OBJECTIVE: The objective of this study was to assess the role of iodine (125I) plaque brachytherapy in the management of uveal melanoma.
METHODS: This is a retrospective study of 50 patients (median age 67 years; range=33-86 years) with uveal melanoma, treated with 125I plaque brachytherapy at the University Hospital of Pisa. Uveal melanoma was diagnosed with A-scan and B-scan standardized echography, fluorescein angiography, indocyanine green-angiography, optical coherence tomography, and/or magnetic resonance imaging. The primary outcomes assessed were local control, overall survival, disease progression, globe preservation, and metastases. Secondary outcomes were acute and late radiation adverse effects.
RESULTS: Inclusion criteria comprised Eastern Cooperative Oncology Group performance status ≤2, life expectancy >6 months, and tumor thickness ≤10 mm and\\or diameter ≤20 mm. All the patients were treated with 125I plaque brachytherapy, with a prescription dose of 85 Gy to the tumor apex. The 5-year rate of local control, progression-free survival, metastasis-free survival, enucleation-free survival, and overall survival were 83.0%, 81.4%, 90.3%, 83.1%, and 92.1% respectively. Twenty-four patients (48.0%) had one or more acute and late toxicities. The most common acute adverse events (CTCAE vs. 5.0) grade 1-3 were conjunctivitis and eye pain (6.0%). Regarding late events, radiation retinopathy grade 1-3 occurred in 18.0% of cases, while grade 1-3 vitreous hemorrhage in 2.5%.
CONCLUSIONS: 125I plaque brachytherapy offers an effective and safe approach for selected cases of uveal melanoma, due to the reported satisfactory results in terms of local control, eye conservation and survival.

Uveal melanoma (UM), a distinct subtype of melanoma, presents unique challenges in its clinical management due to its complex molecular landscape and tendency for liver metastasis. This review highlights recent advancements in understanding the molecular pathogenesis, genetic alterations, and immune microenvironment of UM, with a focus on pivotal genes, such as GNAQ/11, BAP1, and CYSLTR2, and delves into the distinctive genetic and chromosomal classifications of UM, emphasizing the role of mutations and chromosomal rearrangements in disease progression and metastatic risk. Novel diagnostic biomarkers, including circulating tumor cells, DNA and extracellular vesicles, are discussed, offering potential non-invasive approaches for early detection and monitoring. It also explores emerging prognostic markers and their implications for patient stratification and personalized treatment strategies. Therapeutic approaches, including histone deacetylase inhibitors, MAPK pathway inhibitors, and emerging trends and concepts like CAR T-cell therapy, are evaluated for their efficacy in UM treatment. This review identifies challenges in UM research, such as the limited treatment options for metastatic UM and the need for improved prognostic tools, and suggests future directions, including the discovery of novel therapeutic targets, immunotherapeutic strategies, and advanced drug delivery systems. The review concludes by emphasizing the importance of continued research and innovation in addressing the unique challenges of UM to improve patient outcomes and develop more effective treatment strategies.

UNASSIGNED: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable.
UNASSIGNED: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57).
UNASSIGNED: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively).
UNASSIGNED: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.

The identification of novel non-invasive biomarkers is imperative for the early diagnosis and monitoring of malignant melanoma. The objective of this study is to examine the expression levels of miR-155-5p, miR-181b-5p, and miR-454-3p in circulating cell-free RNA obtained from plasma samples of the 72 uveal malignant melanoma patients and to compare these levels with those of 72 healthy controls. The analysis showed that the expression level of the miR-181b-5p has increased 9.25 fold, and expression level of miR-155-5p has increased 6.67 fold, and miR-454-3p expression level has increased 4.14 fold in the patient group compared with the levels in the healthy control group (p = 0.005). It was found that the high expression levels of the three miRNAs were statistically significant in patients compared with in the healthy control group. The statistical evaluations between miRNA expression levels and clinical data showed that miR-155-5p had significant association with radiation therapy (p = 0.040), and miR-454-3p showed a significant association with smoking and alcohol use respectively (p = 0.009, and p = 0.026). The significantly elevated expression levels of miR-181b-5p, miR-155-5p, and miR-454-3p in the circulating cell-free RNA of plasma from uveal melanoma patients, in comparison to those in the healthy control group, suggest the potential usefulness of these biomarkers for both early diagnosis and disease monitoring. However, more extensive and future studies are needed to use these molecules in early diagnosis and disease monitoring.

OBJECTIVE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients.
METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms.
RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin\'s lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies.
CONCLUSIONS: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.

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UNASSIGNED: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized.
UNASSIGNED: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome.
UNASSIGNED: BAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1, BRAF V600 and NRAS Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating BAP1 mutations.
UNASSIGNED: In contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.

(1) Background: to analyze the impact of the COVID-19 pandemic on the characteristics and management of uveal melanoma (UM) in the National Referral Center in Poland. (2) Materials and Methods: the retrospective analysis of 1336 patients who were newly diagnosed with UM at the Department of Ophthalmology and Ophthalmic Oncology, Jagiellonian University Collegium Medicum Krakow, Poland between 1 January 2018 and 31 December 2021. The demographic and clinical data were compiled, including localization, size, and treatment methods of tumors. (3) Results: In total, 728 patients with UM were included before the COVID-19 pandemic, in the years 2018-2019, and 608 were included during the COVID-19 pandemic, in the years 2020-2021. Fixed-base dynamics indicators for the incidence of uveal melanoma (base year 2018) in the National Referral Center in Poland were 80.22% and 86.81% in the years 2020 and 2021, respectively. UMs were statistically significantly larger and more frequently localized anterior to the equator of the eye globe in the year 2021 than in the year 2018 (Chi-square Pearson test p = 0.0001 and p = 0.0077, respectively). The rate of patients treated with enucleation increased from 15.94% in the year 2018 to 26.90% in the year 2021 (Chi-square Pearson test p = 0.0005). (4) Conclusions: Statistically significant differences were found in the management of uveal melanoma in the National Referral Center in Poland during the COVID-19 pandemic with tumors being larger, more frequently localized anterior to the equator of the eye globe, and more often enucleated.

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma.

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM.