Validating a nonhuman primate model of super-selective intraophthalmic artery chemotherapy: comparing ophthalmic artery diameters.

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.

Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis.

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.

Real-time ophthalmoscopic findings of superselective intraophthalmic artery chemotherapy in a nonhuman primate model.

OBJECTIVE: To report real-time ophthalmoscopic findings during superselective intraophthalmic artery chemotherapy (SSIOAC) in a nonhuman primate model. METHODS: 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. RESULTS: 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%). CONCLUSION: Real-time ophthalmic investigations are useful and, in our nonhuman primate model, indicate prevalent, acute ocular vascular toxicities during SSIOAC. CLINICAL RELEVANCE: 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.

Prospective screening for blunt cerebrovascular injuries: analysis of diagnostic modalities and outcomes.

OBJECTIVE: To prospectively examine outcomes associated with an aggressive screening protocol for blunt cerebrovascular injury (BCVI), and to compare the accuracy of computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) versus conventional angiography with respect to BCVI diagnosis. SUMMARY BACKGROUND DATA: In the past 5 years, BCVI (carotid and vertebral arteries) has been recognized with increasing frequency. Initial studies described blunt carotid injuries and their associated morbidity, while more recent reports have established the devastating potential of blunt vertebral injuries. It has been suggested that early diagnosis and anticoagulation will improve outcomes and that less-invasive diagnostic techniques than conventional angiography are desirable for screening. However, there are neither established screening criteria nor studies comparing optimal diagnostic modalities. METHODS: The screened population included all patients with cervical spine fractures, LeFort II or III facial fractures, Horner's syndrome, skull base fractures involving the foramen lacerum, neck soft tissue injury, or neurological abnormalities unexplained by intracranial injuries. Patients underwent screening with four-vessel cerebral angiography. During the first half of the study, patients also underwent helical CTA. Selected patients during this same period underwent MRA. At the time of diagnosis, anticoagulant or antiplatelet therapy was instituted unless clinically contraindicated. Results of this screening protocol were compared to a previously published cohort with cerebrovascular injuries (1995-1999) from the authors' institution. RESULTS: Two hundred sixteen patients were screened over a 2-year period (3.5% of all blunt trauma admissions). Angiography identified 24 patients with carotid artery injuries (CAI) and 43 patients with vertebral artery injuries (VAI) for an overall screening yield of 29%. While the incidence of CAI remained similar between the current study and the previous study group, the incidence of VAI diagnosis increased. Stroke rates in those with CAI were also similar between the two periods. The stroke rate in VAI, however, was markedly lower at 0% as compared to 14% in the previous group. Comparison of CTA and MRA with cerebral angiography in 143 patients demonstrated sensitivities of 47% and 50%, respectively, for CAI; sensitivities were 53% (CTA) and 47% (MRA) for VAI. CONCLUSIONS: Aggressive screening of patients with blunt head and neck trauma identified an incidence of BCVI in 1.03% of blunt admissions. Early identification, which led to early treatment, significantly reduced stroke rates in patients with VAI, but provided no outcome improvement with CAI. More encompassing screening may be required to improve outcomes for patients with CAI. However, less-invasive diagnostic techniques (CTA and MRA) are inadequate for screening. Technological advances are necessary before abandonment of conventional angiography, which remains the standard for diagnosis.