## 4 Discussion  
The search for novel potential reliable prognostic factors is one of the most significant objectives of cancer research in the field of UM, as it allows a stratification of patients into two large groups: those with higher risk and those with lower risk of developing distant metastases [10; 29]. The absence of standardized guidelines on the exact times after which control tests should be performed and the type of tests that should be done during follow-up time makes this topic of extreme practical significance. The potential identification of a high-risk group of patients could allow the performance of more frequent controls in order to earlier diagnose cases with liver metastases that could be safely surgically excised [30]. Accordingly, in the last decade our research group reported some novel potential immunohistochemical factors with prognostic impact [5; 31; 32; 33; 34; 35], which may be included into the list of the classically reported markers of UM, such as tumor location, tumor size, extraocular invasion, cell type, pathological T stage and immunohistochemical staining with BAP1 [14]. Recently, [PERSON] et al. identified a ten-gene signature (SIRT3, HMCES, SLC44A3, TCTN1, STPG1, POMGNT2, RNF208, ANXA2P2, ULBP1 and CA12), able to better stratify the outcome of UM patients [36]; in detail, ANXA2P2, ULBP1, CA12 had a poor prognostic role, while the other genes a positive one. It has been also hypothesized that conventional and alternative splicing events were correlated to the overall survival of patients with cutaneous and uveal melanoma [37]. In this regard, [PERSON] et al. found recurrent mutations of the splicing factor SF3B1 in 3/12 cases from their cohort and in 15/105 cases from an extension cohort [38]; these authors demonstrated that SF3B1 mutations were linked to differential alternative splicing of ABCC5 and UQCC genes and correlated to better outcome and lower rate of BAP1 mutations in UM [38].  
SRSF1 is an RNA-binding protein with proto-oncogenic function, being involved in angiogenesis, cell migration and tumor proliferation of several types of human neoplasms, including gliomas, malignant mesotheliomas, and breast, colorectal and prostate cancers [18; 20; 21; 22; 23; 24; 25]. SRSF1 immunoassay was positively associated with worse outcome, androgen-receptor status and Ki-67 proliferation rate in prostatic adenocarcinoma [27]; a significant correlation between SRSF1, MVD and shorter overall survival times was also found in fluoro-edenite-induced malignant mesothelioma [26]. In the present paper we provided the first immunohistochemical evidence of the poor prognostic role of this protein in UM; in more detail, we found a statistically significant correlation between higher SRSF1 immunohistochemical expression, higher MVD levels and poorer prognosis in terms of metastatic spread and lower metastasis-free-survival in UM. Regarding the relationship between SRSF1 and MVD, previous studies demonstrated that SRSF1 had a stimulatory function on tumor angiogenesis, resulting in a switch in the pro-angiogenic/anti-angiogenic ratio of VEGFA [17; 18; 19; 20; 21]; in this regard, [PERSON] et al. first reported the complex relationship between circSMARC45, a specific subtype of circRNAs with a tumor-suppressor role, and SRSF1, demonstrating that the downregulation of circSMARC45 along with the concomitant upregulation of SRSF1 led to increased cell migration and angiogenesis in human glioblastoma tissue and cell lines [17; 18; 19]. The MVD count, despite not representing the best method to evaluate tumor angiogenesis, is a semi-quantitative \"surrogate\" of this process [27]; accordingly, the positive correlation found in our cohort between SRSF1 and MVD led us to hypothesize that SRSF1 has a pro-angiogenic role also in UM.