Validating a Nonhuman Primate Model of Super-Selective Intraophthalmic Artery Chemotherapy: Comparing Ophthalmic Artery Diameters

Ditta, Lauren C.; Choudhri, Asim F.; Tse, Brian C.; Landers, Mark M.; Haik, Barrett G.; Steinle, Jena J.; Williams, James S.; Wilson, Matthew W.

doi:10.1167/iovs.12-10605

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…Similar FA anomalies have been seen in a nonhuman primate model of IAC,23 and direct evidence of embolus formation was reported in this primate model 8. However, in order to allow for larger animals to be used in those primate experiments, older animals were used 8,23,24. As with humans, older nonhuman primates are more likely to have carotid atherosclerosis, which could be dislodged by endovascular microcatheter intervention 25.…”

Section: Discussionsupporting

confidence: 62%

Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

Daniels

Froehler

Nunnally

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PurposeTo use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.MethodsRabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25–50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.ResultsNo toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.ConclusionsIAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.

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Section: Discussionsupporting

confidence: 62%

Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

Daniels

Froehler

Nunnally

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Our findings are expected based on the acute vasculopathies observed with real-time fundus imaging in the same NHP model during SSIOAC. 2 Because we have validated our NHP model, finding comparable diameters of eyes and OAs in a control pediatric population younger than 6 years, 22 our results are directly translatable to children with retinoblastoma. To that end, separate studies by Eagle et al 6 and Shields et al 12 of the histopathologic and clinical findings in eyes of children with retinoblastoma treated with SSIOAC parallel our findings in an NHP model.…”

Section: Discussionmentioning

confidence: 73%

Superselective Intraophthalmic Artery Chemotherapy in a Nonhuman Primate Model

Tse¹,

Steinle²,

Johnson³

et al. 2013

JAMA Ophthalmol

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“…Finally, various tumor and non-tumor bearing animal models have been used to study the pharmacokinetic of different drugs depending on the intraocular delivery model. Large animals such as primates, pigs and rabbits are preferentially chosen because of their appropriate size, their similar proportion between ocular compartments compared to human eyes and the possibility they allow for repeated or continuous sampling of the ocular fluids and the cannulation of the ophthalmic arteries (Carcaboso et al, 2007(Carcaboso et al, , 2010Daniels et al, 2018;Ditta et al, 2012;Schaiquevich et al, 2012c;Vézina, 2013). Macaques and rabbits have been successfully used to characterize the toxicity of intra-ophthalmic artery and intravitreal melphalan in the retina (Francis et al, Fundus showing nasal incomplete choroidal atrophy and preserved temporal choroid.…”

Section: Animal Modelsmentioning

confidence: 99%

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

Munier

Beck‐Popovic

Chantada

et al. 2019

Progress in Retinal and Eye Research

163

157

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Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.

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Validating a Nonhuman Primate Model of Super-Selective Intraophthalmic Artery Chemotherapy: Comparing Ophthalmic Artery Diameters

Abstract: 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.

Cited by 7 publications

References 29 publications

Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

Superselective Intraophthalmic Artery Chemotherapy in a Nonhuman Primate Model

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

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