Angiographic characteristics and treatment approach in patients undergoing intra-arterial chemotherapy for retinoblastoma.

PURPOSE: To identify the specific clinical and angiographic variables that determine the success of intra-arterial chemotherapy (IAC) in a patient with retinoblastoma. METHODS: Medical records from patients undergoing intra-arterial chemotherapy for the treatment of retinoblastoma between January 2015 and June 2020 within a large academic ocular oncology practice were retrospectively reviewed. Demographics were recorded together with clinical, ocular, and angiographic variables such as the diameter of the ophthalmic artery (OA), angle of ophthalmic artery takeoff, and branching pattern of ophthalmic vasculature. RESULTS: Forty-four eyes from 33 patients with retinoblastoma treated with IAC were identified. Over the total 32 mean months of follow-up, these patients received 144 total catheterizations and a mean of 3.2 IAC cycles for each eye. The number of IAC cycles and the chemotherapeutic agent used did not vary significantly with worsening International Classification of Retinoblastoma (ICRB) groups (P > 0.1). Cumulative dose did not vary with the ICRB group for eyes treated with melphalan, topotecan, or carboplatin (P > 0.1). A higher ICRB group was associated with a smaller mean ophthalmic artery diameter across all procedures (P = 0.016), and femoral artery diameter did not vary significantly between ICRB groups (P = 0.906). A higher cumulative dose of IAC was significantly associated with a smaller takeoff angle of the OA (melphalan, P = 0.011; topotecan, P = 0.009; carboplatin, P = 0.031) in patients who underwent successful IAC procedures. Ophthalmic artery diameter and femoral artery diameter did not have a significant association (P > 0.1) with higher IAC doses in successful IACs. Cumulative IAC dose was not significantly associated with ophthalmic vasculature branching pattern, presence of choroidal blush, temporary OA vasospasm reported during the procedure, and OA occlusion upon microcatheter placement. CONCLUSION: In this study, neurosurgical angioanatomy appeared to influence the cumulative dose of chemotherapy needed during IAC for retinoblastoma. In the future, these anatomic variables may be used to guide the frequency of monitoring, dosing, and estimation of recurrence risk.

Vitreoretinal Abnormalities during Macular Hole Repair in Alport Syndrome.

PURPOSE: To describe abnormal vitreoretinal findings during macular hole repair in Alport syndrome (AS). METHODS: Case report of preoperative, intraoperative, and postoperative findings related to macular hole surgery in a patient with AS. OBSERVATIONS: A 50-year-old woman with Alport syndrome was found to have bilateral full-thickness macular holes. Surgery was recommended for her left eye given recent onset of vision loss and smaller hole size (313 um). Intraoperatively, the vitreous was found to have fine fibrillar strands and to be abnormally adherent to the retinal surface. There was little to no internal limiting membrane (ILM) present. Vitrectomy was performed with posterior cortical hyaloid peeling and 15% C3F8 gas tamponade. Two months after surgery, the macular hole was successfully closed. CONCLUSIONS: Abnormal vitreous composition and adherence to the retinal surface may contribute to macular hole formation in AS patients. Standard surgical approaches including ILM peeling may not be feasible, though thorough removal of the posterior cortical hyaloid may be sufficient to achieve macular hole closure.

Morphological characteristics of eyes with neovascular age-related macular degeneration and good long-term visual outcomes after anti-VEGF therapy.

PURPOSE: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy. METHODS: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands. RESULTS: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 µm) compared with the intermediate (86.25 µm) or good (97.92 µm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 µm) compared with eyes with intermediate vision (64.37 µm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 µm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001). CONCLUSION: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment.

Association of Ultrasound Features in Uveal Melanoma With Metastatic Risk as Defined by Preferentially Expressed Antigen in Melanoma Status.

BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the association between clinical and ultrasound features of uveal melanoma and preferentially expressed antigen in melanoma (PRAME), given its role as a biomarker for metastatic mortality. MATERIALS AND METHODS: Ultrasonographic characteristics and PRAME expression status of patients with uveal melanoma (2016 to 2021) were retrospectively analyzed using univariate and multivariate regression. RESULTS: Of the 81 eyes included, 49 (60%) were PRAME negative and 32 (40%) were PRAME positive. Univariate analysis showed that only largest basal diameter (LBD) was significantly associated with PRAME positivity (P = .006). There was a borderline association between shape and PRAME positivity (P = .054), whereas height, internal reflectivity, vascularity, and location showed no effect. Multivariate regression identified LBD as the sole significant predictor of PRAME positivity (odds ratio, 1.196; 95% CI, 1.055 to 1.379; P = .008). CONCLUSION: In this cohort, ultrasonographic LBD was significantly associated with PRAME status. No other clinical or ultrasound variables were predictive of molecular testing results. The results of this PRAME analysis are like prior reports, which suggested a strong association between gene expression profiling class 2 and increasing LBD. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:374-378.].

