Pegaptanib Sodium for Macular Edema Secondary to Central Retinal Vein Occlusion FREE

Macular edema following central retinal vein occlusion (CRVO) is a major cause of vision loss.^{1 - 3} No United States Food and Drug Administration–approved pharmacologic treatments exist for macular edema in the setting of CRVO.^{4 - 5} Grid photocoagulation does not improve visual acuity when compared with controls,³ and surgical interventions have not been evaluated in controlled randomized trials.

Central retinal vein occlusion is thought to result from an obstruction of unknown etiology in the central retinal vein at or variable distances posterior to the lamina cribrosa.⁶ Based on histopathology of eyes with CRVO that were enucleated owing to neovascular glaucoma, ischemic CRVO may result from the formation of focal thrombi at or just posterior to the lamina cribrosa.⁷ The site of occlusion in nonischemic CRVO is likely to be further posterior to the lamina cribrosa. Subsequent hypoxia leads to upregulation of vascular endothelial growth factor (VEGF),⁸ resulting in increased retinal capillary permeability⁹ and leakage of fluid and blood into the intraretinal space.^{10 - 11} In addition, VEGF is a key promoter of angiogenesis,¹² potentially contributing to the development of the neovascularization associated with CRVO. In patients with ischemic CRVO, defined by the presence of 10 to 75 or more disc areas of capillary nonperfusion determined by fluorescein angiography,⁴ aqueous humor levels of VEGF show a close temporal correlation with the course of iris neovascularization and retinal capillary permeability.¹³ Inhibition of VEGF in a nonhuman primate model of CRVO can prevent the development of iris and angle neovascularization.¹⁴ Vascular endothelial growth factor induces expression of thromboplastin,^{15 - 17} a potent procoagulant tissue factor that may aggravate the retinal ischemia induced by the CRVO. Furthermore, VEGF induces retinal endothelial swelling, which may lead to further capillary nonperfusion.^{18 - 19} Given the role of VEGF in the pathophysiology of macular edema and neovascularization following CRVO and the lack of proven and safe methods of rapid restoration of blood flow, inhibition of VEGF is a rational therapeutic strategy for this disease.

Pegaptanib, a 40-kDa RNA aptamer, binds to VEGF₁₆₅, the predominant pathological isoform in ischemia-mediated ocular neovascularization and in diseases such as diabetic macular edema.^{20 - 23} Clinical trials have suggested that intravitreous injection of pegaptanib sodium can be effective in the treatment of diabetic macular edema,²⁴ proliferative diabetic retinopathy,²⁵ and neovascular age-related macular degeneration.^{26 - 27} As increased intraocular VEGF contributes to the pathogenesis of vision loss following CRVO, a phase 2 sham-controlled trial was conducted to examine the 30-week safety and efficacy of intravitreous pegaptanib for the treatment of macular edema secondary to CRVO.

This was a randomized, dose-ranging, double-masked, parallel-group, sham-controlled, multicenter, phase 2 clinical trial conducted in practitioners' offices and clinics in Australia, France, Germany, Israel, Spain, and the United States. The study protocol was reviewed and approved by an institutional review board at each study site in accordance with the guidelines for the conduct of clinical research in the 1964 Declaration of Helsinki. All study participants provided signed informed consent before any baseline procedures were performed, and the study sites in the United States were Health Insurance Portability and Accountability Act compliant. Subjects 18 years or older diagnosed with CRVO with onset of symptoms within 6 months prior to baseline and with a best-corrected visual acuity in the study eye of between 65 and 20 Early Treatment of Diabetic Retinopathy Study letters inclusive (approximately 20/50 to 20/400 Snellen equivalents) and better than or equal to 35 letters (approximately 20/200) in the fellow eye were eligible. Macular edema was assessed by optical coherence tomography (OCT). Study eyes were required to have a central retinal thickness at the center point of 250 μm or more at both baseline and the first treatment day. Subjects with an ophthalmic history of any of the following were excluded: subtenon corticosteroid administration for any ophthalmic condition; prior panretinal or sector scatter photocoagulation; signs of old branch retinal vein occlusion or CRVO in the study eye, or any other retinal vascular disease including diabetic retinopathy. Eyes with a brisk afferent pupillary defect; vitreous hemorrhage except for breakthrough hemorrhage from intraretinal hemorrhage; evidence of any neovascularization involving the iris, disc, or retina; or any other clinically significant concomitant ocular diseases were also excluded. There were no angiographic criteria for inclusion in the study. The exclusion of subjects with visual acuity of less than 20 letters or with brisk afferent pupillary defect, features more reliably predictive of ischemic CRVO, was intended to limit the inclusion of subjects in whom vision may not improve despite resolution of macular edema.^{6 ,28}

