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Abstract: Background: This systematic review aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico. We analyzed clinical and demographic data of patients with Rb at select hospitals with Rb programs or that treat and refer patients with Rb, and identified the gaps in practice. We propose solutions to improve diagnosis, provide adequate treatment, and improve patient uptake. Methods: A general review was conducted on PubMed of peer-reviewed literature on Rb in Mexico. Ophthalmology Department Heads or Directors of Rb programs at seven hospitals in Mexico were contacted for data available on their patients with Rb. Results: Five hospitals provided clinical data on 777 patients with Rb in a period spanning 2000-2015. Of the 122 patients with treatment, 83.4% underwent enucleation. From 33 to 45.3% of Rb tumors in Mexico reach an advanced intraocular stage of development. Knowledge of the disease is limited, despite the fact that the Mexican Retinoblastoma Group has elaborated Rb treatment guidelines and is developing a national Rb registry. Especially in the Southern states, prevalence and outcomes are comparable to African and Asian countries, and only few patients are referred to national treatment centers. Only three institutions have comprehensive Rb programs. Conclusions: There is an immediate need in Mexico to expand primary care providers' knowledge of Rb and to expand and upgrade current Rb programs to meet the needs of the population adequately. Diagnosis and care of Rb patients in Mexico can also be improved by the establishment of a national Rb registry and a national early detection program, and by increased use of the national treatment protocol.
Resumen: Introducción: Esta es una revisión sistemática de los conocimientos actuales del retinoblastoma (Rb) y sus implicaciones en los centros de referencia más importantes del país. Se presenta un análisis situacional de los programas de Rb en México, se identificaron las brechas en la práctica, y se proponen soluciones para mejorar el diagnóstico, tratamiento y referencia oportuna de pacientes. Métodos: Se realizó una revisión general de la literatura publicada sobre Rb en México a través de PubMed. Los datos sociodemográficos de pacientes con Rb fueron obtenidos a través de los directores de programas de retinoblastoma en siete hospitales. Resultados: Casi una tercera parte de los casos Rb se diagnostican en estadios avanzados. A pesar de la existencia del Grupo Mexicano de Retinoblastoma, el conocimiento de esta patología entre los médicos es limitado. Las diferencias en el tratamiento son notorias en el sur del país, donde la prevalencia y los resultados son comparables con África y Asia. Solamente tres instituciones a nivel nacional tienen un programa establecido de Rb. Conclusiones: Existe la necesidad inmediata de consolidar los programas de Rb para cubrir las necesidades reales de la población. Se requiere mejorar la educación del médico de primer contacto, establecer el registro nacional de casos y el programa de detección temprana, establecer los programas de salvamento ocular nacional, y reforzar las instituciones que brindan tratamiento.
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Humanos , Retinoblastoma/diagnóstico , Guias de Prática Clínica como Assunto , Neoplasias da Retina/diagnóstico , Encaminhamento e Consulta/estatística & dados numéricos , Retinoblastoma/terapia , Retinoblastoma/epidemiologia , Sistema de Registros , Conhecimentos, Atitudes e Prática em Saúde , Prevalência , Neoplasias da Retina/terapia , Neoplasias da Retina/epidemiologia , Detecção Precoce de Câncer/métodos , México/epidemiologiaRESUMO
PURPOSE: Published anthropometric measurements of the Latino eyelid are limited. This study describes features spanning the morphologic range from non-Latino whites to East Asians in the spectrum of the Latino eyelid. METHODS: A cross-sectional study of 68 people (32 Latinos, 18 non-Latino whites, and 18 East Asians, ages 18-39), approved by the Institutional Review Board and HIPAA-compliant, was performed. Saliva samples determined genetic components. Indirect anthropometric measurements were performed with ImageJ software. Eyelid measurements included margin reflex distance, palpebral fissure height, eyelid crease height, orbital height, horizontal fissure length, inner and outer canthal distances, medial and lateral canthal angles, and lateral canthal angle of inclination. Additionally, exophthalmometry and epicanthal folds were recorded. RESULTS: Analysis of 184 markers from HumanExome Chip data revealed distinct clustering patterns. Genetically, the Asian participants were in 1 group, the whites in another group, and the Latinos spanned the spectrum between these 2 groups. In Latinos, the inner canthal distance and lateral canthal angle of inclination were similar to Asians, whereas the eyelid crease spanned the range from Asians to whites. Half of the Latinos had epicanthal folds. CONCLUSIONS: Latinos possess a spectrum of eyelid features spanning the morphologic characteristics from those of non-Latino whites to those of East Asians. These normative data on Latinos from Texas and Mexico aid in the diagnoses of Latino eyelid disorders and are a reference for optimizing oculofacial surgery outcomes.
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Antropometria/métodos , Pálpebras/anatomia & histologia , Hispânico ou Latino , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Valores de Referência , Adulto JovemRESUMO
BACKGROUND: This systematic review aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico. We analyzed clinical and demographic data of patients with Rb at select hospitals with Rb programs or that treat and refer patients with Rb, and identified the gaps in practice. We propose solutions to improve diagnosis, provide adequate treatment, and improve patient uptake. METHODS: A general review was conducted on PubMed of peer-reviewed literature on Rb in Mexico. Ophthalmology Department Heads or Directors of Rb programs at seven hospitals in Mexico were contacted for data available on their patients with Rb. RESULTS: Five hospitals provided clinical data on 777 patients with Rb in a period spanning 2000-2015. Of the 122 patients with treatment, 83.4% underwent enucleation. From 33 to 45.3% of Rb tumors in Mexico reach an advanced intraocular stage of development. Knowledge of the disease is limited, despite the fact that the Mexican Retinoblastoma Group has elaborated Rb treatment guidelines and is developing a national Rb registry. Especially in the Southern states, prevalence and outcomes are comparable to African and Asian countries, and only few patients are referred to national treatment centers. Only three institutions have comprehensive Rb programs. CONCLUSIONS: There is an immediate need in Mexico to expand primary care providers' knowledge of Rb and to expand and upgrade current Rb programs to meet the needs of the population adequately. Diagnosis and care of Rb patients in Mexico can also be improved by the establishment of a national Rb registry and a national early detection program, and by increased use of the national treatment protocol.
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Guias de Prática Clínica como Assunto , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Detecção Precoce de Câncer/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , México/epidemiologia , Prevalência , Encaminhamento e Consulta/estatística & dados numéricos , Sistema de Registros , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/terapia , Retinoblastoma/epidemiologia , Retinoblastoma/terapiaRESUMO
PURPOSE: To report the use of punctal plugs as a new modality to assist in the localization of lesions providing symptomatic relief in patients with haemolacria during their workup. METHODS: Retrospective case series. RESULTS: One boy and one girl, ages 16 and 20, respectively, reported spontaneous bloody tearing. Workup included probing and irrigation of the nasolacrimal system, blood and coagulation profiles, blood typing, serum hormone levels, conjunctival biopsy, and imaging. All findings were normal and failed to suggest a cause in any of the cases. Punctal plugs were inserted into each patient's inferior punctum OS without complication. On initial follow-up visits, each patient reported cessation of bloody tears OS with continued bloody tears OD. Over time, both patients experienced complete cessation of haemolacria in both eyes. CONCLUSIONS: Haemolacria is a condition caused by a group of disorders that result in the production of tears that are partially composed of blood. The large majority of cases result in a specific diagnosis. Only rarely does workup result in undetermined etiology. The novel approach of utilizing punctal plugs in the management of haemolacria may not only provide symptomatic relief for lesions distal to and including the punctum, but also assists in anatomic localization in idiopathic cases.
