Subretinal Hyperreflective Material in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: The 1185 CATT participants. METHODS: Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks. MAIN OUTCOME MEASURES: Presence of SHRM, as well as location and size, and associations with VA, scar, and GA. RESULTS: Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P < 0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 µm, 120 µm, and 122 µm, respectively. Visual acuity was decreased with greater SHRM height and width (P < 0.05). CONCLUSIONS: In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.

IDENTIFICATION OF FLUID ON OPTICAL COHERENCE TOMOGRAPHY BY TREATING OPHTHALMOLOGISTS VERSUS A READING CENTER IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENTS TRIALS.

PURPOSE: To examine treatment decisions by ophthalmologists versus reading center fluid identification from optical coherence tomography in Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). METHODS: Fluid in 6,210 optical coherence tomography scans (598 patients) in "as needed treatment" arm of CATT Year 1 was compared with ophthalmologist's treatment: positive fluid agreement (PFA, fluid+, treatment+) and positive fluid discrepancy (PFD, fluid+, treatment-), negative fluid agreement (fluid-, treatment-) and negative fluid discrepancy (fluid-, treatment+). For PFDs, fluid location and visual acuity were characterized. RESULTS: Treatment and reading center fluid determination agreed in 72.1% (53.0% PFA, 19.1% negative fluid agreement) and disagreed in 27.9% (25.7% PFD, 2.2% negative fluid discrepancy) of visits, with no discrepancies for 20.9% of patients. Compared with PFA, PFD occurred more commonly with lower total foveal thickness (mean ± SD: 265 ± 103 PFD, 366 ± 151 µm PFA), presence of intraretinal fluid only, smaller fluid areas (PFA areas greater than twice those of PFD, P < 0.001), and greater decrease in retinal and lesion thickness. Mean acuities before, at, and after PFD were 65.8, 66.9, and 66.3 letters. CONCLUSION: Treatment decisions by ophthalmologists matched reading center fluid determination in the majority of visits. More pronounced response to treatment and smaller foci of fluid likely contributed to PFD. Positive fluid discrepancy did not have substantial impact on subsequent visual acuity.

Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel.

PURPOSE: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer. EXPERIMENTAL DESIGN: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated. RESULTS: The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28-0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20-2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05. CONCLUSION: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility.

Reading Center Characterization of Central Retinal Vein Occlusion Using Optical Coherence Tomography During the COPERNICUS Trial.

PURPOSE: To determine the impact of segmentation error correction and precision of standardized grading of time domain optical coherence tomography (OCT) scans obtained during an interventional study for macular edema secondary to central retinal vein occlusion (CRVO). METHODS: A reading center team of two readers and a senior reader evaluated 1199 OCT scans. Manual segmentation error correction (SEC) was performed. The frequency of SEC, resulting change in central retinal thickness after SEC, and reproducibility of SEC were quantified. Optical coherence tomography characteristics associated with the need for SECs were determined. Reading center teams graded all scans, and the reproducibility of this evaluation for scan quality at the fovea and cystoid macular edema was determined on 97 scans. RESULTS: Segmentation errors were observed in 360 (30.0%) scans, of which 312 were interpretable. On these 312 scans, the mean machine-generated central subfield thickness (CST) was 507.4 ± 208.5 µm compared to 583.0 ± 266.2 µm after SEC. Segmentation error correction resulted in a mean absolute CST correction of 81.3 ± 162.0 µm from baseline uncorrected CST. Segmentation error correction was highly reproducible (intraclass correlation coefficient [ICC] = 0.99-1.00). Epiretinal membrane (odds ratio [OR] = 2.3, P < 0.0001), subretinal fluid (OR = 2.1, P = 0.0005), and increasing CST (OR = 1.6 per 100-µm increase, P < 0.001) were associated with need for SEC. Reading center teams reproducibly graded scan quality at the fovea (87% agreement, kappa = 0.64, 95% confidence interval [CI] 0.45-0.82) and cystoid macular edema (92% agreement, kappa = 0.84, 95% CI 0.74-0.94). CONCLUSIONS: Optical coherence tomography images obtained during an interventional CRVO treatment trial can be reproducibly graded. Segmentation errors can cause clinically meaningful deviation in central retinal thickness measurements; however, these errors can be corrected reproducibly in a reading center setting. TRANSLATIONAL RELEVANCE: Segmentation errors are common on these images, can cause clinically meaningful errors in central retinal thickness measurement, and can be corrected reproducibly in a reading center setting.

Optical coherence tomography grading reproducibility during the Comparison of Age-related Macular Degeneration Treatments Trials.

OBJECTIVE: To report reading center reproducibility during grading of Stratus optical coherence tomography (OCT) (Carl Zeiss Meditec, Dublin, CA) images obtained during the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective, clinical trial. PARTICIPANTS: Independent reading teams reevaluated 270 OCT scans randomly sampled from the first 2 years of CATT enrollment. To assess temporal drift, a cohort of 23 scans submitted during the initial portion of the CATT study was longitudinally followed with serial reproducibility analysis. INTERVENTION: The CATT readers performed standardized grading of OCT images. A reader team, composed of 2 independent readers and a senior reader, evaluated each scan. Grading included the CATT OCT end points of total thickness at the foveal center point and intraretinal fluid (IRF), subretinal fluid (SRF), and subretinal pigment epithelium (RPE) fluid. Independent reading teams masked to the results of initial grading reevaluated scans to determine the reproducibility of qualitative grading and measurements. MAIN OUTCOME MEASURES: Categorical grading agreement was reported using percent agreement and kappa statistic, and measurement agreement was reported using intraclass correlations and paired differences. RESULTS: Reading center teams reproducibly graded IRF (percent agreement = 73%, kappa = 0.48; 95% confidence interval [CI], 0.38-0.58), SRF (percent agreement = 90%; kappa = 0.80; 95% CI, 0.73-0.87), and sub-RPE fluid (percent agreement 88%; kappa = 0.75; 95% CI, 0.67-0.83). For independent reading center team measurements of total thickness at the foveal center point, the intraclass correlation was 0.99 (95% CI, 0.99-0.99), and the mean paired difference between reading center teams was 4 µm (95% limits of agreement, -55 to 47 µm). There was no qualitative or quantitative grading drift. CONCLUSIONS: The standardized protocols used to evaluate OCT scans from the CATT study were reproducible. The methods used are suitable to monitor OCT imaging data from a large, neovascular age-related macular degeneration, interventional, multicenter study. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Characterization of vitreoretinal interface disorders using OCT in the interventional phase 3 trials of ocriplasmin.

PURPOSE: We determined the reproducibility of a novel optical coherence tomography (OCT) protocol designed to evaluate formally vitreoretinal interface abnormalities on scans obtained during two phase 3 studies of intravitreal ocriplasmin to treat symptomatic vitreomacular adhesion with or without macular hole. METHODS: Certified technicians obtained time-domain OCT scans that included a macular thickness map (MTM), Fast MTM, and three high resolution linear scans: one 10 mm horizontal and one 10 mm vertical through the optic nerve head (ONH), and one 10 mm 5-degree-offset through the ONH and fovea. Reading Center teams graded all 3695 scans from 652 study eyes for pre-established quantitative and morphologic features. Grading reproducibility at baseline and follow-up visits was tested for presence of vitreomacular adhesion (VMA), width of vitreous adhesion (focal <1500 µm versus broad >1500 µm), presence and minimum width of full thickness macular hole (FTMH), and presence of epiretinal membrane (ERM). RESULTS: Team grading reproducibility for VMA (kappa 0.91, 95% confidence interval [CI] 0.81-1.00), broad versus focal width of vitreous adhesion (kappa 0.87, 95% CI 0.78-0.95), FTMH (kappa 0.87, 95% CI 0.78-0.95), and ERM (kappa 0.87, 95% CI 0.78-0.95) was high. Percent agreement was 97%, 92%, 95%, and 82% for VMA, vitreous adhesion width, FTMH, and ERM, respectively. For repeated measurements of FTMH width, the intraclass correlation was 0.89 (95% CI 0.85-0.93), and the mean paired difference between grading team measurements was 34.4 µm (95% limits of agreement -149.5-218.2 µm). CONCLUSIONS: Quantitative and morphologic vitreoretinal interface features were assessed reproducibly using a newly developed OCT scan acquisition and grading protocol. This protocol will be useful to evaluate OCT endpoints in future clinical trials, and can facilitate identification of vitreoretinal interface pathology during care of individual patients. (ClinicalTrials.gov number, NCT00781859 and NCT00798317.).

Determination of lead and zinc concentrations in the blood and liver of the captive common green iguana (Iguana iguana).

Heavy metal toxicosis is a well-known phenomenon in wild, captive-animal, and domestic animal medicine. However, the occurrence among reptiles is not well documented. One reason for this is the lack of information regarding reference blood and tissue levels of heavy metals in reptiles. To determine normal blood lead, plasma zinc, and liver lead and zinc concentrations, blood and liver samples were collected from 4 adult and 16 juvenile, healthy green iguanas (Iguana iguana). Lead and zinc levels were measured using atomic absorption spectroscopy. Using the mean +/- two SD as the normal reference range, the present study suggests the following for captive common green iguana: 1) whole blood lead level: 0.06 +/- 0.06 microg/ml; 2) plasma zinc level: 2.68 +/- 1.66 microg/ml; 3) liver lead level (wet-weight basis): <1.0 +/- 0.0 microg/g; 4) liver lead level (dry-weight basis): <3.0 +/- 0.0 microg/g; 5) liver zinc level (wet-weight basis): 24.9 +/- 11.6 microg/g; and 6) liver zinc level (dry-weight basis): 83.4 +/- 44.6 microg/g. These values are fairly consistent with published reference levels in other mammalian and avian species.

Optical coherence tomography reader agreement in neovascular age-related macular degeneration.

PURPOSE: To determine the interreader and intrareader agreement at the Optical Coherence Tomography (OCT) Reading Center at Duke for images produced for an interventional neovascular age-related macular degeneration (AMD) clinical trial. DESIGN: Retrospective, observational case series. METHODS: OCT was performed using the Stratus OCT Fast Macular Thickness Map (Carl Zeiss Meditec, Dublin, California, USA) scan mode and a 7-mm line scan centered on the fovea. Experienced OCT readers, certified to grade scans according to a standardized protocol, independently determined whether a scan was gradable. If gradable, each of the scans was graded for multiple morphologic characteristics. In addition, retinal thickness, subretinal fluid thickness, and choroidal neovascularization (CNV) thickness at the fovea were measured for each gradable scan. Interreader agreement was determined among three reader pairs. Readers regraded a subset of scans and intrareader agreement was determined. RESULTS: The interreader agreement was high for scan gradability and scan grades among three reader pairs, ranging from 84% to 100% and from 84% to 96%, respectively. Similarly, the intrareader agreement for scan gradability and scan grade, including comparison of adjudicated scan grades with readjudicated scan grades, was high and ranged from 91% to 100% and from 79% to 98%, respectively, except for scan grades of retinal pigment epithelium atrophy, when CNV was present. Highly reproducible results also were found for quantitative thickness measurements. CONCLUSIONS: Well-trained OCT readers can grade independently, with a high level of interreader and intrareader agreement, multiple morphologic parameters of OCT scans obtained from eyes with neovascular AMD. Reproducible Stratus OCT scan data will be valuable to monitor treatment efficacy in interventional clinical trials of neovascular AMD.