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BackgroundPigmentation could be a relevant prognostic factor in uveal melanoma (UM) development. Microphthalmia-associated transcription factor (MITF) regulates melanin synthesis by activating tyrosinase-related protein 2 (TYRP2) and silver protein (SILV) that induce the melanogenesis pathway. Although their oncogenic potential has been observed in various malignancies but has not been investigated in UM Asian population. Our aim is to study the ultrastructure of melanosomes and the prognostic significance of pigmentation markers such as TYRP2, MITF and SILV in UM.MethodsTransmission electron microscopy was performed to compare the ultrastructure of melanosomes in the normal choroid and UM cases. Immunoexpression of TYRP2, SILV and MITF was analysed in 82 UM samples. The mRNA expression level of all genes was measured in 70 UM cases. A statistical correlation was performed to determine the prognostic significance of all markers.ResultsPremelanosomes and mature melanosomes undergoing dedifferentiation were observed in high-pigmented UM cases as compared with low-pigmented UM cases. Seventy per cent of UM cases showed high SILV expression while TYRP2 and MITF expression was present in 58% and 56% of cases, respectively. At the mRNA level, upregulation of TYRP2, SILV and MITF markers was seen in around 50% of UM cases, which was statistically significant with high pigmentation. Reduced metastatic-free survival was statistically significant with the MITF protein expression.ConclusionOur results demonstrated that ultrastructural changes in melanosomes and high expression of TYRP2, MITF and SILV could dysregulate the melanogenesis pathway and might be responsible for the aggressive behaviour of UM.

Abstract Background Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone. Patients and Methods This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that after adding CLTs to tebentafusp upon progression (PFS1+PFS2). ctDNA responses were explored. Results Of the 30 eligible patients, 21 (70%) received concurrent LDT, 7 (23%) had extrahepatic irradiation, and 2 (7%) had both. The objective response rate (ORR) was 12% (95% CI, 3-32) for tebentafusp alone and 28% (95% CI, 14-47) after adding CLTs. The disease-control rate with tebentafusp alone was 44% (95% CI, 25-65) vs 63% (95% CI, 44-78) after CLT. Median PFS1 was 5.8 months (95% CI, 2.8-13.4), while median PFS1+PFS2 was 14.8 months (95% CI, 9.2-NA). CLT thereby allowed treatment beyond progression with tebentafusp for approximately 9 months. Two patients (66%) had decreased ctDNA with tebentafusp alone, while 4 (100%) had decreased ctDNA after CLT. There were no treatment discontinuations due to toxicities from tebentafusp with CLT. Conclusions CLT with tebentafusp was well-tolerated, extending the duration of tebentafusp benefit in a highly selected mUM population. This merits further studies to assess clinical utility.

T cells can be divided into two major subtypes based on which chains that make up the T cell receptor (TCR): the conventional αβ T cells and the less common γδ T cells. γδ T cells are attractive targets of cancer immunotherapy due to e.g. their independence from MHC-restricted activation. Despite the successful implementation of immune checkpoint inhibitors for the treatment of metastatic melanoma, not all patients respond favorably to the treatment. In this study we characterized γδ T cells in peripheral blood from patients with cutaneous and uveal melanoma, and from age-matched healthy controls, with ultrasensitive DNA sequencing (SiMSen-Seq) of the δ-chain and flow cytometry to facilitate the introduction of γδ T cell-based treatment strategies. As a general trend, the Vδ1 + subpopulation was found to be more abundant in patients labeled as responders versus non-responders. Regarding clonal diversity, although a high oligoclonality was found in each individual and within each group, clonal diversity was lower in patients labeled as responders to treatment. Cutaneous melanoma patients had a larger total number of clonotypes compared to the healthy controls, and did also express higher levels of the receptor NKG2D on the surface of Vδ2 + cells. Overall, we could see small differences between cutaneous and uveal melanoma patients and healthy controls in regard to distribution of γδ subpopulations, with high clonal diversities and a mostly private repertoire of the δ receptor among all groups.

Background/Aim: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a mean incidence of 5.1 cases per million people per year. At least 40% of uveal melanoma patients ultimately develop distant metastasis. But unlike cutaneous melanoma, targeted therapies and immune checkpoint blockers have shown limited effects. Investigating the metastasis-related pathogenesis mechanisms of uveal melanoma could facilitate the development of potential therapies.Materials and Methods: For this purpose, we integrated microarray gene expression data (GSE22138) and an independent TCGA dataset to identify derlin-1 (DERL1) as our candidate gene. In vitro cellular assays were conducted to examine DERL1’s role in the pathogenesis of uveal melanoma.Results: DERL1 up-regulation was identified in metastatic UM based on the microarray dataset, which was consistent with the TCGA dataset. However, the detailed mechanism has not yet been investigated. Therefore, we manipulated DERL1 expression with siRNA in a uveal melanoma cell line. After confirming the successful knockdown of DERL1, in vitro oncogenicity and chemosensitivity were assessed. Knockdown of DERL1 repressed cell proliferation and impaired cell migration and invasion. Furthermore, uveal melanoma cells with DERL1 knockdown had increased chemosensitivity to cisplatin and a decreased cancer stem cell potential determined by examining the intensity of CD133 and CD271.Conclusion: By analyzing GEO and TCGA datasets combined with in vitro cellular assays, DERL1 was found to be associated with metastasis in uveal melanoma and to be a possible target for further treatment.

Challenges persist in identifying patients with stage IV uveal melanoma. While clinical, histopathologic, and genetic features of the primary tumor have been shown to provide prognostic value for assessing metastatic risk, biopsy-related genetic analyses are expensive and not universally available. Therefore, this review will focus on clinical characteristics. Initial staging and follow-up screening protocols have evolved for patients with uveal melanoma. The Collaborative Ocular Melanoma Study (COMS) required a physical examination, chest X-ray, and hematologic survey (primarily liver function tests). Though these studies were found to have a high specificity, COMS investigators typically found late-stage metastases. More recently, protocols have concentrated on liver imaging (abdominal ultrasound, computed tomography, and magnetic resonance imaging). Though hepatic radiographic imaging has been found more likely to reveal earlier metastatic uveal melanoma, by definition it cannot detect most extrahepatic and multiorgan metastases. An international multicenter registry study recently focused on patients who were diagnosed with stage IV uveal melanoma simultaneously with their primary intraocular melanoma. Therein, utilizing center-specific diagnostic methods, stage IV was found to occur in about 2% of patients. However, subgroup analysis found that a disproportionate number of multi-organ metastases were discovered when whole-body positron emission tomography/computed tomography was used for staging. Herein, we review the literature on patients who present with stage IV uveal melanoma, how they were detected, and their outcomes.

Introduction: Historically, approximately 30–32% of uveal melanoma patients develop metastases and die within 5 years. Larger tumor dimensions and monosomy 3 and/or Class 2 gene expression profile of the tumor are associated with an increased risk of metastasis. We evaluated the performance of these prognostic markers in patients undergoing surveillance in a community medical oncology practice. Methods: Uveal melanoma patients treated by a single vitreoretinal surgical oncologist and monitored by a single medical oncologist were identified via a clinical database search for analysis. Specified prognostic markers were evaluated for sensitivity, specificity, positive and negative predictive value, as well as prognostic accuracy. Results: We identified 37 uveal melanoma patients, followed for a median of 4.0 ± 3.7 years. Twenty-seven (73%) patients underwent plaque brachytherapy with vitrectomy and silicone oil for radiation attenuation; seven (19%) patients underwent brachytherapy alone; three (8%) had enucleation. There were no intraocular treatment failures. Six (16.2%) patients developed metastasis, and only one patient died of metastatic disease. Disomy 3 and Class 1 accurately predicted a low risk for metastasis (>90% negative predictive value). However, monosomy 3 and Class 2 had a low positive predictive value and prognostic accuracy in “high-risk” patients. Conclusions: In this single-center cohort, we observed an unexpectedly low rate of 5-year metastasis. AJCC stage correlated poorly with metastasis or survival. Molecular prognostic results of Disomy 3 and Class 1 gene expression profile accurately predicted a “low” risk for metastasis (>90% negative predictive value). Further evaluation of these unique surgical techniques needs to be carried out.

Background Metastatic uveal melanoma (mUM) has a poor prognosis, with liver metastases typically presenting a therapeutic challenge. Melphalan/Hepatic Delivery System (Melphalan/HDS) is a drug/medical device combination used for liver-directed treatment of unresectable mUM patients. This study assessed efficacy and safety of Melphalan/HDS versus best alternative care (BAC). Methods Eligible patients with unresectable mUM were randomized (1:1) to receive Melphalan/HDS (3 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of 6 cycles or BAC. Due to slow enrollment and patient reluctance to receive BAC treatment, the study design was amended to a single-arm Melphalan/HDS study, and all efficacy analyses of the randomized study were treated as exploratory. Results The study enrolled 85 patients. Eligible patients were randomized to receive Melphalan/HDS ( n = 43) or BAC ( n = 42), and 72 patients received study treatment (Melphalan/HDS [ n = 40]; BAC [ n = 32]). Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the Melphalan/HDS arm versus BAC (median overall survival: 18.5 vs. 14.5 months; median progression-free survival: 9.1 vs. 3.3 months; objective response rate: 27.5% vs. 9.4%; and disease control rate: 80.0% vs. 46.9%). Serious adverse events (SAEs) occurred in 51.2% of Melphalan/HDS and in 21.9% of BAC patients. The most common (>5%) SAEs included thrombocytopenia (19.5%), neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in Melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed. Conclusion Treatment with Melphalan/HDS shows clinically meaningful efficacy and demonstrates a favorable benefit-risk profile in patients with unresectable mUM as compared to BAC.

