Risk, Prevalence, and Progression of Glaucoma in Eyes With Age-Related Macular Degeneration Treated With Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

PURPOSE: To examine the risk, prevalence, and progression of glaucoma development in age-related macular degeneration (AMD) eyes receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections compared to controls. DESIGN: Retrospective clinical cohort study. METHODS: Retrospective review of eyes receiving intravitreal anti-VEGF injections from January 1, 2004, to December 31, 2013, for exudative AMD. Age- and sex-matched control groups of eyes included eyes with nonexudative AMD (NEAMD) and no AMD. Eyes with a diagnosis of glaucoma or glaucoma suspect were reviewed for injection details, type and date of glaucoma diagnosis, glaucoma treatments, standard automated perimetry (SAP), and spectral domain optical coherence tomography (SD-OCT). Qualitative progression was determined by indication of glaucoma progression in provider notes. Quantitative progression was assessed based on change in mean deviation (MD) on SAP, retinal nerve fiber layer thickness on SD-OCT, and intraocular pressure (IOP). RESULTS: There were 707 eyes of 504 patients treated with anti-VEGF injections and 1008 eyes in the NEAMD and no-AMD cohorts. There was no difference in glaucoma or suspect prevalence at initial presentation between eyes treated with injections and NEAMD (6.9% vs 9.7%, P = .22) or no-AMD controls (vs 8.5%, P = .55). There was no difference in cumulative 5-year probability of new glaucoma diagnosis after anti-VEGF injections compared to NEAMD (1.9% vs 1.0%, P = .69) or no-AMD controls (vs 1.6%, P = .88). There was no difference in qualitative progression of glaucoma in the injection cohort vs NEAMD (P = .19) or no-AMD controls (P = .61). The rate of MD change in injection eyes was similar to NEAMD eyes (P = .74) but greater than no-AMD eyes (P = .02). Eyes receiving injections required more topical glaucoma medications compared with NEAMD (P = .03) and more glaucoma laser treatments compared with no-AMD controls (P = .009). Eyes receiving injections did not require more frequent incisional glaucoma surgery compared with NEAMD (21.0% vs 15.0%, P = .95) or no-AMD controls (vs 10.0%, P = .10). CONCLUSION: Eyes treated with intravitreal anti-VEGF injections for exudative AMD did not have increased risk of developing glaucoma compared with controls. Of those with a glaucoma diagnosis, exudative AMD eyes receiving injections required a greater number of topical glaucoma medications compared with NEAMD eyes and had a greater rate of MD loss than no-AMD controls.

INCREASED INCIDENCE OF CUTANEOUS KERATINOCYTIC AND MELANOCYTIC MALIGNANCIES IN PATIENTS WITH AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The relationship between age-related macular degeneration (AMD) and malignancy, especially cutaneous malignancies, is not well studied. We investigated a possible association between AMD and cutaneous malignancies. METHODS: A retrospective, consecutive review of all patients who had received at least 1 intravitreal injection for wet AMD between January 1, 2004, and December 31, 2013, was conducted using the Rochester Epidemiology Project in Olmsted County, Minnesota. Age- and sex-matched control groups included 473 pre-anti-vascular endothelial growth factor era wet AMD patients, 504 concurrent time dry AMD patients, and 504 patients with no AMD. The rates of AMD and overall malignancy, cutaneous malignancies, and specific types of cutaneous malignancies were compared between groups of patients. RESULTS: Patients with wet AMD incurred an increased rate of overall malignancies compared to patients with dry AMD {52.8% wet AMD (confidence interval [CI]: 48.3-57.2) vs. 43.7% dry AMD (CI: 39.3-48.1); P= 0.003} or those without AMD (52.8% wet AMD [CI: 48.3-57.2] vs. 35.3% no AMD [CI: 31.1-39.7]; P = <0.001). Patients with dry AMD also had higher rates of malignancy than those without AMD (43.7% dry AMD [CI: 39.3-48.1] vs. 35.3% no AMD [CI: 31.1-39.7]; P = 0.007). Rate of cutaneous malignancies was increased in patients with wet AMD compared to patients with dry AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 14.6% dry AMD [CI: 11.5-17.9]; P = <0.001) and those with no AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 9.7% no AMD [CI: 7.3-12.7]; P = <0.001). CONCLUSION AND RELEVANCE: To the best of our knowledge, this is the first report to establish an association between AMD and cutaneous malignancies, supporting a possible discussion of the association when a patient presents with one of the two conditions.

