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      Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma

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          Current intra-arterial chemotherapy (IAC) drug regimens for retinoblastoma have ocular and vascular toxicities. No small-animal model of IAC exists to test drug efficacy and toxicity in vivo for IAC drug discovery. The purpose of this study was to develop a small-animal model of IAC and to analyze the ocular tissue penetration, distribution, pharmacokinetics, and treatment efficacy.


          Following selective ophthalmic artery (OA) catheterization, melphalan (0.4 to 1.2 mg/kg) was injected. For pharmacokinetic studies, rabbits were euthanized at 0.5, 1, 2, 4, or 6 hours following intra-OA infusion. Drug levels were determined in vitreous, retina, and blood by liquid chromatography tandem mass spectrometry. To assess toxicity, angiograms, photography, fluorescein angiography, and histopathology were performed. For in situ tissue drug distribution, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was performed. The tumor model was created by combined subretinal/intravitreal injection of human WERI-Rb1 retinoblastoma cells; the tumor was treated in vivo with intra-arterial melphalan or saline; and induction of tumor death was measured by cleaved caspase-3 activity.


          OA was selectively catheterized for 79 of 79 (100%) eyes in 47 of 47 (100%) rabbits, and melphalan was delivered successfully in 31 of 31 (100%) eyes, without evidence of vascular occlusion or retinal damage. For treated eyes, maximum concentration (C max) in the retina was 4.95 μM and area under the curve (AUC 0→∞) was 5.26 μM·h. Treated eye vitreous C max was 2.24 μM and AUC 0→∞ was 4.19 μM·h. Vitreous C max for the treated eye was >100-fold higher than for the untreated eye ( P = 0.01), and AUC 0→∞ was ∼50-fold higher ( P = 0.01). Histology-directed MALDI-IMS revealed highest drug localization within the retina. Peripheral blood C max was 1.04 μM and AUC 0→∞ was 2.07 μM·h. Combined subretinal/intravitreal injection of human retinoblastoma cells led to intra-retinal tumors and subretinal/vitreous seeds, which could be effectively killed in vivo with intra-arterial melphalan.


          This first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.

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          Most cited references 25

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          Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?

          To describe a series of patients with secondary acute myelogenous leukemia (sAML) and retinoblastoma (RB). Retrospective observational cases series. Ocular and pediatric oncologists at referral centers in Europe and the Americas and the RB databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center. Physician survey, retrospective database review, and literature search. History of RB and development of sAML, management of RB (surgery, radiotherapy, chemotherapy), age at diagnosis of RB and leukemia, French-American-British (FAB) subtype, and current status of patient (alive or dead). Fifteen patients with sAML were identified; 13 occurred in childhood. Mean latent period from RB to AML diagnosis was 9.8 years (median, 42 months). Nine cases were of the M2 or M5 FAB subtypes. Twelve patients (79 %) had received chemotherapy with a topoisomerase II inhibitor, 8 (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. Acute myelogenous leukemia is a rare secondary malignancy among retinoblastoma patients, many of whom were treated with primary or adjuvant chemotherapy. Additional studies are needed to assess potential risk factors contributing to sAML development in this cohort.
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            Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma.

            To evaluate the occurrence of second malignant neoplasms (SMN) following chemoreduction (CRD) with carboplatin, vincristine, and etoposide (CEV) as frontline therapy in patients with retinoblastoma (RB). PRODECURE: We conducted a two-institution retrospective chart review of 245 patients with intraocular RB treated with six cycles of vincristine, carboplatin, and etoposide for treatment of intraocular retinoblastoma. Cumulative incidence of SMN was calculated with adjustment for the competing risk of death. There were 187 patients with germline retinoblastoma and 58 with non-germline disease. External beam radiotherapy was subsequently utilized in 46 (24%) of germline cases and six (10%) of non-germline cases. Mean follow-up of germline and non-germline patients was 80 and 70 months, respectively. Seven subsequent cancers were found in six patients for an overall incidence of 3% at a mean of 11 years. For germline cases, following CEV alone (n = 156), SMN were found in 4% following the RB diagnosis. We found no SMN in patients with non-germline RB. One patient developed pineoblastoma. SMN included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), orbital and conjunctival melanoma (n = 1), low-grade glioma (n = 1), and acute promyeloctic leukemia (n = 1). Five of the six patients with a second malignancy survive at mean of 46 months (range 15-71 months). At a mean of 11 years, 4% of children with germline RB treated with CEV as frontline therapy developed SMN's. No SMN was found in non-germline patients. Concerns regarding CEV-induced second cancers should not deter clinicians from using life and vision preserving therapy in patients with retinoblastoma. Copyright © 2011 Wiley Periodicals, Inc.
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              Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma.

              Carboplatin plays an important role in the conservative management of retinoblastoma, but is associated with risk of ototoxicity in these young children whose sensory prognosis may be also compromised by their loss of vision. This retrospective study analyzed the impact of carboplatin on hearing in the context of conservative management of children with retinoblastoma. Data for 175 children treated at the Institut Curie between 1994 and 2002 were analyzed. Median age at diagnosis was 8 months (0-60). Carboplatin was administered on 3 days (200 mg/m(2)/day) or 5 days (160 mg/m(2)/day) with etoposide and with diode-laser therapy at the dose of 560 mg/m(2) (chemothermotherapy). Median cumulative dose of carboplatin was 2,880 mg/m(2) (560-6,160). Ototoxicity was investigated by pure-tone audiometry and scored by Brock's grading scale before and after treatment. The median follow-up of hearing assessment was 5 years (1.8-11). Ototoxicity was detected in 8 children: 3 grade 1, 1 grade 2, and 2 grade 4. The two patients with grade 4 hearing-loss required a hearing aid. Two children developed bilateral high frequency hearing-loss, considered to be secondary to carboplatin but with less than Brock grade 1. Ototoxicity was observed for a median cumulative dose of carboplatin of 3,120 mg/m(2) (1,200-5,830). Only one child developed ototoxicity during treatment. All other cases were discovered after the last dose of carboplatin with a median interval of 3.7 years (0-7.6). No other risk factor for ototoxicity was able to account for these lesions. Children receiving carboplatin require long-term audiometric follow-up. (c) 2009 Wiley-Liss, Inc.

                Author and article information

                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                Invest Ophthalmol Vis Sci
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                January 2018
                : 59
                : 1
                : 446-454
                [1 ]Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [2 ]Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
                [3 ]Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [4 ]Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [5 ]Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [6 ]Surgical Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [7 ]Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
                [8 ]Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
                [9 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [10 ]Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States
                [11 ]Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
                [12 ]Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, United States
                Author notes
                Correspondence: Anthony B. Daniels, Vanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN 37232, USA; anthony.b.daniels@ .
                iovs-58-14-50 IOVS-17-22302
                Copyright 2018 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                Anatomy and Pathology/Oncology


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