Abstract Background Metastatic uveal melanoma (UM) primarily affects the liver, and due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for hepatic tumor control. Direct head-to-head trials comparing these LDTs are still lacking. Methods A retrospective multicenter explorative analysis was conducted to evaluate the clinical outcomes of transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT), and percutaneous hepatic perfusion (PHP, chemosaturation). Results The present analysis was conducted on a cohort of 121 patients who had been treated for metastatic UM with LDT at five different skin cancer centers. A total of n = 15 patients received TACE (12.4%), n = 51 SIRT (42.1%), and n = 55 PHP (45.5%). The estimated median overall survival (OS) for SIRT was 25.1 months (95% confidence interval [CI], 15.3-34.8), for TACE, 11.4 months (95% CI, 7.8-14.9), and for PHP, 24.9 months (95% CI, 13.7-36.0). In the multivariate analysis that included LDH and additional systemic therapies, there was no significant difference in OS between SIRT and PHP (HR 1.14, 95% CI 0.67-1.93, P = .63), whereas TACE was found to be associated with a substantially reduced in OS compared to PHP (HR 3.25, 95% CI 1.31-8.04, P = .01). Adverse events occurred in 41.6% of patients undergoing SIRT, 64.3% of patients receiving TACE, and 84.6% of patients receiving PHP. Conclusion The findings of this study indicate that SIRT and PHP demonstrate equivalent survival rates in a real-world setting.

Abstract Introduction Metastatic uveal melanoma (MUM) has a poor prognosis, but hepatic arterial infusion chemotherapy (HAIC) may improve outcomes in patients with hepatic metastases. To identify reliable prognostic factors for patient stratification and treatment allocation, we analyzed the clinical and imaging data from a large single-center cohort using machine learning (ML) models. Methods Pre– and post–first treatment clinical data of 235 patients with MUM treated with HAIC between 2009 and 2019 were retrospectively analyzed using Cox regression to identify prognostic factors for overall survival (OS) and time to change treatment strategy (TTCS). Furthermore, ML models were trained on clinical and computed tomography (CT) data for endpoint prediction. Results Pre-treatment multi-variate analysis identified elevated lactate dehydrogenase (LDH) (OS: 6.5 vs. 16.4 months, hazard ratio [HR]) = 1.87, P = 0.006) and gamma-glutamyl transpeptidase (GGT) (OS: 7.6 vs. 16.4 months, HR = 1.67, P = 0.012) as prognostic factors for inferior OS. Decreased albumin (TTCS: 1.3 vs. 6.1 months, HR = 6.26, P < 0.001) and elevated LDH (TTCS: 2.9 vs. 7.6 months, HR = 1.72, P = 0.011) and alanine aminotransferase (ALT) (TTCS: 3.7 vs. 6.4 months, HR = 1.65, P = 0.004) predicted shorter TTCS. Scoring enhanced the power of the prognosticators for OS and TTCS. Post–first treatment multi-variate analysis emphasized the importance of inflammation management and liver protection. ML models incorporating radiomics features from baseline CT imaging were not superior to models based on pre-treatment clinical data alone. Conclusion We identified independent but synergistic prognostic factors for outcome stratification to guide treatment decisions and optimize patient management. ML-based radiomics features did not significantly enhance prognostic performance.

Purpos. To present promising research in the treatment of patients with metastatic uveal melanoma. Material and methods. The literature review included published full-text articles, as well as abstracts and thesis on the results of clinical trials that were presented at major oncological congresses (ESMO and ASCO) for the period from 2023 to 2025. Results. This review presents options for available drug alternatives for patients with metastatic uveal melanoma, indicating efficiency data. The results of clinical studies on the use of potentially new targeted and immunological molecules and combinations of treatment methods presented at international oncological congresses are described in detail. Conclusion. New research makes it possible to expect a change in the fatal prognosis in the treatment of metastatic uveal melanoma.