title: Superselective intraophthalmic artery chemotherapy in a nonhuman primate model: histopathologic findings.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Comparative interventional case series.
  
  
  METHODS
  Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee.
  
  
  METHODS
  Six adult male rhesus macaques (Macacca mulatta).
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Tse
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
authors.forename: Dianna
authors.initials: D
authors.lastname: Johnson
authors.forename: Barrett G
authors.initials: BG
authors.lastname: Haik
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Wilson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001160:Arterioles; D015415:Biomarkers / Q000378:metabolism; D016190:Carboplatin / Q000633:toxicity*; D002833:Choroiditis / Q000139:chemically induced / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D007124:Immunoenzyme Techniques; D007261:Infusions, Intra-Arterial / Q000009:adverse effects*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D018921:Leukostasis / Q000139:chemically induced / Q000473:pathology*; D008253:Macaca mulatta; D008297:Male; D008558:Melphalan / Q000633:toxicity*; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009880:Ophthalmic Artery / Q000187:drug effects* / Q000648:ultrastructure; D015356:Retinal Artery Occlusion / Q000139:chemically induced / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D016209:Interleukin-8; D018799:Intercellular Adhesion Molecule-1; D016190:Carboplatin; D008558:Melphalan