What's New In Retina

Highlights of the Retina Congress.

By Andrew E. Mathis, Medical Editor

The growing interest in retina among comprehensive ophthalmologists has made it more important than ever for all practitioners to keep abreast of events in posterior segment research. As the gatekeeper who first encounters most retina patients and directs them to the appropriate subspecialist, you play a vital role in initiating care.

Below are highlights of the research presented last month at the Retina Congress, a coming together of three professional societies that attracted well over 1,000 retinal specialists from around the world.

RVO

Perhaps the biggest news to come out of the Retina Congress took place on the final day, when several prominent studies yielded new insights on treatment of macular edema subsequent to retinal vein occlusion (RVO).

Data from a trial of Allergan's new Ozurdex dexamethasone implant for RVO were presented by Julia A. Haller, MD, of the Wills Eye Institute. Dr. Haller reported that improvements in visual acuity were noted as early as one month post-injection and peaked at 60 days. At six months, a cumulative 41% of treated patients had gained three or more lines of vision, compared with 23% of sham-treated patients. Around 20% of patients required only a single treatment to maintain improvements in visual acuity and retinal thickness (for more, see Rx Perspectives).

Three highly anticipated phase 3 clinical trials — the CRUISE, BRAVO and SCORE studies — provided hard data on off-label regimens involving anti-VEGF or steroid agents previously used in the absence of conclusive studies.

David M. Brown, MD, presented the CRUISE study in which patients were randomized to two doses of ranibizumab or a sham injection. The lower-dose arm showed improvement of 12.7 letters on average, and the higher-dose arm 14.9 letters, after six monthly intravitreal injections. Changes in visual acuity were seen in as short a time as one week. The similarly designed BRAVO trial, in which patients were randomized to the same arms, had BCVA gains of 16.6 letters in the lower-dose group and 18.3 letters in the higher-dose group. Peter Campochiaro, MD, presented these data.

Another treatment for RVO discussed was steroid therapy, with Michael Ip, MD, presenting the data from the SCORE study group, which tested an intravitreal injection of triamcinolone in two doses (1 mg and 4 mg) in nearly 700 patients. Patients with central RVO improved by 27% in the 1-mg arm and 26% in the 4-mg arm, and both dosage groups were superior to the control group. Since the 1-mg dose is deemed safer, the study suggests that, for CRVO patients, this dosage is the optimal one. However, SCORE study patients with branch RVO, the data from whom were presented by Ingrid U. Scott, MD, of Penn State University, ended with the conclusion that the standard of care was superior to triamcinolone in either dose.

AMD

The Canadian Retina Trials Group presented data from the CAVE trial, which sought to determine whether treatment with PDT could extend the time between intravitreal injections of bevacizumab. One study arm also received intravitreal triamcinolone acetonide as triple therapy. The group determined that combination therapy of bevacizumab and PDT extended the treatment-free interval over bevacizumab alone, though triamcinolone appeared to have no added benefit.

Two studies focused on genetic therapies in development. Donald J. D'Amico, MD, gave a presentation on gene therapy for retinal diseases. Specifically, Dr. D'Amico's team designed and constructed an adeno-associated virus gene transfer vector (AAV-alpha-VEGF) by incorporating complementary DNA from a precursor to bevacizumab found in mice. They found the vector they created bound itself to VEGF-A, the chief target of bevacizumab, showing that it is possible to use gene therapy to cause the eye to produce an anti-VEGF effect similar to that caused by bevacizumab.

The University of Kentucky's Jayakrishna Ambati, MD, PhD spoke about chemokine receptor CCR3, which he believes could serve as an early diagnostic marker for choroidal neovascularization, as well as perhaps a new therapeutic target. Dr. Ambati found that CCR3 was actually superior to VEGF-A as a therapeutic target.

K. Bailey Freund, MD, of New York, gave his presentation on the "treat and extend" dosing regimen being used more and more often in retinal practices for anti-VEGF therapies. Dr. Freund conducted a retrospective analysis of 19 eyes from 17 patients with newly diagnosed AMD with type 1 lesions. These patients were treated with either bevacizumab or ranibizumab and followed up for at least two years. Dr. Freund found that long-term visual acuity remained stable with the treat and extend dosing regimen, although these results were limited to type 1 lesions. He suggested that combination therapies could be another way of extending time between intravitreal injections.

One such combination — epimacular brachytherapy used in conjunction with bevacizumab — was the focus of a talk by Pravin Dugel, MD, of Phoenix. Subjects received two bevacizumab injections plus strontium 90 radiation and were followed for two years, with additional bevacizumab injections performed at the investigator's discretion. Dr. Dugel noted that 76% of subjects required no additional injections; the mean number of injections was 2.4 (including the two at the outset). A majority of patients maintained visual acuity and at least 20% also experienced a marked improvement in vision at month 24.

Duke University's Glenn J. Jaffe, MD, opened the dry AMD symposium with a presentation of the data from a phase 2 study of an encapsulated ciliary neurotrophic factor (CNTF) implant for patients with geographic atrophy. Forty-eight participants in the study were followed for up to 12 months, with dose-dependent increases in retinal thickness being the most marked change. Visual acuity was also stabilized and adverse events were minor.

Diabetic Retinopathy

The diabetic retinopathy symposium offered a variety of viewpoints on the treatment of eye disease consequent to diabetes. Thomas A. Ciulla, MD, presented results from the FAMOUS study of the Iluvien fluocinolone acetonide implant in cases of DME. Safety and efficacy data through 18 months suggested that two different doses of the Iluvien implant decreased retinal thickness and improved vision. While IOP elevation (>30 mm Hg) occurred in no patients in the lower-dose group, nearly a quarter of the patients in the high-dose group had large increases in IOP, which Dr. Ciulla suggested may be statistically significant.

Allen B. Thach, MD, provided 12-month results from the READ 2 study of ranibizumab for DME. Patients in this trial were randomized to either laser photocoagulation or injections of triamcinolone in two dosages. One year after enrollment and treatment, 21% of patients receiving laser therapy had progression in their retinopathy, while 19% had progression in the 1-mg group and 15% in the 4-mg group. However, these results were not statistically significant. There was statistical significance in both triamcinolone groups at the two- and three-year marks.

Philip J. Ferrone, MD, presented data from a phase 1/2 study of treatment of clinically significant DME with two doses (0.5 mg and 1 mg) of ranibizumab. The 12-month interim data on 31 eyes from 25 patients indicated that, while the lower-dose group gained an average of 1.88 ETDRS letters, the larger-dose group gained over nine letters. Furthermore, decrease in central foveal thickness was more than twice as much in the higher-dose group.

Oncology

The symposium on ocular oncology featured presentations on melanoma, optic neuropathy and retinoblastoma. The first five presentations were all on uveal melanoma, with two of these presentations focusing on gene therapies.

The Collaborate Ocular Oncology Group at the Washington University School of Medicine in St. Louis, presented data on uveal melanoma gene expression profile (UM-GEP) prognostic assay. The study they conducted compared the accuracy of UM-GEP vs. chromosome 3 status, and the group found that UM-GEP was a highly accurate predictor of metastasis after studying 172 specimens.

Frederick H. Davidorf, MD, gave the next presentation, this time focusing on the mesenchymal-epithelial transition factor (MET) oncogene as a target for gene therapy. Fiftyfive uveal melanomas were examined histologically for expression of the MET oncogene, and then a MET inhibitor was tested against three different cell lines. Dr. Davidorf found moderate-to-strong overexpression of MET in 75% of the tumors that he tested and that selective MET inhibition slowed tumor cell proliferation.

Two other melanoma presentations focused on the use of charged particles.

The Harvard Medical School's Evangelos S. Gragoudas, MD, reported on the long-term survival rates of patients with uveal melanoma treated with proton therapy between 1975 and 1998. Of 2,266 patients followed through December 2006, Dr. Gragoudas found that 530 of these patients had died of melanoma, with rates of melanomarelated death peaking between three and six years after treatment. At 14 years, the mortality percentage dropped from between 3% and 4% to under 1%. The most important predictor of mortality found by Dr. Gragoudas was tumor size.

Devron H. Char, MD, gave the next presentation — another long-term follow-up, this time of patients with uveal melanoma treated with iodine 125 brachytherapy. Brachytherapy was compared to charged-particle therapy, with several endpoints followed, including survival. Dr. Char's study found that local control of radiation was better with charged particles than with iodine 125. Furthermore, there were no later failures with charged particles, while iodine 125 incurred failures even 15 years after brachytherapy had ended. Dr. Char's presentation clearly demonstrated that iodine 125 brachytherapy remains inferior to charged-particle therapy.

Infection Risk

Several presentations dealt with prevention and treatment of endophthalmitis. H. Logan Brooks, MD, provided evidence that endophthalmitis was eight times more likely in eyes vitrectomized with 23-g instruments when fluid was left in the eye and sutures were not used. Intraocular tamponade, he demonstrated, reduced the risk significantly, whether with air, gas or oil.

Jay M. Stewart, MD, focused in his presentation on bacterial contamination of needles, presenting data from 101 patients who underwent intravitreal injections of either ranibizumab or bevacizumab. In 18% of patients injected in Dr. Stewart's study, the needle used was culture-positive — most often with Propionibacterium acnes or with a Staphylococcus species. This high rate of contamination (nearly one in five) suggests that bacterial infection of needles may be a cause of endophthalmitis. Dr. Stewart laid out the design for a second phase of this study.

While most of the endophthalmitis presentations dealt with anti-VEGF agents, David G. Dowdell, MD, gave a talk on endophthalmitis from intravitreal triamcinolone. Dr. Dowdell conducted a retrospective case series of 87 patients who received injections of preservative-free triamcinolone over a six-month period, finding sterile endophthalmitis in four cases. All of these patients had a posterior-chamber IOL, though Dr. Dowdell did not see this as a direct cause of endophthalmitis. He noted that smaller particle size may be a contributing factor, but that further research is needed.

Technology and Surgery

Richard B. Rosen, MD, presented on 30 subjects (with a variety of retinopathies) imaged with a new ultra-high resolution confocal microscope and ultra-high speed spectraldomain OCT. Dr. Rosen found that structural changes were often detected before changes in visual acuity, but he cautioned that the opposite was sometimes true.

Jans Fromow-Guerra, MD, PhD, of Mexico City, spoke about the use of spectral-domain OCT in patients with retinitis pigmentosa to determine macular changes. In the study, 63 eyes in 32 patients with retinitis pigmentosa were subjected to clinical, electrophysiologic and angiographic diagnoses and then scanned using SD-OCT to examine the macula. Only 9.4% of examined eyes showed no changes on the macula, while 89% of the eyes had at least one alteration and 46% had three or more coexisting changes. Dr. Fromow-Guerra said that this study provides evidence of underdiagnosis of macular disease comorbid with retinitis pigmentosa.

Cynthia Ann Toth, MD, of the Duke Medical Center, gave a presentation on using OCT on infants with retinopathy of prematurity (ROP) to track developmental changes. Dr. Toth's team performed SD-OCT imaging of the maculas of 14 infants ranging in age from 30 to 56 weeks postmenstrual. While Dr. Toth conceded that further studies are needed, she stated that macular abnormalities normally not visible in a clinical exam can be seen with SD-OCT in infants with ROP.

Turning to surgical topics, Chicago's Kirk H. Packo, MD, presented on video evaluation of infusion fluidics during vitrectomy. Dr. Packo's study involved an in vitro model of an eye, into which cannulas of various size were inserted. Infusion with methylene blue was done and infusion patterns were followed, as were cut rates, duty-cycle bias, flow rates and IOP. Dr. Packo noted a "jet stream" effect on the retina during infusion; flow patterns were affected by, among other variables, gauge size. He found that low flow rates and high cut rates reduce contact of infusion fluid on the retina and noted that such impact may have undesirable effects in vivo.

Edwin H. Ryan, MD, talked about 6-0 plain gut "tape" for small-gauge wound closure in patients who underwent 23-g vitrectomy. Dr. Ryan found 48 wounds in 35 patients that leaked enough to need intervention, while 180 wounds in 60 other patients had no leakage. Only two of 95 patients experienced hypotony requiring air injection, leading Dr. Ryan to conclude that reduction of hypotony is the procedure's greatest benefit.

The surgical symposium ended with two studies comparing immediate vs. delayed vitreoretinal surgery to remove lens fragments following phacoemulsification. The first presentation, by Michael Cusick, MD, of the Duke Medical School, found that immediate pars plana vitrectomy did not influence visual outcomes or complications, though it did eliminate the need for a second operation. The second presentation, by Marcus H. Colyer, MD, concluded that there was no statistically significant difference between immediate and delayed pars plana vitrectomy. OM