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Purpose: To determine whether the availability of a cytopathology-confirming diagnosis is correlated with the prognostic accuracy of a gene expression profiling assay. Methods: A single-center retrospective review was performed of patients diagnosed with uveal melanoma who had a fine-needle aspiration biopsy and gene expression profiling before proton therapy from 2012 to 2020. The development of metastases was compared in patients with gene expression profiling and cytopathology (gene expression profiling+cytopathology group) and patients with gene expression profiling only (gene expression profiling only group). Results: Of 141 patients with gene expression profiling, 98 (69.5%) had cytopathology results and 43 (30.5%) did not. The median tumor thickness was greater in the gene expression profiling+cytopathology group (5.0 mm) than in the gene expression profiling only group (3.1 mm) ( P  = .0003). The distribution of gene expression profiling class in these 2 groups, respectively, was class 1A, 38 (38.8%) vs 20 (46.5%); class 1B, 20 (20.4%) vs 15 (34.9%); class 2, 40 (40.8%) vs 8 (18.6%). Class 1A tumors metastasized in 4 patients (10.5%) in the gene expression profiling+cytopathology group and 3 patients (15.0%) in the gene expression profiling only group. Class 1B tumors metastasized in 3 patients (15.0%) and 1 patient (6.7%), and class 2 tumors metastasized in 18 patients (45.0%) and 5 patients (62.5%) in these 2 groups, respectively. The median months from initial treatment to metastasis diagnosis within each gene expression profiling class for the gene expression profiling+cytopathology and gene expression profiling only groups, respectively, was class 1A, 36.7 vs 33.6 ( P  = .86); class 1B, 37.8 vs 68.6 ( P  = 1.0); class 2, 19.0 vs 15.8 ( P  = .70). Conclusions: We found no evidence that the lack of confirmatory cytology negatively affects the accuracy of gene expression profiling, and no significant differences were found in the overall rates of metastasis between patients with and patients without cytopathology or rates within each class of gene expression profiling., Competing Interests: The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Gragoudas owns stock in Aura Biosciences. Dr. Kim receives research support from Allergan and is a consultant to Biophytis, Genentech, and Kodiak Sciences. None of the other authors declared potential conflicts of interest with respect to the research, authorship, and/or publication of the article., (© The Author(s) 2024.)

Objective: Proton beam re-irradiation (PBI) remains an effective and globe-preserving alternative to enucleation in the treatment of local recurrence in uveal melanoma. The study aimed to assess visual outcomes and prognostic factors in visual acuity (VA) after proton beam salvage therapy., Design: Retrospective study., Subjects: A retrospective study evaluated patients with recurrent uveal melanoma treated with PBI from 1984 through 2019 at a single academic tertiary center., Methods: Patient and tumor characteristics were collected from the medical record, as well as best visual acuity (BVA) and ocular outcomes after treatment of recurrent uveal melanoma with PBI., Main Outcome Measures: The primary outcome of the study was the BVA of patients after PBI for recurrent uveal melanoma. Additional outcome measures included enucleation rate of patients after salvage PBI and analysis of tumor and patient characteristics in the prognostication of VA., Results: The study comprised 67 patients who received PBI for recurrent uveal melanoma. The median age at recurrence was 67.6 years (range, 31.6-91.0 years), and median follow-up from the time of recurrence to last examination was 4.4 years (range, 0.23-17.1 years). The median final BVA was hand motions (range, 20/20 to no light perception) and 6 (9.1%) patients maintained a Snellen VA 20/40 or better. The 5-year probability of VA retention of 20/200 or better was 19%. In a multivariable Cox model, VA at tumor recurrence of worse than 20/40 was found to be significantly associated with a VA of 20/200 or worse after retreatment with PBI. Twelve (18%) patients underwent enucleation after retreatment with PBI., Conclusions: Proton beam irradiation for the treatment of recurrent uveal melanoma allows for ocular preservation and functional vision in select patients., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024. Published by Elsevier Inc.)