Facial Asymmetry in Children With Unilateral Congenital Ptosis.

PURPOSE: To analyze facial asymmetry in children with unilateral congenital ptosis. METHODS: This is a retrospective review of pediatric patients undergoing ptosis repair between January 1, 2017, and December 31, 2020. Charts were reviewed to ensure a diagnosis of idiopathic unilateral congenital ptosis. Sex, age, laterality, margin to reflex distance 1, levator function, and surgical intervention were collected.Clear preoperative photos without head turn were included. Using the ImageJ software ( nih.gov ), landmarks of the periorbital region, midface, and lower face were marked, and measurements between these landmarks were taken.Two-tailed Student t tests were used to compare measurements between the ptotic and non-ptotic sides. Relationships between different measurements on the same side of the face were analyzed using paired-variable regressions. RESULTS: Forty-four patients with unilateral congenital ptosis were included. The surgical management consisted of Mullerectomy in 9 of 44 (20%), levator resection in 15 of 44 (34%), and frontalis suspension in 20 of 44 (46%) patients. The side of the face with blepharoptosis was found to more often have smaller margin to reflex distance 1 ( p < 0.001), smaller margin to reflex distance 2 ( p < 0.005), smaller horizontal palpebral fissure ( p < 0.05), shorter midface height ( p < 0.001), and a more inferiorly displaced lateral canthus (canthal angle, p < 0.001) relative to the non-ptotic side of the face. The mean head tilt of patients with right sided ptosis (1.37° right tilt) was statistically significantly different from those with left sided ptosis (0.85° left tilt; p = 0.04). CONCLUSIONS: In children with unilateral congenital ptosis, the ptotic side of the face was found to be the nondominant side of the face. Patients were also found to have ipsilateral head tilt.

Association of Intravitreal Aflibercept With Optical Coherence Tomography Angiography Vessel Density in Patients With Proliferative Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Although previous studies have evaluated the association between anti-vascular endothelial growth factor therapy and macular vessel density, they were confounded by the presence of macular edema, which may be associated with artifacts and segmentation errors in optical coherence tomography angiography (OCTA). Objective: To evaluate the association of intravitreal aflibercept with changes in macular vascular density using OCTA in patients with proliferative diabetic retinopathy without diabetic macular edema. Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial used data on 40 eyes of 40 patients with proliferative diabetic retinopathy without diabetic macular edema who were enrolled in the Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy (RECOVERY) clinical trial from August 1, 2016, to June 31, 2017. Three patients were lost to follow-up at month 12, and 5 patients were excluded from analysis because of poor OCTA image quality, leaving 16 patients in each cohort in the final analysis. Data analysis was performed from March 1, 2018, to January 15, 2019. Intervention: In the RECOVERY trial, patients were randomized into cohorts receiving 2 mg of aflibercept injections monthly (n = 20) or quarterly (n = 20) and treated for 12 months. Main Outcomes and Measures: The percentage of vascular density (in total scan and foveal and parafoveal regions) was compared before and after 12 months of therapy. Results: The sample for this OCTA analysis included 32 eyes from 32 patients (mean [SD] age, 48.37 [12.30] years; 17 [53.1%] male). The mean (SD) total scan vascular density for the superficial vascular complex was 42.28% (4.03%; 95% CI, 40.63%-43.93%) at baseline and 39.64% (4.01%; 95% CI, 37.91%-41.37%) at month 12 (P = .69). For the deep vascular complex, the mean (SD) vascular density was 48.42% (4.99%; 95% CI, 46.36%-50.47%) at baseline and 45.69% (4.63%; 95% CI, 43.69%-47.70%) at month 12 (P = .40). For the choriocapillaris, the mean (SD) vascular density was 64.42% (3.36%; 95% CI, 63.04%-65.81%) at baseline and 62.55% (4.79%; 95% CI, 60.48%-64.62%) at month 12 (P = .16). There was no difference in vascular density parameters between monthly and quarterly injection arms at month 12. Conclusions and Relevance: In this study, macular vascular density did not change after 12 months of intravitreal aflibercept therapy. Because nonperfusion is expected to progress in diabetic retinopathy, this finding may represent a beneficial association between anti-vascular endothelial growth factor therapy and macular vascular density. Trial Registration: ClinicalTrials.gov Identifier: NCT02863354.

Loss to Follow-Up Among Patients With Proliferative Diabetic Retinopathy in Clinical Practice.

PURPOSE: To determine the proportion of patients with proliferative diabetic retinopathy (PDR) who were counted as loss to follow-up (LTFU) patients and to investigate predictive factors. DESIGN: Retrospective cohort study. METHODS: Information was collected for 4,423 patients with PDR between April 30, 2012, and April 30, 2017. Two definitions of LTFU were used. Complete LTFU referred to the population who never returned to care within the study period. Interval LTFU referred to the population who did not adhere to clinical recommendations and missed scheduled appointments, resulting in intervals longer than 6 months or 1 year between 2 appointments. Age, average gross income, and insurance were assessed as potential predictors of interval LTFU. RESULTS: Among 4,423 patients with PDR, 2,407 (54.4%) and 2,320 (52.4%) were complete LTFU at 6 months and 1 year, respectively; 782 (17.7%) and 468 (10.6%) patients were interval LTFU for 6 months and 1 year, respectively. Age and average gross income were not found to be significant predictors of interval LTFU. Compared to self-pay, government and private insurance patients were more likely to be interval LTFU at 6 months (government, P = .035; private, P = .005). Private insurance patients were also more likely to be interval LTFU at 1 year (P = .003). CONCLUSIONS: The identified complete LTFU rates were notably high and warrant further study. More than 1 of 6 patients were interval LTFU for at least 6 months, and 1 of 10 patients was interval LTFU for more than 1 year. Insurance status was significant in determining interval LTFU status. Consistent with other analyses, these results indicate that compliance with clinical appointments among patients with PDR is a substantial clinical challenge.

RETINAL LEAKAGE INDEX DYNAMICS ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN EYES TREATED WITH INTRAVITREAL AFLIBERCEPT FOR PROLIFERATIVE DIABETIC RETINOPATHY IN THE RECOVERY STUDY.

PURPOSE: Characterization of leakage indices on ultra-widefield fluorescein angiography in proliferative diabetic retinopathy treated with intravitreal aflibercept. METHODS: Prospective study enrolling subjects for treatment of proliferative diabetic retinopathy randomized 1:1 to receive 2-mg intravitreal aflibercept every 4 weeks (2q4) or every 12 weeks (2q12). Ultra-widefield fluorescein angiography images obtained at baseline, 24, and 48 weeks were analyzed using a semiautomated leakage segmentation platform. Panretinal and zonal leakage indices were calculated. RESULTS: Forty eyes of 40 subjects were included, and mean age was 48 ± 12.1 years. Mean number of injections was 11 ± 1.7 in the 2q4 arm and 4 ± 0.4 in the 2q12 arm. Median baseline leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (P = 0.28). At 24 and 48 weeks, the 2q4 group significantly improved to 1.1% (-79%, P < 0.0001). At Week 24, the 2q12 group demonstrated nonsignificant improvement (3.4%; -21%, P = 0.47); by Week 48, improvement was significant (1.4%; -68%, P = 0.02). The 2q4 group resulted in lower leakage index compared with the 2q12 group at 24 weeks (1.1% vs. 3.4%, respectively; P = 0.008), but by 48 weeks, leakage index was similar between both groups (1.1% vs. 1.4%, respectively; P = 0.34). CONCLUSION: Proliferative diabetic retinopathy treated with intravitreal aflibercept demonstrated significant leakage index reductions at 1 year. Monthly dosing provided more rapid reduction in leakage index compared with quarterly dosing. TRIAL REGISTRATION: RECOVERY study (NCT02863354); https://clinicaltrials.gov/ct2/show/NCT02863354.

Noncompliance in Prospective Retina Clinical Trials: Analysis of Factors Predicting Loss to Follow-up.

