Michael M. Altaweel

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics.

PURPOSE To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) trial and the baseline characteristics of enrolled patients. DESIGN Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) with fluocinolone acetonide implant placement. METHODS Eligible patients had active or recently active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The study design had 90% power (2-sided type I error rate, 0.05) to detect a 7.5-letter (1.5-line) difference between groups in the mean visual acuity change between baseline and 2 years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photographs, optical coherence tomography images, and fluorescein angiograms. RESULTS Over 3 years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200). Lens opacities (39% of gradeable phakic eyes), macular edema (36%), and epiretinal membrane (48%) were common. Mean health utility was 74.1. CONCLUSIONS The MUST trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis. Patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema, and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.

Bevacizumab (Avastin) for the Treatment of Ocular Disease

The use of intravitreal bevacizumab (Avastin) has greatly expanded since its introduction into ophthalmic care 3 years ago. A PubMed search on 1 August 2008 revealed 51 ocular disease processes that have been treated with bevacizumab. The majority of publications consist of case reports or retrospective case series and their number is increasing quickly. It is important to collate the experiences gained to date to properly inform our clinical decision making and improve the design of future clinical trials. Current studies cannot easily be combined in a meta-analysis given the lack of standardized data and the wide variety of disorders studied in small numbers. This paper will describe the attempted uses of intravitreal bevacizumab and its efficacy for each ocular disease in addition to discussing safety. Comments regarding appropriate use of this treatment are based on our current level of knowledge. It is clear that the initial encouraging results described in this paper warrant further study of intravitreal bevacizumab in larger, controlled, randomized trials.

Treatment of central retinal vein occlusion with triamcinolone acetonide: an optical coherence tomography study.

Central retinal vein occlusion is one of the most common retinal vascular disorders. Many patients have decreased visual acuity as a result of macular edema. We report a retrospective review of 8 patients at the University of Wisconsin with macular edema from CRVO who were treated with an intravitreal injection of triamcinolone acetonide. Optical coherence tomography (OCT) was used to help assess the effect of this intervention. Mean baseline visual acuity was 20/500. Mean visual acuity at the 3-month follow up was 20/220. The average gain in visual acuity was 3.3 lines (range -1 to +10). Four of 8 patients experienced a visual acuity gain of 2 or more lines at the 3-month follow up. Four of 8 patients were unchanged (within 2 lines of baseline) at the 3-month follow up. No patient had a decrease in visual acuity (2 or more line decrease from baseline). Seven of 8 patients had complete resolution of macular edema on clinical examination at the 3-month follow up. No adverse effects such as cataract, glaucoma, retinal detachment or endophthalmitis were noted. We conclude that intravitreal injection of triamcinolone acetonide may be a safe and effective treatment in some patients with macular edema due to CRVO. Optical coherence tomography demonstrated significant anatomic improvement in the majority of patients with macular edema due to CRVO treated with intravitreal injection of triamcinolone acetonide.

Diabetic Macular Edema: What Is Focal and What Is Diffuse?

PURPOSE To review the available information on classification of diabetic macular edema (DME) as focal or diffuse. DESIGN Interpretive essay. METHODS Literature review and interpretation. RESULTS The terms focal diabetic macular edema and diffuse diabetic macular edema frequently are used without clear definitions. Published definitions often use different examination methods and often are inconsistent. Evaluating published information on the prevalence of focal and diffuse DME, the responses of focal and diffuse DME to treatments, and the importance of focal and diffuse DME in assessing prognosis is hindered because the terms are used inconsistently. A newer vocabulary may be more constructive, one that describes discrete components of the concepts such as extent and location of macular thickening, involvement of the center of the macula, quantity and pattern of lipid exudates, source of fluorescein leakage, and regional variation in macular thickening and that distinguishes these terms from the use of the term focal when describing one type of photocoagulation technique. Developing methods for assessing component variables that can be used in clinical practice and establishing reproducibility of the methods are important tasks. CONCLUSIONS Little evidence exists that characteristics of DME described by the terms focal and diffuse help to explain variation in visual acuity or response to treatment. It is unresolved whether a concept of focal and diffuse DME will prove clinically useful despite frequent use of the terms when describing management of DME. Further studies to address the issues are needed.

Identifying a Clinically Meaningful Threshold for Change in Uveitic Macular Edema Evaluated by Optical Coherence Tomography

PURPOSE To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in visual acuity. DESIGN Cross-sectional and longitudinal study. METHODS One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more. RESULTS A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a -0.4-letter change (95% confidence interval, -4.1 to 3.3) in visual acuity for those without a 20% reduction (P < .01). CONCLUSIONS In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.

Macular hole: improved understanding of pathogenesis, staging, and management based on optical coherence tomography

Optical coherence tomography (OCT) has improved the understanding and management of idiopathic macular hole. Images of precursor lesions and their progression demonstrate that antero-posterior as well as tangential traction are involved in macular hole formation. The staging of macular holes with biomicroscopic examination can be paralleled by optical coherence tomography staging with some modification. OCT is useful in differentiating simulating lesions and in allowing better counseling of patients regarding their disorder. Finally, OCT findings are prognostic of surgical success and can assist in evaluating the results of surgery.

The Impact of Macular Edema on Visual Function in Intermediate, Posterior, and Panuveitis

Purpose: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis. Design: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis. Patients & Methods: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing. Results: Macular edema was associated with impaired visual acuity (p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (–5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (–13 letters) and with both cysts and thickening (–19 letters). Uveitis sufficient to satisfy the study’s inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity (p < 0.01). Conclusions: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24-2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma.

Fluorescein Angiography versus Optical Coherence Tomography for Diagnosis of Uveitic Macular Edema

OBJECTIVE To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis. DESIGN Multicenter cross-sectional study. PARTICIPANTS Four hundred seventy-nine eyes with uveitis from 255 patients. METHODS The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used. MAIN OUTCOME MEASURES Macular thickening (MT; center point thickness, ≥ 240 μm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema. RESULTS Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent. CONCLUSIONS Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis.

OBJECTIVE To evaluate the 3-year incremental cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for the treatment of noninfectious intermediate, posterior, and panuveitis. DESIGN Randomized, controlled, clinical trial. PARTICIPANTS Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment Trial. METHODS Data on cost and health utility during 3 years after randomization were evaluated at 6-month intervals. Analyses were stratified by disease laterality at randomization (31 unilateral vs 224 bilateral) because of the large upfront cost of the implant. MAIN OUTCOME MEASURES The primary outcome was the incremental cost-effectiveness ratio (ICER) over 3 years: the ratio of the difference in cost (in United States dollars) to the difference in quality-adjusted life-years (QALYs). Costs of medications, surgeries, hospitalizations, and regular procedures (e.g., laboratory monitoring for systemic therapy) were included. We computed QALYs as a weighted average of EQ-5D scores over 3 years of follow-up. RESULTS The ICER at 3 years was