Superselective Intraophthalmic Artery Chemotherapy in a Nonhuman Primate Model: Histopathologic Findings

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Abstract

Importance

We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects.

Objective

To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model.

Design

Comparative interventional case series.

Setting

Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee.

Participants

Six adult male rhesus macaques (Macacca mulatta).

Interventions

The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves.

Main Outcome Measures

Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs.

Results

We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal.

Conclusions and Relevance

Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.

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