Emerging opportunities for C3 inhibition in the eye.

The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3's functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3's relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.

FACTORS ASSOCIATED WITH OUTCOMES OF SUPRACHOROIDAL HEMORRHAGE: An Individual Participant Data Systematic Review.

PURPOSE: To determine factors associated with visual and anatomic outcomes of suprachoroidal hemorrhage in studies published between 1990 and 2022. METHODS: Individual participant data systematic review. The protocol was prospectively registered on Open Science Framework ( https://osf.io/69v3q/ ). PubMed, EMBASE, Web of Science, and Google Scholar were searched for peer-reviewed studies of suprachoroidal hemorrhage with ≥3 patients published between January 1, 1990, and September 1, 2022. The primary outcome was the change in logarithm of the minimum angle of resolution visual acuity from the time of suprachoroidal hemorrhage diagnosis to last follow-up. RESULTS: Four hundred thirteen eyes from 49 studies were included, with mean (SD) age 60.8 (22.4) years and mean (SD) follow-up of 13.8 (12.6) months. Among 145 eyes with at least 6 months of follow-up, the mean (SD) gain in visual acuity was -0.98 (0.89) logarithm of the minimum angle of resolution. In multivariable regression, treatment with systemic steroids was associated with greater improvement in logarithm of the minimum angle of resolution visual acuity (adjusted mean [SE] -1.29 [0.09] vs. -0.16 [0.30] for no systemic steroids; P < 0.001) and greater odds of achieving anatomic success (adjusted OR 10.59, 95% confidence interval 2.59-43.3; P = 0.001). CONCLUSION: The use of systemic steroids was associated with better visual and anatomic outcomes for suprachoroidal hemorrhage.

COMBINED RHEGMATOGENOUS RETINAL AND CHOROIDAL DETACHMENT: A Systematic Review.

PURPOSE: To review the literature on eyes with concurrent rhegmatogenous retinal and choroidal detachment (RRD-CD). METHODS: Several databases were searched for "rhegmatogenous retinal detachment" and "choroidal detachment" through October 2022. All English language primary literature was reviewed. RESULTS: Studies demonstrated that eyes with RRD-CD were very uncommon and had diminished baseline visual acuity (VA) and intraocular pressure (IOP) compared with eyes with RRD only. Although no randomized trials have been performed, pars plana vitrectomy with or without scleral buckle (SB) have reported higher surgical success rates than SB alone. Reattachment rates were affected by age, IOP, adjuvant steroids, and grade of proliferative vitreoretinopathy. CONCLUSION: Low IOP and poor initial VA are salient features of eyes with RRD-CD. Steroids can be useful adjuvants administered safely using several routes including periocular and intravitreal injection. PPV ± SB may result in best surgical outcomes.

CLINICAL UTILITY OF BETA-D-GLUCAN TESTING FOR ENDOGENOUS FUNGAL CHORIORETINITIS OR ENDOPHTHALMITIS.

PURPOSE: To evaluate serum beta-D-glucan (BDG) as a biomarker for endogenous fungal eye infection. METHODS: Retrospective case-control study of 88 patients with a BDG test and eye examination at UPenn (2013-2018). Cases had endogenous fungal chorioretinitis or endophthalmitis diagnosed by eye examination and confirmed with positive culture; controls were without these fungal eye findings. Charts were reviewed for BDG values, blood/vitreous cultures, and eye examinations. Outcomes were BDG sensitivity, specificity, positive predictive value, and negative predictive value for fungal chorioretinitis or endophthalmitis, using prespecified BDG cut-off points of ≥80, ≥250, and ≥500 pg/mL as test positive. RESULTS: Cases included six chorioretinitis and four endophthalmitis patients. Controls included 78 patients without chorioretinitis or endophthalmitis. Defining BDG ≥80 pg/mL as test positive, the BDG sensitivity (95% confidence interval) was 66.7% (22.3%-95.7%) for chorioretinitis and 100% (39.8%-100%) for endophthalmitis. The specificity was 74.4% (63.2%-83.6%) when BDG values ≥80 pg/mL were test positive, and 85.9% (76.2%-92.7%) when values ≥250 pg/mL were test positive. For a 1% endophthalmitis prevalence and BDG cut-off value of ≥80 pg/mL, the positive predictive value was 3.8% (2.4%-5.2%) and negative predictive value was 100% (99.1%-100%). CONCLUSION: For endogenous fungal endophthalmitis, BDG's sensitivity and specificity seem good and the negative predictive value is high; a larger ophthalmic study is indicated.

BETA-PERIPAPILLARY ATROPHY AND GEOGRAPHIC ATROPHY IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENTS TRIALS.