The University of Wisconsin Fundus Photograph Reading Center, the independent reading center for this study, determined angiographic and OCT baseline measures and end points and confirmed the eligibility of all subjects prior to their enrollment and randomization. Eligible subjects were allocated equally (1:1:1) to 1 of 3 treatment arms, 0.3 mg of pegaptanib sodium, 1 mg of pegaptanib sodium, or sham injections, with randomization stratified by center and baseline visual acuity (≤34 letters vs >34 letters; approximately 20/200); a maximum of 40 subjects with baseline visual acuity of 34 letters or less were to be randomized. Treatment assignment was based on a dynamic minimization procedure that used a stochastic treatment allocation algorithm based on the variance method. Medication kits were identified by randomization number. All kits were similar in appearance, regardless of dose. To maintain investigator masking, the injection was not administered by the study ophthalmologist responsible for patient care and assessments. The study coordinator conveyed the treatment assignment to the study ophthalmologist administering the injection in a fashion that did not inform the treating ophthalmologist or the subject.

Intravitreous pegaptanib sodium or sham injections were administered every 6 weeks for 24 weeks, for a total of 5 injections. Antisepsis procedures were the same for all subjects including those receiving sham; all subjects received injected subconjunctival anesthetic. Masking was maintained by treating subjects receiving sham identically to those receiving pegaptanib sodium, with the exception that sham subjects did not have scleral penetration; rather, they had blunt pressure applied to the globe without a needle. During the study, panretinal photocoagulation was permitted at any time point for neovascularization according to the Central Vein Occlusion Study protocol; intravitreous steroids were not permitted at any time.

An ophthalmologic history and all baseline assessments were conducted within 14 days prior to the first study treatment. At baseline and at weeks 0, 6, 12, 18, 24, and 30, vital signs were recorded, and the following assessments were performed prior to study treatment: best-corrected visual acuity by certified examiners masked to treatment arm and results of previous visual acuity measurements; applanation tonometry (before and 30 minutes after injection; also at least once between each 6-week visit); ophthalmic examination (also at least once between each 6-week visit); examination of the iris including gonioscopy (prior to dilation); and laboratory tests (eg, hematology, renal function, hepatic function, and electrolytes). Fluorescein angiography was performed at baseline and week 30, and stereoscopic color fundus photographs were taken at baseline and at weeks 12 and 30. Optical coherence tomography was performed at weeks 0, 1, 3, 6, 12, 18, 24, and 30.

The primary efficacy end point was the percentage of treated eyes gaining 15 letters or more of visual acuity from baseline up to 30 weeks for each dose group. The main secondary efficacy end points were differences in mean change in visual acuity over time and from baseline to week 30; percentage of eyes losing 15 letters or more of visual acuity from baseline to week 30; percentage of eyes with visual acuity of 35 letters or more (better than approximately 20/200) and 65 letters or more (better than approximately 20/50) at week 30; the mean change from baseline in OCT center point and central subfield values at week 30 and over time; and the percentage of eyes developing retinal or iris neovascularization postbaseline before week 30.

Safety end points included all adverse events spontaneously reported, elicited, or observed by investigators. Adverse events were graded as mild, moderate, or severe and were assessed as being either related to the injection procedure or to the study drugs or unrelated to study treatment. All serious adverse events were recorded whether deemed related to treatment or not.

Efficacy analyses were conducted on the intent-to-treat population, which included all randomized subjects. Missing data were imputed using the last-observation-carried-forward method, except for repeated-measures analyses of variance in which no imputation of missing data was performed. Subjects were analyzed in the treatment group and stratum to which they were assigned by randomization. The significance of associations between binary end points, including the primary end point, and treatment was analyzed by applying pairwise comparisons using the Cochran-Mantel-Haenszel test adjusted for vision at randomization (≤34 letters or >34 letters). Analysis of covariance was used to analyze continuous data or changes in continuous end points at a given time; the model included main effects of treatment, vision at randomization (≤34 letters or >34 letters), and the baseline value of the corresponding end points (except for visual acuity). A repeated-measures analysis of variance that used all visual acuity and OCT data over time was performed to compare each dose group with sham. All statistical tests were 2-sided, and the α level was set to .05. No adjustment for multiplicity was performed.

