Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

Mechanical behaviors of tension and relaxation of tongue and soft palate: Experimental and analytical modeling.

This study is to characterize mechanical properties of uniaxial tension and stress relaxation responses of muscle tissues of tongue and soft palate. Uniaxial tension test and stress relaxation test on 39 fresh tissue samples from four five-month-old boars (65 ±â€¯15 kg) are conducted. Firstly, the rationality of the samples' dimension design and experimenal data measurement is validated by one-way ANOVA F-type test. Mechanical properties, including stress-strain relationship and stress relaxation characteristic, are then investigated in details to show the nonlinear behaviors of the tissue samples clearly. Finally, a constitutive model of representing the mechanical properties is formulated within the nonlinear integral representation framework proposed by Pinkin and Rogers, and corresponding material parameters are fitted to the experimental data based on the Levenberg-Marquardt minimization algorithm. The results of the fitting comparison prove that the formulated constitutive model can capture the observed nonlinear behaviors of the muscle tissue samples in both the axial tension and stress relaxation experiments.

PROSPECTIVE EVALUATION OF A SUSTAINED-RELEASE DEXAMETHASONE INTRAVITREAL IMPLANT FOR CYSTOID MACULAR EDEMA IN QUIESCENT UVEITIS.

PURPOSE: To investigate dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc) in the treatment of uveitic cystoid macular edema that had persisted in the absence of intraocular inflammation. METHODS: In this prospective interventional case series, 10 patients with uveitic cystoid macular edema and quiescent uveitis were treated with dexamethasone intravitreal implant at baseline and evaluated monthly for one year. Patients were retreated whenever cystoid macular edema recurred. The primary outcome measure was best-corrected visual acuity (BCVA) at day 90. RESULTS: At day 90, mean improvement from baseline BCVA was 14.4 letters (P = 0.0003), 70% of patients had a ≥10 letter BCVA improvement, 50% of patients had a ≥15 letter BCVA improvement, and the mean decrease from baseline central subfield retinal thickness was 140 µm (P = 0.008). Improvements were maintained through day 360 with retreatment as needed. At day 360, mean improvement in BCVA was 16.5 letters (P = 0.006) and the mean decrease in central subfield retinal thickness was 158 µm (P = 0.002). One patient experienced intraocular pressure >25 mmHg (managed with topical medication). Two phakic patients (2/8; 25%) had worsening of lens opacity requiring cataract extraction. CONCLUSION: Dexamethasone intravitreal implant may be an effective treatment for patients with persistent cystoid macular edema in quiescent uveitis.

THE ASSOCIATION OF EPIRETINAL MEMBRANE WITH MACULAR HOLE FORMATION AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR.

PURPOSE: To describe the clinical and optical coherence tomography findings associated with the development of full-thickness macular holes after rhegmatogenous retinal detachment (RRD) repair. METHODS: Retrospective, interventional case series. All patients who developed full-thickness macular holes after successful RRD repair from 3 clinical practices were reviewed. All cases of combined/simultaneous full-thickness macular hole and RRD were excluded. The main outcome measure was the presence of an epiretinal membrane at time of diagnosis of macular hole. RESULTS: Twenty-five full-thickness macular holes were diagnosed after successful retinal detachment repair. Surgical approach to RRD repair included pneumatic retinopexy (6, 24%), scleral buckle alone (5, 20%), pars plana vitrectomy only (8, 32%), and combined scleral buckle and pars plana vitrectomy (6, 24%). The preceding RRD involved the macula in 19 patients (76%) before the formation of the macular hole. The median time to full-thickness macular hole diagnosis after RRD repair was 63 days (range, 4-4,080 days). An epiretinal membrane was present in all 25 (100%) macular holes. Two macular holes (8%) spontaneously closed, whereas the other 23 (92%) were successfully closed with a single surgical procedure. Mean visual acuity improved by approximately 5 lines to 20/72 (range, 20/20 to counting fingers at 1 foot) from 20/240 (range, 20/30 to hand motions) after macular hole repair (P < 0.0001). CONCLUSION: Full-thickness macular hole formation can occur after all types of RRD repair and is associated with an epiretinal membrane. The epiretinal membrane may play a role in the pathogenesis of secondary macular hole formation after RRD repair.