PURPOSE: To determine associations between beta-peripapillary atrophy (B-PPA) and incidence and growth of geographic atrophy (GA) in eyes treated with anti-vascular endothelial growth factor agents in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). METHODS: We included 245 cases with incident GA and 245 controls matched by baseline demographics and characteristics associated with development of GA in the CATT. Baseline color images were graded for the type of B-PPA, defined as presence of hypopigmentation with visible choroidal vessels and sclera that is adjacent to the optic disk. Beta-peripapillary atrophy was further classified as scleral ring, sclera, sclera/choroidal blood vessels, or combination. Areas of each type of B-PPA and the circumferential extent of B-PPA were measured. RESULTS: Beta-peripapillary atrophy was present in 58% of eyes developing GA and in 52% without GA (P = 0.17). The greater circumferential extent of sclera/choroidal blood vessels B-PPA in relation to the optic disk was associated with incident GA (P = 0.02) and the GA size at first observation (P = 0.047). Beta-peripapillary atrophy was not associated with GA growth rates (P>0.05). Patients without B-PPA had a higher number of GA-associated risk alleles of ARMS2 (P = 0.0003) and HTRA1 (P = 0.001). CONCLUSION: The extent of sclera/choroidal blood vessel B-PPA was associated with the GA incidence and size but not with the growth rate in eyes treated for neovascular age-related macular degeneration. Beta-peripapillary atrophy and GA may share some common pathophysiologic pathways unrelated to the GA-associated risk alleles evaluated.

Prolonged intraocular residence and retinal tissue distribution of a fourth-generation compstatin-based C3 inhibitor in non-human primates.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased C3 turnover, retinal inflammation and photoreceptor loss. Therapeutic targeting of C3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tissue. In this regard, a PEGylated second-generation derivative of the compstatin family of C3-targeted inhibitors is currently in late-stage clinical development as a treatment option for geographic atrophy, an advanced form of AMD which lacks approved therapy. While efficacy has been strongly suggested in phase 2 clinical trials, crucial aspects still remain to be defined with regard to the ocular bioavailability, tissue distribution and residence, and dosing frequency of such inhibitors in AMD patients. Here we report the intraocular distribution and pharmacokinetic profile of the fourth-generation compstatin analog, Cp40-KKK in cynomolgus monkeys following a single intravitreal injection. Using a sensitive surface plasmon resonance (SPR)-based competition assay and ELISA, we have quantified both the amount of inhibitor and the concentration of C3 retained in the vitreous of Cp40-KKK-injected animals. Cp40-KKK displays prolonged intraocular residence, being detected at C3-saturating levels for over 3 months after a single intravitreal injection. Moreover, we have probed the distribution of Cp40-KKK within the ocular tissue by means of immunohistochemistry and highly specific anti-Cp40-KKK antibodies. Both C3 and Cp40-KKK were detected in the retinal tissue of inhibitor-injected animals, with prominent co-localization in the choroid one-month post intravitreal injection. These results attest to the high retinal tissue penetrance and target-driven distribution of Cp40-KKK. Given its subnanomolar binding affinity and prolonged ocular residence, Cp40-KKK constitutes a promising drug candidate for ocular pathologies underpinned by deregulated C3 activation.

Five-Year Follow-up of Nonfibrotic Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To describe changes in visual acuity (VA) and macular morphologic features at 5 years in eyes with nonfibrotic scar (NFS) identified at 1 year in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: Participants in CATT. METHODS: Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years. Nonfibrotic scar was identified on color images at year 1 as flat, small, well-circumscribed areas of pigmentation with varying degrees of central hypopigmentation without exposure of underlying choroidal vessels at the site of baseline choroidal neovascularization. Follow-up images were assessed for changes in and around NFS. MAIN OUTCOME MEASURES: Pigmentation changes, VA, development of fibrotic scar (FS), nongeographic atrophy (NGA), geographic atrophy (GA), retinal fluid on OCT, and fluorescein leakage. RESULTS: Among 474 eyes with images obtained at 1, 2, and 5 years, 39 (8.2%) showed NFS at 1 year with a mean VA of 80 letters (Snellen equivalent, 20/25). Among these eyes, FS developed in 5% at 2 years and 28% at 5 years. Nongeographic atrophy was observed in 34%, 47%, and 65% of eyes at 1, 2, and 5 years, respectively. Geographic atrophy developed in 5% of eyes at 2 years and 21% at 5 years. Among eyes with NFS, FS, or no scar at 1 year, mean VA at 5 years was 73 letters (20/32), 48 letters (20/100), and 62 letters (20/63), respectively. At 5 years, NFS eyes demonstrated less GA, less intraretinal fluid, more subretinal fluid, and less subretinal pigment epithelium fluid (all P < 0.01). Among NFS eyes, mean thickness of the retina, subretinal tissue complex, and total retina did not change across years 1 to 5 (P > 0.50). The proportion of eyes with fluid on OCT also did not change (P = 0.36). Subretinal hyperreflective material disappeared by 5 years in 40% of eyes with NFS. CONCLUSIONS: These results indicate that, on average, eyes with NFS after anti-VEGF treatment have good VA not only at 1 and 2 years, but also through 5 years.

FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial.

PURPOSE: To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma. METHODS: Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment. RESULTS: There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged. CONCLUSION: BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

Development and Course of Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To describe risk factors for scar formation and changes to fibrotic scar through 5 years in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). DESIGN: Multicenter, prospective cohort study. PARTICIPANTS: A total of 1061 subjects in CATT. METHODS: Color photographic and fluorescein angiographic images from baseline and 1, 2, and 5 years were evaluated. Incidence of scar formation was estimated with Kaplan-Meier curves. Risk factors were assessed with Cox regression models. MAIN OUTCOME MEASURES: Scar formation, fibrotic scar area, and macular atrophy associated with fibrotic scar ("atrophy"). RESULTS: Cumulative proportion of eyes with scar was 32%, 46%, and 56% at years 1, 2, and 5, respectively. Baseline factors associated with increased risk (adjusted hazards ratio [aHR] and 95% confidence interval [CI]) were classic choroidal neovascularization (CNV) (aHR, 4.49; 95% CI, 3.34-6.04) versus occult, hemorrhage >1 disc area (DA) (aHR, 2.28; 95% CI, 1.49-3.47) versus no hemorrhage, retinal thickness >212 µm (aHR, 2.58; 95% CI, 1.69-3.94) versus <120 µm, subretinal tissue complex thickness >275 µm (aHR, 2.64; 95% CI, 1.81-3.84) versus ≤75 µm, subretinal fluid thickness >25 µm (aHR, 1.31; 95% CI, 0.97-1.75) versus no fluid, visual acuity (VA) in fellow eye 20/20 (aHR, 1.72; 95% CI, 1.25-2.36) versus 20/50 or worse, retinal pigment epithelium elevation absence (aHR, 1.71; 95% CI, 1.21-2.41), and subretinal hyperreflective material (aHR, 1.72; 95% CI, 1.25-2.36). Among 68 eyes that developed fibrotic scar at year 1, VA decreased by a mean of additional 13 letters between years 1 and 5. Mean scar area was 1.2, 1.2, and 1.9 DA at 1, 2, and 5 years, respectively. Atrophy was present in 18%, 24%, and 54% of these eyes at years 1, 2, and 5, respectively; the mean areas were 1.6, 2.0, and 3.1 DA, respectively. Atrophy replaced fibrotic scar in 8 eyes at year 5. There was no significant correlation between scar growth and atrophy growth. The rate of growth for both was similar between the clinical trial and observation periods. CONCLUSIONS: Several morphologic features, including classic CNV and large hemorrhage, are associated with scar formation. Rate of new scar formation declined after 2 years. Most fibrotic scars and accompanying macular atrophy expanded over time, reducing VA.

BETA-D-GLUCAN TESTING IN PATIENTS WITH FUNGAL ENDOPHTHALMITIS.

PURPOSE: To review the literature on beta-D-glucan (BDG) testing in fungal endophthalmitis. METHODS: Review of primary literature using PubMed through April 2017 and presentation of an illustrative case report. A total of 231 articles were identified and 43 were ultimately chosen for review based on relevance and presence of ophthalmologic examination and objective data. RESULTS: Beta-D-glucan is a major component of fungal cell walls. It is quantified using a calorimetry-based Fungitell assay based on modification of the limulus amebocyte lysate. Serum BDG levels are commonly used clinically in conjunction with other tests for early surveillance and diagnosis of invasive fungal infections. In the ophthalmic literature, elevated levels of BDG have been detected in vitreous fluid of patients undergoing vitrectomy for fungal endophthalmitis, tear fluid of patients with mycotic keratitis, and serum of a patient with bilateral endogenous subretinal abscesses. Elevated serum BDG levels appear to be highly associated with fungal endophthalmitis. Potential uses and considerations with regards to test limitations are discussed. CONCLUSION: Beta-D-glucan testing may be used as an adjunct to support a diagnosis, initiate pharmacologic therapy or surgical intervention, and optimize overall clinical management in patients diagnosed with or under clinical suspicion for invasive fungal infections, including endophthalmitis. Additional clinical studies are necessary to fully characterize the utility of BDG testing in patients with fungal endophthalmitis.