Surveillance frequency for metastasis is guided by gene expression profiling (GEP). This study evaluated the effect of GEP on time to diagnosis of metastasis, subsequent treatment and survival. A retrospective study was conducted of 110 uveal melanoma patients with GEP (DecisionDx-UM, Castle Biosciences, Friendswood, Texas, USA) and 110 American Joint Committee on Cancer-matched controls. Surveillance testing and treatment for metastasis were compared between the two groups and by GEP class. Rates of metastasis, overall survival and melanoma-related mortality were calculated using Kaplan-Meier estimates. Baseline characteristics and follow-up time were balanced in the two groups. Patients' GEP classification was 1A in 41%, 1B in 25.5% and 2 in 33.6%. Metastasis was diagnosed in 26.4% ( n  = 29) in the GEP group and 23.6% ( n  = 26) in the no GEP group ( P  = 0.75). Median time to metastasis was 30.5 and 22.3 months in the GEP and no GEP groups, respectively ( P  = 0.44). Median months to metastasis were 34.7, 75.8 and 26.1 in class 1A, 1B and 2 patients, respectively ( P  = 0.28). Disease-specific 5-year survival rates were 89.4% [95% confidence interval (CI): 81.0-94.2%] and 84.1% (95% CI: 74.9-90.1%) in the GEP and no GEP groups respectively ( P  = 0.49). Median time to death from metastasis was 10.1 months in the GEP group and 8.5 months in the no GEP group ( P  = 0.40). There were no significant differences in time to metastasis diagnosis and survival outcomes in patients with and without GEP. To realize the full benefit of GEP, more sensitive techniques for detection of metastasis and adjuvant therapies are required., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: We evaluated a large cohort of patients treated for local recurrence of choroidal or ciliary body melanomas at the Massachusetts Eye and Ear (MEE) to quantify the risk of melanoma-related mortality associated with recurrence, independent of other risk factors., Methods: Patients treated with radiation therapy from 1982 to 2017 were identified through the Uveal Melanoma Registry at MEE. Competing risks regression was performed to investigate the risk of melanoma-related mortality associated with recurrence, treating recurrence as a time-varying covariate., Results: Of 4196 patients treated, 4043 patients remained recurrence-free and 153 patients experienced a recurrence (median follow-up: 9.9 years). Median time from initial treatment to recurrence was 30.5 months (range: 2.0-238.7). Seventy-nine (69.9%) patients with recurrences and 826 (37.9%) patients in the recurrence-free group died of metastatic uveal melanoma (p<0.001). Median time from initial treatment to melanoma-related death was 4.9 years (1.0-31.8) for patients who developed recurrences and 4.3 years (0.59-33.8) for patients who did not (p=0.17). Five-year and 10-year probabilities of melanoma-related mortality were 9.5% and 15.0%, respectively, in patients without local recurrences compared with 32.0% and 46.6% in patients with recurrences (p<0.001)., Conclusion: These data confirm previous reports that local recurrence is associated with an increased risk of dying of melanoma and quantify the risk that can be attributed to local recurrence independent of other risk factors. This group of patients should be strongly considered for adjuvant therapies when available., Competing Interests: Competing interests: Dr. Kim receives research support from Aura Biosciences and Allergan and is a consultant for Castle Biosciences. Dr. Gragoudas is a consultant for Aura Biosciences.Ms. Lane, Mr. Hartley, Ms. Go, and Dr. Wu have no competing interests to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Somatic chromosomal alterations, particularly monosomy 3 and 8q gains, have been associated with metastatic risk in uveal melanoma (UM). Whole genome-scale evaluation of detectable alterations in cell-free DNA (cfDNA) in UM could provide valuable prognostic information. Our pilot study evaluates the correlation between genomic information using ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA in UM and associated clinical outcomes., Materials and Methods: ULP-WGS of cfDNA was performed on 29 plasma samples from 16 patients, 14 metastatic UM (mUM) and two non-metastatic, including pre- and post-treatment mUM samples from 10 patients treated with immunotherapy and one with liver-directed therapy. We estimated tumor fraction (TFx) and detected copy-number alterations (CNAs) using ichorCNA. Presence of 8q amplification was further analyzed using the likelihood ratio test (LRT)., Results: Eleven patients with mUM (17 samples) of 14 had detectable circulating tumor DNA (ctDNA). 8q gain was detected in all 17, whereas monosomy 3 was detectable in 10 of 17 samples. TFx generally correlated with disease status, showing an increase at the time of disease progression (PD). 8q gain detection sensitivity appeared greater with the LRT than with ichorCNA at lower TFxs. The only patient with mUM with partial response on treatment had a high pretreatment TFx and undetectable on-treatment ctDNA, correlating with her profound response and durable survival., Conclusion: ctDNA can be detected in mUM using ULP-WGS, and the TFx correlates with DS. 8q gain was consistently detectable in mUM, in line with previous studies indicating 8q gains early in primary UM and higher amplification with PD. Our work suggests that detection of CNAs by ULP-WGS, particularly focusing on 8q gain, could be a valuable blood biomarker to monitor PD in UM.

Introduction: Vision loss is common in patients treated with radiotherapy for uveal melanoma. With proton beam irradiation (PBI), the prescribed dose is delivered to the tumor with a sharp dose reduction outside the target volume. However, radiation complications are likely to develop when tumors are located near the optic nerve or fovea. Treatment with light-activated AU-011 (belzupacap sarotalocan), an investigational drug which specifically targets tumor cells, may avoid these complications. We evaluated outcomes in a historical group of patients who fit eligibility criteria for AU-011 therapy and were treated with PBI., Methods: A consecutive series of patients who received PBI for small choroidal melanoma at a single center between 1986 and 2016 were identified. Consistent with eligibility criteria in clinical trials of AU-011, patients were included when tumor dimensions did not exceed 2.5 mm in maximum thickness and 10.0 mm in largest basal diameter (LBD). Snellen visual acuities were converted to logMAR for analysis. Visual acuity outcomes were analyzed in patients with an initial acuity of logMAR 0.7 or better (equivalent to Snellen 20/100). Rates of visual acuity loss and mortality were calculated using the Kaplan-Meier method. Acuity loss by tumor location was compared using log-rank testing. Rates of tumor recurrence, neovascular glaucoma (NVG), and eye loss were also described., Results: Two hundred and 22 patients were included in the study. The median age was 60.7 years (range 21.3-94.8 years). Median tumor thickness was 2.0 mm (range 1.2-2.5 mm), and median LBD was 8.0 mm (range 4.0-10.0 mm). Median follow-up was 6.9 years (range 1.0-30.2 years). In 204 patients with a baseline logMAR visual acuity of 0.7 or better, the mean baseline acuity was 0.15 (equivalent to Snellen 20/25), which decreased to 0.52 (approximately Snellen 20/70) by 5 years after PBI. Visual outcomes were significantly worse for patients with tumors located within 3 mm of the optic disc and/or fovea. Tumor recurrence (1.4%), NVG (4.5%), and eye loss (2.7%) were uncommon., Discussion: Despite the advantageous dose distribution of protons, over half of patients with small choroidal melanomas located near the optic disc or fovea had a visual acuity equivalent to 20/80 or worse at 5 years after PBI. Treatment with AU-011 may allow better vision preservation in small tumors that carry a high risk of vision loss with radiotherapy., Competing Interests: Dr. Kim receives research support as a clinical trial investigator for Aura Biosciences. Dr. Gragoudas is a consultant for Aura Biosciences., (© 2023 S. Karger AG, Basel.)

Purpose: Small choroidal melanocytic lesions have a low rate of metastasis and can be reasonably managed with surveillance until they demonstrate evidence of growth or clinical risk factors for melanoma. However, even choroidal nevi are not stationary, with many exhibiting slow growth over time. We sought to quantify the growth rates of indeterminate choroidal lesions that were initially observed prior to a clinical diagnosis of melanoma., Methods: A single-center retrospective study was performed of patients diagnosed with choroidal melanoma based upon clinical characteristics who were initially followed for indeterminate lesions over at least 6 months. Subjects were included if they had a minimum of two B-scan ultrasound measurements prior to the visit at which melanoma was diagnosed. Demographic and tumor characteristics were collected from the medical record. Growth rates were calculated as the change in lesion thickness in mm per month and were recorded at 6-month intervals; ultrasound measurements less than 1 month apart were excluded. The characteristics of indeterminate lesions with faster versus slower growth rates prior to melanoma diagnosis were compared., Results: Fifty-four patients met inclusion criteria. The mean age at melanoma diagnosis was 67.4 years, and 53.7% were female. Subjects had a median of four B-scan ultrasound measurements prior to melanoma diagnosis (range 2-19) and were followed for a median of 40.6 months (range 9.9-138.0 months). The mean lesion thickness was 1.4 mm (range 0.5-2.2 mm) at presentation, and increased to 2.3 mm (range 1.5-5.7 mm) at melanoma diagnosis. The mean growth rate did not exceed 0.021 mm/month (95% CI: 0.004-0.039; equivalent to 0.25 mm/year) for indeterminate lesions, but increased to 0.057 mm/month (95% CI: 0.043-0.071 mm/month; equivalent to 0.68 mm/year) at the time of melanoma diagnosis. Rapidly growing lesions had a greater tumor thickness and shorter duration of observation at the time of melanoma diagnosis., Conclusion: For most indeterminate choroidal lesions eventually diagnosed as melanoma, the lesion thickness was relatively stable for a period of time, then rose significantly between the penultimate visit and the final visit. These findings confirm the recommendation for continued monitoring of suspicious choroidal lesions, as the growth rate may accelerate just prior to melanoma diagnosis. Lesions with a mean growth rate of up to 0.25 mm/year were observed, whereas lesions clinically determined to have transformed into melanoma demonstrated a mean growth rate of 0.68 mm/year. These values provide a baseline for future studies and potential therapies directed at stabilizing or reducing the growth of indeterminate choroidal lesions or small choroidal melanomas. Limitations of this study include its retrospective nature and reliance on clinical diagnostic criteria., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To characterize dose distributions with 125 I plaque brachytherapy compared with proton radiation therapy for ocular melanoma for relevant clinical scenarios, based on tumor base diameter (d), apical height (h), and location., Methods and Materials: Plaque and proton treatment plans were created for 4 groups of cases: (1) REF: 39 instances of reference midsize circular-base tumor (d = 12 mm, h = 5 mm), in locations varying by retinal clock hours and distance to fovea, optic disc, and corneal limbus; (2) SUP: 25 superiorly located; (3) TEMP: 25 temporal; and (4) NAS: 25 nasally located tumors that were a fixed distance from the fovea but varying in d (6-18 mm) and h (3-11 mm). For both modalities, 111 unique scenarios were characterized in terms of the distance to points of interest, doses delivered to fovea, optic disc, optic nerve at 3 mm posterior to the disc (ON@3mm), lens, and retina. Comparative statistical evaluation was performed with the Mann-Whitney U test., Results: Superior dose distributions favored plaque for sparing of (1) fovea in large (d + h ≥ 21 mm) NAS tumors; (2) ON@3mm in REF cases located ≤4 disc diameters from disc, and in NAS overall. Protons achieved superior dose sparing of (1) fovea and optic disc in REF, SUP, and TEMP; (2) ON@3mm in REF >4 disc diameters from disc, and in SUP and TEMP; and (3) the lens center overall and lens periphery in REF ≤6 mm from the corneal limbus, and in TEMP with h = 3 mm. Although protons could completely spare sections of the retina, plaque dose was more target conformal in the high-dose range (50% and 90% of prescription dose)., Conclusions: Although comparison between plaque and proton therapy is not straightforward because of the disparity in dose rate, prescriptions, applicators, and delivery techniques, it is possible to identify distinctions between dose distributions, which could help inform decisions by providers and patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Management of pediatric choroidal hemangioma complicated by large exudative retinal detachment can be challenging, with few options available. Limited data have been published on outcomes following proton radiotherapy (PRT) for management of these patients. In this retrospective case series, nine patients were treated with a low-dose PRT regimen of 20 Gy(relative biological effectiveness [RBE]) in 10 fractions, and two were treated with 15 Gy(RBE) in four fractions. Visual acuity improved in seven patients (64%) and remained stable in the remaining four (36%). In patients with imaging follow-up (10 patients), subretinal fluid resolved in nine patients (90%) and tumor thickness decreased or remained stable in 10 (100%). Complications were observed in eight of 11 patients (73%). One patient developed grade 2 cataract; otherwise, no grade ≥2 complications were observed., (© 2022 Wiley Periodicals LLC.)

Objective: To compare outcomes in a large patient cohort with small-medium tumors located within 1 disc diameter (DD) of the optic nerve and/or fovea treated with 50 Gy or 70 Gy proton therapy., Design: Retrospective cohort study., Subjects: A total of 1120 patients with uveal melanomas ≤ 15 mm in largest basal diameter, ≤ 5 mm in height, located within 1 DD of the optic nerve and/or fovea, who received primary treatment with protons between 1975 and 2016 at Massachusetts Eye and Ear/Massachusetts General Hospital., Methods: The rates of outcomes were estimated using the Kaplan-Meier method. Differences between the radiation dose groups were tested using the log-rank test., Main Outcome Measures: Local tumor recurrence, melanoma-related mortality, and visual acuity preservation (≥ 20/200, ≥ 20/40)., Results: Local tumor recurrence was observed in 1.8% of the 50 Gy group and 1.5% of the 70 Gy group. The median time to recurrence was 30.7 months for patients treated with 50 Gy and 32.0 months for those treated with 70 Gy (P = 0.28). Five-year rates of vision retention (≥20/40, ≥ 20/200) were 19.4% and 49.3% for patients treated with 50 Gy and 16.4% and 40.7% in those treated with 70 Gy. Ten-year rates of melanoma-related mortality were 8.4% in the 50 Gy group and 8.9% in the 70 Gy group (P = 0.47)., Conclusions: Comparable rates of local control are achieved treating small-medium tumors near the optic nerve and/or fovea with 50 Gy or 70 Gy proton therapy, supporting the use of the lower dose in patients with these tumor characteristics., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Medication samples of anti-VEGF agents can represent a good option for retina specialists to provide timely treatment for newly converted neovascular age-related macular degeneration (nvAMD) while prior-authorizations (PA) are pending. Our study examines the effect of medication sample use (ranibizumab or aflibercept) on future anti-vascular endothelial growth factor (VEGF) agent selection in nvAMD., Design: Retrospective cohort study., Participants: nvAMD patients who underwent an initial anti-VEGF injection with a sample medication were compared to nvAMD control patients who never received a medication sample., Methods: Charts from 2017 through 2020 were reviewed for data regarding demographics, anti-VEGF agent selection, and visual acuity outcomes for both groups. The utilization of different anti-VEGF agents in each group was compared at various time points using chi-square tests for independence of proportions., Main Outcome Measures: Anti-VEGF agent selection for the first four injections and at one year were examined., Results: Adherence to the initial agent was high between first and subsequent injections (2 nd , 3 rd , 4 th injection, and 1 year) in sample (96.2%, 95.9%, 91.9%, 93.4%, respectively), and control groups (98.1%, 94.2%, 94.9%, 87.8%, respectively). Bevacizumab usage was significantly lower among eyes receiving samples relative to controls at the second (1.9% vs. 38.7%, p < .001), third (3.1% vs. 41.3%, p < .001), fourth injections (4.7% vs. 40.4%, p < .001), and at 1 year (0% vs. 33.8%, p < .001). Aflibercept usage was significantly higher in sample eyes relative to controls at the second (78.3% vs. 43.4%, p < .001), third (76.3% vs. 41.5%, p < .001), and fourth injections (76.7% vs. 43.4%, p < .001), and at 1 year (77.0% vs. 52.7%, p < .001)., Conclusions: Sample medications in nvAMD may be initiated for many reasons, including awaiting PA approval. Our study found that eyes receiving a sample anti-VEGF agent (ranibizumab or aflibercept) for their initial injection were less likely to receive bevacizumab at future visits relative to eyes that did not receive an anti-VEGF sample, even after one year of treatment. Given the persistent use of more expensive medications at subsequent injections for patients who were initiated on samples, insurance payors may consider waiving PA requirements for bevacizumab to avoid a paradoxical increase in health-care costs.

Aims: To assess treatment outcomes after proton beam irradiation (PBI) without surgical localisation of uveal melanomas involving the iris, ciliary body and anterior choroid., Methods: Retrospective chart review of 125 patients evaluated at Massachusetts Eye and Ear and treated with PBI using a light field set-up without localisation surgery between November 1975 and April 2017. The tumours were characterised as follows: iris (n=18, 14.4%), ciliary body (n=12, 9.6%), iridociliary (n=58, 46.4%), ciliochoroidal (n=24, 19.2%) and iridociliochoroidal (n=13, 10.4%). The tumours were measured by transillumination and ultrasonography before treatment. Tumours with posterior margin located less than two disc diameters from the ora serrata were treated using the light field technique. Patient outcomes after PBI were evaluated., Results: Most patients had good vision at the time of tumour diagnosis (69.6% had baseline visual acuity (VA) of ≥20/40). Median VA at last follow-up (median follow-up: 72.1 months) was 20/63. Recurrences occurred in 12 patients (9.6%) at a median time of 4.0 years post-treatment. Recurrences were treated by repeat PBI (n=5) or enucleation (n=7). Secondary enucleation was performed in 18 patients (14.4%), and 61.1% of these were due to complications. Neovascular glaucoma (NVG) developed in 21 patients (16.8%). Of seven patients who developed NVG after anti-vascular endothelial growth factor (anti-VEGF) therapies became available, five were treated with intravitreal Avastin injections (23.8% of patients with NVG). Of 69 patients diagnosed with cataract after treatment, 51 (73.9%) were characterised as radiation-related. Death from metastatic uveal melanoma occurred in 20.8% of the cohort, with a median follow-up of 10.1 years., Conclusions: Patients treated with PBI using a light field set-up technique experience good outcomes after irradiation. Eye preservation and retention of good VA are seen in the majority of cases, and tumour recurrence is low., Competing Interests: Competing interests: IKK: Novartis; Castle Biosciences; Biophytis; Kodak. ESG: Astellas Institute for Regenerative Medicine; Aura Pharmaceuticals; Valeant. HS: UpToDate (writer); Radiosurgery Society (Board of Directors); Cleveland Clinic (expert testimony); prIME Oncology (Educational Symposium Speaker)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)