Classification of Strokes in Patients Receiving Intravitreal Anti-Vascular Endothelial Growth Factor.

BACKGROUND AND OBJECTIVE: The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations. PATIENTS AND METHODS: We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified. RESULTS: A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all). CONCLUSION: The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140-e157.].

Association of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy With Risk of Stroke, Myocardial Infarction, and Death in Patients With Exudative Age-Related Macular Degeneration.

Importance: Current studies assessing the risk of stroke, myocardial infarction (MI), and death in patients undergoing intravitreal anti-vascular endothelial growth factor (VEGF) therapy are inconclusive. To our knowledge, no population-based studies have been performed to examine these potential risks. Objective: To examine whether patients with exudative age-related macular degeneration (AMD) receiving intravitreal anti-VEGF injections have a higher incidence of MI, stroke, or death compared with control populations. Design, Setting, and Participants: This population-based, retrospective cohort study included 504 patients from Olmsted County, Minnesota, identified through the Rochester Epidemiology Project (REP) database as receiving at least 1 intravitreal anti-VEGF injection for exudative AMD from January 1, 2004, to December 31, 2013. Three age- and sex-matched control groups of individuals who did not receive anti-VEGF treatment and were derived from the REP database were also studied: control individuals with exudative AMD in the era before anti-VEGF (January 1, 1990, to December 31, 2003), controls with dry AMD, and controls without AMD. Data analysis was performed from September 1, 2016, to September 1, 2017. Main Outcomes and Measures: Five-year risk of stroke, MI, and death were assessed in patients compared with controls using Kaplan-Meier and multivariate analysis with Cox proportional hazards regression models. Results: The study included 504 patients (321 female [63.7%]; mean [SD] age, 76.5 [10.0] years) who received at least 1 intravitreal anti-VEGF injection for exudative AMD during the study period. Kaplan-Meier analysis revealed a 5-year risk of 7.2% for stroke, 6.1% for MI, and 30.0% for death. Patients who received anti-VEGF had no increased risk of stroke or MI compared with controls with dry AMD (n = 504), controls with exudative AMD (n = 473), or controls without AMD (n = 504). There was an increased risk of mortality compared with controls with exudative AMD in the era prior to anti-VEGF therapy but not the other control groups on multivariate analysis (hazard ratio, 1.63; 95% CI, 1.30-2.04; P < .001). Conclusions and Relevance: This population-based study revealed that intravitreal anti-VEGF therapy for exudative AMD was not associated with consistent increases in the risk of stroke, MI, or death compared with no therapy in patients with or without AMD. It appears to be likely the cardiac events these patients experience are not attributable to their anti-VEGF therapy.

Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma.

Glioblastoma (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen-presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in modifying DC function. We found that VEGF blockade results in a more mature DC phenotype in the brain, as demonstrated by an increase in the expression of the co-stimulatory molecules B7-1, B7-2, and MHC II. Furthermore, we observed reduced levels of the exhaustion markers PD-1 and Tim-3 on brain-infiltrating CD8 T cells, indicating improved functionality. Thus, anti-angiogenic therapy has the potential to be used in conjunction with and enhance immunotherapy for GBM.

NONINVASIVE GRADING OF RADIATION RETINOPATHY: The Use of Optical Coherence Tomography Angiography.

PURPOSE: Previous studies have shown that spectral domain optical coherence tomography can diagnose radiation retinopathy (RR) before ophthalmoscopic findings. Recently, optical coherence tomography angiography (OCT-A) has been helpful in seeing vascular findings undetected by spectral domain optical coherence tomography. The authors wish to demonstrate the OCT-A grading at varying levels of RR. METHODS: The OCT-A, spectral domain optical coherence tomography, and ophthalmoscopic findings on 7 patients from December 2014 to March 2015 with varying levels of RR are demonstrated. RESULTS: Findings on OCT-A could be demonstrated before spectral domain optical coherence tomography findings. Patients can be graded on a scale of increasing severity from 0 to 5, based on positive or negative clinical findings of RR between OCT-A. Optical coherence tomography increased central macular thickness, optical coherence tomography evident cysts, and ophthalmoscopy (Grade 0: -,-,-,-; Grade 1: +,-,-,-; Grade 2: +,+,-,-; Grade 3: +,+,+,-; Grade 4: ++,+,+,+; Grade 5: unreadable,++,++,+). CONCLUSION: The use of OCT-A allows for earlier detection of RR; thus, existing grading systems should be modified to include OCT-A.