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Background: Despite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival., Methods: A retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis., Results: A total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively., Conclusions: Development of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death., Plain Language Summary: Metastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma., (© 2023 American Cancer Society.)

Purpose: To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value., Design: Retrospective analysis., Participants: Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center., Methods: Patients' demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome., Main Outcome Measures: Metastasis-free survival (MFS)., Results: Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%)., Conclusions: Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023. Published by Elsevier Inc.)

Background/aims: Uveal lymphoid hyperplasia (formerly benign reactive hyperplasia of the choroid) spans histopatholological characteristics ranging from reactive hyperplasia to low-grade lymphoid neoplasm. There is strong evidence that other low-grade lymphoid neoplasms, particularly of gastric derivations, respond to oral antibiotics. Here, we explore that response of uveal lymphoid hyperplasia to treatment with only oral antibiotics and steroids., Methods: Four eyes of three patients with clinically diagnosed uveal lymphoid hyperplasia were treated with a course of oral antibiotics and steroids. The main outcome was clinical response of choroidal infiltrate by optical coherence tomography (OCT) measurements of choroidal thickness and visual acuity. Secondary outcome measure included local and systemic recurrence. Clinical response was evaluated by clinical exam, fundus photography, ultrasound and OCT., Results: All 4 eyes displayed a clinical response at a median 2 weeks after starting oral antibiotics and steroid course. The choroidal infiltration regressed as evidenced by: decrease of choroidal thickness by a median of 421 nm, myopic shift in refractive error by a median of 0.50 Diopters, and improved vision by a median of 1.5 Snellen lines. At a median of 51-month follow-up, all four eyes had a sustained complete response and no patient has developed systemic disease to date., Conclusions: In this small cohort of patients with uveal lymphoid hyperplasia, measurable and sustained clinical responses were observed with antibiotics/steroids, without systemic recurrence. This suggests combination antibiotic/steroid therapy is a reasonable treatment for select cases of uveal lymphoid hyperplasia, and may avoid the need for systemic chemotherapy/monoclonal antibody and/or external beam irradiation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the presence of plasma circulating tumor DNA (ctDNA) in patients with uveal melanoma during and after primary tumor treatment., Methods: Detectability and variant allele frequency of ctDNA were assessed using a 129-oncogene panel using next-generation deep sequencing and hybridization capture in 69 patients with uveal melanoma undergoing primary treatment with enucleation (n = 8, during surgery) or plaque brachytherapy (n = 61; postoperative day 0, 1, 2, or 3). Follow-up assessments were performed in 39 patients over a median of 21 months (range, 3.2-31.9 months) of follow-up. Correlations between genomic data and disease parameters were performed., Results: Overall, ctDNA was detectable in 20 of 69 patients with uveal melanoma (28.9%) during the perioperative period. On the day of enucleation, ctDNA was detected in two of eight patients (25%). In patients undergoing brachytherapy, ctDNA was significantly more detectable on postoperative days 2 or 3 compared with postoperative day 0 or 1 (32.4% vs 0.0%; P = 0.0015). Patients with follow-up ctDNA that became detectable or had an increased variant allele frequency were significantly more likely to develop metastasis compared with patients with follow-up ctDNA that became undetectable or decreased variant allele frequency (P = 0.04). In patients with detectable vs. undetectable ctDNA, there was no significant difference in tumor size, stage or location., Conclusions: ctDNA is significantly more detectable at 48 to 72 hours after plaque brachytherapy compared with less than 48 hours. ctDNA can be detected during enucleation. Relative increases in ctDNA levels may herald the development of clinically apparent metastases.

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.

Detectable metastasis at the time of initial diagnosis of uveal melanoma (UM) is rare. The purpose of this investigation was to evaluate the characteristics and outcomes in patients with metastatic UM (MUM) at initial diagnosis. An institutional review board-approved retrospective case series analysis was performed in 21 patients that presented for management of MUM at initial diagnosis. Patient, tumor and treatment parameters were recorded, and ophthalmic symptoms, metastasis response and overall survival were assessed. Among 21 patients, median tumor diameter was 18 mm (range, 9.1-35 mm), with 76% classified as a Collaborative Ocular Melanoma Study (COMS) large size. Sites of metastasis included liver (95%), bone (29%) and lung (29%), among others, and were confirmed by biopsy in 95% of patients studied. Symptomatic primary tumors were present in 81%, causing pain (24%) or vision loss (57%). Primary tumor therapy (PTT) was provided upfront for 52% of patients with enucleation (24%) and brachytherapy (29%). Eye pain developed 3-6 months after diagnosis in four of 10 patients who did not receive upfront PTT, whereas it did not occur in any of the 11 patients who received upfront PTT (P = 0.04). PTT palliated pain in all cases. The median overall survival was 11.9 months (range, 2.5-21.1 months). Patients presenting with MUM at initial diagnosis have high-risk tumors and experience survival like patients who develop metastases metachronously. PTT is not associated with survival but may mitigate ophthalmic symptoms, especially in patients with large tumors at risk for causing symptoms., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention., (© 2021. The Author(s).)

Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gα q ) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gα q have shown promising preclinical results, but their therapeutic activity in distinct Gα q mutational contexts and in vivo have remained elusive., Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of Gα q inhibition as a single agent and in combination with MEK inhibition., Results: We demonstrate that the Gα q inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo , YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo ., Conclusions: These data suggest that the combination of Gα q and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gα q in uveal melanoma. See related commentary by Neelature Sriramareddy and Smalley, p. 1217 ., (©2020 American Association for Cancer Research.)

