15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSE: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS: 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Levodopa Positively Affects Neovascular Age-Related Macular Degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology. METHODS: In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months. RESULTS: Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002). CONCLUSIONS: Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.

Rapid and progressive decline despite early intervention in a case of bilateral hemorrhagic occlusive retinal vasculitis.

PURPOSE: To present a case of severe bilateral hemorrhagic occlusive retinal vasculitis (HORV) after uncomplicated cataract surgery with intracameral vancomycin. We present a report of a single patient with bilateral presentation of HORV that demonstrated classic features of the disease and progressed to profound vision loss despite early and aggressive intervention. OBSERVATIONS: On initial presentation, the patient had good Snellen visual acuity of 20/25 PH 20/20 OD and 20/60 PH 20/30 OS with retinal hemorrhages in both eyes and sub-hyaloid hemorrhage in the left eye. Early therapeutic intervention with intravitreal corticosteroids, anti-vascular endothelial growth factor (anti-VEGF) agents and oral steroids was pursued. Even with treatment, the clinical picture rapidly deteriorated with progression of occlusive and hemorrhagic complications in both eyes resulting in bilateral ischemic retinopathy and breakthrough vitreous hemorrhage. After a prolonged course of treatment including the aforementioned along with panretinal photocoagulation (PRP) in both eyes and vitreoretinal surgery in the left eye, the final visual acuity was light perception (LP) OD and 20/100 OS. CONCLUSIONS AND IMPORTANCE: Hemorrhagic occlusive retinal vasculitis remains a feared complication of uncomplicated cataract surgery utilizing intracameral vancomycin. Despite early recognition and appropriate intervention, our patient still had a poor visual outcome with significant ischemic damage.

Presentation of Ocular Syphilis in a HIV-Positive Patient with False-Negative Serologic Screening.

PURPOSE: The ocular sequelae of syphilis are devastating and may cause blindness. The ambiguous nature of its ocular manifestations makes syphilis difficult to detect. Though uncommon, the rise of syphilis in the United States requires a renewed understanding of its ophthalmic presentation to prevent devastating outcomes. We present this case to raise awareness for the increasing prevalence of ocular syphilis and appropriate serologic testing. OBSERVATIONS: We describe a 65-year-old HIV-positive male with worsening retinitis, uveitis, and rapid visual loss. Initial lab results showed a nonreactive rapid plasma reagin (RPR) for syphilis. However, subsequent Treponema pallidum antibody testing was positive 48 hours after initial false-negative serologic screening. The patient had a rapid and successful recovery following treatment with penicillin. CONCLUSIONS AND IMPORTANCE: The incidence of syphilis is on the rise once again, and patients living with HIV are at increased risk. Ocular syphilis should be considered in susceptible populations in the clinical setting of retinitis, uveitis, and worsening visual loss with unknown cause. In addition, retesting for syphilis will decrease the prevalence of false-negative results, especially in patients with high clinical suspicion.

Prescribing to tumor apex in episcleral plaque iodine-125 brachytherapy for medium-sized choroidal melanoma: A single-institutional retrospective review.

PURPOSE: To report an institutional experience with episcleral plaque brachytherapy for medium-sized uveal melanoma. Variations in prescription dose point and dose rate were compared with Collaborative Ocular Melanoma Study (COMS) Group. METHODS AND MATERIALS: A retrospective review was performed for 116 patients treated with iodine-125 plaque brachytherapy. About 85 Gy was prescribed to either the tumor apex (108 patients) or at 5 mm (8 patients) with dose rate ranging from 50.6 to 98.2 cGy/h. Patients were followed up for local tumor control, eye preservation, and vision retention. Dose and dose rate to tumor and sensitive structures were calculated. Multivariate and univariate analyses were performed to investigate correlation between clinical outcomes and dose/dose rate variables. RESULTS: Patients in this study were slightly older with worse visual acuity at baseline, but tumor size and position and ratio of ciliary body involvement were comparable to COMS population. Outcomes data were comparable to COMS: 95.3% local tumor control at 5 years and 77.7% vision preservation at 3 years. Only 4 patients needed enucleation because of tumor growth. Significant correlation was found between enucleation and tumor height and maximal scleral dose/dose rate as well as vision retention and tumor height and macula dose/dose rate. CONCLUSIONS: For tumors with <5 mm height, prescribing to tumor apex enabled to decrease dose to all sensitive structures without any loss of local control. Although dose rate was lowered to 50.6 cGy/h from the American Brachytherapy Society guidelines (60-105 cGy/h) because of limited availability of operating room (i.e., weekly), there was no difference in either local tumor control or complications.