Efficacy, Safety, and Durability of Brolucizumab: An 8-Month Post-Marketing Surveillance Analysis.

Importance: Brolucizumab (Beovu®) is an anti-vascular endothelial growth factor (anti-VEGF) agent approved for the treatment of neovascular age-related macular degeneration (nvAMD). Brolucizumab was marketed for its noninferiority to aflibercept and its potential for greater durability. However, post-marketing utilization has been tempered by safety concerns. Objective: We evaluate the visual and anatomic efficacy of brolucizumab, examine changes in treatment intervals after switching to brolucizumab, and estimate the incidence of drug-related adverse events in the real world. Design Setting and Participants: This was a retrospective consecutive case series of 626 eyes (543 patients) with nvAMD treated with 1438 brolucizumab injections at a single retina practice between 10/1/2019 and 5/15/2020. Main Outcomes and Measures: Changes in visual acuity (VA); anatomic outcomes assessed by optical coherence tomography (OCT) including central subfield thickness (CST), macular volume (MV), presence of intraretinal fluid (IRF), subretinal fluid (SRF), and serous pigment epithelial detachment (sPED) on foveal line scans; treatment intervals before and after receiving brolucizumab; and the incidence of brolucizumab-related adverse events. Results: The majority of eyes (N = 531, 89.7%) had received prior anti-VEGF therapy with aflibercept, ranibizumab, and/or bevacizumab. VA improved in treatment-naïve eyes (+3.7 letters, p = 0.04), and was maintained in previously treated eyes. There were significant improvements in all anatomic outcomes in both groups (p < 0.001). We observed a 4.8% incidence of intraocular inflammation (IOI) and a 0.6% incidence of retinal vasculitis. The average treatment interval increased from 6.3 to 6.8 weeks (p = 0.001). Conclusions and Relevance: Brolucizumab treatment was associated with VA improvement in naïve eyes and maintenance of VA in previously treated eyes. Switching to brolucizumab was associated with improved anatomic outcomes and extended treatment intervals in most eyes. We observed a similar incidence of IOI and a lower incidence of retinal vasculitis compared to the Safety Review Committee's analysis of HAWK and HARRIER.

Autoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review.

OBJECTIVE: To demonstrate the spectrum of autoimmune retinopathy (AIR) associated with immunotherapy for advanced cutaneous melanoma. METHODS AND ANALYSIS: Retrospective chart review on patients with advanced cutaneous melanoma who developed AIR after initiating immunotherapy. Complete ophthalmic examination and relevant ancillary testing were performed on each patient. The presence of AIR-associated anti-retinal antibodies was confirmed by western blot and/or immunohistochemical staining. Ophthalmic and systemic outcomes after treatment for AIR were followed over time. A systematic review of AIR associated with immunotherapy for cutaneous or non-ocular mucosal melanoma was carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Case 1 developed photopsia and nyctalopia with electroretinographic findings characteristic for melanoma-associated retinopathy 1 week after initiating ipilimumab/nivolumab immunotherapy. Case 2 experienced new severe bilateral visual field loss associated with anti-retinal and anti-optic nerve antibodies while on maintenance nivolumab immunotherapy. Case 3 developed decreased visual acuity due to acute exudative polymorphous vitelliform maculopathy within 2 weeks of initiating ipilimumab/nivolumab immunotherapy. All patients had concurrent extraocular immune-related adverse events in addition to the presence of anti-retinal antibodies on serological testing. 14 published cases of AIR associated with immunotherapy for cutaneous or non-ocular mucosal melanoma were identified and reviewed. CONCLUSIONS: Immune checkpoint inhibition can trigger the development of AIR with varied clinical manifestations in patients with advanced cutaneous melanoma. This study highlights the need for close monitoring in cutaneous melanoma patients receiving immunotherapy who develop new visual symptoms with or without funduscopic changes, as well as the potential role for screening of patients prior to initiating immunotherapy.

BILATERAL INTRAVITREAL 0.19-MG FLUOCINOLONE ACETONIDE IMPLANT FOR PERSISTENT NONDIABETIC CYSTOID MACULAR EDEMA AFTER VITRECTOMY.

BACKGROUND/PURPOSE: Iluvien (Alimera Science, Alpharetta, GA) is an injectable, nonbiodegradable, sustained-release 0.19-mg fluocinolone acetonide intravitreal implant. Although currently approved by the Food and Drug Administration only for diabetic macular edema previously treated with a course of corticosteroids without a clinically significant intraocular pressure response, the 0.19-mg fluocinolone acetonide implant could theoretically be used to treat other noninfectious inflammatory conditions including persistent cystoid macular edema because of nondiabetic etiologies. METHODS: Interventional case report. A 79-year-old man had persistent cystoid macular edema after pars plana vitrectomy in both eyes that was refractory to topical treatments and intravitreal anti-vascular endothelial growth factor. His cystoid macular edema was responsive to preservative-free intravitreal triamcinolone acetonide after which he developed noninfectious endophthalmitis or pseudoendophthalmitis in both eyes precluding further intravitreal triamcinolone acetonide injections. He was subsequently treated with bilateral intravitreal 0.19-mg fluocinolone acetonide implants. RESULTS: At the most recent post-treatment follow-up (11 months for the right eye and 13 months for the left eye), the patient demonstrated an improvement in visual acuity, 20/126 to 20/50 in the right eye and 20/80 to 20/40 in the left eye, and in central subfield thickness, 592 µm to 288 µm in the right eye and 565 µm to 287 µm in the left eye, without intraocular pressure elevation. CONCLUSION: The intravitreal 0.19-mg fluocinolone acetonide implant is an effective and potentially safe off-label therapeutic option for persistent nondiabetic cystoid macular edema after vitrectomy.

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab.

PURPOSE: To evaluate features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6 mg/0.05 ml for treatment of neovascular age-related macular degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Fifteen eyes from 12 patients identified from 10 United States centers. METHODS: Review of patient demographics, ophthalmologic examination results, and retinal imaging findings. MAIN OUTCOME MEASURES: Baseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography results, and treatment strategies. RESULTS: The number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days after brolucizumab IVI. Mean VA before brolucizumab IVI was 0.426 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/53) and VA at diagnosis of retinal vasculitis was 0.981 logMAR (Snellen equivalent, 20/191; range, 20/25-20/1600; P = 0.008). All affected eyes showed IOI with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular nonperfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages, and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular nonperfusion, and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients, and 3 patients showed negative laboratory assessment for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, and topical), and 2 eyes underwent vitrectomy without improvement in vision. After a mean follow-up of 25 days, mean VA was 0.833 logMAR (Snellen equivalent, 20/136), which was reduced compared with baseline (P = 0.033). CONCLUSIONS: Retinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required because vitreous cells may obscure visualization of retinal details.

Intraocular Dissemination of Uveal Melanoma Cells Following Radiotherapy: Evolving Management Over the Past Decade.

BACKGROUND AND OBJECTIVE: To describe the presentation and the authors' evolving management strategy for intraocular dissemination of uveal melanoma cells following radiotherapy during the past decade. PATIENTS AND METHODS: Patients with uveal melanoma who developed intraocular dissemination of pigmented cells following radiotherapy. Histopathology was available in two cases. RESULTS: Four patients underwent treatment for progressive intraocular dissemination of uveal melanoma cells at 9 to 41 months following I-125 plaque radiotherapy (three patients) or proton beam radiotherapy (one patient). Treatments included primary enucleation (one patient), vitrectomy followed later by enucleation (one patient), and vitrectomy followed by intravitreal chemotherapy (two patients). Enucleated eyes demonstrated diffuse invasion of intraocular tissues by viable melanoma cells. No patient has developed systemic metastasis to date. CONCLUSIONS: Intraocular dissemination of pigmented cells following radiotherapy for uveal melanoma should raise suspicion for viable invasive melanoma cells. Prompt vitrectomy with intravitreal chemotherapy can be effective in avoiding enucleation in selected cases. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:573-579.].

Intraocular Metastasis in Unilateral Multifocal Uveal Melanoma Without Melanocytosis or Germline BAP1 Mutations.