Introduction: Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown., Methods: We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation., Results: Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1)., Conclusions: Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Metastases to the liver are often the first finding in patients with uveal melanoma with extraocular disease, but little has been published on the utility of staging MRI at initial diagnosis. We aimed to evaluate the proportion of abnormal hepatic findings on baseline MRI and accuracy of MRI in patients with newly diagnosed uveal melanoma., Methods: This is a single-centre, retrospective, institutional review board-approved study of 145 consecutive patients diagnosed with uveal melanoma, at Memorial Sloan Kettering Cancer Center between 2004 and 2016, who had staging MRI within 1 month of diagnosis. Scans were classified as normal or abnormal, and further distinguished as abnormal non-metastatic, uncharacterisable lesions and suspicious for metastasis. Where available, follow-up MRI (at ~1 year) or biopsies were reviewed., Results: MRI in 145 patients revealed 62% (90) with abnormal hepatic findings; out of these 87% (78) had non-metastatic benign findings, 6.7% (6) had unclassifiable lesions and 6.7% (6) were suspicious for metastasis (6). Abnormal non-metastatic findings included 72 focal (36 solitary and 36 multiple) and 12 diffuse lesions. Lesions suspicious for metastases were found in 6 of 145 patients (4%), despite normal liver function tests. Of these, five had confirmed liver metastases and one patient had a stable, presumed non-metastatic lesion on follow-up. In this study, the sensitivity and specificity of staging MRI for all findings were 83.3% (95% CI 35.9 to 99.6) and 99.0% (95% CI 94.3 to 99.9), respectively., Conclusion: Staging MRI of patients with newly diagnosed uveal melanoma accurately identified early metastases. Furthermore, imaging revealed hepatic abnormalities in the majority of patients, although as expected few of these represented metastatic disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care., Competing Interests: RDC received non-financial support from AstraZeneca, during the conduct of this work; RDC has received grants, personal fees and non-financial support from AstraZeneca, personal fees from Janssen, personal fees from Thompson Reuters, personal fees from Merck, personal fees from Biogen Idec, personal fees from Aura Biosciences, grants from Melanoma Research Foundation, grants from Melanoma Research Alliance, grants from NIH and grants from ASCO, outside the submitted work. PDN reports personal fees from AstraZeneca, outside the submitted work., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: The aim of this study was to review peer-reviewed articles on ophthalmic oncology (specifically retinoblastoma and uveal melanoma) published from January to December 2014., Design: This study is a literature review., Methods: The terms retinoblastoma and uveal melanoma were used in a MEDLINE literature search. Abstracts were studied, and the most relevant articles were selected for inclusion and further in-depth review., Results: In retinoblastoma, more eyes are being salvaged due to intravitreal melphalan. The year 2014 marks a deepening in our understanding of the biological basis of the disease and the cell of origin. Knowledge on the genetic underpinnings of uveal melanoma has broadened to include other pathways, interactions, and potential therapeutic targets., Conclusions: In 2014, there were valuable advancements in our knowledge of retinoblastoma and uveal melanoma. Some of these resulted in improved patient management.

Purpose: Plaque brachytherapy is a common form of treatment for uveal melanoma, and the Collaborative Ocular Melanoma Study (COMS) used (125)I. Recently, (106)Ru has been reintroduced for plaque brachytherapy in the United States. We reviewed our experience treating uveal melanoma with (106)Ru plaque brachytherapy using COMS planning techniques, hypothesizing that we would observe similar outcomes to those in the COMS., Methods and Materials: Medical records of patients undergoing (106)Ru plaque brachytherapy were reviewed retrospectively. Patient, tumor, and treatment characteristics were recorded. Outcomes including visual acuity, local tumor recurrence, salvage treatment, metastasis, and survival were recorded. Cox regression analyses were used to determine factors associated with local tumor recurrence and enucleation., Results: Twenty-eight patients were studied. Median age was 60 years, and 50% were men. Median tumor base diameter and height were 9.4 and 2.6 mm, respectively. Ophthalmic complications were rare. Local tumor recurrence and enucleation occurred in 13 and 4 patients, respectively. Local tumor recurrence was associated with low visual acuity in the tumor-bearing eye, posterior tumors, small plaque size, and difference in plaque-tumor diameter of <6 mm. Enucleation was associated with low visual acuity and posteriorly located tumor. Estimated 5-year rate of death and metastasis was 18.5% and 11.4%, respectively., Conclusions: Among patients treated with (106)Ru plaque brachytherapy using COMS planning techniques, we found a greater than expected rate of local tumor recurrence. Planning (106)Ru plaque brachytherapy should be done carefully at centers that have previously used COMS protocols and (125)I., (Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Even though less than 1% of uveal melanoma patients are found to have radiographic or clinical evidence of distant disease at the time of treatment for their intraocular disease, they carry a lifetime risk of disease recurrence, with approximately 50% of patients ultimately developing fatal metastases. Despite this significant risk, there is no consensus within the ophthalmologic or oncologic community regarding the role of surveillance for detection of metastatic disease in these patients. The lack of consensus is due to the notable absence of clear data regarding the best radiologic or serum surveillance modalities, the optimal frequency of testing, or the ideal length of follow-up. Given the ability to assess prognosis by cytogenetics, gene expression profiling, or other methods, questions remain about whether surveillance strategies should be tailored by level of risk. Importantly, no survival benefit from the early detection of asymptomatic disease in uveal melanoma has been documented, resulting in controversy over the value of routine surveillance and advocacy from some clinicians to forego surveillance altogether. However, there are several factors supporting surveillance: the patient's enhanced emotional well-being, the potential to identify oligometastatic disease amenable to surgery or other local therapies, decreased morbidity/complications from advanced disease, and identification of patients eligible for clinical trials that assess novel therapies for advanced uveal melanoma. The selection of surveillance modality used varies according to local expertise and resources and may include serum markers (liver function tests and others) and/or imaging (chest x-ray, abdominal ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging).