1. Angiofibrotic Response to Vascular Endothelial Growth Factor Inhibition in Diabetic Retinal Detachment: Report No. 1 Sohn EH, He S, Kim LA, et al. Angiofibrotic response to vascular endothelial growth factor inhibition in diabetic retinal detachment. Arch Ophthalmol. 2012;130(9):1127-1134. Copyright restrictions may apply

2. Introduction Factors responsible for traction retinal detachment (TRD) in proliferative diabetic retinopathy (PDR) are unclear. –Vascular endothelial growth factor (VEGF) drives neovascularization. –Connective tissue growth factor (CTGF) is linked to fibrosis. Decreasing VEGF levels (with laser or intravitreal bevacizumab) can accelerate fibrosis and TRD. Aims of this report: (1) Describe study design and summarize patient baseline characteristics. (2) Provide early clinical results. (3) Report the effect of VEGF inhibition on VEGF and CTGF in ocular fluid. (4) Examine the correlation of aqueous to vitreous levels of these growth factors. Copyright restrictions may apply

3. Methods Prospective, randomized, double-masked, interventional study of eyes needing vitrectomy for TRD due to PDR. –Two study arms: intravitreal bevacizumab injection (1.25 mg) vs sham injection (control). –Vitrectomy was performed 3-7 days after injection. Preoperative and intraoperative assessments of fibrovascular membranes were performed; intraoperative bleeding was recorded. Samples were extracted for laboratory analysis: –Preinjection aqueous. –Intraoperative aqueous, vitreous, and membranes. Copyright restrictions may apply

4. Ocular fluid levels were analyzed by enzyme-linked immunosorbent assay: –VEGF and CTGF. Statistical analysis of clinical data was performed. Limitations: –Small sample size (20 eyes of 19 patients). –Severe disease with predominantly fibrotic membranes. –Fluid samples were extracted within 7 days after injection, which may be too early to assess for an increase in fibrosis or an effect on growth factors. Copyright restrictions may apply Methods

5. 15 of 20 enrolled eyes had severe TRD or TRD/rhegmatogenous retinal detachment. 5 eyes had clinically observable regression of neovascularization (all in the treated group). Visual acuity changes from preoperatively  3 months postoperatively: –Controls: 20/400  20/400. –Treated: 8/200  20/100 –P =.30 between controls and treated at 3 months postoperatively. Vitreous: VEGF higher in controls than treated (P =.03); CTGF levels unchanged between the 2 arms. Aqueous: VEGF and CTGF unchanged between the 2 arms. Copyright restrictions may apply Results

6. Copyright restrictions may apply Results Preoperative, Intraoperative, and POM3 Results With Vitreous VEGF and CTGF Levels

7. Results Copyright restrictions may apply Correlation of aqueous levels of CGTF with vitreous levels of CTGF. Spearman correlation coefficient of 0.95 indicates high correlation (P <.001).

8. Vitreous (but not aqueous) VEGF levels are suppressed within 4 days after intravitreal bevacizumab injection (1.25 mg). 3-7 days after bevacizumab injection may be too early to see upregulation of CTGF levels in the vitreous. –Suggests scientific rationale for performing vitrectomy within 1 week of preoperative intravitreal bevacizumab injection for eyes with TRD in PDR. Aqueous CTGF level may be a useful surrogate for vitreous CTGF level in this subset of eyes with severe PDR. –Same cannot be said for VEGF. Copyright restrictions may apply Comment

9. CTGF is involved in intraocular fibrosis, but the precise relationship to VEGF is still unclear. Analysis of membranes extracted from study eyes may provide more insight into the mechanism of “angiofibrotic switch.” Detailed anatomic retinal analysis and long-term follow-up of clinical outcomes will be presented in future reports. Copyright restrictions may apply Comment

10. If you have questions, please contact the corresponding author: –Elliott H. Sohn, MD, Department of Ophthalmology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 (elliott.sohn@gmail.com). Funding/Support This study was supported by the Eugene de Juan Jr Award for Innovation (Dr Sohn), the Heed Foundation (Drs Kim and Javaheri), grant K12- EY16335 from the National Eye Institute, National Institutes of Health (Dr Kim), The Arnold and Mabel Beckman Foundation (Dr Hinton), Research to Prevent Blindness (Department of Ophthalmology, University of Iowa Hospitals and Clinics), and core grant EY03040 from the National Eye Institute (Doheny Eye Institute). Copyright restrictions may apply Contact Information