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Metastatic uveal melanoma (mUM) is associated with poor prognosis. Ipilimumab/nivolumab has shown antitumor efficacy in phase II studies. Tebentafusp resulted in longer overall survival (OS) compared to investigator`s choice in a phase III study. We sought to describe the radiological response patterns of mUM patients treated with immunotherapy. Patients with mUM treated with ipilimumab/nivolumab and tebentafusp between July 2018 and December 2022, with available radiological assessment per RECISTv1.1 and/or imPERCIST5, were retrospectively identified and included. Progression-free survival (PFS) and OS rates, liver-specific response and pathological assessment in available liver biopsies were evaluated. In the ipilimumab/nivolumab group, median PFS (mPFS) was 2.9 months (95% CI 2.2-28.6) and mOS 28.9 months (95% CI 12.7-NR). Complete (CMR) and partial (PMR) metabolic response per imPERCIST5, and partial response (PR) per RECISTv1.1 were associated with longer PFS and OS by trend, compared to morphologically and metabolically stable or progressive disease. In the tebentafusp group, mPFS was 2.7 months (95% CI 2.2-3) and mOS 18.6 months (95% CI 11.5-NR). PMR and PR were associated with longer PFS by trend. In both treatments, the overall treatment response was associated with the radiological response at the liver site. In available liver tumor biopsies, differences in pathological and radiological responses were noted. ImPERCIST5 and RECIST v1.1 are valuable tools in the radiological response assessment, but both methods display limitations. Accurate biomarkers to stratify patients at risk for disease progression and future translational studies to investigate mechanisms of response and resistance are required., (© 2024. The Author(s).)

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/ PRAME classifier.MATERIALS AND METHODSThis study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/ PRAME (-), 80.6% (95% CI, 73.9 to 87.9) for class 1/ PRAME (+), 58.3% (95% CI, 51.1 to 66.4) for class 2/ PRAME (-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/ PRAME (+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.CONCLUSIONIn the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/ PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Purpose: To investigate if the interval between diagnosis and treatment of posterior uveal melanoma (UM) is associated with metastatic death., Design: Retrospective, single-center cohort study., Participants: A total of 1145 patients consecutively diagnosed with posterior UM at St. Erik Eye Hospital, Stockholm, Sweden, from 2012 to 2022, with recorded dates of diagnosis and primary treatment. This cohort represents 81% of all diagnosed patients in Sweden during this period., Methods: Data on the interval between diagnosis and treatment were collected for all patients. Its prognostic importance was examined with univariate and multivariate competing risks regressions, and cumulative incidence analyses., Main Outcome Measures: Incidence of metastatic death (UM mortality) for patients with prompt (< 1 month from diagnosis) versus delayed treatment (≥ 1 month) and subdistribution hazard ratios (exp(β j )) for every additional 10-day delay in treatment., Results: The mean interval between diagnosis and treatment was 34 days (SD, 56, range, 0-932). Patients treated promptly had larger tumors at diagnosis, but there were no differences in patient age, tumor distance to the optic disc, rates of ciliary body involvement (CBI) or extraocular extension (EXE), or symptom duration before diagnosis. Those who were treated more than 1 month after diagnosis had greater UM mortality in American Joint Committee on Cancer (AJCC) stage II and III. In stage I, UM mortality for delayed treatment was lower for the first 10 years, followed by a marked spike in the 11 th year. In multivariate competing risks regressions of all 1145 patients with tumor diameter, thickness, CBI, and EXE as covariates, the risk for UM mortality increased with 1% for every additional 10-day delay in treatment (exp(β j ) 1.01). Among 355 patients treated with enucleation, this delay was associated with UM mortality, independent of AJCC stage, cytomorphology, and level of immunohistochemical BAP-1 expression., Conclusions: Increasing time between diagnosis and treatment of UM is associated with a higher risk of metastatic death. These results challenge a central concept in the understanding of metastatic progression and may indicate the existence of late metastatic seeding. They also underscore the importance of prompt treatment. Validation in independent cohorts is recommended., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3., Experimental Design: B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models., Results: B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody., Conclusions: These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM., (©2024 American Association for Cancer Research.)

Patients with cutaneous melanoma can develop in-transit metastases (ITM), most often localized to limbs. For patients with uveal melanoma that develop metastatic disease, the overall majority develop isolated liver metastases. For these types of metastases, regional cancer therapies have evolved as effective treatments. Isolated limb perfusion (ILP), isolated limb infusion (ILI), isolated hepatic perfusion (IHP) and percutaneous hepatic perfusion (PHP) achieve a high local concentration of chemotherapy with minimal systemic exposure. This review discusses the mechanism and available literature on locoregional treatment modalities in the era of modern immunotherapy., (© 2023. The Author(s).)

Uveal and conjunctival melanomas are relatively rare tumors; nonetheless, they pose a significant risk of mortality for a large number of affected individuals. The pathogenesis of melanoma at different sites is very similar, however, the prognosis for patients with ocular melanoma remains unfavourable, primarily due to its distinctive genetic profile and tumor microenvironment. Regardless of considerable advances in understanding the genetic characteristics and biological behaviour, the treatment of uveal and conjunctival melanoma remains a formidable challenge. To enhance the prospect of success, collaborative efforts involving medical professionals and researchers in the fields of ocular biology and oncology are essential. Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors. Despite advancements in the development of effective melanoma therapeutic strategies, all current treatments for uveal melanoma (UM) and conjunctival melanoma (CoM) remain unsatisfactory, resulting in a poor long-term prognosis. Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors. A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy, with various potential therapeutic targets currently under consideration. Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents, with the hope of improving the prognosis for patients with metastatic disease., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 Kaštelan et al.)

Uveal melanoma (UM) is an ocular cancer predominantly affecting adults, characterized by challenging diagnostic outcomes. This research endeavors to develop an innovative multifunctional nanocomposite system sensitive to near-infrared (NIR) radiation, serving as both a non-oxygen free-radical generator and a photothermal agent. The designed system combines azobis isobutyl imidazoline hydrochloride (AIBI) with mesoporous copper sulfide (MCuS) nanoparticles. MCuS harnesses NIR laser energy to induce photothermal therapy, converting light energy into heat to destroy cancer cells. Simultaneously, AIBI is activated by the NIR laser to produce alkyl radicals, which induce DNA damage in remaining cancer cells. This distinctive feature equips the designed system to selectively eliminate cancers in the hypoxic tumor microenvironment. MCuS is also beneficial to scavenge the overexpressed glutathione (GSH) in the tumor microenvironment. GSH generally consumes free radicals and hiders the PDT effect. To enhance control over AIBI release in cancer cells, 1-tetradecyl alcohol (TD), a phase-changing material, is introduced onto the surface of MCuS nanoparticles to create the final AMPT nanoparticle system. In vitro and in vivo experiments confirm the remarkable anti-tumor efficacy of AMPT. Notably, the study introduces an orthotopic tumor model for UM, demonstrating the feasibility of precise and effective targeted treatment within the ocular system., (© 2024 Wiley‐VCH GmbH.)

Uveal melanoma (UM) is a highly aggressive and fatal tumor in the eye, and due the special biology of UM, immunotherapy showed little effect in UM patients. To improve the efficacy of immunotherapy for UM patients is of great clinical importance. Single-cell RNA sequencing(scRNA-seq) provides a critical perspective for deciphering the complexity of intratumor heterogeneity and tumor microenvironment(TME). Combing the bioinformatics analysis, scRNA-seq could help to find prognosis-related molecular indicators, develop new therapeutic targets especially for immunotherapy, and finally to guide the clinical treatment options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Zhang, Huang, Zhu and Huang.)

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.

Background: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: JM: Declares travel support from Bristol Myers Squibb, Novartis and Sun Pharmaceutical Industries, outside the submitted work. J-MP: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos, outside the submitted work. GL: Declares travel support from Sun Pharma, outside the submitted work. AZ: Declares travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work. JU: Is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. PT: served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. CP: Received honoraria speaker honoraria and advisory-board honoraria and travel support from BMS, MSD, Novartis, Merck Serono, Pierre Fabre, Sunpharma, AbbVie, LEO, and Kyona Kirin, outside the submitted work. RH: Is an employee of Helios Kliniken Erfurt GmbH. JW: Received honoraria and travel support from Almirall, Bristol Myers Squibb, Novartis, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. EL: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. LZ: Served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol- Myers Squibb, Amgen, Pierre-Fabre, Sunpharma and Novartis, outside the submitted work. SU: Research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma, outside the submitted work. DS: Reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matull, Placke, Lodde, Zaremba, Utikal, Terheyden, Pföhler, Herbst, Kreuter, Welzel, Kretz, Möller, Sucker, Paschen, Livingstone, Zimmer, Hadaschik, Ugurel, Schadendorf, Thielmann and Griewank.)

Aims: Adenomas of the ciliary body epithelium, including adenoma of the pigmented ciliary body epithelium (APCE) and adenoma of the non-pigmented ciliary body epithelium (ANPCE), are extremely rare, and most knowledge about them comes from sporadic case reports. The purpose of this study was to provide a comprehensive understanding of adenomas of the ciliary body epithelium and to identify the similarities and differences between APCE and ANPCE., Methods: This study was a retrospective case series comprising data from 41 patients obtained from retrieved publications and five cases diagnosed at the Shanghai Ninth People's Hospital. The clinicopathological features, treatment and prognosis of APCE and ANPCE were compared using the non-parametric rank sum test, t-test and the χ 2 test., Results: The clinical and histopathological features and treatment were analogous between APCE (n=23) and ANPCE (n=23). The overall visual prognosis associated with the two tumours was good, with 63% of the patients having stable or improved vision after treatment. Enucleation was the primary cause of eventual vision loss (three in APCE vs two in ANPCE, p=0.001). Notably, iris invasion was commonly observed in patients with APCE (six in APCE vs zero in ANPCE, p=0.014), and iris invasion was associated with decreased vision eventually (p=0.003). Tumour size was irrelevant to the vision outcome (p=0.65). Metastasis or recurrence did not occur in any of the patients., Conclusion: In most cases, the clinicopathological features of ANPCE and APCE were similar. Iris invasion was commonly observed in patients with APCE, which was associated with poor visual prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Uveal cancer (UM) offers a complex molecular landscape characterized by substantial heterogeneity, both on the genetic and epigenetic levels. This heterogeneity plays a critical position in shaping the behavior and response to therapy for this uncommon ocular malignancy. Targeted treatments with gene-specific therapeutic molecules may prove useful in overcoming radiation resistance, however, the diverse molecular makeups of UM call for a patient-specific approach in therapy procedures. We need to understand the intricate molecular landscape of UM to develop targeted treatments customized to each patient's specific genetic mutations. One of the promising approaches is using liquid biopsies, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), for detecting and monitoring the disease at the early stages. These non-invasive methods can help us identify the most effective treatment strategies for each patient. Single-cellular is a brand-new analysis platform that gives treasured insights into diagnosis, prognosis, and remedy. The incorporation of this data with known clinical and genomics information will give a better understanding of the complicated molecular mechanisms that UM diseases exploit. In this review, we focused on the heterogeneity and molecular panorama of UM, and to achieve this goal, the authors conducted an exhaustive literature evaluation spanning 1998 to 2023, using keywords like "uveal melanoma, "heterogeneity". "Targeted therapies"," "CTCs," and "single-cellular analysis"., (© 2024. The Author(s).)

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo-YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable., (© 2024. The Author(s).)

In recent years, advances in melanoma treatment have renewed patient hope. This comprehensive review emphasizes the evolving treatment landscape, particularly highlighting first-line strategies and the interplay between immune-checkpoint inhibitors (ICIs) and targeted therapies. Ipilimumab plus nivolumab has achieved the best median overall survival, exceeding 70 months. However, the introduction of new ICIs, like relatlimab, has added complexity to first-line therapy decisions. Our aim is to guide clinicians in making personalized treatment decisions. Various features, including brain metastases, PD-L1 expression, BRAF mutation, performance status, and prior adjuvant therapy, significantly impact the direction of advanced melanoma treatment. We also provide the latest insights into the treatment of rare melanoma subtypes, such as uveal melanoma, where tebentafusp has shown promising improvements in overall survival for metastatic uveal melanoma patients. This review provides invaluable insights for clinicians, enabling informed treatment choices and deepening our understanding of the multifaceted challenges associated with advanced melanoma management., Competing Interests: Declaration of Competing Interest FS has reported Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre and for advisory board for Novartis, Philogen, SunPharma, MSD. The other authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1-2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

Abstract: Uveal melanoma (UM), arising from intraocular melanocytes, poses a complex clinical challenge with a substantial risk of distant metastasis, often to the liver. Molecular profiling, encompassing genetic, cytogenetic, gene expression, and immunological subsets, plays a pivotal role in determining prognoses. The evolving landscape includes promising systemic treatments, such as tebentafusp, a novel immune-modulating bispecific fusion protein, and targeted therapies. Combined regional and systemic approaches, including immune checkpoint inhibitors and innovative liver-directed therapy, are also under investigation. Although recent progress has improved outcomes, ongoing research aims to address the unique challenges of UM and develop effective therapies, particularly for HLA-A*02:01-negative patients who represent a significant unmet medical need. This review comprehensively discusses the molecular characteristics of UM, risk stratification methods, and the current and future spectrum of regional and systemic therapeutic modalities., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Uveal Melanoma (UM) is a rare disease, yet it is the most common primary intraocular malignancy in adult patients. Despite continuous advancements and research, the risk of metastasis remains high. It is possible to stratify patients according to their risk of metastases using a variety of known risk factors. Even though there is no gold standard for the prognostication of patients with uveal melanoma, it is becoming increasingly clear that combining histo-pathological, patient-related and molecular prognostic markers allows a more accurate prediction of the metastatic risk than by using one parameter. Primary UM in the eye are treated very effectively with eye-sparing radiation-based techniques or enucleation. However, it is not yet possible to prevent or treat metastases with the current therapeutic options. Nonetheless, the efforts to find new therapeutic targets continue and progress is being made, especially in the field of targeted therapy, as exemplified by the anti-gp100 bispecific molecule Tebentafusp. This review delves into the history of uveal melanoma, its incidence, presentation and diagnosis, the known prognostic factors and the treatment options, both for the primary tumour and for metastases. We show that different populations may have different risks for developing UM, and that each country should evaluate their own patients., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial., (© 2024. The Author(s).)

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Conventional methods of UM treatment are based on chemotherapy and radiotherapy, which have been able to control tumor growth in a limited way. But due to the inadequacy and many side effects of these treatments, many UM patients die during treatment, and approximately 50% of patients develop metastasis. Meanwhile, the 2-year survival rate of these patients from the time of metastasis is 8%. Since immunotherapy has the potential to be the most specific and efficient method in the treatment of tumors, it is considered an attractive and promising research field in the treatment of UM. This review highlights recent advances in UM immunotherapy and provides new immunological approaches on how to overcome the challenges of UM immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult population. Primary methods for treatment of UM involves surgery Proton Beam Therapy (PBT), Plaque Brachytherapy, phototherapy, and Charged Particle Radiation Therapy (CPT). It has been found that approximately 50 % of patients diagnosed with UM ultimately experience development of metastatic disease. Furthermore, it has been identified that majority of the patient experience metastasis in liver with a prevalence of 95 %. Management of metastatic UM (MUM) involves various therapeutic modalities, including systemic chemotherapy, molecular targeted therapy, immunotherapy and liver directed interventions. We outline gene mutation in UM and addresses various treatment modalities, including molecular targeted therapy, miRNA-based therapy, and immunotherapy. Additionally, inclusion of ongoing clinical trials aimed at developing novel therapeutic options for management of UM are also mentioned., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Uveal melanoma is a rare cancer, in which metastases occur in approximately one half of cases. In metastatic disease, the prognosis is unfavorable and the median of survival does not exceed 6 months. Effective treatment options were very limited up to date. Tebentafusp is a bispecific fusion protein, which as the first drug proved efficacy in uveal melanoma., Case: The patient was referred for suspected uveal melanoma of the left eye. She was treated for Hodgkin's disease in the past. Primarily, the tumor was treated by radiosurgery with radiotherapy of a small lesion of the vertebral body. However, later the patient had to undergo bulbus enucleation with confirmation of a large tumor category pT4b. PET/CT revealed metastases of the bones and the liver; simultaneously, haplotype A*02: 01 was confirmed. The patient underwent radiotherapy of the sternum and later, after confirmation of payment from the health insurance company, she started treatment with tebentafusp. The first three doses were administered during admission to the hospital, with a need to treat cytokine release syndrome by corticosteroids. Later, the administration was performed in an out-patient regimen, without complications, except for a transient elevation of transaminases. The first CT restaging confirmed stable disease; however, the second restaging confirmed a new osteolytic lesion in the processus of Th11. Because of progression, the treatment with tebentafusp was withdrawn after 6 months. Unfortunately, the lesion could not be treated by radiotherapy. Two months later, the patient was urgently admitted to the hospital because of right-sided hemiplegia; MRI revealed bleeding metastatic lesion in the brain stem., Conclusion: In this case report, we present the case of the first patient treated with this drug in the Czech Republic.

Primary uveal melanoma is rare and affects approximately 8,000 persons per year worldwide. This malignancy can involve the iris, ciliary body, and choroid. Of these three structures, the iris is the least commonly affected site, representing only 4% of all uveal melanomas. Iris melanoma can arise from iris melanocytic nevus, iris melanocytosis, or de novo. In a longitudinal study of 1,611 patients with iris nevus, transformation into melanoma, using Kaplan-Meier estimates, was found in 2.6% by five years and in 4.1% by 10 years. The factors that predicted growth of iris melanocytic nevus into melanoma are denoted by a letter (ABCDEF) guide: A for age ≤40 years old at presentation (hazard ratio [HR] = 3, P = .01), B for blood (hyphema) (HR = 9, P < .0004), C for clock hour of tumor inferiorly (tumor location) (HR = 9, P = .03), D for diffuse flat tumor configuration (HR = 14, P = .02), E for ectropion uveae (HR = 4, P = .002), and F for feathery ill-defined margins (HR = 3, P = .02). At diagnosis, iris melanoma has a mean cross-sectional diameter of 5.5 mm and thickness of 2.1 mm, often with tumor seeding (28%) and secondary glaucoma (35%). We provide a comprehensive review of iris nevus and melanoma to explore relevant demographic and clinical data, risk factors for tumor growth, management, and prognosis, with the hope that clinicians will be more comfortable in understanding this rare malignant condition., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Uveal melanoma (UM) is the most common intraocular tumour in adults, with dismal prognosis once metastases develop, since therapeutic options for the metastatic disease are ineffective. Over the past decade, novel cancer therapies based on immunotherapy have changed the landscape of treatment of different forms of cancer leading to many hopes of improvement in patient overall survival (OS). VISTA, LAG-3 and PRAME are novel promising targets of immunotherapy that have recently gained attention in different solid tumours, but whose relevance in UM remained to be comprehensively evaluated until now. Here, we studied the protein expression of VISTA, LAG-3 and PRAME using immunohistochemistry in representative whole tissue sections from primary UM cases in a cohort of 30 patients from a single centre (Nice University Hospital, Nice, France). The expression of each of these markers was correlated with different clinical and pathological parameters, including onset of metastases and OS. We demonstrated the protein expression of VISTA and LAG-3 in small lymphocytes infiltrating the tumour, while no expression of the proteins was detected in UM cells. For PRAME, nuclear expression was observed in UM cells, but no expression in tumour infiltrating immune cells was identified. Increased levels of VISTA expression in tumour infiltrating lymphocytes (TILs) were associated with nuclear BAP1 expression and better prognosis. Higher levels of LAG-3 in TILs were associated with higher levels of CD8-positive TILs. PRAME nuclear positivity in melanoma cells was associated with epithelioid cell dominant (>90%) UM histological subtype, higher mitotic numbers and a higher percentage of chromosome 8q gain. This study proposes VISTA as a novel relevant immune checkpoint molecule in primary UM and contributes to confirm LAG-3 and PRAME as potentially important immunotherapy targets in the treatment of UM patients, helping to expand the number of immunotherapy candidate molecules that are relevant to modulate in this aggressive cancer., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Epidemiological studies of ocular melanomas have largely focused on Caucasian populations. This study reviewed the course and outcomes of uveal melanoma (UM) and conjunctival melanoma (CM) in Chinese patients., Methods: This retrospective study included patients with UM and CM who received treatment in a tertiary eye centre in Hong Kong from January 1994 to December 2019. Data were recorded concerning patient demographics, tumour laterality, tumour characteristics, investigations performed, treatment regimen, and final outcomes., Results: During the 25-year study period, there were 13 patients with UM and 11 patients with CM who did not display nodal or systemic involvement at diagnosis. The mean ± standard deviation ages at diagnosis of UM and CM were 59 ± 15.8 and 57 ± 13.9 years, respectively. There were more men among patients with UM than among those with CM (P=0.042). Most patients with UM underwent primary enucleation (n=12; 92.3%), whereas most patients with CM underwent orbital exenteration (n=9; 81.8%). The prognosis was significantly worse for CM than for UM. The median disease-free survival were 5.2 years (range, 0.7-20.5) and 2.1 years (range, 0.1-24.9) for UM and CM, respectively. Melanoma-related mortality was significantly higher among patients with CM than among those with UM (P=0.006)., Conclusion: Compared with UM, CM has higher rates of systemic metastasis and tumour-related mortality in Hong Kong Chinese patients, regardless of prior definitive treatment., Competing Interests: All authors have disclosed no conflicts of interest.

Purpose: Uveal melanoma (UM) is a rare disease with a high mortality, and new therapeutic options are being investigated. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer testis antigen, expressed in the testis, but also in cancers, including uveal melanoma. PRAME is considered a target for immune therapy in several cancers, and PRAME-specific T cell clones have been shown to kill UM cells., Methods: We studied the literature on PRAME expression in hematological and solid malignancies, including UM, and its role as a target for immunotherapy. The distribution of tumor features was compared between PRAME-high and PRAME-low UM in a 64-patient cohort from the Leiden University Medical Center (LUMC) and in the Cancer Genome Atlas (TCGA) cohort of 80 cases and differential gene expression analysis was performed in the LUMC cohort., Results: PRAME is expressed in many malignancies, it is frequently associated with a negative prognosis, and can be the target of T cell receptor (TCR)-transduced T cells, a promising treatment option with high avidity and safety. In UM, PRAME is expressed in 26% to 45% of cases and is correlated with a worse prognosis. In the LUMC and the TCGA cohorts, high PRAME expression was associated with larger diameter, higher Tumor-Node-Metastasis (TNM) stage, more frequent gain of chromosome 8q, and an inflammatory phenotype., Conclusions: We confirm that PRAME is associated with poor prognosis in UM and has a strong connection with extra copies of 8q. We show that PRAME-specific immunotherapy in an adjuvant setting is promising in treatment of malignancies, including UM.

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset ( n  = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations., Competing Interests: Dr Josep M Piulats has acted as a consultant or advisor for Roche, Novartis, Bristol Meyers Squibb, MSD Merck Serono, AstraZeneca, Clovis, VCN Biosciences, Janssen, Astellas, Bayer, Sanofi Genzyme, and Pfizer; received research funding from Pfizer, Merck Serono, MSD, Bristol Myers Squibb, Incyte, VCN Biosciences, Astellas, and Janssen; and received financial support for attending symposia from Roche, Janssen, and Ipsen., (© 2023 IDIBELL. Published with license by Taylor & Francis Group, LLC.)

Purpose: Tumor stem cells have emerged as a crucial focus of investigation and a therapeutic target in the context of cancer metastasis and drug resistance. They represent a promising novel approach to address the treatment of uveal melanoma (UVM)., Methods: According to the one-class logistic regression (OCLR) approach, we first estimated two stemness indices (mDNAsi and mRNAsi) in a cohort of UVM (n = 80). The prognostic value of stemness indices among four subtypes of UVM (subtype A-D) was investigated. Moreover, univariate Cox regression and Lasso-penalized algorithms were conducted to identify a stemness-associated signature and verify in several independent cohorts. Besides, UVM patients classified into subgroups based on the stemness-associated signature. The differences in clinical outcomes, tumor microenvironment, and probability of immunotherapeutic response were investigated further., Results: We observed that mDNAsi was significantly linked with overall survival (OS) time of UVM, but no association was discovered between mRNAsi and OS. Stratification analysis indicated that the prognostic value of mDNAsi was only limited in subtype D of UVM. Besides, we established and verified a prognostic stemness-associated gene signature which can classify UVM patients into subgroups with distinct clinical outcomes, tumor mutation, immune microenvironment, and molecular pathways. The high risk of UVM is more sensitive to immunotherapy. Finally, a well-performed nomogram was constructed to predict the mortality of UVM patients., Conclusions: This study offers a comprehensive examination of UVM stemness characteristics. We discovered mDNAsi-associated signatures improved the prediction capacity of individualized UVM prognosis and indicated prospective targets for stemness-regulated immunotherapy. Analysis of the interaction between stemness and tumor microenvironment may shed light on combinational treatment that targets both stem cell and the tumor microenvironment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Uveal melanoma (UM) is the primary ocular cancer with upto 50% of patients dying from metastasis. Although rare, it is deadly as patients with metastatic UM seldom survive beyond 18 months after diagnosis. Chemotherapeutics have no proven efficacy, including immunotherapies that have been tried as current treatment options but produce marginal improvement in overall survival for UM patients. While therapeutics are low in efficacy, there is an urgent need to explore novel targets in the treatment of UM. This review provides an update on the contribution of inflammation to UM with a focus on exploring potential therapeutic targets related to the inflammatory tumour microenvironment. As a tumour promoting event, inflammation is one of the hallmarks of cancers. The presence of the inflammatory phenotype characterised by the abundance of immune mediators and proinflammatory cytokines surrounding UM tumours, is a potential area to explore novel therapeutic targets. Despite decades of investigation regarding the role UM tumour microenvironment has played, that of inflammation in UM progression remains poorly understood. With advancement of technologies, an understanding of the prognosis of UM has been accelerated. Excitingly, novel therapeutic targets related to the inflammatory tumour microenvironment have been identified and relevant studies are underway in their preliminary phases, illustrating optimistic results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Purpose of Review: The aim of this article is to provide an update on the latest applications of deep learning (DL) and classical machine learning (ML) techniques to the detection and prognostication of intraocular and ocular surface malignancies., Recent Findings: Most recent studies focused on using DL and classical ML techniques for prognostication purposes in patients with uveal melanoma (UM)., Summary: DL has emerged as the leading ML technique for prognostication in ocular oncological conditions, particularly in UM. However, the application of DL may be limited by the relatively rarity of these conditions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Extracellular vesicles secreted from uveal melanoma (UM) cells are involved in the establishment of the premetastatic niche and display transforming potential for the formation of metastases, preferentially in the liver. In this study, we cultivated human primary UM cells and uveal melanoma-associated fibroblasts in vitro to be transduced by infection with a retrovirus containing the suicide gene-fused yeast cytosine deaminase::uracil phospho-ribosyl transferase ( yCD::UPRT ). A homogenous population of yCD::UPRT -UM cells with the integrated provirus expressed the gene, and we found it to continuously secrete small extracellular vesicles (sEVs) possessing mRNA of the suicide gene. The yCD::UPRT -UM-sEVs were internalized by tumor cells to the intracellular conversion of the prodrug 5-fluorocytosine (5-FC) to the cytotoxic drug 5-fluorouracil (5-FU). The host range of the yCD::UPRT -UM-sEVs was not limited to UMs only. The yCD::UPRT -UM-sEVs inhibited the growth of the human cutaneous melanoma cell line A375 and uveal melanoma cell line MP38, as well as other primary UMs, to various extents in vitro. The yCD::UPRT -UM-sEVs hold the therapeutic and prophylactic potential to become a therapeutic drug for UM. However, the use of yCD::UPRT -UM-sEVs must first be tested in animal preclinical studies.

Objective: To analyse the impact of the COVID-19 pandemic on the diagnosis and management of uveal melanoma (a tumour included in the Orphanet catalogue of rare diseases) in a Spanish national reference unit for intraocular tumours during the first year of the pandemic., Method: An observational retrospective study of patients with uveal melanoma in the National Reference Unit for Adult Intraocular Tumors of the Hospital Clínico Universitario de Valladolid (Spain) was performed, analysing the pre- and post-COVID-19 periods: from March 15, 2019 to March 15, 2020 and from March 16, 2020 to March 16, 2021. Demographic data, diagnostic delay, tumour size, extraocular extension, treatment and evolution were collected. A multivariable logistic regression model was used to identify factors that were associated with the variable: enucleation., Results: Eighty-two patients with uveal melanoma were included, of which 42 (51.21%) belonged to the pre-COVID-19 period and 40(40.78%) to the post-COVID-19 period. An increase in tumour size at diagnosis and in the number of enucleations was observed during the post-COVID-19 period (p < 0.05). Multivariable logistic regression demonstrated that both medium-large tumour size and patients diagnosed in the post-COVID-19 period were independently related to an increased risk of enucleation (OR 250, 95%CI, 27.69-2256.37; p < 0.01 and OR 10; 95%CI, 1.10-90.25; p = 0.04, respectively)., Conclusions: The increase in tumour size observed in uveal melanomas diagnosed during the first year of the COVID-19 pandemic may have favored the increase in the number of enucleations performed during that period., (Copyright © 2023 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Melanomas arising in the uveal tract of the eye are a rare form of the disease with a biology and clinical phenotype distinct from their more common cutaneous counterparts. Treatment of primary uveal melanoma with radiotherapy, enucleation or other modalities achieves local control in more than 90% of patients, although 40% or more ultimately develop distant metastases, most commonly in the liver. Until January 2022, no systemic therapy had received regulatory approval for patients with metastatic uveal melanoma, and these patients have historically had a dismal prognosis owing to the limited efficacy of the available treatments. A series of seminal studies over the past two decades have identified highly prevalent early, tumour-initiating oncogenic genomic aberrations, later recurring prognostic alterations and immunological features that characterize uveal melanoma. These advances have driven the development of a number of novel emerging treatments, including tebentafusp, the first systemic therapy to achieve regulatory approval for this disease. In this Review, our multidisciplinary and international group of authors summarize the biology of uveal melanoma, management of primary disease and surveillance strategies to detect recurrent disease, and then focus on the current standard and emerging regional and systemic treatment approaches for metastatic uveal melanoma., (© 2023. Springer Nature Limited.)