PURPOSE: Noncompliance during prospective studies can bias results and limit conclusions. The current study retrospectively investigated the relationship between study subject characteristics and rates of noncompliance in interventional trials involving common causes of blindness. DESIGN: Retrospective analysis of 10 randomized clinical trials. METHODS: Subjects were enrolled in investigator-initiated trials studying proliferative diabetic retinopathy, neovascular age-related macular degeneration, diabetic macular edema, and retinal venous occlusive disease. Records were reviewed for hypothesized risk factors of noncompliance and rates of noncompliance, which were defined as at least 1 missed visit or exiting the study early. Demographic information, systemic medical history, and ocular medical history, including visual acuity and central retinal thicknesses, were examined retrospectively using Student t test, Pearson χ2 test, and logistic regression. RESULTS: Of 390 subjects included, 212 (54.4%) were compliant with all scheduled study visits and 178 (45.6%) met criteria for noncompliance, with 53 (13.6%) subjects exiting early. Regression models identified 17 variables that were significant in determining subject noncompliance. Among those, distance, comorbidities, diabetic status, concomitant medications, previous clinic visits, length of study, disease under study, and severe adverse events were highly significant risk factors of noncompliance. CONCLUSION: The current research identified a substantial proportion of subjects who met the criteria for noncompliance within the trials analyzed. The factors identified in the current work are consistent with published clinical observations and the results of previous clinical trials. These results highlight the importance of considering study design and medical history when designing prospective clinical trials in an attempt to minimize data loss.

Quarterly Anti-Vascular Endothelial Growth Factor Dosing for Neovascular Age-Related Macular Degeneration: Real-World Clinical Outcomes.

BACKGROUND AND OBJECTIVE: Characterize eyes managed with quarterly intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: Treatment-naïve nAMD eyes managed predominately using a treat-and-extend approach that received five or more consecutive quarterly injections from 2005 to 2017. RESULTS: One hundred fifty eyes were retrospectively identified. During quarterly dosing, a mean of 9.8 injections were given over a mean of 29 months. Ninety-one eyes (61%) had no exudative disease recurrence during quarterly dosing. Thirty-three eyes (22%) experienced exudative activity recurrence, with a mean cumulative yearly recurrence rate of 12% and a mean 6-letter loss of visual acuity (VA). Twenty-four eyes (16%) stopped quarterly treatments; nine (38%) of these subsequently experienced exudative activity recurrence with a mean 8-letter VA loss. CONCLUSION: In this real-world analysis of nAMD managed with quarterly dosing over a mean of more than 2 years' follow-up, 22% experienced disease recurrence during quarterly dosing, and 38% of eyes that stopped quarterly dosing experienced subsequent exudative disease recurrence. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e250-e256.].

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial.

PURPOSE: Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). DESIGN: Prospective, randomized clinical trial. PARTICIPANTS: Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema. METHODS: Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly). MAIN OUTCOME MEASURES: The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome. RESULTS: Through 1 year, the monthly (n = 20) and quarterly (n = 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm2 to 266 mm2 (P = 0.18) and ISI increased from 25.8% to 31.9% (P = 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm2 at baseline to 268 mm2 (P = 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm2 at baseline and 1 year (P = 0.70) in the monthly cohort (P = 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n = 24 [66.7%]), this was more common with quarterly dosing (n = 14 [77.8%]), and a proportion of eyes (n = 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n = 8 [44.4%]). CONCLUSIONS: Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation.

The PTEN tumor suppressor is a lipid phosphatase that has a central role in regulating the phosphatidylinositol-3-kinase (PI3K) signal transduction cascade. Nevertheless, the mechanism by which the PTEN activity is regulated in cells needs further elucidation. Although previous studies have shown that ubiquitination of PTEN can modulate its stability and subcellular localization, the role of ubiquitination in the most critical aspect of PTEN function, its phosphatase activity, has not been fully addressed. Here, we identify a novel E3 ubiquitin ligase of PTEN, Ret finger protein (RFP), that is able to promote atypical polyubiquitinations of PTEN. These ubiquitinations do not lead to PTEN instability or relocalization, but rather significantly inhibit PTEN phosphatase activity and therefore modulate its ability to regulate the PI3K signal transduction cascade. Indeed, RFP overexpression relieves PTEN-mediated inhibitory effects on AKT activation; in contrast, RNAi-mediated knockdown of endogenous RFP enhances the ability of PTEN to suppress AKT activation. Moreover, RFP-mediated ubiquitination of PTEN inhibits PTEN-dependent activation of TRAIL expression and also suppresses its ability to induce apoptosis. Our findings demonstrate a crucial role of RFP-mediated ubiquitination in controlling PTEN activity.