ADAM10 promotes uveal melanoma development by regulating the wnt/β-catenin pathway.

Elevated Lactic Acid Levels in the Aqueous Humor May Be an Indicator of Uveal Melanoma.

Assessment of Sensorimotor Complications After Plaque Brachytherapy for Patients With Uveal Melanoma.

Regulation of BAP1 activity by novel cancer-associated glutamate residues through ubiquitin binding and PARylation.

Background/Objectives: Uveal melanoma is a rare but aggressive intraocular malignancy that metastasizes in up to half of patients, most commonly to the liver, despite effective local treatment. In the absence of robust evidence, there are no standardized guidelines for post-treatment surveillance, resulting in wide variation in imaging modalities, frequency, and duration across physicians and institutions. This study aimed to develop expert consensus recommendations for surveillance strategies in patients with uveal melanoma. Methods: A modified Delphi method was conducted across three iterative survey rounds between September 2024 and February 2025 using an online platform. Panelists included medical oncologists, ocular oncologists, radiologists, and surgical oncologists from North America. A multidisciplinary steering committee developed statements addressing risk-based surveillance using both molecular and clinical prognostic factors, including gene expression profiling (GEP) and PRAME status. Consensus was defined a priori as ≥70% of panelists rating a statement 7–9 on a 9-point Likert scale. Results: Forty-nine experts were invited, and 41 completed at least one survey round. The panel represented 17 U.S. states, Washington, D.C., and two Canadian provinces. Twelve statements reached stable consensus, including recommendations for imaging modality, frequency, and duration in intermediate- and high-risk patients. Although there was agreement that low-risk patients warrant surveillance, no consensus was reached on the optimal approach for this group. Conclusions: This is the first study to provide consensus-based guidance incorporating GEP and PRAME status into surveillance recommendations for uveal melanoma, offering a standardized framework to guide clinical practice and future research.

PurposeTo assess efficacy and safety in subgroups of patients treated with Melphalan/Hepatic Delivery System (melphalan/HDS), a drug/device combination for liver-directed treatment of metastatic UM (mUM) patients. Previously reported FOCUS study results indicated melphalan/HDS treatment provides a clinically meaningful response rate and favorable benefit-risk ratio in patients with unresectable mUM.MethodsPatients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) every 6–8 weeks for up to 6 cycles. Post hoc analyses of efficacy and safety were conducted for patient subgroups based on demographic and baseline disease characteristics.Results102 patients with mUM were enrolled; treatment was attempted in 95 patients; 91 patients received treatment. Subgroup analyses showed consistent tumor response regardless of age, sex, geographic region, presence/absence of extrahepatic lesions, and prior therapy. Patients with lower tumor burden had better objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) than those with higher tumor burden (ORR: 51.1 vs. 22.2%, p = 0.008; mPFS: 11.3 vs. 5.8 months, p = 0.007; mOS: 26.7 vs. 15.4 months, p = 0.008). Patients with 1–25% liver involvement had higher mOS than those with 26–50% liver involvement (22.4 vs. 16.9 months; p = 0.030); patients with low or normal lactate dehydrogenase (LDH) had higher mOS than those with elevated LDH (23.5 vs. 15.3 months; p = 0.019). The overall safety profile was similar across subgroups without evidence of cumulative toxicity with successive treatment cycles.ConclusionResults demonstrate a favorable benefit-risk profile for melphalan/HDS across clinically relevant subgroups. However, early treatment in patients with low tumor burden may offer best results.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-025-06291-x.

ABSTRACT Choroidal melanoma, a primary intraocular malignancy, often causes severe vision loss and carries a high risk of metastasis, largely due to the absence of precise and noninvasive theranostic strategies. To address these challenges, we developed a biomimetic NIR‐II theranostic nanoplatform (TPB CNPs) that integrates a nonconjugated polymer (TPB) created by covalently linking NIR‐II fluorescent monomers through flexible C6 alkyl chain spacers to increase brightness. The biomimetic TPB CNPs were camouflaged with the tumor cell membrane to enable efficient uptake and tumor‐specific homing. Upon NIR irradiation, TPB CNPs displayed pronounced NIR‐II fluorescence (quantum yield: 18.3%), primarily type‐I photodynamic reactivity, and an efficient photothermal conversion rate of 77.5%. The bright NIR‐II emission enabled high‐resolution whole‐body angiography and real‐time tumor localization. In vivo studies confirmed that precise imaging‐guided TPB CNPs nearly completely eradicated tumors and significantly prolonged survival in tumor‐bearing mice, with no detectable toxicity. This work introduces a biomimetic NIR‐II nanoplatform that integrates monomers with nonconjugated segments to increase the fluorescence brightness of NIR‐II emissive conjugated polymers, enabling precise, noninvasive imaging‐guided phototherapy of choroidal melanoma.