Importance: There has been speculation on the pathogenesis of unilateral multifocal uveal melanoma, but there remains no convincing explanation. Genetic analysis suggests that unilateral multifocal uveal melanoma may represent intraocular metastasis with increased risk of systemic metastasis. Objective: To evaluate the pathogenesis of unilateral multifocal uveal melanoma. Design, Setting, and Participants: This clinical case series was conducted in tertiary academic ocular oncology referral centers and included patients with unilateral multifocal uveal melanoma. Main Outcomes and Measures: Gene expression and mutation profiling of tumor samples. Results: Four patients (all male; age range, 54-77 years) who were diagnosed with uveal melanoma were treated with plaque brachytherapy, and subsequently developed a second discrete uveal melanoma in the same eye were included. None demonstrated ocular or oculodermal melanocytosis. All 8 tumors available for analysis exhibited class 2 gene expression profiles. In all 4 cases, the initial and subsequent tumors were available for targeted DNA sequencing and identical driver mutations were present in both tumors. Data were collected from September 2015 to August 2018. Conclusions and Relevance: Unilateral multifocal uveal melanoma in the absence of ocular melanocytosis appears to occur preferentially in tumors with the class 2 gene expression profile and a BRCA1-associated protein 1 gene (BAP1) mutation. The presence of identical BAP1 mutations in multiple tumors in the same eye in the absence of a germline BAP1 mutation suggests intraocular metastasis rather than independent primary tumors. These findings indicate that the first site of metastasis can be within the eye itself and suggest that patients with unilateral multifocal uveal melanoma may be at increased risk of systemic metastasis.

Dosimetric comparison of circular Eye Physics and Collaborative Ocular Melanoma Study plaques to treat uveal melanoma.

PURPOSE: We sought to formally compare Collaborative Ocular Melanoma Study (COMS) and similar-shaped (circular) eye physics (EP) plaques dosimetrically by examining both tumor coverage and critical structure doses. METHODS AND MATERIALS: The plans of patients with uveal melanoma treated consecutively with eye plaque brachytherapy at a single institution from January 2016 to December 2017 were reviewed. Both a COMS plan and an EP plan using plaques of the same shape were generated for each patient using the Isoaid Plaque Simulator software such that >90% of the tumor + 2 mm margin received 85 Gy over 72 hours from iodine-125 sources. Dose statistics were recorded and analyzed using standard statistical methods. RESULTS: Plans from a total of 62 patients were analyzed. The mean tumor volume was 0.46 cm3 (range: 0.02-2.02), and tumors were located on average 5.89 mm (range: 0-15.0) from the macula and 6.25 mm (range: 0-16.0) from the optic disc. All plans met the treatment planning criteria for tumor coverage and were optimized to reduce dose to the adjacent organs at risk. There were no significant differences in the mean doses to the fovea (mean difference [MD] = -0.87 Gy; 95% confidence interval [CI]: -4.90 to 3.16; p = 0.80), macula (MD = -1.02 Gy; 95% CI: -4.15 to 2.11; p = 0.65), or optic disc (MD = 1.07 Gy; 95% CI: -0.77 to 2.91; p = 0.34) between the COMS and circular EP plaques. CONCLUSIONS: Overall, neither the COMS plaques nor the circular EP plaques provided consistently superior dosimetry for the treatment of uveal melanoma. The choice of plaque may be based on other considerations such as cost and surgeon preference.

Are Risk Factors for Growth of Choroidal Nevi Associated With Malignant Transformation? Assessment With a Validated Genomic Biomarker.