Visual and Anatomic Outcomes of Suprachoroidal Hemorrhage: A Systematic Review and Meta-Analysis.

TOPIC: To characterize the presentation, management, and outcomes of suprachoroidal hemorrhage (SCH). CLINICAL RELEVANCE: Suprachoroidal hemorrhage is a potentially devastating condition but there is no high-quality evidence for the prognosis or management of SCH. METHODS: We performed a systematic review and meta-analysis of peer-reviewed studies of SCH published in PubMed, EMBASE, Web of Science, or Google Scholar between January 1, 1990, and September 1, 2022. The protocol was prospectively registered on the Open Science Framework (https://osf.io/69v3q/). Random-effects models were used to calculate the pooled estimate and 95% confidence intervals (CIs) for visual acuity (VA) and anatomic outcomes. Univariable and multivariable random-effects meta-regressions were performed to determine factors associated with VA outcomes and anatomic success, defined as the retina attached at the last follow-up. RESULTS: Sixty-eight studies comprising 1246 eyes of 1245 patients were included, with mean (standard deviation [SD]) follow-up of 14.0 (9.4) months. The pooled estimate (95% CI) for mean change in logarithm of the minimum angle of resolution (logMAR) VA from baseline to the last follow-up was -0.98 (-1.22 to -0.74) (I2 = 88.4%), with 72.0% (63.5%-80.5%) (I2 = 74.3%) achieving VA improvement of ≥ 0.3 logMAR (3-line improvement in ETDRS VA), 39.6% (32.5%-46.7%) (I2 = 83.2%) achieving final VA of 1.0 logMAR (Snellen equivalent 20/200) or better, and 75.5% (68.4%-82.7%) (I2 = 74.7%) achieving anatomic success. Studies with predominantly nonspontaneous SCH and greater percent of eyes receiving systemic steroids were associated with greater improvement in logMAR VA, a greater proportion of eyes with VA improvement ≥ 0.3 logMAR, and greater proportion of eyes achieving anatomic success (all P < 0.05 univariable meta-regression). Studies with greater percent of eyes treated surgically were associated with greater proportion of eyes with VA improvement of ≥ 0.3 logMAR in (P < 0.05, univariable and multivariable analysis). The mean (SD) quality score across studies was 13.9 (2.3) out of 24, and outcomes were of very low certainty of evidence. CONCLUSION: Although limited by heterogeneous observational studies, published reports of SCH indicate that most eyes with SCH experience some degree of VA improvement and anatomic success. However, final VA outcomes remain poor, with most cases resulting in severe visual impairment or blindness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Bilateral retinal hemorrhages after sequential endovascular treatment of bilateral unruptured cerebral aneurysms.

PURPOSE: To report a case of bilateral retinal hemorrhages in a patient undergoing two separate endovascular interventions for bilateral cerebral aneurysms. METHODS: A comprehensive ophthalmic examination was performed after the patient underwent each of two separate endovascular interventions for bilateral cerebral aneurysms. Multimodal imaging including widefield pseudocolor fundus photography, optical coherence tomography, and widefield fluorescein angiography (FA) was obtained. A systemic workup including genetic testing and hypercoagulability studies was performed. RESULTS: Dilated fundus examination revealed new visually significant ipsilateral retinal hemorrhages after each endovascular procedure. FA showed evidence of a peripheral retinal microangiopathy present in both eyes before the patient underwent her second endovascular procedure. Systemic workup revealed persistently elevated serum anticardiolipin IgM antibody levels at >99th percentile. CONCLUSION: Retinal complications after endovascular intracranial interventions are uncommon. This patient who developed bilateral retinal complications was found to have persistently elevated anticardiolipin antibody levels, a risk factor for thrombosis. Patients who develop retinal complications after endovascular intracranial intervention may benefit from systemic workup for hypercoagulable conditions.

OUTER RETINOPATHY AND MICROANGIOPATHY IN ACUTE MYELOGENOUS LEUKEMIA.

PURPOSE: To describe a patient with acute myelogenous leukemia who presented with a recurrent, bilateral, outer retinopathy, before and after consolidative peripheral blood stem cell transplantation complicated by chronic graft-versus-host disease. METHODS: This is a retrospective review of records from a 23-year-old woman with acute myelogenous leukemia who underwent comprehensive ophthalmic evaluations for over a year including chromatic perimetry and multifocal electroretinograms, imaging with spectral domain optical coherence tomography, near-infrared and short-wavelength fundus reflectance and autofluorescence, fluorescein and optical coherence tomography angiography. RESULTS: The patient presented with recurrent, unilateral paracentral scotomas. There was localized loss of inner segment ellipsoid (EZ) and photoreceptor outer segment signals (IZ) in the pericentral retina of both eyes co-localizing with hyperreflective lesions on near-infrared reflectance. She subsequently lost vision (visual acuity = 20/200) in the right eye a year after consolidative peripheral blood stem cell transplantation complicated by steroid-resistant-chronic graft-versus-host disease. There was loss of the EZ and IZ signals corresponding to a dense central cone scotoma and multifocal electroretinograms depression. Near-infrared autofluorescence, fluorescein and optical coherence tomography angiography were within normal limits. Visual acuity (20/20) and retinal sensitivities improved with restoration of the EZ/IZ signals after oral prednisone and intravenous rituximab, but left a residual photoreceptor loss and paracentral scotoma. CONCLUSION: We propose that an immune-mediated microangiopathy may explain the protracted, recurrent course of primary photoreceptor abnormalities in our patient, which was further complicated by manifestations of chronic graft-versus-host disease following consolidative peripheral blood stem cell transplantation. Outer retinal findings previously documented in leukemia may be explained by a similar mechanism.

UTILITY OF OCULAR ß- d -GLUCAN TESTING IN PATIENTS WITH FUNGAL ENDOPHTHALMITIS.

PURPOSE: To assess the diagnostic utility of (1→3)-ß- d -glucan (BDG) in ocular fluid of patients with fungal endophthalmitis. METHODS: This prospective pilot single-center study evaluated aqueous and vitreous humor BDG levels of suspected fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls with the standard Fungitell assay and the Fungitell STAT assay. ß- d -Glucan levels were compared using generalized linear models followed by post hoc pairwise comparisons. RESULTS: Seven fungal endophthalmitis, 6 bacterial endophthalmitis, and 17 noninfectious ocular samples were evaluated. Mean aqueous BDG concentrations were 204, 11.0, and 9.6 pg/mL for fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls, respectively ( P = 0.01, fungal vs. bacterial; P = 0.0005, fungal vs. noninfectious controls). Mean vitreous BDG concentrations were 165, 30.3, and 5.4 pg/mL, respectively ( P = 0.001 for fungal vs. bacterial; P < 0.0001 for fungal vs. noninfectious controls). Mean vitreous BDG index (Fungitell STAT) values were 1.7, 0.4, and 0.3, respectively ( P = 0.001, fungal vs. bacterial; P = 0.0004, fungal vs. noninfectious controls). The Pearson correlation between BDG levels and BDG index was high (correlation coefficient = 0.99, P < 0.001). CONCLUSION: Significantly elevated ocular BDG levels were found in fungal endophthalmitis compared with bacterial endophthalmitis and noninfectious controls. Our study suggests a potential utility for BDG testing in the diagnosis of fungal endophthalmitis, and a larger study is warranted.

Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer's disease.

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity. Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change.

Approach of an Academic Ophthalmology Department to Recovery During the Coronavirus Pandemic.

Introduction: A methodology for safe recovery of an ophthalmology department during a pandemic does not currently exist. This study describes successful recovery strategies for an urban, multi-specialty ophthalmology department serving a high-risk patient population. Methods: The study took place at a large multi-specialty tertiary care academic ophthalmology department in a metropolitan city during a seven-month period (March-October 2020). Five recovery ad hoc committees were charged with formulating metrics and initiatives to manage clinical volumes while maintaining safe practices, providing patient access, and minimizing financial damage. A six-tier system was created to resume non-urgent appointments in May 2020. Educational and research activities were maintained through the development of virtual curricula and research platforms. Results: The number of clinical and surgical visits per month in 2020 compared to 2019 and the time to reach ≥95% of pre-COVID patient volumes were monitored. In October 2020, ≥95% of pre-COVID volumes were attained (11,975 vs 12,337 patient visits in October 2019; 266 vs 272 surgical cases in October 2019). Despite significant financial losses, the department surpassed December 2019 collections in December 2020. No faculty, staff, or trainees received furloughs or pay cuts. There was no COVID-19 transmission between faculty, staff, and patients. Discussion: With strategic implementation of recovery strategies following CDC safety measures, it was possible to safely deliver care to patients with urgent and non-urgent eye conditions. Patient volumes were fully recovered in an ambulatory urban healthcare setting within a high-risk COVID-19 population within seven months while educational and research missions were successfully sustained.

BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma.

PURPOSE: Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T). PATIENTS AND METHODS: We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. RESULTS: Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. CONCLUSIONS: HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.