Safety analyses included all subjects receiving at least 1 dose of the study drug (pegaptanib sodium or sham). Adverse events were summarized using Medical Dictionary for Regulatory Activities 5.1 terms. Summary statistics were calculated for safety end points.

The sample size calculation was based on the following assumptions: the test of significance should be 2-sided, with a significance level of P = .05; and the percentage of subjects gaining 15 letters or more of vision at week 30 was expected to be 30% in the sham group, increasing to 65% in groups treated with 0.3 mg or 1 mg of pegaptanib sodium. Using these assumptions, it was determined that a sample of at least 30 subjects per treatment group was required for an overall power of 80%.

The study was conducted between August 2004 and September 2006. A total of 98 subjects entered the study, with 33 subjects in both the 0.3-mg and 1-mg pegaptanib sodium groups and 32 in the sham group. At baseline, subject characteristics were comparable and visual acuity was well balanced across study arms (Table). Overall, the mean age was 62.6 years and the mean visual acuity in the study eye at baseline was 48.1 letters (20/100 Snellen lines).

Few subjects (7% overall) withdrew from the study between baseline and week 30. Three subjects in the 0.3-mg group requested to be discontinued from the study, as did 1 subject in the 1-mg group and 2 subjects in the sham group. The only other discontinuation during the study occurred in 1 subject in the sham cohort as a result of noncompliance. Most subjects adhered to the study regimen, receiving all 5 planned injections from baseline to week 30: 81% of subjects in the 0.3-mg group, 90% in the 1-mg group, and 88% of subjects in the sham group.

In the primary analysis of this phase 2 study, although not statistically significant, 12 of 33 (36%) 0.3-mg pegaptanib sodium and 13 of 33 (39%) 1-mg subjects gained 15 or more letters from baseline to week 30 vs 9 of 32 (28%) subjects in the sham group (P = .48; relative risk [RR], 1.29; 95% confidence interval [CI], 0.63-2.64 and P = .35; RR, 1.40; 95% CI, 0.70-2.81 vs sham, respectively). Secondary analyses consistently showed better visual results in subjects treated with pegaptanib sodium. Both doses of pegaptanib sodium had an early and sustained effect on mean visual acuity (Figure 1). At week 30, subjects receiving 0.3 mg and 1 mg of pegaptanib sodium had gained an average of 7.1 and 9.9 letters, respectively, while those treated with sham had lost an average of 3.2 letters (P = .09; 95% CI, −1.3 to 21.8 and P = .02; 95% CI, 1.5 to 24.6 for 0.3 mg and 1 mg of pegaptanib sodium vs sham, respectively). Less than 10% of those receiving either dose of pegaptanib (9% and 6% for 0.3-mg and 1-mg pegaptanib sodium groups, respectively) lost 15 letters or more of visual acuity by week 30 compared with 31% of subjects treated with sham (P = .03; RR, 0.29; 95% CI, 0.09-0.96; and P = .01; RR, 0.19; 95% CI, 0.05-0.82 for 0.3 mg and 1 mg of pegaptanib sodium vs sham, respectively) (Figure 2). Approximately 90% (59/66) of subjects receiving pegaptanib had visual acuities of 20/200 or better at week 30 compared with 63% (20/32) of those treated with sham (P = .02 and P = .01 for 0.3 mg and 1 mg of pegaptanib sodium vs sham, respectively), but there was no difference in the percentage of subjects with visual acuity of 20/50 or better at week 30 (33% for both pegaptanib doses and 34% for sham).

The mean decrease from baseline in retinal thickness at both the center point and the center subfield were greater in both pegaptanib sodium treatment groups than in the subjects receiving sham (Figure 3) at all time points. The mean reduction in retinal thickness at the center point and at the center subfield from baseline to week 30 were 95 μm and 112 μm lower, respectively, in the 0.3-mg pegaptanib sodium group compared with sham (P = .13; 95% CI, −209 to 26 and P = .06; 95% CI, −170 to 63, respectively; last observation carried forward data). Significant changes were identified on OCT scans obtained at weeks 1 and 3. Between baseline and week 1, the mean decrease in center point thickness was 269 μm in the 0.3-mg pegaptanib sodium and 210 μm in the 1-mg pegaptanib sodium group compared with 5 μm in the sham group. The mean decrease from baseline to week 3 was 329 μm in the 0.3-mg pegaptanib sodium and 198 μm in the 1-mg pegaptanib sodium groups compared with 40 μm in the sham group (P < .001) (Figure 3).

A total of 23, 25, and 26 subjects in the 0.3-mg, 1-mg, and/or sham groups, respectively, had gradable fluorescein angiograms for the presence of capillary nonperfusion at baseline. Assessing the center, inner, and outer subfields (central 16 disc areas) in those subjects, the median and first quartile of the measurement of capillary nonperfusion was zero disc areas in all study arms. The third quartiles of capillary nonperfusion were 0.01, 0.03, and 0.00 disc areas in the 0.3-mg pegaptanib sodium, 1-mg pegaptanib sodium, and sham groups, respectively. There was no assessment of peripheral retinal nonperfusion. The development of retinal or iris neovascularization was uncommon, but occurred more frequently in the sham arm (3 subjects [9%]) than in either of the pegaptanib treatment arms (1 subject [3%] in both pegaptanib arms; P = .29). All 5 subjects who developed ocular neovascularization were submitted to panretinal photocoagulation.

No serious ocular adverse events were reported, and no subject developed endophthalmitis, traumatic cataract, or retinal detachment. No evidence of a sustained effect on intraocular pressure was noted. No evidence of an increased risk of systemic adverse events related to VEGF inhibition was detected.

In this phase 2, randomized, controlled, 30-week trial that evaluated intravitreous pegaptanib sodium given at 6-week intervals for subjects with macular edema secondary to CRVO, analysis of the primary efficacy end point of the percentage of subjects gaining 15 letters or more measured at the 30-week follow-up visit revealed a trend favoring eyes treated with pegaptanib sodium, although without statistical significance. Secondary analyses, however, showed a significant reduction in the percentage of subjects treated with pegaptanib sodium losing 15 or more letters and a significant increase in the percentage of subjects treated with pegaptanib sodium remaining above the threshold for legal blindness. The combination of the results of these 2 binary analyses—only a positive trend for doubling with a significant difference for avoiding halving the visual angle—explains the substantial (2-3 Snellen lines) shift in the mean visual acuity distribution favoring the groups treated with pegaptanib sodium. These results illustrate one of the disadvantages of binary vs continuous variable analyses for visual acuity. Binary variables (eg, proportions of subjects gaining or losing at least 15 letters) are often selected as primary end points for clinical trials in retina. However, as recently discussed by Beck et al,²⁹ despite some regulatory advantages, there is an intrinsic loss of information in binary variable analyses compared with continuous variable analyses such as mean visual acuity score. When using a binary outcome, a cutoff point is chosen (eg, 15-letter gain, 15-letter loss). All results on the same side of the cutoff point contribute equal weight to the results, ie, a subject with a 16-letter gain and a subject with a 25-letter gain contribute equally. In contrast, in a continuous variable analysis such as mean visual acuity, each subject's visual acuity score contributes its specific value to the analysis so distribution shifts between groups are reflected without loss of information. Although the difference in the proportion of subjects who gained 15 letters in this trial was not statistically significant, the differences in the proportion of those who lost 15 letters and the mean visual acuity were substantial, providing support for a potential benefit of pegaptanib sodium in visual acuity of patients with macular edema secondary to CRVO.

In addition to having a positive treatment effect on macular edema, fewer eyes in the groups treated with pegaptanib sodium showed retinal or iris neovascularization, a known and frequent complication of CRVO. This suggests that pegaptanib sodium may help limit the development of retinal or iris neovascularization, although a larger trial would need to confirm this finding. In keeping with the favorable safety record of pegaptanib sodium in larger longer-term trials,³⁰ these benefits accrued without the generation of any systemic or ocular safety concerns.

This is the first randomized, controlled, 30-week, pharmacologic trial that has shown any treatment benefit for CRVO compared with sham³¹ and is consistent with the clinical benefit already observed for intravitreous pegaptanib sodium in treating diabetic retinopathy.^{24 - 25} These results are especially encouraging in that there is no proven effective therapy for macular edema secondary to CRVO. A plethora of treatment options have been examined in prospective or retrospective uncontrolled studies that rely on comparison with historical controls to demonstrate potential benefits but never in randomized controlled trials.⁵

In a small trial of 27 eyes with CRVO randomized to 4 mg of intravitreous triamcinolone or sham injections, the mean visual acuity was better in the triamcinolone group at 1 month, but both the treated and control groups had similar improvements in visual acuity at the 4-month final assessment.³² Intravitreous bevacizumab, another anti-VEGF agent, has been reported to provide short-term improvements in visual acuity and macular edema subsequent to CRVO in several recent uncontrolled small studies.^{33 - 37} It is uncertain if all anti-VEGF drugs will share similar safety profiles in the context of retinal vein occlusions. However, preclinical data suggest that, in contrast to selective inhibition of VEGF_165,nonselective inhibition of all VEGF isoforms rendered retinal neurons more sensitive to apoptosis under ischemic conditions such as CRVO.³⁸

As recently demonstrated in patients with diabetic macular edema, there was poor correlation between macular thickness and visual acuity. In general, visual acuity gains are believed to lag behind OCT-documented center point thickness and central subfield thickness reductions. In this study, the macular thickness decrease was similar in the 1-mg and sham arms from baseline to week 30, yet the mean change in visual acuity for subjects receiving 1 mg of pegaptanib was superior to subjects receiving sham. A possible explanation for this finding is that other mechanisms such as ischemia-mediated neuronal death may influence vision outcomes in subjects with retinal vascular disease.³⁸ Additional important factors influencing visual acuity in this disorder are the presence of foveal ischemia, retinal hemorrhages, exudates, or retinal pigment epithelium atrophy at the center of the macula, any of which may limit the potential for vision improvement. Further, chronic macular edema can lead to underlying retinal pigment epithelium atrophy and/or hyperplasia that prevent visual acuity improvement despite macular detergescence, reinforcing the importance of early treatment of macular edema in CRVO to avoid irreversible functional damage.

Compared with previous pegaptanib studies, there were no new safety signals reported in this trial. However, this trial was not designed to detect small differences in safety events with statistical significance between treated and control subjects. The positive results of the study merit further examination in a larger trial in which these more subtle pegaptanib effects may be investigated with the added rigor afforded by larger treatment groups.

In conclusion, treatment of macular edema secondary to CRVO with pegaptanib sodium, a selective VEGF₁₆₅inhibitor, resulted in both visual and anatomical benefits when compared with controls. These results support those of the prior pegaptanib sodium trial for diabetic macular edema. Pegaptanib may provide a clinically important treatment option for patients with macular edema following CRVO. A phase 3 randomized clinical trial to confirm this hypothesis seems warranted.

Correspondence:John J. Wroblewski, MD, Cumberland Valley Retina Consultants, 1150 Opal Ct, Hagerstown, MD 21740 (johnw@retinacare.net).

Submitted for Publication:April 21, 2008; final revision received September 9, 2008; accepted September 16, 2008.

Author Contributions:Dr Wroblewski had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis

Financial Disclosure:Drs Wroblewski and Wells report being consultants to (OSI Pharmaceuticals) Eyetech; Dr Adamis, a consultant to (OSI Pharmaceuticals) Eyetech and currently employee of Jerini Ophthalmic; Dr Buggage, an employee of Pfizer Inc; Dr Goldbaum, a consultant to (OSI Pharmaceuticals) Eyetech; Dr Guyer, officership in, ownership in, and compensation from (OSI Pharmaceuticals) Eyetech; Drs Adamis, Cunningham, Katz, and Goldbaum, employees of (OSI Pharmaceuticals) Eyetech Inc, New York, New York at the time the study was designed and conducted. Drs Altaweel, Cunningham, and Katz do not report any financial disclosures.

Funding/Support:This study was supported by (OSI Pharmaceuticals) Eyetech, Inc, and Pfizer Inc.

Role of the Sponsors:Both sponsors participated in the study design, data analysis and interpretation, and preparation and review of the manuscript.

Previous Presentation:Poster presented at the American Academy of Ophthalmology Annual Meeting; November 11-14, 2006; Las Vegas, Nevada.

Additional Contributions:Editorial support, including contribution to the first draft of the manuscript, revising the manuscript based on author feedback, and styling the paper for journal submission, was provided by Jane G. Murphy, PhD, of Zola Associates and was funded by (OSI Pharmaceuticals) Eyetech, Inc and Pfizer Inc (Dr Murphy). The following individuals participated in conducting the study: Independent Data Monitoring Committee: A. Bird, Moorfields Eye Hospital, London, United Kingdom (chair); D. D’Amico, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (chair emeritus); J. Herson, Johns Hopkins University, Baltimore, Maryland; R. Klein, University of Wisconsin, Madison; H. Lincoff, New York-Presbyterian Weill Cornell Center, New York; A. Patz, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland. Data Management and Statistics Group: M. Buyse (study design), S. de Gronckel, G. Fesneau (data management), E. Quinaux, K. Wang (statistical analyses), D. Tremolet, X. Li (central randomization), International Drug Development Institute, Brussels, Belgium and Boston, Massachusetts; and N. Ting, J. Finman, and A. Brailey, Pfizer Inc, Groton, Connecticut. Eligibility and image analysis were performed by the Fundus Photograph Reading Center, University of Wisconsin, Madison; M. M. Altaweel, MD (principal investigator), D. Hafford (color, fluorescein), L. Kastorff (data management), D. Meyers (optical coherence tomography), and M. Daywalt (project management).

The Pegaptanib in Central Retinal Vein Occlusion Study Group Investigators:Australia: J. Arnold, Marsden Eye Specialists, Sydney; I. J. Constable, Lions Eye Institute, Nedlands; M. Gillies, University of Sydney, Sydney. France: G. Soubrane, Clinique Ophthalmologique Centre Hospitalier, Creteil. Germany: A. Joussen, Universitätsklinik Köln, Köln; F. Gelisken, U. Schneider, Universitätsklinkum Tübingen, Tübingen. Israel: M. Goldstein, Tel Aviv Sourasky Medical Center, Tel Aviv; A. Pollack, Kaplan Hospital, Rehovot; I. Rosenblatt, Rabin Medical Centre, Petah-Tikva. Spain: F. Gomez-Ulla, Instituto Tecnologico de Oftalmologia, Santiago de Compostela; J. M. Ruiz-Moreno, Vissum Instituto Oftalmologico de Alicante, Alicante. United States: A. N. Antoszyk, Charlotte Eye, Ear, Nose and Throat Associates, PA, Charlotte, North Carolina; B. B. Berger, Retina Research Center, Austin, Texas; D. M. Brown, VitreoRetinal Consultants, Houston, Texas; A. Capone, Associated Retinal Consultants, Royal Oak, Michigan; T. Ciulla, Macula-Retina-Vitreous Service, Indianapolis, Indiana; T. Connor, The Eye Institute, Milwaukee, Wisconsin; R. Garfinkel, Retina Group of Washington, Chevy Chase, Maryland; C. Gonzales, Jules Stein Eye Institute, Los Angeles, California; V. H. Gonzalez, Valley Retina Institute, PA, McAllen, Texas; J. C. Hoskins, Southeastern Retina Associates, Knoxville, Tennessee; C. Javid, Retina Associates SW, Tucson, Arizona; R. Kaiser, Retina Diagnostic and Treatment Associates LLC, Philadelphia, Pennsylvania; S. Koh, Georgia Retina PC, Lawrenceville; D. Eliott, T. Mahmoud, Kresge Eye Institute, Detroit, Michigan; J. Marx, Lahey Clinic, Peabody, Massachusetts; S. S. Patel, Retina Research Institute of Texas LLC, Abilene; S.D. Pendergast, Retina Associates of Cleveland, Inc, Lakewood, Ohio; A. Rogers, New England Eye Center, Boston, Massachusetts; N. Sabates, Eye Foundation of Kansas City, Kansas City, Missouri; S. Sneed, Retinal Consultants of Arizona, Phoenix; M. Varenhorst, Vitreo-Retinal Consultants and Surgeons, PA, Wichita, Kansas; J. A. Wells III, Palmetto Retina Center, Columbia, South Carolina; R. Willson, Retina Associates, New Orleans, Louisiana; J. J. Wroblewski, Cumberland Valley Retina Consultants, Hagerstown, Maryland; I. Kim, L. Young, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.