PURPOSE: To test the hypothesis that widely used clinical risk factors for growth of choroidal nevi are associated with malignant transformation. METHODS: Fine needle biopsy for assignment of gene expression profile (class 1 or class 2) was performed in 207 choroidal melanocytic tumors < 3.5 mm in thickness. The class 2 profile was employed as a validated biomarker for malignant transformation. The following data were collected: patient age and sex, tumor diameter and thickness, distance of posterior tumor margin from the optic disc, and the presence or absence of serous retinal detachment, orange lipofuscin pigment, drusen, retinal pigment epithelial fibrosis, retinal pigment epithelial atrophy, visual symptoms, and documented tumor growth. RESULTS: Clinical features associated with the class 2 profile included patient age > 60 years and tumor thickness > 2.25 mm (Fisher exact test, P = .002 for both). Documented growth was not associated with the class 2 profile (P = .5). The odds ratio of a tumor having the class 2 profile was 2.8 (95% confidence interval 1.3-5.9) for patient age > 60 years and 3.5 (95% confidence interval 1.4-8.8) for tumor thickness > 2.25 mm. For patients with both risk factors, the "number needed to treat" to identify 1 patient with a class 2 tumor was 4.3 (P = .0002). No other clinical feature or combination of features was associated with the class 2 profile. CONCLUSIONS: None of the widely used choroidal nevus risk factors for tumor growth, nor documented growth itself, is pathognomonic of malignant transformation as defined by class 2 gene expression profile. Patient age and tumor thickness may be helpful for identifying small choroidal melanocytic tumors that are more likely to have the class 2 profile. Observation for growth prior to treatment continues to be reasonable for most patients with suspicious choroidal nevi. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Diagnosis of Bilateral Retinocytoma in an Adolescent Patient Using Multimodal Imaging and Genetic Testing.

A 12-year-old male presented for evaluation of asymptomatic bilateral retinal tumors. Both eyes contained whitish-gray retinal tumors with intralesional calcifications. Enhanced depth optical coherence tomography and high-resolution (20 MHz) ultrasonography narrowed the differentiation diagnosis to astrocytic hamartoma versus retinocytoma. Genetic testing of a saliva sample was negative for tuberous sclerosis complex but positive for a novel mutation in the retinoblastoma gene (RB1). Taken together, these findings were consistent with a diagnosis of bilateral retinocytoma in a patient with germline RB1 mutation. This case demonstrates the importance of combining clinical imaging and genetic testing in the evaluation of bilateral intraocular tumors. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:812-814.].

Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma.

PURPOSE: To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM). DESIGN: Retrospective cohort study. METHODS: The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint. RESULTS: GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10-8), largest basal tumor diameter (P = 2.5 × 10-6), PRAME status (P = 2.6 × 10-6), and TNM stage (P = 3.7 × 10-6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10-14) was superior to an optimized TNM model (P = 1.3 × 10-5). CONCLUSIONS: In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.

A Frag Bag for Efficient Removal of Dislocated Nuclear Material.

Dislocated nuclear material may be present in the vitreous cavity following complicated cataract surgery, closed globe injury, or spontaneous dislocation of the crystalline lens. The authors report herein a method to remove larger pieces of retained nuclear material during vitrectomy surgery with a retractable basket made from nitinol referred to as the "Frag Bag" (patent pending). Although originally designed for cystoscopic removal of kidney stones, this instrument fits easily through a 23-gauge vitrectomy port. The basket allows for retrieval of larger pieces of retained nuclear material with stabilization of the lens material in the mid-vitreous cavity and softening of the nuclear material to allow efficient and safe removal with the vitreous cutter, away from the retinal surface. Use of the Frag Bag may potentially improve the safety and efficiency of a pars plana lensectomy by obviating the need for a phacofragmatome and decreasing the number of times instruments are brought close to the retinal surface. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1006-1008.].

Neuro-oculo-cutaneous cavernous hemangiomas: a CCM1 mutation-associated phakomatosis.

Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life-threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene.

Venous Loop Reveals an Occult Retinoblastoma Tumor.

A 14-day-old girl presented with bilateral hereditary retinoblastoma. At 3 months, a slight bend in the superotemporal arcade was observed to have developed into a venous loop. With concern for an occult lesion along the arcade, handheld optical coherence tomography (hhOCT) confirmed a small tumor and helped to guide prompt laser treatment while sparing the venous arcade. A venous loop is a previously unrecognized clinical finding that preceded the clinical detection and hhOCT confirmation of the tumor. The authors hypothesize that the venous loop was induced by pro-angiogenic factors secreted by the tumor. Portable hhOCT is a valuable adjunct imaging modality in the diagnosis and management of small retinoblastoma tumors. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:768-770.].