Periurbano platense : Usos del suelo y dinámicas en curso sobre el área noroeste

Los espacios periurbanos, de ser considerados ámbitos residuales de lo urbano pasaron a constituir lugares estratégicos donde diversos actores y sectores sociales compiten por acceder. Allí crece la demanda de suelo residencial por sectores de mayor poder adquisitivo para un “acercamiento a la naturaleza”; por sectores medios en busca de valores del suelo accesibles, y por los bajos que se asientan de modo informal en tierras vacantes de baja aptitud. En todos los casos sus efectos se visualizan en el retroceso y desplazamiento de los usos agropecuarios intensivos característicos y necesarios de la dinámica del periurbano. Como parte sur del cinturón hortícola metropolitano de Buenos Aires el periurbano platense genera una importante producción florhortícola, susuperficie representa el 9% de la superficie productivatotal provincial. En la última década, se verificaron transformaciones en el uso del suelo sobre el eje de crecimiento Norte de la ciudad La Plata, que conjugan efectos de cambios en la dinámica productiva, y las nuevas tendencias de expansión urbana. Este trabajo intenta describir y explicar las transformaciones en curso en la configuración de ese espacio periurbano, los vínculos entre los procesos sociales y económicos, y los cambios en los usos del suelo en el sector.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Periurbano platense : Usos del suelo y dinámicas en curso sobre el área noroeste

Los espacios periurbanos, de ser considerados ámbitos residuales de lo urbano pasaron a constituir lugares estratégicos donde diversos actores y sectores sociales compiten por acceder. Allí crece la demanda de suelo residencial por sectores de mayor poder adquisitivo para un “acercamiento a la naturaleza”; por sectores medios en busca de valores del suelo accesibles, y por los bajos que se asientan de modo informal en tierras vacantes de baja aptitud. En todos los casos sus efectos se visualizan en el retroceso y desplazamiento de los usos agropecuarios intensivos característicos y necesarios de la dinámica del periurbano. Como parte sur del cinturón hortícola metropolitano de Buenos Aires el periurbano platense genera una importante producción florhortícola, susuperficie representa el 9% de la superficie productivatotal provincial. En la última década, se verificaron transformaciones en el uso del suelo sobre el eje de crecimiento Norte de la ciudad La Plata, que conjugan efectos de cambios en la dinámica productiva, y las nuevas tendencias de expansión urbana. Este trabajo intenta describir y explicar las transformaciones en curso en la configuración de ese espacio periurbano, los vínculos entre los procesos sociales y económicos, y los cambios en los usos del suelo en el sector.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Periurbano platense : Usos del suelo y dinámicas en curso sobre el área noroeste

Los espacios periurbanos, de ser considerados ámbitos residuales de lo urbano pasaron a constituir lugares estratégicos donde diversos actores y sectores sociales compiten por acceder. Allí crece la demanda de suelo residencial por sectores de mayor poder adquisitivo para un “acercamiento a la naturaleza”; por sectores medios en busca de valores del suelo accesibles, y por los bajos que se asientan de modo informal en tierras vacantes de baja aptitud. En todos los casos sus efectos se visualizan en el retroceso y desplazamiento de los usos agropecuarios intensivos característicos y necesarios de la dinámica del periurbano. Como parte sur del cinturón hortícola metropolitano de Buenos Aires el periurbano platense genera una importante producción florhortícola, susuperficie representa el 9% de la superficie productivatotal provincial. En la última década, se verificaron transformaciones en el uso del suelo sobre el eje de crecimiento Norte de la ciudad La Plata, que conjugan efectos de cambios en la dinámica productiva, y las nuevas tendencias de expansión urbana. Este trabajo intenta describir y explicar las transformaciones en curso en la configuración de ese espacio periurbano, los vínculos entre los procesos sociales y económicos, y los cambios en los usos del suelo en el sector.Área temática 4: Ciudad, Territorio y Paisaje. Gestión - Eje InvestigaciónFacultad de Arquitectura y Urbanism

Pharmacokinetics, Safety, and Efficacy of Intravitreal Digoxin in Preclinical Models for Retinoblastoma

