors is important to understand the biology of the disease and to be able to monitor patients more effectively. At the same time, it creates an opportunity to find new therapeutic targets. We focused our attention on immunohistochemical research because it is a widely used method, relatively cheap, technically simple, and gives reproducible results. The analysis of this study will enable other researchers to verify their research plans and may also be a source of inspiration for creating new ones. Uveal melanoma is the most common primary intraocular neoplasm in adults. As there are currently no effective methods of treating the disease in the metastatic stage, there is a need to search for new prognostic factors that would enable a reliable assessment of the patient's condition and constitute a possible therapeutic target. In this review, we have prepared the results of English-language studies on new prognostic factors determined with immunohistochemical methods. We found 64 articles in which the expression of various proteins was associated in a statistically significant manner with the histopathological and clinical prognostic factors identified by AJCC. The results of our work clearly show that the biology of uveal melanoma is extraordinarily complex. Numerous studies have shed new light on the complexity of the processes involved in the development of this cancer. Moreover, a careful analysis of the expression of individual proteins may allow the identification of homogeneous groups of patients requiring different treatment regimens. [ABSTRACT FROM AUTHOR]