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R. Penland, L. Kong, H. Mintz-Hittner, F. Kretzer, P. Chevez-Barrios; Bevacizumab as Anti-VEGF Therapy for Retinopathy of Prematurity: A Histopathologic Study. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1390.
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To evaluate the toxicity and effectiveness of bevacizumab (Avastin), a vascular endothelial growth factor (VEGF)-specific antibody, in the treatment of ROP.
A 350 gm male infant born at 22 wks developed stage 2 ROP in small zone I with plus disease at 31 wks. Under adequate consent form, an intravitreal bevacizumab (Avastin) injection of 0.5 mg in 0.02 ml volume (40% of the adult dose) was given in each eye. Recurrence of stage 3 ROP in posterior zone II with plus disease at 41.6 wks required a second injection of 0.5 mg of bevacizumab in each eye. Thereafter, vessels extended beyond medium zone II. The infant expired at 50.6 wks. The enucleated eyes were donated and fixed within 90 minutes in 10% formalin, and sections were submitted for evaluation. Slides were stained with H&E, PAS and by immunohistochemistry using: CD3, CD5, CD43, CD68, L-26, CD31, CD34, GFAP, Vimentin and factor VIII. The expression of VEGF was evaluated at both protein (VEGF 165 antibody) and mRNA level [in situ hybridization (ISH)].
No ocular complications related to the intravitreal injections were noted. Histopathology from both eyes showed no inflammation at any level (CD3, CD5, CD43, CD68, L-26). No retinal detachment, neuronal degeneration, or scarring was found (GFAP and Vimentin). The retinal vessels extended peripherally to large zone II of the retina ( CD31, CD34, factor VIII). Rare vascularization tufts through the ILM into the vitreous were seen at the junction of small and medium zone II, but no pre-retinal fibrovascular membrane was seen. VEGF expression in the retina and other ocular tissues was detected by both immunohistochemistry and ISH. The level of VEGF expression was higher in the avascular zone than the vascularized zone, and higher in newly formed retinal vessels than mature vessels.
Bevacizumab, a humanized anti-VEGF antibody, effectively eliminated neovascularization of stage 2 ROP in small zone I with plus disease and recurrent stage 3 ROP in posterior zone II with plus disease. Short term toxicity to retina, optic nerve and other ocular tissues was not found in this case. The expression of VEGF appears not to be uniformly blocked in developing tissues allowing maturation of the peripheral retina while restricting abnormal neovascularization.
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