PURPOSE:To assess in vitro cytotoxic activity and antiangiogenic effect, ocular and systemic disposition, and toxicity of digoxin in rabbits after intravitreal injection as a potential candidate for retinoblastoma treatment.METHODS:A panel of two retinoblastoma and three endothelial cell types were exposed to increasing concentrations of digoxin in a conventional (72-hour exposure) and metronomic (daily exposure) treatment scheme. Cytotoxicity was defined as the digoxin concentration that killed 50% of the cells (IC50) and was assessed with a vital dye in all cell types. Induction of apoptosis and cell-cycle status were evaluated by flow cytometry after both treatment schemes. Ocular and systemic disposition after intravitreal injection as well as toxicity was assessed in rabbits. Electroretinograms (ERGs) were recorded before and after digoxin doses and histopathological examinations were performed after enucleation.RESULTS:Digoxin was cytotoxic to retinoblastoma and endothelial cells under conventional and metronomic treatment. IC50 was comparable between both schedules and induced apoptosis in all cell lines. Calculated vitreous digoxin Cmax was 8.5 μg/mL and the levels remained above the IC50 for at least 24 hours after intravitreal injection. Plasma digoxin concentration was below 0.5 ng/ml. Retinal toxicity was evident after the third intravitreal dose with considerable changes in the ERG and histologic damage to the retina.CONCLUSIONS:Digoxin has antitumor activity for retinoblastoma while exerting antiangiogenic activity in vitro at similar concentrations. Metronomic treatment showed no advantage in terms of dose for cytotoxic effect. Four biweekly injections of digoxin led to local toxicity to the retina but no systemic toxicity in rabbits.Fil: Winter, Ursula Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Buitrago, Emiliano. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Mena, Hebe Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: del Sole, Maria Jose. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Laurent, Viviana Eunice. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Francis, Jasmine. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Arana, Eloisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Croxatto, Juan Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Oftalmología Argentina "J. Malbrán"; ArgentinaFil: Djaballah, Hakim. Core Facility Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Abramson, David. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration

A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.Fil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aschero, María del Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Buontempo, Fabian. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. Memorial Sloan-kettering Cancer Center; Estados UnidosFil: Carcaboso, Angel M.. Hospital Sant Joan de Deu Barcelona; EspañaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Clinical, genomic, and pharmacological study of MYCN-amplified RB1 wild-type metastatic retinoblastoma

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNampl RB1+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNampl RB1+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNampl RB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.Fil: Zugbi, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ganiewich, Daiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Bhattacharyya, Arpita. Tata Memorial Hospital; IndiaFil: Aschero, María del Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ottaviani, Daniela. Centre National de la Recherche Scientifique; FranciaFil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Cafferata, Eduardo Gustavo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mena, Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lamas, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; EspañaFil: Daroqui, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Baialardo, Edgardo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Salas, Beatriz. Hospital Asencio Villaroel; BoliviaFil: Das, Anirban. Tata Memorial Hospital; IndiaFil: Fandiño, Adriana Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Francis, Jasmine H.. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; EspañaFil: Garippa, Ralph. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Abramson, David. Memorial Sloan-kettering Cancer Center.; Estados UnidosFil: Radvanyi, François. Centre National de la Recherche Scientifique; FranciaFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Ocular findings in children with acute leukemia at a tertiary care center in South America

PURPOSE: The purpose of this study was to evaluate ophthalmological findings in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in a Latin American population. MATERIALS AND METHODS: This was a single-center, retrospective study. The observational analysis was conducted in AML and ALL patients seen as a routine examination at the department of ophthalmology of tertiary care center in Argentina between March 1, 2017, and February 28, 2018. RESULTS: Overall, 137 patients with acute leukemia were included. The mean age was 7.9 ± 5.2 years (0–18), and 55% were male (n = 75) and 45% female (n = 45). At least one-fifth (n = 31) of the patients presented some type of ocular manifestation (23%). The most frequently observed manifestation was retinal hemorrhages (n = 14), followed by papilledema (n = 9) and ocular surface involvement (n = 5). The eye involvement was more frequently identified in the AML group (24%), compared to the ALL group (22%), especially papilledema with central nervous system compromise ALL (5%) and AML (11%), P < 0.01. The presence of hemorrhages was similar in both groups. In patients with retinal hemorrhage (n = 14), the mean hematological findings were hemoglobin 7.4 ± 0.4 g/dL (6.5–8.0), erythrocytes 2.5M ± 0.3/mm3 (confidence interval [CI], 2.0–3.1), and platelets 76,000 ± 32,000/mm3 (CI, 8000–384,000). Patients without retinal findings (n = 123), the mean hematological findings were hemoglobin 9.1 ± 0.6 g/dL (8.0–10.2), erythrocytes 3.2M ± 0.6/mm3 (CI, 2.5–3.5), and platelets 92,000 ± 44,000/mm3 (CI, 42.000–390.000). Multivariable analysis found that hemoglobin levels were the most reliable predictive factor for retinal findings. It was observed that the risk diminishes in patients with levels higher than 8.5 g/dL, and that it increased in patients with levels ranging between 6.5 and 7.5 g/dL at least twice (P < 0.01). CONCLUSIONS: Our results show that ocular involvement occurs in a high percentage of patients with leukemia with a clear clinical, humoral, and sometimes prognostic correlation, suggesting routine ophthalmologic evaluation in these patients

The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries

Background Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. Methods We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1,2017, and Dec 31,2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. Findings The cohort included 4064 children from 149 countries. The median age at diagnosis was 23.2 months (IQR 11.0-36.5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0.8%) of 636 children from high-income countries, 55 (5.4%) of 1027 children from upper-middle-income countries, 342 (19. 7%) of 1738 children from lower-middle-income countries, and 196 (42.9%) of 457 children from low-income countries. Enudeation surgery was available for all children and intravenous chemotherapy was available for 4014 (98.8%) of 4064 children. The 3-year survival rate was 99.5% (95% CI 98.8-100.0) for children from high-income countries, 91.2% (89.5-93.0) for children from upper-middle-income countries, 80.3% (78.3-82.3) for children from lower-middle-income countries, and 57.3% (524-63-0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16.67; 95% CI 4.76-50.00), cT4 advanced tumour compared to cT1 (8.98; 4.44-18.18), and older age at diagnosis in children up to 3 years (1.38 per year; 1.23-1.56). For children aged 3-7 years, the mortality risk decreased slightly (p=0.0104 for the change in slope). Interpretation This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Queen Elizabeth Diamond Jubilee TrustQueen Elizabeth Diamond Jubilee Trust

Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery

Extraocular retinoblastoma is a major challenge worldwide, especially in developing countries. Current treatment involves the administration of systemic chemotherapy combined with radiation, but there is a clear need for improvement of chemotherapy bioavailability in the optic nerve. Our aim was to study the ophthalmic artery chemosurgery (OAC) local route for drug delivery assessing ocular and optic nerve exposure to chemotherapy and to compare it to exposure after intravenous infusion (IV) of the same dose in an animal model. Topotecan was used as a prototype drug that is active in retinoblastoma and based on the extensive knowledge of its pharmacokinetics in preclinical and clinical settings. Five Landrace pigs received 4mg of topotecan via OAC as performed in retinoblastoma patients. At the end of the infusion, the eyes were enucleated, the optic nerve and retina were dissected, and the vitreous and plasma were separated. After recovery and a wash-out period, the animals received a 30-min IV infusion of topotecan (4 mg). The remaining eye was enucleated and tissues and fluids were separated. All samples were stored until quantitation using HPLC. A significantly higher concentration of topotecan in the optic nerve, vitreous, and retina was obtained in eyes after OAC compared to IV infusion (p0.05). The median optic nerve-to-plasma ratio after OAC and IV was 44 and 0.35, respectively. Topotecan OAC delivery attained an 80-fold higher concentration in the optic nerve compared to the systemic infusion of the same dose with similar plasma concentrations in a swine model. Patients with retinoblastoma extension into the optic nerve may benefit from OAC for tumor burden by increased chemotherapy bioavailability in the optic nerve without increasing systemic exposure or toxicity.Fil: Taich, Paula Juliana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Requejo, Flavio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Gobin, Pierre. Memorial Sloan-Kettering Center Cancer Center; Estados UnidosFil: Abramson, David H.. Memorial Sloan-Kettering Center Cancer Center; Estados UnidosFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin