Corneal Substructure Dosimetry Predicts Corneal Toxicity in Patients With Uveal Melanoma Treated With Proton Beam Therapy.

PURPOSE: This study examines the relationship between dose to corneal substructures and incidence of corneal toxicity within 6 months of proton beam therapy (PBT) for uveal melanoma. We aim to develop clinically meaningful dose constraints that can be used to mitigate corneal toxicity. METHODS AND MATERIALS: Ninety-two patients were treated with PBT between 2015 and 2017 and evaluated for grade 2+ (GR2+) intervention-requiring corneal toxicity in our prospectively maintained database. Most patients were treated with 50 Gy (relative biological effectiveness [RBE]) in 5 fractions, and all had complete six-month follow-up. Analyses included Mann-Whitney, χ2, Fisher exact, and receiver operating curve tests to identify risk factors for GR2+ toxicity. Bivariate logistic regression was used to identify independent dose-volume histogram (DVH) predictors of toxicity after adjustment for the most important clinical risk factor. RESULTS: The 6-month PBT GR2+ corneal toxicity rate was 10.9%, with half of patients experiencing grade 2 toxicity and half experiencing grade 3 toxicity, with no grade 4 events. Patients with anterior chamber tumors had a higher risk (58.3%) for toxicity than those with posterior tumors (0%) or posterior tumors extending past the equator (25%, P < .0001). On univariate analysis, larger size according to Collaborative Ocular Melanoma Studies was associated with increased toxicity rate (P < .004). DVH analysis revealed that cutoffs of 58% for V25, 32% for V45, 51.8 Gy (RBE) for maximum dose, and 32 Gy (RBE) for mean dose to the cornea separated patients into groups experiencing and not experiencing toxicity with 90% sensitivity and ≥96% specificity. Bivariate logistic regression indicated that corneal V25, V45, and mean dose independently predicted for toxicity after adjusting for tumor location. CONCLUSIONS: Patients receiving PBT for anterior uveal melanomas experience a high rate of GR2+ corneal toxicity because of increased corneal dose. Anterior location and corneal DVH parameters independently predict toxicity risk. We propose dosimetric constraints to facilitate treatment planning and toxicity mitigation.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate.

PURPOSE: Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether these cells can also survive and integrate into the retina of a nonhuman primate, Saimiri sciureus, following transplantation into the subretinal space. METHODS: hESCs were differentiated toward retinal neuronal fates using our previously published technique and cultured for 60 to 70 days. Differentiated cells were further treated with 20 µM N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) for a period of 5 days immediately prior to subretinal transplantation. Differentiated cells were labeled with a lentivirus expressing GFP. One million cells (10,000 cells/µL) were injected into the submacular space into a squirrel monkey eye, using an ab externo technique. RESULTS: RetCam imaging demonstrated the presence and survival of human donor cells 3 months after transplantation in the S. sciureus eye. Injected cells consolidated in the temporal macula. GFP+ axonal projections were observed to emanate from the central consolidation of cells at 1 month, with some projecting into the optic nerve by 3 months after transplantation. CONCLUSIONS: Human ES cell-derived retinal neurons injected into the submacular space of a squirrel monkey survive at least 3 months postinjection without immunosuppression. Some donor cells appeared to integrate into the host inner retina, and numerous donor axonal projections were noted throughout, with some projecting into the optic nerve. TRANSLATIONAL RELEVANCE: These data illustrate the feasibility of hESC-derived retinal cell replacement in the nonhuman primate eye.

Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial.

OBJECTIVE: To examine the effects of ranibizumab on patient-reported visual function using the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) in patients with neovascular age-related macular degeneration (AMD). DESIGN: In MARINA, a randomized, double-masked clinical trial, 716 patients with AMD with recent disease progression and minimally classic or occult with no classic lesion component were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections. The NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months. Main Outcome Measure Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. RESULTS: At 12 months, ranibizumab-treated patients (0.3 mg [n = 238] and 0.5 mg [n = 240]) had mean improvements in NEI VFQ-25 composite scores of +5.2 (95% confidence interval [CI], 3.5 to 6.9) and +5.6 (95% CI, 3.9 to 7.4), respectively; sham-injected patients (n = 238) had a mean decline of -2.8 (95% CI, -4.6 to -1.1; P < .001 vs each dose). Ranibizumab-treated patients were more likely to improve in near activities, distance activities, and vision-specific dependency through 24 months. CONCLUSIONS: In MARINA, ranibizumab-treated patients were more likely than sham-treated patients to report visual function improvements at 12 and 24 months. APPLICATION TO CLINICAL PRACTICE: Treatment of neovascular AMD with ranibizumab can improve patient-reported visual function in a meaningful way compared with sham treatments. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056836.