A proposed approach for analyzing post-study therapy effect in survival analysis.

Clinical trials that explore long-term endpoints may confound the analysis when post-study therapy effects are considered. This article introduces a procedure to mediate the effects of confounding and allow inferences of first-line experimental treatments in the presence of post-study therapy. The procedure is evaluated by intensive simulation analyses and applied to an analysis of a clinical cancer trial.

[Influencing factors and evaluation indicators for asthma control level in children].

OBJECTIVE: To investigate the influencing factors for asthma control level in children and the practicability of evaluation indicators for asthma. METHODS: A total of 185 children with asthma were enrolled. Questionnaires and pulmonary function test were used to evaluate the asthma control level and the factors influencing the control level. The correlation between evaluation indicators and asthma control level was analyzed. RESULTS: Among the 185 children with asthma, 139 (75.1%) achieved full control, 36 (19.5%) achieved partial control, and 10 (5.4%) had uncontrolled asthma. Application of inhaled corticosteroids and eosinophil count showed significant effects on asthma control level (P<0.05). There were significant differences in the percentage of forced expiratory volume in 1 second (FEV1%), fractional exhaled nitric oxide (FeNO), childhood asthma control test (C-ACT) questionnaire score, and pediatric asthma quality of life questionnaire (PAQLQ) score between the full control, partial control, and uncontrolled groups (P<0.05). In the children with asthma, FEV1% was positively correlated with C-ACT and PAQLQ scores (P<0.05), while there was no significant correlation between FEV1% and FeNO (P=0.214). CONCLUSIONS: Application of inhaled corticosteroids and eosinophil count are factors influencing asthma control in children. A combination of FEV1%, FeNO, C-ACT score, and PAQLQ score helps with the evaluation of asthma control level.

Time-Varying Pattern and Prediction Model for Geopolymer Mortar Performance under Seawater Immersion.

In this study, immersion experiments were conducted on the geopolymer mortar (GPM) by using artificial seawater, and the effects of alkali equivalent (AE) and waterglass modulus (WGM) on the resistance of geopolymer mortar (GPM) to seawater immersion were analyzed. The test subjected 300 specimens to 270 days of artificial seawater immersion and periodic performance tests. Alkali equivalent (AE) (3-15%) and waterglass modulus (WGM) (1.0-1.8) were employed as influencing factors, and the mass loss and uniaxial compressive strength (UCS) were used as the performance evaluation indexes, combined with X-ray diffraction (XRD) and scanning electron microscopy (SEM) to analyze the time-varying pattern of geopolymer mortar (GPM) performance with seawater immersion. The findings demonstrated a general trend of initially growing and then declining in the uniaxial compression strength (UCS) of geopolymer mortar (GPM) under seawater immersion. The resistance of geopolymer mortar (GPM) to seawater immersion decreased with both higher or lower alkali equivalent (AE), and the ideal range of alkali equivalent (AE) was 9-12%. The diffusion layer of the bilayer structure of the waterglass particle became thinner with an increase in waterglass modulus (WGM), which ultimately led to the reduction in the resistance of the geopolymer structure to seawater immersion. Additionally, a support vector regression (SVR) model was developed based on the experimental data to predict the uniaxial compression strength (UCS) of GPM under seawater immersion. The model performed better and was able to achieve accurate prediction within 1-2 months, and provided an accurate approach to predicting the strength of geopolymer materials in a practical offshore construction project.

Influence of In-Situ Stress on Cut Blasting of One-Step Raise Excavation Using Numerical Analysis Based on a Modified Holmquist-Johnson-Cook Model.

Due to different tensile and compressive properties of rock material, the corresponding tensile and compressive damage evolution show major differences. To investigate the tensile and compressive damage evolution in deep cut blasting with different in-situ stresses, an improved Holmquist-Johnson-Cook (HJC) material model considers the tensile and compressive damage separately is developed. The improved HJC model is implemented into LS-DYNA via a user-defined subroutine in this study. Then, a numerical model with different in-situ stresses loading schemes is modelled. Numerical simulation results show that in-situ stress can inhibit the development of tensile damage evolution, while promote the development of compressive damage evolution. The overall damage zone presents a decreasing trend with the increase of in-situ stress, because the tensile damage is more sensitive than the compressive damage for rock material. In addition, the maximum principal stress can determine the development of the direction of damage. Further, for a field test of blind cut raise in deep, the actual in-situ stress values are loaded on the numerical model. Then, in order to overcome the difficulties caused by in-situ stress, the cut blasting design is optimized by reducing hole spacing. Subsequently, the optimized cut parameters are applied in the blind cut raise. However, the one-step raise excavation method is adjusted to two steps to ensure success due to a serious borehole deviation between drilling and design drawing. After these steps, the formation of the blind cut raise with 8.7 m depth is met the requirements of design.

A variation of a 2-in-1 adaptive design to seamlessly expand a selected dose from a phase 2 trial to a phase 3 trial for oncology drug development.

In a recent article, Zhang et al. proposed a 2-in-1 adaptive design to seamlessly expand a selected dose, based on efficacy compared to the control arm, from a Phase 2 trial to a Phase 3 trial for oncology drug development. In this article, we communicate a variation of the proposed design which selects a dose to expand based on direct comparison of high dose to low dose when both doses demonstrate promising efficacy compared to the control arm.

Sector laser photocoagulation for the prevention of macular edema after plaque radiotherapy for uveal melanoma: a pilot study.

OBJECTIVE: To investigate the role of sector laser photocoagulation for prevention of macular edema after plaque radiotherapy for uveal melanoma. METHODS: Noncomparative, pilot interventional case series. The main outcome measure was optical coherence tomography-evident macular edema. RESULTS: A total of 29 patients had sector laser photocoagulation (sector panretinal photocoagulation) and sub-Tenon triamcinolone injection. The median tumor thickness and base was 3.3 mm and 10.0 mm. The median radiation dose and rate to the macula was 2,944 cGy and 31.0 cGy/hour. At the 12-month and 24-months follow-up, cystoid macular edema was found in 17% and 24% of the sector panretinal photocoagulation group. There were no major side effects registered. CONCLUSION: Sector panretinal photocoagulation in combination with sub-Tenon triamcinolone appears to show potential as a safe and beneficial intervention for the prevention of macular edema after plaque radiotherapy for uveal melanoma in this series.

Telemedicine-based digital retinal imaging vs standard ophthalmologic evaluation for the assessment of diabetic retinopathy.

OBJECTIVE: To study the cost benefit analysis of using a telemedicine-based digital retinal imaging evaluation compared to conventional ophthalmologic fundus examination of diabetic patients for diabetic retinopathy. METHODS: In this study, diabetic patients from Community Health Center, Inc. (CHCI), a large multi-site Federally Qualified Health Center) were evaluated by teleophthalmology using the Canon CR-1 nonmydriatic fundus camera. Digital images were acquired in the CHCI offices and saved on the EyePACS server network. The images were later evaluated by retinal specialists at the Yale Eye Center, Yale University Department of Ophthalmology and Visual Science. The costs for the standard of care ophthalmic examinations were calculated based on 2009 Medicaid reimbursement rates. The process of telemedicine-based diagnosis was based on a take-store-forward-visualize system. The cost of telemedicine-based digital retinal imaging examination included cost for devices, training, annual costs and a transportation fee. Current Medicaid reimbursement, transportation, and staff labor costs were used to calculate the conventional retinal examination cost as a comparison. RESULTS: Among the 611 patients digital retinal images screened in the first year of this program and for whom data are available, 166 (27.2%) cases of diabetic retinopathy were identified. Seventy-five (12.3%) patients screened positive with clinically significant disease and were referred for further ophthalmological evaluation and treatment. The primary direct cost of the telemedicine was $3.80, $15.00, $17.60, $1.50, and $2.50 per patient for medical assistant, ophthalmologist, capital cost (Equipment + Training), equipment maintenance, and transportation fee, respectively. The total cost in the telemedicine-based digital retinal imaging and evaluation was $40.40. The cost of conventional retinal examination was $8.70, $65.30, and $3.80 per patients for round-trip transportation, 2009 national Medicaid Physician Fee Schedule allowable for bilateral eye examination, and medical assistant personnel, respectively. The total costs of conventional fundus examination were $77.80. An additional conventional ophthalmologic retinal examination was required for 75 (12.3%) patients with clinically significant disease on telemedicine evaluation, which involves an averaged additional cost of $ 9.55 per patient for all the patients in the study. If the cost of subsequent examination was added, the total cost of telemedicine-based digital fundus imaging was $49.95 per patient in our group of 611 patients evaluated. CONCLUSIONS: Our cost analysis indicates that telemedicine-based diabetic retinopathy screening cost less ($49.95 vs $77.80) than conventional retinal examination and the telemedicine-based digital retinal imaging examination has the potential to provide an alternative method with greater convenience and access for the remote and indigent populations. Diabetes mellitus and diabetic retinopathy are growing problems in the United States and worldwide. Large scale adoption of telemedicine should be encouraged as a means toward providing improved access, increasing compliance with annual evaluation, at a low cost for patients with diabetes with direct access to an eye care specialist.

Utilization and life cycle assessment of low activity solid waste as cementitious materials: A case study of titanium slag and granulated blast furnace slag.

The dumping of cement production and industrial solid waste can cause severe environmental impact. In order to reduce the environmental impact of cement production and reasonably dispose of solid waste, a new type of cementing material was developed using industrial solid waste as raw materials. It solves the problem that low activity solid waste is difficult to reuse and makes up for the less research, which considered both preparation and environmental evaluation. The orthogonal tests of cement mortar strength as well as life cycle assessment were carried out. The results from variance and range analyses of the orthogonal tests revealed that the fraction of solid waste mainly affected the compressive strength of the solid waste cement mortar, and its specific surface area primarily influenced the flexural strength. After curing for 28 days, the compressive and flexural strength values of the developed cementing material were 40.6 MPa and 8.6 MPa, respectively. The results of life cycle impact assessment indicated that the developed solid waste cement had more environmental advantages than ordinary cement in 18 midpoints environmental impact types, and could diminish environmental impact by 16.1 % on the whole. The solid waste cement has achieved great environmental gains in the human toxicity, natural land transformation, metal depletion, climate change and other environmental impact categories. In addition, the clinker calcination, transportation and material mining were identified as critical processes responsible for the human toxicity, natural land transformation and metal depletion. Through sensitivity and uncertainty analyses, the development of the solid waste cement was proved to be the most effective method to decrease the environmental impact of cement. Finally, the methods of further reducing the environmental impact of cement were proposed.

A 2-in-1 adaptive design to seamlessly expand a selected dose from a phase 2 trial to a phase 3 trial for oncology drug development.

In oncology, dose-finding studies are largely performed only in Phase I clinical trials and the maximum tolerated dose (MTD), a dose initially developed for systemic chemotherapies, is by default selected for the Phase 3 confirmatory trial. With the advent of anti-cancer therapies such as molecular targeted agents and immunotherapies, a paradigm shift is underway from the use of conventional MTD approaches to improved dose selection strategies for oncology programs. In response to this new challenge, new study designs are needed to optimize dose selection while still bring life-changing new therapies to patients as soon as possible. In this paper, we propose a 2-in-1 adaptive design starting with a Phase 2 trial with randomized evaluation of multiple doses and only select one dose to expand to a Phase 3 trial if efficacy evidence is observed based on an interim evaluation. The lowest dose will be selected if multiple doses show promising efficacy unless the higher dose demonstrates a more compelling treatment effect, and study will be seamlessly expanded to a Phase 3 trial with the selected dose with patients enrolled in the Phase 2 portion also used for the statistical inference in the Phase 3 portion. The overall Type I error can be controlled under a mild assumption. Simulation studies are conducted to confirm the control of Type I error and to demonstrate the desirable operating characteristics of the proposed design.

A comparison of association methods correcting for population stratification in case-control studies.

Population stratification is an important issue in case-control studies of disease-marker association. Failure to properly account for population structure can lead to spurious association or reduced power. In this article, we compare the performance of six methods correcting for population stratification in case-control association studies. These methods include genomic control (GC), EIGENSTRAT, principal component-based logistic regression (PCA-L), LAPSTRUCT, ROADTRIPS, and EMMAX. We also include the uncorrected Armitage test for comparison. In the simulation studies, we consider a wide range of population structure models for unrelated samples, including admixture. Our simulation results suggest that PCA-L and LAPSTRUCT perform well over all the scenarios studied, whereas GC, ROADTRIPS, and EMMAX fail to correct for population structure at single nucleotide polymorphisms (SNPs) that show strong differentiation across ancestral populations. The Armitage test does not adjust for confounding due to stratification thus has inflated type I error. Among all correction methods, EMMAX has the greatest power, based on the population structure settings considered for samples with unrelated individuals. The three methods, EIGENSTRAT, PCA-L, and LAPSTRUCT, are comparable, and outperform both GC and ROADTRIPS in almost all situations.

Compare diagnostic tests using transformation-invariant smoothed ROC curves().

Receiver operating characteristic (ROC) curve, plotting true positive rates against false positive rates as threshold varies, is an important tool for evaluating biomarkers in diagnostic medicine studies. By definition, ROC curve is monotone increasing from 0 to 1 and is invariant to any monotone transformation of test results. And it is often a curve with certain level of smoothness when test results from the diseased and non-diseased subjects follow continuous distributions. Most existing ROC curve estimation methods do not guarantee all of these properties. One of the exceptions is Du and Tang (2009) which applies certain monotone spline regression procedure to empirical ROC estimates. However, their method does not consider the inherent correlations between empirical ROC estimates. This makes the derivation of the asymptotic properties very difficult. In this paper we propose a penalized weighted least square estimation method, which incorporates the covariance between empirical ROC estimates as a weight matrix. The resulting estimator satisfies all the aforementioned properties, and we show that it is also consistent. Then a resampling approach is used to extend our method for comparisons of two or more diagnostic tests. Our simulations show a significantly improved performance over the existing method, especially for steep ROC curves. We then apply the proposed method to a cancer diagnostic study that compares several newly developed diagnostic biomarkers to a traditional one.

Treat and extend regimen with aflibercept for chronic central retinal vein occlusions: 2 year results of the NEWTON study.

BACKGROUND: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) could continue to extend the macular edema free interval in patients on a treat and extend (TAE) with non-ischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) in the second year. METHODS: Twenty patients with macular edema secondary to non-ischemic CRVOs previously treated with ranibizumab or bevacizumab were prospectively treated with intravitreal aflibercept injection (IAI) using a TAE dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. In the second year of the study, patients who have recurrences of macular edema could be re-challenged with a longer treatment interval under the following criterion: absence of any macular edema on three consecutive visits with the same treatment interval. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range 7-90) and averaged an anti-VEGF treatment every 42 days (range 28-60 days). The macular edema free interval increased from 38 to 75 days when switched to aflibercept (p = 0.000003) at month 24. There was an average increase of 37 days (median 34 days; range 0-91 days) in the macular edema free interval with aflibercept. At the month 24 visit, 50% (8/16) went > 12 weeks with a macular edema free interval between IAI. There was an improvement in vision (+ 8 ETDRS letters, p = 0.006) and decreased retinal thickness (158 µm, p = 0.00003) with aflibercept treatment at month 24. CONCLUSIONS: The 2-year results of the NEWTON study demonstrated the sustained benefits of a TAE dosing regimen with aflibercept in patients with chronic CRVOs. The visual acuity gains and anatomic improvements observed at year one were maintained through month 24 with less visits and treatments. This may help minimize the treatment burden in patients with recurrent macular edema secondary to non-ischemic CRVO.Trial Registration ClinicalTrials.gov, NCT01870427, Registered June 6, 2013, https://clinicaltrials.gov/ct2/show/NCT01870427?cond=NEWTON&rank=1.Presented at the RETICON 2017: The Retina Congress with Live Surgery, Chennai, India-April 2017.

AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma.

PURPOSE: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

An adaptive approach to designing comparative diagnostic accuracy studies.

Comparative diagnostic studies usually involve comparison of the area under receiver operating characteristic curves when biomarkers are measured on a continuous or ordinal scales. In designing such studies, specification of a number of nuisance parameters is often required to compute sample sizes. When these parameters are incorrectly specified, statistical power to detect a meaningful difference in area can be substantially adversely affected. We propose an adaptive method to calculate the sample size and show these procedures to be effective in controlling error rates.

Point and interval estimation of primary and secondary parameters in a two-stage adaptive clinical trial.

Investigated in this paper is the point estimation and confidence intervals of the treatment efficacy parameter and related secondary parameters in a two-stage adaptive trial. Based on the minimal sufficient statistics, several alternative estimators to the sample averages are proposed to reduce the bias and to improve the precision of estimation. Confidence intervals are constructed using Woodroofe's pivot method. Numerical studies are conducted to evaluate the bias and mean squared error of the estimators and the coverage probability of the confidence intervals.

Aflibercept for Previously Treated Macular Edema Associated with Central Retinal Vein Occlusions: 1-Year Results of the NEWTON Study.

PURPOSE: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY) can extend the macular edema-free interval in patients with nonischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech, South San Francisco, CA). DESIGN: Prospective, single-arm, interventional study. PARTICIPANTS: Twenty patients with chronic nonischemic CRVOs. METHODS: Patients with nonischemic CRVOs previously treated with ranibizumab or bevacizumab were switched to aflibercept. The inclusion criteria included treatment for ≥6 months with ≥3 initial loading doses and evidence of recurrence of edema when treatment with either ranibizumab or bevacizumab extended beyond 4 weeks. Intravitreal aflibercept was administered with a treat-and-extend dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. MAIN OUTCOME MEASURES: Macular edema-free interval at week 52. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range, 7-90 months) and averaged an anti-vascular endothelial growth factor (anti-VEGF) treatment every 42 days (range, 28-60 days). These patients received a mean of 15 treatments (range, 5-47 treatments) of ranibizumab or bevacizumab for macular edema secondary to nonischemic CRVO. Among the 17 patients who completed 1 year of follow-up, 94% had a greater macular edema-free interval with aflibercept treatment. The macular edema-free interval increased from 5.4 weeks to 9.1 weeks when treatment was switched to aflibercept (P = 0.000003). There was an average increase of 26 days (range, 0-63 days) in the macular edema free interval with aflibercept. There was an improvement in vision (+6 Early Treatment Diabetic Retinopathy Study letters, P = 0.02) and decreased retinal thickness (152 µm, P = 0.0002) with aflibercept treatment. CONCLUSIONS: In patients previously treated with ranibizumab or bevacizumab for macular edema due to nonischemic CRVO, aflibercept increased the macular edema free interval. This may help minimize the treatment burden in patients with recurrent macular edema secondary to nonischemic CRVO.