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. 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. Pre-treatment multivariate 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 multivariate analysis emphasized the importance of inflammation management and liver protection. ML models incorporating radiomics features from base line CT imaging were not superior to models based on pre-treatment clinical data alone. 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.

Uveal melanoma (UM) is the most common intraocular tumor, and despite being rare, it accounts for nearly 13% of melanoma-related deaths. Indeed, patients with metastatic disease have typically survival rates of less than one year, with little improvement over the past few decades. Although TP53 mutations are uncommon in UM, recent findings highlight a dysfunctional p53 pathway in this cancer. Given its crucial role in mediating DNA damage responses, we analyzed the p53 protein functionality and downstream target activation in a panel of UM cell lines in response to standard-of-care treatments (i.e., cisplatin and proton-beam irradiation). Although most of the analyzed cells retained a wild-type p53, we observed a wide range of p53 protein stabilization and targets' activation. Recently, p53 isoforms have been recognized as modifiers of p53 activity, and their biology and functions depend on cellular context. We observed that UM cells express a broad spectrum of p53 isoforms, including Δ160p53α and Δ133p53β and the longer variants Δ40p53β and p53β. Interestingly, the down-regulation of the short p53 isoforms (Δ133/Δ160) revealed their contribution to promoting cell growth and in mitigating cell death triggered by standard-of-care therapies. Moreover, we verified the wild-type p53 status in a panel of 32 UM cases and analyzed the expression levels of p53 isoforms. Our results indicated a correlation between higher expression levels of Δ40p53α or Δ133p53γ isoforms and the development of more aggressive cancers. Our findings suggest that shorter p53 isoforms can promote cancer aggressiveness and therapy resistance, thereby providing crucial insights into UM pathogenesis.

To assess the outcomes of a modified surgical approach for the treatment of uveal melanoma involving endoresection with intentional residual tumor at the margins, combined with adjuvant ruthenium-106 brachytherapy. This technique aims to reduce surgical morbidity, while preserving visual function and maintaining effective local tumor control and survival. We conducted a retrospective observational study including 33 patients with choroidal melanoma treated between January 2017 and August 2024 at a single tertiary ocular oncology center in Spain. Patients underwent pars plana vitrectomy and endoresection leaving residual tumor followed by ruthenium-106 brachytherapy. Clinical, functional, and oncological outcomes were analyzed, including tumor recurrence, metastasis, visual acuity, complications, and cytogenetic findings. Kaplan-Meier analysis was used to estimate survival and recurrence rates. After a mean follow-up of 41.7 months, local tumor recurrence occurred in 2 patients (6.06%) and enucleation was performed in 1 patient (3.03%). Two patients (6.06%) developed metastases, with one disease-specific death, resulting in a 5-year survival rate of 97%. Visual acuity of 20/200 or better was preserved in 60.61% of patients. The most frequent complications were retinal detachment (36.36%) and macular edema (45.45%). Cytogenetic analysis showed a significant association between chromosome 1p loss and both recurrence and metastasis (p = 0.032). No cases of phthisis bulbi or severe hypotony were observed. This modified endoresection technique with intentional tumor residuals and adjuvant ruthenium-106 brachytherapy offers a safe and function-preserving option for selected patients with choroidal melanoma. It achieves good tumor control and visual outcomes, with a low rate of enucleation and metastasis. Further studies are required to validate its long-term efficacy.

