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.].

Topical 5-fluorouracil 1% for moderate to extensive ocular surface squamous neoplasia in 73 consecutive patients: Primary versus secondary treatment.

IMPORTANCE: Ocular surface squamous neoplasia (OSSN) is a spectrum of malignancies that generally includes conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC). OSSN can be treated with topical therapies including interferon α-2b (IFN), mitomycin C (MMC), or 5-fluorouracil 1% (5FU). Recently, due to unavailability of IFN and toxicity associated with MMC, therapy has shifted towards 5FU. OBJECTIVE: Herein, we compare the use of 5FU 1% as a primary versus (vs) secondary treatment regimen in eyes with moderate to extensive OSSN. DESIGN SETTING AND PARTICIPANTS: Retrospective cohort study of 73 consecutive patients with unilateral moderate to extensive OSSN treated at a single tertiary ocular oncology center from 2016 to 2023. Mean follow up time was 478.2 days overall, with 283.0 days for primary 5FU group and 860.3 days for secondary 5FU group. INTERVENTION: Topical 5FU 1% 4 times daily for 2 weeks with option for 2-weekly extension until tumor control, either as primary treatment or as secondary treatment to surgical resection, topical IFN or topical MMC, or cryotherapy. MAIN OUTCOMES: Outcome measures included tumor response, need for additional surgery, complications, and visual outcomes. RESULTS: A comparison (primary vs secondary treatment) revealed no difference in mean tumor basal dimension (19.6 vs 17.2 mm, P = 0.46), thickness (3.7 vs 3.4 mm, P = 0.64), or tumor extent (4.4 vs 4.5 clock hours, P = 0.92). The primary treatment group showed greater complete tumor control (77% vs 38%, P = 0.04). Multivariable analysis comparison (primary vs secondary treatment) showed primary treatment more likely to achieve complete tumor control (P = 0.01). There was no difference in the complication rate from 5FU treatment between the groups. There was no difference in visual outcome, and no tumor-related metastasis (0%) or death (0%). CONCLUSION AND RELEVANCE: Topical 5FU 1% is efficacious and safe as a primary or secondary treatment for moderate to extensive OSSN. Tumors treated with primary 5FU 1% demonstrated more complete resolution. In patients with moderate to extensive OSSN, primary treatment with topical 5FU 1% may be warranted.

Strabismus management in retinoblastoma survivors.

PURPOSE: To report the result of strabismus surgery in eye-salvaged retinoblastoma (Rb) patients. METHODS: A retrospective case series including 18 patients with Rb and strabismus who underwent strabismus surgery after completing tumor treatment by a single pediatric ophthalmologist. RESULTS: A total of 18 patients (10 females and 8 males) were included with a mean age of 13.3 ± 3.0 (range, 2-39) months at the time tumor presentation and 6.0 ± 1.5 (range, 4-9) years at the time of strabismus surgery. Ten (56%) patients had unilateral and 8(44%) had bilateral involvement and the most common worse eye tumor's group was D (n = 11), C (n = 4), B (n = 2) and E (n = 1). Macula was involved by the tumors in 12 (67%) patients. The tumors were managed by intravenous chemotherapy (n = 8, 47%), intra-arterial chemotherapy (n = 7, 41%) and both (n = 3, 17%). After complete treatment, the average time to strabismus surgery was 29.9 ± 20.5 (range, 12-84) months. Except for one, visual acuity was equal or less than 1.0 logMAR (≤ 20/200) in the affected eye. Seven (39%) patients had exotropia, 11(61%) had esotropia (P = 0.346) and vertical deviation was found in 8 (48%) cases. The angle of deviation was 42.0 ± 10.4 (range, 30-60) prism diopter (PD) for esotropic and 35.7 ± 7.9 (range, 25-50) PD for exotropic patients (P = 0.32) that after surgery significantly decreased to 8.5 ± 5.3 PD in esotropic cases and 5.9 ± 6.7 PD in exotropic cases (P < 0.001). The mean follow-up after surgery was 15.2 ± 2.0 (range, 10-24) months, in which, 3 (17%) patients needed a second surgery. CONCLUSION: Strabismus surgery in treated Rb is safe and results of the surgeries are acceptable and close to the general population. There was not associated with tumor recurrence or metastasis.

Multifocal Unilateral Orange Fundus Tumors in a Young Man.

A 38-year-old man had an asymptomatic, orange, macular choroidal mass with macular choroidal folds and a retinal pigment epithelial detachment in the right eye and a second orange mass nasal to the optic disc also in the right eye. What would you do next?

Spontaneous onset and resolution of optic disk pit maculopathy in a young patient.

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.

Correlation of fitzpatrick skin type and iris color with tumor size in 823 patients with uveal melanoma.

PURPOSE: To determine the correlation of Fitzpatrick Skin Type (FST) and iris color with tumor size (tumor thickness and basal diameter) in patients with uveal melanoma. DESIGN: Retrospective Cohort METHODS: Retrospective cohort from a single ocular oncology center of 823 patients with uveal melanoma and documented FST, iris color, and tumor size. Patients were classified by FST (type I, II, and III-V) and iris color (blue, green, and brown) on the basis of external facial photography. There were no FST type VI patients. Tumor thickness was classified into small [< 3 millimeter (mm)], medium (3.1-8.0 mm), or large (> 8.0 mm), and basal diameter into small (< 10 mm), medium (10.1-15 mm) or large (> 15 mm). The correlation of FST and iris color with tumor thickness and basal diameter was evaluated using the Kruskal-Wallis H test. RESULTS: The FST classification was type I (n = 92, 11%), type II (n = 643, 78%), or III-V (n = 88, 11%), and iris color was blue (n = 472, 57%), green (n = 102, 12%), or brown (n = 249, 30%). A comparison of FST revealed differences in mean tumor thickness (P = 0.04) and basal diameter (P = 0.006). Iris color showed no difference for mean tumor thickness (P = 0.41) or basal diameter (P = 0.48). There was a statistically significant difference with brown iris color relative to FST III-V for mean tumor thickness (P = 0.003) and basal diameter (P = 0.001) but no difference with blue or green iris color (P > 0.05). CONCLUSIONS: Iris color alone showed no difference in tumor size, but those with brown iris color and FST type III-V demonstrated larger tumor thickness and basal diameter.

Impact of iris color on uveal melanoma-related outcomes in 7245 patients at a single ocular oncology center.

PURPOSE: To determine the relationship between iris color and uveal melanoma (UM)-related metastasis and death in a large cohort of patients from a single ocular oncology center. DESIGN: Retrospective case series. SUBJECTS: Patients diagnosed with UM between February 1971 and August 2007. METHODS: Patient information was obtained from chart documentation. MAIN OUTCOME MEASURES: UM-related metastasis and death. RESULTS: Out of 7245 patients, iris color was blue in 3702 (51%), green in 1458 (20%), and brown in 2085 (29%). Mean age was 58 ± 15 years and mean tumor thickness was 5.5 ± 3.3 millimeters. Some clinical features differed between iris color groups, with the blue irides group having a larger proportion of post-equatorial tumors with significantly closer proximity to the foveola and optic disc compared to the brown irides group. At a mean follow-up of 75 months, there was no statistically significant difference in metastasis between the various iris color groups. On univariate analysis, those with blue irides showed a higher incidence of UM-related death compared to the green and brown irides groups (8.3%, 5.9% and 7.5% respectively, p value = 0.02). Kaplan-Meier event free survival from UM-related death significantly differed only between the blue and green irides groups (p value = 0.007) with the green irides group showing the highest survival. However, on multivariate analysis, iris color was not predictive of UM-related death. CONCLUSION: Iris color was not predictive of UM-related metastasis or death. However, Kaplan-Meier survival at 20 years was poorest for blue irides group compared to green.