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Purpose: To compare the clinical outcomes of children with unilateral retinoblastoma (Rb) and high-risk histopathology features (HRHF) following upfront enucleation with/without adjuvant chemotherapy, and investigate cases locally considered non-HRHF but converted to a standardized HRHF definition., Design: Retrospective multinational clinical cohort study., Methods: Children with Rb who presented to 21 centers from 12 countries between 2011-2020, and underwent primary enucleation were recruited. Centers retrieved clinical data and were asked to report detailed histopathology findings, as well as indicate cases defined locally as high-risk. For analysis, only unilateral cases with standardized HRHF, defined as retrolaminar optic nerve invasion, massive choroidal invasion, scleral invasion, anterior-segment involvement, and/or combined nonmassive choroidal and prelaminar/laminar optic nerve invasion, were included. Main outcome measures included orbital tumor recurrence, systemic metastasis, survival and number, and outcome of cases converted to standardized HRHF., Results: A total of 600 children presenting to 14 centers in 9 countries were included. Of these, 505 (84.2%) were considered locally as HRHF and received adjuvant chemotherapy. After a median follow-up period of 39.2 ± 1.6 months (range: 0.8-60.0 months), 36 (6.0%) had orbital tumor recurrence, 49 (8.2%) metastasis, and 72 (12.0%) children died. Children not receiving adjuvant chemotherapy were at significantly increased risk of orbital tumor recurrence, metastasis, and death (P ≤ .002). Of the study children, 63/600 (10.5%) were considered locally non-HRHF, but converted to standardized HRHF and included in the analysis. Of these, 6/63 (9.5%) had orbital tumor recurrence, 5/63 (7.9%) metastasis, and 6/63 (9.5%) children died. Isolated minor choroidal invasion with prelaminar/laminar optic nerve invasion was reported in 114 (19.0%) children, but considered locally as HRHF only in 68/114 (59.6%). Of these, 6/114 (5.3%) children developed metastasis and subsequently died, yielding a number needed to treat of 15., Conclusion: Based on this multinational cohort of children with Rb, we recommend the use of adjuvant chemotherapy following upfront enucleation and diagnosis of HRHF. Variation exists worldwide among centers when defining HRHF, resulting in adverse patient outcomes, warranting standardization., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate tissue glue-assisted plaque placement regarding accuracy, stability, and longer-term outcomes for choroidal tumors with scleral thinning., Methods: All patients with tissue glue-assisted plaque radiotherapy at a single ocular oncology center were evaluated for patient demographics, tumor features, surgical details, tumor response, and glue-related complications., Results: There were 13 patients (mean age 72 years) treated with tissue glue-assisted plaque radiotherapy for choroidal melanoma (n=12) or choroidal metastasis (n=1). At presentation, the tumor was mean 4.3 mm to the optic disc and 2.0 mm to the foveola with mean basal diameter of 9.5 mm and thickness of 4.2 mm. In all cases, the tissue glue-assistance was employed due to extreme scleral thinning in the bed of proposed radiation. The plaque size was 15 mm (n=5), 18 mm (n=7), or 20 mm (n=1). At application, there was no immediate glue hypersensitivity, ultrasonography confirmed accuracy of placement, and the glue remained adherent for the entire treatment duration (mean 113 hours) with stable plaque location at removal. At removal, the plaque-glue composite was peeled off the globe without need for glue dissolvent and without scleral disruption. At 12 months mean melanoma thickness (2.7 mm, regression 36%). There were no conjunctival, corneal, or scleral complications., Conclusion: Tissue glue-assisted plaque radiotherapy is safe and effective for treatment of choroidal tumors with thin sclera.

Purpose: To determine the impact of uveal melanoma thickness on patient survival from the date of presentation and at specific time intervals following metastasis-free survival., Methods: In this retrospective cohort study, we evaluated data from 8034 consecutive uveal melanoma patients diagnosed at a tertiary care ocular oncology center between May 1972 and August 2007. The patients were categorized on the basis of tumor thickness (per each 1-mm increment) and evaluated for non-conditional survival (from date of presentation) and conditional survival (with 3-years, 5-years, and 10-years of metastasis-free survival) on the cumulative incidence of melanoma-related metastasis at 5-, 10-, 15-, 20-, 25- and 30-years., Results: For the entire cohort, Non-conditional incidence of metastasis at 5-, 10-, 15-, and 30-years was 8%, 11%, 12%, and 12%. Conditional cumulative incidence of metastasis with 5-year and 10-year metastasis-free survival revealed 30-year incidence of metastasis at 10% and 8%, respectively. The multivariate Cox regression analysis showed that each 1-mm increase in tumor thickness was associated with a significant ( p  < .05) increase in the risk of metastasis [HR: 1.08 (95% CI: 1.05-1.11) for non-conditional survival, HR: 1.07 (95% CI: 1.03-1.11) for 3-year metastasis-free survival, HR: 1.09 (95% CI: 1.03-1.15) for 5-year metastasis-free survival, and HR: 1.17 (95% CI: 1.05-1.30) for 10-year metastasis-free survival]., Conclusion: In this study, we emphasize that increasing the thickness of uveal melanoma at presentation demonstrates a poorer ultimate prognosis. However, those with longer metastasis-free intervals were found to have a lower risk of ultimate metastatic disease, highlighting the importance of conditional and non-conditional survival.

Purpose: To assess histopathology and outcomes following primary enucleation of eyes with retinoblastoma presenting with neovascular glaucoma (NVG)., Methods: This was an international multi-centre case series study across five continents. Retrospective review of patient charts was performed for all patients undergoing primary enucleation for retinoblastoma (n=1420) using a standardised data-collection spreadsheet. Clinical features, pathological grade, and outcomes were compared between NVG patients and those with an American Joint Commission on Cancer (AJCC) 8th edition clinical stage of cT2. High-risk histopathology was defined as AJCC 8th edition pathological stage ≥pT2b., Results: NVG was seen in 224/1420 (16%) patients. Mean age at presentation of those with NVG was 30 months (median 25, range 0-120 months) and 131(58%) patients had high-risk histopathology. The univariate logistic regression odds ratio for NVG predicting high-risk histopathology was 1.73 (95% confidence interval: 1.3 to 2.31) and from multivariate logistic regression was 1.77 (95% confidence interval: 1.23 to 2.56). Patients with a longer duration of symptoms (p=0.03), buphthalmos (p=0.02) and ectropion uveae (p<0.01) were more likely to have high-risk histopathology. Patients with NVG were more likely to develop metastasis than cT2 patients (p=0.04)., Conclusions: There is a significant association between NVG at presentation, high-risk histopathology and metastatic risk.

Protein S (PROS1) has recently been identified as a ligand for the TAM receptor MERTK, influencing immune response and cell survival. The PROS1-MERTK interaction plays a role in cancer progression, promoting immune evasion and metastasis in multiple cancers by fostering a tumor-supportive microenvironment. Despite its importance, limited structural insights into this interaction underscore the need for computational studies to explore their binding dynamics, potentially guiding targeted therapies. In this study, we investigated the PROS1-MERTK interaction using advanced computational analyses to support immunotherapy research. High-resolution structural models from ColabFold, an AlphaFold2 adaptation, provided a baseline structure, allowing us to examine the PROS1-MERTK interface with ChimeraX and map residue interactions through Van der Waals criteria. Molecular dynamics (MD) simulations were conducted in GROMACS over 100 ns to assess stability and conformational changes using RMSD, RMSF, and radius of gyration (Rg). The PROS1-MERTK interface was predicted to contain a heterogeneous mix of amino acid contacts, with lysine and leucine as frequent participants. MD simulations demonstrated prominent early structural shifts, stabilizing after approximately 50 ns with small conformational shifts occurring as the simulation completed. In addition, there are various regions in each protein that are predicted to have greater conformational fluctuations as compared to others, which may represent attractive areas to target to halt the progression of the interaction. These insights deepen our understanding of the PROS1-MERTK interaction role in immune modulation and tumor progression, unveiling potential targets for cancer immunotherapy., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests. Ethics Approval This is an observational study. The University of Miami Research Ethics Committee has confirmed that no ethical approval is required., (© 2024. The Author(s).)

Purpose: Suture preplacement by the ocular oncology surgeon is a critical step before inserting a radioactive plaque for ocular melanoma brachytherapy. We report on a novel 3D-printing method to create a custom "dummy" plaque applicator for the 22 mm notched gold plaque using in-house 3D-printing., Methods: A computer-aided design (CAD) file was created replicating a heavily used gold plaque that no longer has a satisfactory "dummy" plaque. The file was exported as a 3D file (surface tessellation language, STL) and prepared using Formlabs' PreForm print software. The 3D-printed dummies were oriented on the printer to have no cups or supports on the surfaces that would come in contact with the patient's external sclera. The dummies were printed in FormLabs BioMed Clear V1 on a Formlabs Form-3 3D printer. Postprinting, the dummies were processed in isopropyl alcohol and cured according to manufacturer instructions. They were polished utilizing a rotary tool to improve transparency. Chemical and sterilization cycle tests were performed to ensure dummy integrity., Results: Four "dummy" plaques were printed. The 3D-printed "dummy" dimensions were verified to be within 0.5-mm of the notched plaque using digital calipers. The polishing process created acceptable light opacity for the eye plaque procedure in the operating room. No impactful discoloration or material change was observed during the chemical and sterilization cycle tests performed., Conclusions: 3D printing can produce custom eye plaque dummies using transparent, biocompatible, chemically inert materials suitable for human use. This capability introduces an additional layer of patient-specific hygienics., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the association between insurance status and uveal melanoma (UM) care., Methods: We utilized the National Cancer Database to identify patients diagnosed with UM from 2004 to 2017. We examined the associations between patient sociodemographic characteristics, specifically insurance status, and UM care., Results: Of 7677 patients, 50% had private, 41% Medicare, 4% Medicaid, 3% other government, and 3% no insurance. Most initially received brachytherapy (66%), followed by enucleation/resection (19%) and other treatment (15%). Compared to private, Medicaid and no insurance were associated with higher odds of late-stage disease presentation ( p  < .05). Patients with Medicare, Medicaid, and no insurance had higher odds of enucleation/resection and lower odds of brachytherapy versus enucleation/resection ( p  < .05 for all). Medicaid and no insurance were associated with lower odds of other treatment versus enucleation/resection ( p  < .05)., Conclusions: Access barriers to UM care may exist based on insurance status and may be associated with later-stage presentation and more radical treatment.

Purpose: A lack of representative human disease models has limited the translation of new and more effective treatments in uveal melanoma (UM), the most common primary adult intraocular malignancy. To fill this critical need, we developed and characterized a multicenter biobank of UM patient-derived organoids (PDOs)., Methods: UM patients requiring enucleation from 2019 to 2024 donated tumor tissue for PDO generation. PDOs were cultured in Cultrex and compared to donor primary tumor using exome sequencing, RNA sequencing, and immunohistochemistry. The ability of PDOs to maintain the transformed phenotype was evaluated in an orthotopic xenograft model and monitored with fundus imaging. ATAC sequencing and drug response assays were done in a subset of PDOs to explore the feasibility of their use for mechanistic and translational studies., Results: PDOs were successfully established in 40 of 44 cases (91%), retained clinically relevant mutations and molecular markers from the primary tumor, and displayed similar gene expression profiles and well-validated clinical prognostic markers of the disease. PDOs retained tumorigenic capacity in an in vivo model resembling human disease progression. Finally, we demonstrated that PDOs were a feasible platform to identify and evaluate novel therapeutic targets and investigate differential, personalized drug response., Conclusions: PDO models offer a new platform with improved representation of human UM to aid in translational research for this dismal condition.

Background: The color variation in fundus images from differences in melanin concentrations across races can affect the accuracy of artificial intelligence and machine learning (AI/ML) models. Hence, we studied the performance of our AI model (with proven efficacy in an Asian-Indian cohort) in a multiracial cohort for detecting and classifying intraocular RB (iRB). Methods: Retrospective observational study. Results: Of 210 eyes, 153 (73%) belonged to White, 37 (18%) to African American, 9 (4%) to Asian, 6 (3%) to Hispanic races, based on the U.S. Office of Management and Budget's Statistical Policy Directive No.15 and 5 (2%) had no reported race. Of the 2473 images in 210 eyes, 427 had no tumor, and 2046 had iRB. After training the AI model based on race, the sensitivity and specificity for detection of RB in 2473 images were 93% and 96%, respectively. The sensitivity and specificity of the AI model were 74% and 100% for group A; 88% and 96% for group B; 88% and 100% for group C; 73% and 98% for group D, and 100% and 92% for group E, respectively. Conclusions: The AI models built on a single race do not work well for other races. When retrained for different races, our model exhibited high sensitivity and specificity in detecting RB and classifying RB.

Background: Uveal melanoma (UM) can be classified by tumour size category and by The Cancer Genome Atlas (TCGA) groups (cytogenetic-based, 4-category prognostic classification into Groups A-D). This study was conducted to assess impact on metastasis-free survival (MFS) in UM by tumour size category based on correlation with TCGA classification., Methods: Retrospective analysis of 1001 cases categorised as small (0.0-3.0 mm), medium (3.1-8.0 mm) and large (≥8.1 mm), grouped by TCGA classification., Results: Of 1001 cases, TCGA Groups (A/B/C/D) included small (n = 270, 75%/11%/13%/1%), medium (n = 503, 46%/14%/27%/13%) and large (n = 228, 23%/19%/38%/20%) UM. The 5-and 10-year Kaplan-Meier MFS for small UM revealed Group A (98%, 98%), Group B (100%, 100%), Group C (86%, NA) and Group D (100%, NA). For medium UM, the values dropped with Group A (95%, 93%), Group B (90%, 90%), Group C (68%, 38%), and Group D (44%, NA). For large UM, the values dropped further with Group A (94%, 86%), Group B (85%, NA), Group C (40%, 28%), and Group D (23%, NA). Additionally, a comparison (small vs. medium vs. large tumour size category) revealed TCGA low-risk grouping (Groups A or B) in 86% vs. 60% vs. 58% cases with UM., Conclusion: By tumour size category, favourable cytogenetics (Groups A or B) is found in 86% of small tumours, 60% of medium tumours, and 58% of large tumours. The MFS at 10 years for favourable cytogenetics was 98% for small tumours, 92% for medium tumours, and 54% for large tumours. Tumour size category can serve as a surrogate for TCGA., (© 2024 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To evaluate the efficacy and safety of high-dose intravitreal topotecan (IvitTopo) for recurrent retinoblastoma., Methods: There were 13 patients with recurrent retinoblastoma treated with high-dose IvitTopo (90 micrograms (μg)/0.18cc-100 μg/0.20cc). The primary outcome measures were tumor control, globe salvage, and treatment complications., Results: At date first seen (DFS), median patient age was 9 months, and the affected eye was classified as International Classification of Retinoblastoma (ICRB) Group B (n=2, 15%), Group C (n=3, 23%), or Group D (n=8, 62%) retinoblastoma with initial therapy of intravenous chemotherapy (n=9, 69%) or intra-arterial chemotherapy (n=4, 31%). Recurrent tumor was detected at median 10 months as solid tumor (n=3), subretinal seeds (n=10), and/or vitreous seeds (n=3) and high-dose IvitTopo (median 3 injections) delivered at monthly intervals. Additional chemotherapy was delivered by intra-arterial (n=8, 62%) or intravenous (n=1, 8%) routes, and 1 eye received additional cryotherapy (n=1, 8%). In 3 cases (23%) there was no additional therapy. At mean follow-up of 9 months, regression of solid tumor, subretinal seeds and vitreous seeds was achieved in 12 cases (92%), and globe salvage was achieved in all cases (n=13, 100%). Of those 3 eyes treated with high-dose IvitTopo alone, tumor control was initially achieved in all cases (100%), but one case that previously demonstrated massive vitreous seeding showed late recurrence of a solitary vitreous seed at 8 months. There were no complications., Conclusions: High-dose IvitTopo is an effective and safe therapy for recurrent retinoblastoma, in conjunction with other therapy, and possibly as a stand-alone therapy., Competing Interests: The authors report no competing interests or conflicts of interest.