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma," addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's well-being. This review highlights the meeting's presentations in the context of the published literature., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Choroid, ciliary body, and iris melanomas are often grouped as uveal melanoma, the most common intraocular primary malignancy. The purpose of the current study was to analyze the tumor profile of newly diagnosed cases of choroidal melanoma at a reference center in Sao Paulo, Brazil, and to investigate the frequency of eyes treated by enucleation that could have been treated with brachytherapy if available in the service., Methods: Medical records of patients referred to our service with initial diagnostic hypothesis of choroidal melanoma from July 2014 to June 2020 were analysed on demographics, diagnosis confirmation, tumor measurement by ultrasonography and established treatment. Data were evaluated on clinical and demographic characteristics as age, sex, affected eye, ultrasound parameters, and treatment management of patients with clinically diagnosed choroidal melanoma. Among the patients submitted to enucleation, we investigated how many could have been selected to receive brachytherapy., Results: From the 102 patients referred with the choroidal melanoma diagnosis hypothesis, 70 (68.62%) were confirmed. Mean measurements from the tumors in millimetres were: 9.19 ± 3.69 at height and 12.97 ± 3.09 by 13.30 ± 3.30 at basal. A total of 48 cases (68.57%) were enucleated, 8 (11.43%) were treated by brachytherapy in a different service, and 14 patients (20.00%) returned for enucleation at their original referral center. Out of the 48 patients enucleated, 26 (54.17%) could have been selected to brachytherapy treatment., Conclusions: The results indicate a late diagnosis of choroidal melanoma cases referred to our service. Most enucleated cases could have been treated with brachytherapy if it was broadly available at the national public health insurance. Further public health political efforts should focus on early diagnosis and better quality of life post-treatment for oncologic patients., (© 2022. The Author(s).)

Uveal melanoma is a rare subtype of melanoma that once metastatic portends a poor prognosis. Likely due to the distinct differences in biology, metastatic potential, and immunologic profile as compared to cutaneous melanoma, uveal melanoma's response to immune checkpoint inhibition has been disappointing. Bi-specific fusion protein therapies (T cell engagers) are a novel strategy to forcibly bridge the immune system with a target on a cancer cell. This approach has been explored in a number of cancer types and has recently demonstrated success in uveal melanoma. Tebentafusp, a first in class ImmTAC (Immune-mobilizing monoclonal TCRs against cancer), has now shown an overall survival benefit when compared to investigator's choice. This review aims to summarize the experience with this first in class bi-specific T cell engager as well as highlight bi-specifics as a novel treatment strategy in uveal melanoma., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, and the main treatment for UM is currently surgery and plaque brachytherapy. UM is highly susceptible to metastasis, which eventually occurs in nearly half of all patients; once metastasis occurs, patients have a poor prognosis and the condition is difficult to treat. Therefore, the identification of new and effective UM biomarkers is vital for the application of therapeutic strategies. Immunogenic cell death (ICD) is a type of regulatory cell death that activates adaptive immune responses and generates long-term immunological memory. ICD can promote antitumor immunity, which may be a potential immunotherapeutic strategy for UM., Methods: The data of UM from the Cancer Genome Atlas (TCGA) was used as a training set and the data from Gene Expression Omnibus (GEO) was used as a validation set. To determine the expression pattern of ICD-related genes in UM, survival analysis and difference analysis was conducted. The ICD-related risk signature was constructed by employing the least absolute shrinkage and selection operator (LASSO) Cox regression. Subsequently, immune profile and somatic mutation analysis were performed. In addition, cell experiments were performed to verify the role of immunogenic cell death-related genes in UM., Results: In this study, we analyzed the relationship between ICD-related gene expression and UM patient prognosis, somatic mutations, and the tumor immune microenvironment. Importantly, we constructed a 5-gene ICD-related risk signature and confirmed it as a novel prognostic biomarker in UM patients. We found that the high-risk group had more immune cell infiltration and a worse prognosis than the low-risk group. In cellular experiments, we confirmed the high expression of FOXP3 inMUM2B andOCM-1A cell lines and that knockdown of FOXP3 markedly inhibited the proliferation of UM tumor cells., Discussion: ICD-related genes play a critical role in the tumor immune microenvironment. Our results may contribute to the development of effective immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Cai, Ye, Mou, Zhao, Sun, Lou, Zhang and Zhao.)

Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To analyze the clinical characteristics and survival of Chinese uveal melanoma (UM) patients. Methods: It was a retrospective case series study. Clinical data and demography characteristics of 1 166 UM patients who were diagnosed in Beijing Tongren Hospital from January 2004 to January 2020 were collected. The disease was followed up after informed consent was obtained. Kaplan-Meier plots were used to visualize survival outcomes, and the different risk groups were compared using the Log-rank test. The multivariate Cox proportional hazards model was used to select independent prognostic risk factors. Results: A total of 1 166 individuals (598 men, 568 women) were included in this study. The average age was (47.6±12.2) years. Median follow-up time was 38 months. Treatment included episcleral brachytherapy in 881 (75.6%) patients, local tumor resection in 38 (3.2%) patients, laser therapy in 115 (9.9%) patients and primary enucleation in 119 (10.2%) patients. In 120 patients out of the 881 patients with primary brachytherapy, enucleation was performed due to an increasing tumor size or uncontrolled neovascular glaucoma. The Kaplan-Meier survival analysis showed the 5-and 10-year metastasis rates were 18.5% and 26.8%, and the melanoma-related mortality rates were 13.6% and 22.2%, respectively. The Log-rank test showed that patient age ( χ ²=5.01) and gender ( χ ²=7.19), as well as tumor grade ( χ ²=49.11), shape ( χ ²=34.73), location ( χ ²=18.60), pathological type ( χ ²=8.07), presence of subretinal fluid ( χ ²=15.71) and ciliary body involvement ( χ ²=19.72) were factors influencing patient prognoses (all P <0.05). In the multivariate Cox analysis, the T2, T3, T4 tumors (compared with the T1 tumor, HR =4.41, 6.82, 10.49), subretinal fluid ( HR =1.98), ciliary body involvement ( HR =1.79), being male ( HR =1.53) and advanced age (greater than 53 years old) ( HR= 1.83) were independent risk factors for poor prognoses (all P <0.05). Conclusions: UM occurs at a significantly earlier age and non-pigmented tumors represent smaller proportion in Chinese patients. Higher T-stage, presence of subretinal fluid, ciliary body involvement, advanced age, and being male are independent risk factors for poor outcomes.

Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11, respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events and establish the role of MITF in UM tumors. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP, and phospholipase C-β (PLCβ)–ERK was also investigated in this system and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLCβ4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K or Tg(mitfa:CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53–wild type UM development and allowed Tg(mitfa:PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa−/− UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa−/− zebrafish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCβ signaling. Collectively, these data show that YAP signaling is the major mediator of UM and that MITF acts as a bona fide tumor suppressor in UM in direct opposition to its essential role in CM.

Uveal melanoma (UM) is a unique disease in that patients with primary UM are well stratified based on their risk of developing metastasis, yet there are limited effective treatments once metastases occur. There is an urgent need to better understand the distinct molecular pathogenesis of UM and the characteristics of patients at high risk for metastasis to identify neoantigenic targets that can be used in immunotherapy and to develop novel therapeutic strategies that may effectively target this lethal transition. An important and overlooked area of molecular pathogenesis and neoantigenic targets in UM comes from human endogenous retroviruses (HERVs). We investigated the HERV expression landscape in primary UM and found that tumors were stratified into 4 HERV-based subsets that provide clear delineation of risk outcome and support subtypes identified by other molecular indicators. Specific HERV loci are associated with the risk of uveal melanoma metastasis and may offer mechanistic insights into this process, including dysregulation of HERVs on chromosomes 3 and 8. A HERV signature composed of 17 loci was sufficient to classify tumors according to subtype with greater than 95% accuracy, including at least 1 intergenic HERV with coding potential (HERVE&#95;Xp11.23) that could represent a potential HERV E target for immunotherapy.

Purpose: To examine patient survival in untreated primary uveal melanoma., Methods: Systematic review and meta-analysis., Results: Seven studies with a total of 19 patients were included. Fifteen patients died from metastases during a median follow-up of > 20 years. When excluding two patients with iris melanoma, fifteen of 17 patients with choroidal or ciliary body melanoma developed metastases. The cumulative disease-specific survival for these 17 patients was 71% at five years, 29% at 10 years, 18% at 15 years and 11% at 30 years. This was significantly worse than the survival in comparison cohorts of both medium-sized and large treated tumors (p < 0.001)., Conclusions: Among the exceedingly rare published patients with untreated primary uveal melanoma, 80-90% have developed metastases and their disease-specific survival seems to be shorter than treated patients. This could indicate that some metastases might be prevented by primary tumor treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To explore the research trends for uveal melanoma with bibliometric methods using Web of Science Core Collection (WoSCC) and PubMed (PM)., Methods: To find UM-related studies, "uveal melanoma" was used as search term in the WoSCC and PM for the period time from 2000 to 2020. Bibliographic coupling analysis was used to investigate the journals with the highest number of UM-related publications. VOSviewer (VV) was used for mapping the knowledge domain and visualizing the co-occurrence of terms, authors, organizations, countries, co-citation literature, and keywords. The knowledge map based on WoSCC and PM was compared., Results: In the WoSCC 3,748 articles were found, while in PM the search resulted in 3,403 articles. The number of original articles has steadily grown in general in the past two decades. The top ten authors were contributing to 23% (n = 856) of all publications, while the top 10 institutions published 41% (n = 1524) of all articles. The top 3 journals with the highest number of publications for UM-related research included Investigative ophthalmology & visual science, Ophthalmology, and British Journal of Ophthalmology. Co-occurrence analysis based on author keywords showed 6 clusters. The most frequent keywords included are metastasis, prognosis, and brachytherapy. The latest research hotspots focused on BAP1, immunotherapy and GNAQ., Conclusions: Genetics and immunology are the latest research frontiers in uveal melanoma. There is a clear need for interdisciplinary, molecular and clinical research approaches to improve the fatal prognosis of uveal melanoma patients., (© 2021. The Author(s).)