Predicting Choroidal Nevus Transformation to Melanoma Using Machine Learning.

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.

High-Dose Intravitreal Topotecan for Recurrent Retinoblastoma, Subretinal Seeds, and Vitreous Seeds in 13 Consecutive Cases.

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.

Subconjunctival Mass 30 Years After Melanoma Resection.

A 70-year-old male is referred for evaluation of a conjunctival mass in the right eye, which has grown slowly over 27 years. Examination reveals a superonasal, multilobulated, pigmented lesion with episcleral feeder vessels and spontaneous vascular pulsations within the intraocular component. What would you do next?

Metastasis-free survival of uveal melanoma by tumour size category based on The Cancer Genome Atlas (TCGA) classification in 1001 cases.

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.

Treatment Outcomes and Definition Inconsistencies in High-Risk Unilateral Retinoblastoma: Outcomes and Definition Variances in High-Risk Rb.

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 non-massive 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 ≤0.002). 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.

Retinoblastoma Outcomes Based on the 8th Edition American Joint Committee on Cancer Pathological Classification in 1411 Patients.

PURPOSE: To evaluate the outcomes of retinoblastoma (RB) based on the 8th edition of the American Joint Committee on Cancer (AJCC) pathological classification in a global cohort of patients. DESIGN: Retrospective, multicentre, intercontinental collaborative study PARTICIPANTS: 1411 patients INTERVENTION(S): Primary enucleation with/without adjuvant chemotherapy/radiotherapy MAIN OUTCOMES(S): Orbital tumor recurrence, tumor-related metastasis, tumor-related death RESULTS: Based on the 8th edition AJCC pathological classification, 645 (46%) eyes belonged to pT1, 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 to 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 to those who received adjuvant therapy. CONCLUSION: The 8th 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.

Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center.

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.

Thirteen-Year Follow-Up of Conjunctival Amyloidosis.

This case report discusses a diagnosis of conjunctival amyloidosis in an otherwise asymptomatic male aged 71 years with 13-year follow-up.

Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification.

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.

High-Risk Histopathological Features of Retinoblastoma following Primary Enucleation: A Global Study of 1426 Patients from 5 Continents.

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.

Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.

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.

Vitreoretinal Lymphoma Masquerading as Central Serous Chorioretinopathy.

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.].