J Scott Williams

University of Tennessee, Knoxville, Tennessee, United States

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Publications (3)11.21 Total impact

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    ABSTRACT: Purpose: Superselective intraophthalmic artery chemotherapy (SSIOAC) is being used for treatment of retinoblastoma; however, the hemodynamic consequences and toxicities are not fully known. We developed a nonhuman primate (NHP) model of SSIOAC and reported our clinical observations. For validation, we compared ophthalmic artery (OA) diameters between NHPs and children (<6 years). Methods: Endovascular cannulation of the right OA was performed three times each in six adult male Rhesus macaques. Angiographic OA images were obtained and measured, and postmortem OAs were histologically sectioned and measured. Retrospectively, computed tomography (CT) and magnetic resonance (MR) angiography images of the head in children and adolescents (as an adult reference) were used to measure the OA luminal diameter at its origin. Results: The median angiographic diameter of treated NHP OA origins (n = 6) was 1.06 mm (range 0.94-1.56). Histologic measurements (8 of 12 NHP OAs) gave a median diameter of 1.09 mm (range 0.95-1.41). In 98 children (from 169 consecutive CT and MR angiography studies; median age 1.01 years, range 0.01-5.74), 186 OAs were measurable at the origin (median luminal diameter 1.28 mm, range 0.82-2.00; P = 0.16 for the angiographic NHP diameters versus pediatric cohort). Angiographic measurements of 34 OAs (of 20 consecutive studies of adolescents; median age 16.55 years, range 14.40-18.18) gave a median luminal diameter of 1.45 mm (origin, range 1.13-1.66; P < 0.0001, adolescent versus pediatric). Conclusions: Measurements of the OA luminal diameter at its origin were similar between our NHP and pediatric cohort, validating our NHP model for testing both the hemodynamic consequences and toxicities of SSIOAC.
    Investigative ophthalmology & visual science 10/2012; 53(12). DOI:10.1167/iovs.12-10605 · 3.40 Impact Factor
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    ABSTRACT: Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies.
    Investigative ophthalmology & visual science 03/2012; 53(4):2439-45. DOI:10.1167/iovs.12-9466 · 3.40 Impact Factor
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    ABSTRACT: To report real-time ophthalmoscopic findings during superselective intraophthalmic artery chemotherapy (SSIOAC) in a nonhuman primate model. Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned to 1 of 2 treatment cohorts: melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Each animal underwent 3 separate SSIOAC procedures at 3-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure. All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in 1. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Of the 18 procedures, retinal artery sheathing was found during 17 (94%), and retinal artery precipitates were seen in 10 (56%); choroidal hypoperfusion was seen by fluorescein angiogram in 18 (100%). Real-time ophthalmic investigations are useful and, in our nonhuman primate model, indicate prevalent, acute ocular vascular toxicities during SSIOAC. Real-time retinal imaging is feasible in a nonhuman primate model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities.
    Archives of ophthalmology 11/2011; 129(11):1458-65. DOI:10.1001/archophthalmol.2011.330 · 4.40 Impact Factor