Objective: To evaluate the effectiveness of preventing metastasis for each major treatment modality for iris melanoma., Design: Retrospective case series., Participants: Three hundred consecutive eyes with iris melanoma at a single tertiary referral centre for ocular oncology., Methods: Retrospective analysis of eyes with iris melanoma, both with (n = 69 eyes) and without (n = 231 eyes) ciliary body extension, was undertaken for metastasis-free survival at 5, 10, and 20 years based on type of treatment, including globe-sparing surgical resection (n = 169 eyes), plaque radiotherapy (n = 74 eyes), or enucleation (n = 57 eyes)., Results: For the total population, 5-, 10-, and 20-year metastasis-free survival rates were 95%, 93%, and 87%, respectively, and there was no difference in metastatic rates for tumours with versus without ciliary body extension (p = 0.95). Noninferiority was demonstrated for surgical resection and plaque radiotherapy, with metastasis-free survival rates of 98%, 97%, and 94% for surgical resection and 94%, 94%, and 89% for plaque radiotherapy (p = 0.002). The rates for globe salvage were 94%, 92%, and 90% for surgical resection and 94%, 86%, and 86% for plaque radiotherapy (p = 0.003). However, metastasis-free survival was worse in patients who underwent enucleation (86%, 67%, and NA; p < 0.001)., Conclusions: Metastasis-free survival and globe salvage following plaque radiotherapy and surgical resection are not inferior to either, but eyes undergoing enucleation demonstrated a lower metastasis-free survival, likely because enucleation is performed for larger, more extensive melanomas, often with secondary glaucoma. In this analysis, iris melanoma with ciliary body involvement did not increase the risk of metastasis., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the outcomes of retinoblastoma (RB) based on the 8 th edition of the American Joint Committee on Cancer (AJCC) pathological classification in a global cohort of patients., Design: Retrospective, multicenter, intercontinental, collaborative study., Participants: A total of 1411 patients., Intervention: Primary enucleation with or without adjuvant chemotherapy or radiotherapy., Main Outcome Measures: Orbital tumor recurrence, tumor-related metastasis, and tumor-related death., Results: According to the 8 th edition AJCC pathological classification, 645 eyes (46%) belonged to pathological T (pT)1, 164 (11%) to pT2, 493 (35%) to pT3, and 109 (8%) to pT4 categories. At a mean follow-up of 38 months (median, 35 months; < 1-149 months), orbital tumor recurrence was seen in 8 (1%), 5 (3%), 22 (4%), and 25 (23%) of pT1, pT2, pT3, and pT4 (P < 0.001) categories, respectively; tumor-related metastasis was seen in 7 (1%), 5 (3%), 40 (8%), and 46 (43%) of pT1, pT2, pT3, and pT4 (P < 0.001) categories, respectively; tumor-related death was seen in 12 (2%), 7 (4%), 64 (13%), and 64 (59%) of pT1, pT2, pT3, and pT4 (P < 0.001) categories, respectively. Multivariate Cox proportional hazards analysis of outcomes revealed pT category and adjuvant therapy as independent predictors of outcomes. Categories pT3b (P = 0.005), pT3c (P < 0.001), pT3d (P < 0.001), and pT4 (P < 0.001) had a greater hazard for orbital recurrence; categories pT2a (P = 0.015), pT3a (P < 0.001), pT3b (P < 0.001), pT3c (P < 0.001), pT3d (P < 0.001), and pT4 (P < 0.001) had a greater hazard for tumor-related metastasis; and categories pT2a (P = 0.068), pT2b (P = 0.004), pT3a (P < 0.001), pT3b (P < 0.001), pT3c (P < 0.001), pT3d (P < 0.001), and pT4 (P < 0.001) had a greater hazard for tumor-related death when compared with the pT1 category. Patients who did not receive adjuvant therapy had greater hazards of orbital tumor recurrence in categories pT3b (P = 0.005), pT3c (P = 0.003), and pT4 (P = 0.002); greater hazards of tumor-related metastasis in categories pT3a (P = 0.001), pT3b (P = 0.01), pT3c (P = 0.001), and pT4 (P = 0.007); and tumor-related death in categories pT3a (P < 0.001), pT3b (P = 0.009), pT3c (P = 0.018), and pT4 (P < 0.001) when compared with those who received adjuvant therapy., Conclusions: The 8 th edition AJCC pathological classification predicts outcomes in patients undergoing primary enucleation for RB, and adjuvant therapy is associated with a lower risk of orbital recurrence, tumor-related metastasis, and tumor-related death in the pT3 and pT4 categories., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy., Experimental Design: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models., Results: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival., Conclusions: GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas., (©2024 American Association for Cancer Research.)

Purpose: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents., Methods: Retrospective study of 1426 primarily enucleated RB eyes from five continents., Results: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients., Conclusion: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Conjunctival melanoma, a rare malignancy of the ocular surface, is increasing in incidence. When small, straightforward excision with "no touch" surgery and cryotherapy at an experienced centre can provide excellent outcomes. When advanced, management is more complex and highly individualized. The risk of metastatic disease from conjunctival melanoma is as high as 30% and depends on tumour origin, American Joint Committee on Cancer (AJCC) classification, biomarkers, and perhaps most important, management technique. Metastatic disease can result in melanoma-associated death. Therefore, early detection and prompt directed treatment at an experienced centre are important for protection from metastasis. In this review, we provide an update on conjunctival melanoma clinical features, diagnostic modalities, AJCC staging, genetic markers, and the most critical, controlled management with minimization of tumour seeding. We detail the new era of characterization of conjunctival melanoma with molecular biomarkers that predict melanoma prognosis. This could lead to precision medicine with targeted approaches to specific mutations that improve patient survival. As we work together, the field of conjunctival melanoma is moving forward., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

The following is a case of vitreoretinal lymphoma masquerading as central serous chorioretinopathy (CSCR). A 74-year-old man presented with blurred vision in the left eye with unilateral subretinal fluid in the setting of exogenous corticosteroid use, which was diagnosed as CSCR and resolved with corticosteroid cessation. He later experienced a similar self-limited episode in the right eye. Subsequently, he developed bilateral vitritis with yellow-white subretinal pigment epithelial infiltrates. Vitreous biopsy confirmed a diagnosis of large B-cell lymphoma. Vitreoretinal lymphoma can masquerade as a number of ocular pathologies, including CSCR. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:467-470.] .

Purpose: To evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body., Design: Retrospective observational study., Subjects: Six thousand nine hundred thirty-four consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center., Methods: Data on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20%-80%), and nonpigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan-Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis., Main Outcome Measures: Extraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death., Results: There were 6934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n = 3762; 54%), partially pigmented (n = 2115; 31%), or nonpigmented (n = 1057; 15%). Pigmented UM was associated with extraocular extension ( P  < 0.001), ocular melanocytosis ( P  = 0.003), earlier tumor recurrence ( P  < 0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) ( P  < 0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared with 19% for partially pigmented UMs and 16% for nonpigmented UMs ( P  < 0.001). Kaplan-Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis ( P  < 0.001) and melanoma-related death ( P  < 0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared with partially pigmented UMs ( P  = 0.002) and a 54% higher relative risk of developing metastasis compared with nonpigmented UMs ( P  < 0.001)., Conclusions: Pigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and nonpigmented UMs., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 patients with pUM with stage T2-T4 and at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (N = 24) and the EPIC BeadChip (N = 17). Findings were validated in the TCGA cohort with known metastatic outcome (N = 69). Differentially methylated probes were identified in patients who developed metastasis. Unsupervised consensus clustering revealed three epigenomic subtypes associated with metastasis. To identify a prognostic signature, recursive feature elimination and random forest models were utilized within repeated cross-validation iterations. The 250 most commonly selected probes comprised the final signature, named MethylSig-UM. MethylSig-UM could distinguish individuals with pUM at diagnosis who develop future metastasis with an area under the curve of ~81% in the independent validation cohort, and remained significant in Cox proportional hazard models when combined with clinical features and established genomic biomarkers. Altered expression of immune-modulating genes were detected in MethylSig-UM positive tumors, providing clues for pUM resistance to immunotherapy. The MethylSig-UM model is available to enable additional validation in larger cohort sizes including T1 tumors.

Purpose: To develop and validate machine learning (ML) models to predict choroidal nevus transformation to melanoma based on multimodal imaging at initial presentation., Design: Retrospective multicenter study., Participants: Patients diagnosed with choroidal nevus on the Ocular Oncology Service at Wills Eye Hospital (2007-2017) or Mayo Clinic Rochester (2015-2023)., Methods: Multimodal imaging was obtained, including fundus photography, fundus autofluorescence, spectral domain OCT, and B-scan ultrasonography. Machine learning models were created (XGBoost, LGBM, Random Forest, Extra Tree) and optimized for area under receiver operating characteristic curve (AUROC). The Wills Eye Hospital cohort was used for training and testing (80% training-20% testing) with fivefold cross validation. The Mayo Clinic cohort provided external validation. Model performance was characterized by AUROC and area under precision-recall curve (AUPRC). Models were interrogated using SHapley Additive exPlanations (SHAP) to identify the features most predictive of conversion from nevus to melanoma. Differences in AUROC and AUPRC between models were tested using 10 000 bootstrap samples with replacement and results., Main Outcome Measures: Area under receiver operating curve and AUPRC for each ML model., Results: There were 2870 nevi included in the study, with conversion to melanoma confirmed in 128 cases. Simple AI Nevus Transformation System (SAINTS; XGBoost) was the top-performing model in the test cohort [pooled AUROC 0.864 (95% confidence interval (CI): 0.864-0.865), pooled AUPRC 0.244 (95% CI: 0.243-0.246)] and in the external validation cohort [pooled AUROC 0.931 (95% CI: 0.930-0.931), pooled AUPRC 0.533 (95% CI: 0.531-0.535)]. Other models also had good discriminative performance: LGBM (test set pooled AUROC 0.831, validation set pooled AUROC 0.815), Random Forest (test set pooled AUROC 0.812, validation set pooled AUROC 0.866), and Extra Tree (test set pooled AUROC 0.826, validation set pooled AUROC 0.915). A model including only nevi with at least 5 years of follow-up demonstrated the best performance in AUPRC (test: pooled 0.592 (95% CI: 0.590-0.594); validation: pooled 0.656 [95% CI: 0.655-0.657]). The top 5 features in SAINTS by SHAP values were: tumor thickness, largest tumor basal diameter, tumor shape, distance to optic nerve, and subretinal fluid extent., Conclusions: We demonstrate accuracy and generalizability of a ML model for predicting choroidal nevus transformation to melanoma based on multimodal imaging., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

We report the case of an 8-year-old boy who presented with an optic disk pit and subsequently developed optic disk pit maculopathy, consisting of cystoid retinal edema in the peripapillary space and in the papillomacular bundle, which slowly and spontaneously resolved without intervention., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: The BRCA-associated protein1 (BAP1) immunohistochemical (IHC) stain has emerged as a powerful and inexpensive prognostic tool in uveal melanoma (UM), correlating with UM genetics and outcome. The data on the reliability of BAP1 immunohistochemistry in previously irradiated UM is scant. We aim to assess BAP1 IHC in post-Iodine-125 plaque brachytherapy-treated UM-enucleated eyes., Methods: In a case-control study, the medical records of all patients who underwent enucleation for UM at a major Ocular Oncology Service from December 1 st , 2007 to December 31 st , 2014 were reviewed. All cases with either chromosome 3 (ch3) status or sufficient follow-up (>5 years or metastasis) were selected. Nuclear BAP1 (nBAP1) immunoreactivity was interpreted as intact (positive in >90% of nuclei), lost (positive in <5% of nuclei), or heterogeneous (positive in 5-90% of nuclei). Retina and intratumoral blood vessels served as internal positive controls., Results: A comparison of 34 postbrachytherapy UM secondary-enucleated eyes with 47 nonbrachytherapy primary enucleated controls revealed no significant difference with respect to nBAP1 IHC (lost in 41% vs 51%, P = 0.19), ch3 status (ch3 monosomy in 59% vs 60%, P = 0.48), and outcome (metastatic disease in 44% vs 47%, P = 0.8). Association of nBAP1 IHC with ch3 status and outcome [intact nBAP1/(ch3 disomy and/or no metastasis) and lost nBAP1 (ch3 monosomy and/or metastasis)] in post-brachytherapy UM was significantly lower when compared with non-brachytherapy tumors [21/30 (70%) vs 41/44 (93%), P = 0.004*]., Conclusion: Although nBAP1 IHC stain is a strong prognostic tool in UM, its association with ch3 status, and outcome in postbrachytherapy UM was significantly lower compared with nonbrachytherapy tumors due to pitfalls in the interpretation of nBAP1 immunoreactivity in irradiated UM. This test should be used judiciously in the prognostication of postbrachytherapy-enucleated UM., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: To assess the accuracy of ophthalmic information provided by an artificial intelligence chatbot (ChatGPT)., Methods: Five diseases from 8 subspecialties of Ophthalmology were assessed by ChatGPT version 3.5. Three questions were asked to ChatGPT for each disease: what is x?; how is x diagnosed?; how is x treated? (x = name of the disease). Responses were graded by comparing them to the American Academy of Ophthalmology (AAO) guidelines for patients, with scores ranging from -3 (unvalidated and potentially harmful to a patient's health or well-being if they pursue such a suggestion) to 2 (correct and complete)., Main Outcomes: Accuracy of responses from ChatGPT in response to prompts related to ophthalmic health information in the form of scores on a scale from -3 to 2., Results: Of the 120 questions, 93 (77.5%) scored ≥ 1. 27. (22.5%) scored ≤ -1; among these, 9 (7.5%) obtained a score of -3. The overall median score amongst all subspecialties was 2 for the question "What is x", 1.5 for "How is x diagnosed", and 1 for "How is x treated", though this did not achieve significance by Kruskal-Wallis testing., Conclusions: Despite the positive scores, ChatGPT on its own still provides incomplete, incorrect, and potentially harmful information about common ophthalmic conditions, defined as the recommendation of invasive procedures or other interventions with potential for adverse sequelae which are not supported by the AAO for the disease in question. ChatGPT may be a valuable adjunct to patient education, but currently, it is not sufficient without concomitant human medical supervision., (© 2024. The Author(s).)

Competing Interests: The authors have no financial or conflicts of interest to disclose.

Large language models (LLMs) show great promise in assisting clinicians in general, and ophthalmology in particular, through knowledge synthesis, decision support, accelerating research, enhancing education, and improving patient interactions. Specifically, LLMs can rapidly summarize the latest literature to keep clinicians up-to-date. They can also analyze patient data to highlight crucial insights and recommend appropriate tests or referrals. LLMs can automate tedious research tasks like data cleaning and literature reviews. As AI tutors, LLMs can fill knowledge gaps and assess competency in trainees. As chatbots, they can provide empathetic, personalized responses to patient inquiries and improve satisfaction. The visual capabilities of LLMs like GPT-4 allow assisting the visually impaired by describing environments. However, there are significant ethical, technical, and legal challenges around the use of LLMs that should be addressed regarding privacy, fairness, robustness, attribution, and regulation. Ongoing oversight and refinement of models is critical to realize benefits while minimizing risks and upholding responsible AI principles. If carefully implemented, LLMs hold immense potential to push the boundaries of care, discovery, and quality of life for ophthalmology patients.

Purpose: To develop guidelines for ocular surveillance and early intervention for individuals with von Hippel-Lindau (VHL) disease., Design: Systematic review of the literature., Participants: Expert panel of retina specialists and ocular oncologists., Methods: A consortium of experts on clinical management of all-organ aspects of VHL disease was convened. Working groups with expertise in organ-specific features of VHL disease were tasked with development of evidence-based guidelines for each organ system. The ophthalmology subcommittee formulated questions for consideration and performed a systematic literature review. Evidence was graded for topic quality and relevance and the strength of each recommendation, and guideline recommendations were developed., Results: The quality of evidence was limited, and no controlled clinical trial data were available. Consensus guidelines included: (1) individuals with known or suspected VHL disease should undergo periodic ocular screening (evidence type, III; evidence strength, C; degree of consensus, 2A); (2) patients at risk of VHL disease, including first-degree relatives of patients with known VHL disease, or any patient with single or multifocal retinal hemangioblastomas (RHs), should undergo genetic testing for pathologic VHL disease gene variants as part of an appropriate medical evaluation (III/C/2A); (3) ocular screening should begin within 12 months after birth and continue throughout life (III/C/2A); (4) ocular screening should occur approximately every 6 to 12 months until 30 years of age and then at least yearly thereafter (III/C-D/2A); (5) ocular screening should be performed before a planned pregnancy and every 6 to 12 months during pregnancy (IV/D/2A); (6) ultra-widefield color fundus photography may be helpful in certain circumstances to monitor RHs, and ultra-widefield fluorescein angiography may be helpful in certain circumstances to detect small RHs (IV/D/2A); (7) patients should be managed, whenever possible, by those with subspecialty training, with experience with VHL disease or RHs, or with both and ideally within the context of a multidisciplinary center capable of providing multiorgan surveillance and access to genetic testing (IV/D/2A); (8) extramacular or extrapapillary RHs should be treated promptly (III/C/2A)., Conclusions: Based on available evidence from observational studies, broad agreement was reached for a strategy of lifelong surveillance and early treatment for ocular VHL disease. These guidelines were endorsed by the VHL Alliance and the International Society of Ocular Oncology and were approved by the American Academy of Ophthalmology Board of Trustees., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)