Tebentafusp is the first systemic therapy to improve survival outcomes for patients with HLA-A*02:01-positive metastatic uveal melanoma (mUM). However, outside the pivotal study, limited data for tebentafusp are reported in literature. To evaluate the efficacy and safety of tebentafusp in patients with human leukocyte antigen (HLA)-A*02:01-positive mUM across cohort studies and clinical trials. PubMed, EMBASE, Cochrane, and Web of Science (up to July 2025) were surveyed for studies evaluating tebentafusp in patients with HLA-A*02:01-positive mUM. A meta-analysis using a random-effects model and the inverse variance method was conducted; Kaplan-Meier curves, where available, were used to recreate the time-to-event data. The primary objective was efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The secondary objective was to evaluate all-grade and severe (grade ≥ 3 or higher) adverse events (AEs). A total of 997 patients from 12 cohorts were included. Using reconstructed time-to-event outcomes from published Kaplan-Meier curves, the estimated median PFS was 3.9 months (95% confidence interval [CI] 3.77-4.92). The median OS was 21.2 months (95% CI 19.2-23.1). When stratified by study design, the median OS was similar between prospective and retrospective studies: 21.2 months (95% CI 19.2-23.8) and 21.1 months (95% CI 18.1-33.6), respectively. Likewise, median progression-free survival (PFS) was comparable between prospective and retrospective studies: 3.8 months (95% CI 3.25-5.5) and 3.9 months (95% CI 3.8-4.9), respectively. The rate of cytokine- and cutaneous-mediated events was 67% (95% CI 45-84; I2 = 94.4%) and 64% (95% CI 28-89; I2 = 97.3%), respectively. Severe AEs for cytokine-mediated events were 3% (95% CI 1-13; I2 = 87.6%), and cutaneous-mediated events were 11% (95% CI 8-14; I2 = 0%). The discontinuation rate was 2% (95% CI 1-4; I2 = 0%). Tebentafusp for patients with HLA-A*02:01-positive mUM is associated with improved survival outcomes and manageable toxicity. These findings support tebentafusp as the standard of care for this patient population.

Uveal melanoma (UM), the most common primary intraocular malignancy in adults, shows racial disparities in incidence, genetic drivers, and clinical outcomes. While most prognostication models are based on Caucasian populations, Asians demonstrate distinct molecular profiles, necessitating population-specific risk stratification. This study analyzed 53 Asian UM tumors, 17 normal choroidal tissues (TRACE database), and 80 Caucasian UM samples (TCGA database). Differential gene analysis, immune microenvironment profiling, and survival modeling were performed. A 7-gene prognostic signature was developed by LASSO regression and validated across cohorts, with drug sensitivity predicted using GDSC2 data. The Asian UM exhibited 3,827 tumor-specific differentially expressed genes (DEGs) compared to the normal choroid, with enrichment in PI3K-Akt signalling, and 3,814 race-specific DEGs compared to Caucasians, suggesting specific disease pathways and variations in the tumor microenvironment. The tumor microenvironment in Asian UM exhibited increased immunological activation (M1 macrophages, PD-L1, CD8; p < 0.05), while Caucasian uveal melanoma was marked by immunosuppressive predominance (M2 macrophages, MDSCs). The seven-gene prognostic model (MMP2, LRAT, NOG, IHH, CDH18, MYH11, and SELE) exhibited strong predictive efficacy in Asians (AUC: 0.979, 0.924, and 0.984 for 1, 3, and 5-year survival) but was less successful in Caucasians. High-risk scores correlated with metastasis (12/26 vs. 4/27; p = 0.02) and had independent prognostic value. This cross-racial UM study reveals significant molecular and immune differences, indicating that Asian UM may be more responsive to immunotherapy The population-specific prognostic model improves our understanding of molecular differences in Asian and Caucasian UM, warranting further validation in multiethnic cohorts.

In uveal melanoma (UM), coexistence of the fatal monosomy 3 with the benign gain of chromosome 6p occurs rarely. The spatial organization of chromosomes can be influenced by the nucleoli, which become larger under hyperglycemia. We therefore hypothesized that hyperglycemia may be responsible for chromosome-specific aberrations in UM and analyzed its effect on nucleolar organization, chromosome territories, and missegregation rates in vitro. UM cell lines 92.1 and OMM2.5, UM cells from the primary tumors of two patients, and Tenon fibroblasts from a control were incubated in normo- or hyperglycemic medium (with 5.5 or 25 mM glucose, respectively) for one day, followed by the mitotic arrest with Nocodazole for 18-24 hours and recovery in fresh medium. Co-detection of proteins with the centromeres of chromosomes 3 and 6 was performed by two-dimensional immunofluorescent in situ hybridization. In the UM cells undergoing interphase, hyperglycemia promoted the dislocation of chromosome 3 toward the center along with nucleolar growth. During prometaphase, the mean angle between the centromeres of chromosome 3 was reduced below 90° under hyperglycemia (P = 0.02). During the later mitotic phases, hyperglycemia resulted in a 3.8-fold increase in the missegregation rate of chromosome 3 in UM cells (P < 0.001), whereas chromosome 6 rather than 3 was more prone to missegregation in the normoglycemic UM cells and hyperglycemic Tenon fibroblasts. Hyperglycemia can favor chromosome-specific aneuploidies by altering chromosome territories in a cell-type dependent manner. Prevention of hyperglycemia may be a simple therapeutic approach to impede the generation of monosomy 3 in UM.

The emerging role of metabolic interventions in uveal melanoma.

Optical Coherence Tomography and Optical Coherence Tomography Angiography Features of Optic Disc Melanocytoma: Peripapillary Hyperreflective Ovoid Mass-like Structures, Perfusion Deficits, and Association With Vision Loss.

Machine Learning-Based Prediction of Local Recurrence in Uveal Melanoma After Ruthenium-106 Plaque Brachytherapy Using Ultrasound Images and Clinical Data.

Multi-responsive nanocomposite hydrogel for synergistic photothermal-chemotherapy to prevent postoperative recurrence and metastasis of uveal melanoma

Cross-section evaluation of the therapeutic radionuclide 103Pd: Different production routes using commercial cyclotrons.

The COMS (Collaborative Ocular Melanoma Study) eye plaques are based on the application of low-energy photon sources such as iodine-125 (125I) and palladium-103 (103Pd). Compared to 125I, 103Pd is characterized by different radiobiological and physical parameters, which include the half-life, relative biological effectiveness (RBE), and average photon energy. Variation of these parameters may increase or decrease the integrated cell-killing effect of eye plaques; therefore, quantitative evaluation of biological effects may be used to optimize the dose prescription and improve the therapeutic ratio. The goal of this article is to show that the higher RBE of lower-energy photons from 103Pd sources counteracts the steeper dose fall-off in heterogeneous eye plaque geometry and the effect of radiation protraction to produce the higher cell killing effect compared to 125I sources. Biological effectiveness of COMS eye plaques with 125I and 103Pd sources is evaluated using the equivalent uniform RBE-weighted dose (EUDRBE). The EUDRBE is defined as the uniform dose distribution with RBE=1 that produces the cell survival equal to a nonuniform dose distribution with variable RBE. The EUDRBE was proposed for comparison of cell survival in radiotherapy with a nonuniform dose and the RBE effect, and such a concept can be applied to both external beam fractionated radiotherapy and continuous irradiation in brachytherapy. The EUDRBE is computed in a 1D model of COMS eye plaques using the dose distributions in a water-equivalent medium with heterogeneity correction from MC calculations. The EUDRBE is computed in five dose fractions using the linear quadratic (LQ) cell survival model corrected for the effects of protracted irradiation and RBE. The EUDRBE for eye plaques is compared to the reference dose of 50 Gy(RBE) that is the lowest total dose (delivered in five fractions) used in hypofractionated proton therapy for ocular melanoma. In the simulations with a hypothetical RBE=1, the EUDRBE for eye plaques with both 125I and 103Pd sources is lower than the reference dose of 50 Gy(RBE) for most of the simulated implant durations and tumor heights. Also, the EUDRBE for eye plaques with 103Pd sources is lower compared to 125I sources. If the measured RBE of 1.4 and 1.9 is applied for 125I and 103Pd, respectively, the EUDRBE for eye plaques becomes larger than the reference dose of 50 Gy(RBE). The range of EUDRBE for 125I is within 50-60 Gy(RBE) depending on the implant duration and tumor height; therefore, the lowest EUDRBE is comparable to the dose used in hypofractionated proton therapy. The range of EUDRBE for 103Pd is within 57-67 Gy(RBE), which is higher compared to 125I. The effects of RBE for COMS eye plaques with 125I and 103Pd sources should be considered to explain the tumor control probability (TCP)>80% observed in clinical practice. The EUDRBE for 103Pd sources is larger than the EUDRBE for both the 125I sources and hypofractionated proton therapy; therefore, the dose de-escalation relative to 85 Gy may be considered.

Lactate metabolism and lactylation in ocular diseases.