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Sangue , Hemorragia Ocular/diagnóstico , Doenças do Aparelho Lacrimal/diagnóstico , Próteses e Implantes , Implantação de Prótese , Lágrimas , Adolescente , Técnicas de Diagnóstico Oftalmológico , Hemorragia Ocular/terapia , Feminino , Humanos , Doenças do Aparelho Lacrimal/terapia , Masculino , Ducto Nasolacrimal/patologia , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
AbstractThis is the first of a two-part review that aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico (including the authors' experience at the leading Rb centers), identify the gaps in practice, and propose solutions to improve diagnosis, treatment, and patient uptake. In this first part, general knowledge of Rb diagnosis and management is summarized with a focus on the latest advances in chemotherapy. A general review of peer-reviewed literature of Rb was conducted on PubMed. Key findings were summarized.Provided there is early detection and referral of patients followed by appropriate conservative management, Rb is curable. In developed countries, the primary treatment outcome is ocular salvage with sight preservation. Advanced chemotherapeutic options such as intra-arterial and intravitreal chemotherapy can now save even the most advanced tumors.Advances in Rb therapy are generally limited to developed countries. The implications in Mexico, of the findings from this review will be discussed in Part 2, which will be a comprehensive situational analysis of the state of Rb programming in Mexico, including a review of current demographic data available from hospitals that have Rb programs or treat Rb.
ResumenEsta es la primera parte de un trabajo de revisión donde se reportan los conocimientos actuales del retinoblastoma (Rb) y sus implicaciones en México (incluyendo la experiencia de los autores en los principales centros de referencia), así como las brechas en la práctica y las posibles soluciones para mejorar el diagnóstico, tratamiento y referencia de pacientes. En esta parte se resumen los conocimientos generales del Rb, su diagnóstico y tratamiento. Se realizó una revisión de los avances más recientes en esta enfermedad publicados en PubMed y se resumieron los hallazgos más importantes.La sospecha oportuna y la referencia adecuada de pacientes permiten que el tratamiento conservador del Rb sea curativo. En países en vías de desarrollo, el tratamiento primario es el salvamento ocular y la preservación de la visión. Las opciones de quimioterapia intraarterial o intravítrea permiten ofrecer opciones terapéuticas en estos pacientes.Los avances en el tratamiento del Rb están generalmente limitados a países industrializados. Las implicaciones de los hallazgos de esta revisión serán discutidas en la segunda parte, la cual será un análisis de la situación de los programas hospitalarios del Rb en México, incluyendo la revisión de los datos demográficos disponibles de los centros de referencia más importantes.
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AIMS: To compare high-risk histopathology of eyes with primary versus secondary enucleation from patients with retinoblastoma. PATIENTS AND METHODS: A retrospective histopathology review identified 207 eyes enucleated from 202 patients between March 1997 and August 2013. Our review considered high-risk histopathological features to include extraocular disease or invasion of the anterior chamber, iris, ciliary body, choroid (massive), postlaminar optic nerve or sclera. RESULTS: Most eyes (144, 70%) were primarily enucleated; 63 (30%) were secondarily enucleated after neoadjuvant therapy. The primary enucleation group had more advanced disease (Reese-Ellsworth group V: 95% vs 59%; International Classification Group D/E: 97% vs 59%; p<0.001). The incidence of high-risk histopathology features was similar between groups (32% vs 21%, n=59; p=0.132). The type of prior therapy was not associated with high-risk histopathology features. Time to enucleation was longer for secondarily enucleated eyes with high-risk features. Choroid and postlaminar optic nerve invasion were more frequent in eyes primarily enucleated (p<0.001). Forty-six of the 59 (78%) patients with high-risk features received adjuvant chemotherapy and/or external beam radiation therapy. Three patients who received primary enucleation and adjuvant therapy died of metastatic recurrence. CONCLUSIONS: Despite the more favourable classification of eyes treated with neoadjuvant therapy, the risk of high-risk histopathology features at enucleation was comparable with eyes undergoing primary enucleation. Delayed enucleation was associated with these features, and the majority of patients required further adjuvant therapy. Caution must be exercised in treating recalcitrant intraocular retinoblastoma to promptly pursue definitive enucleation in an effort to minimise further treatment exposures and metastases.
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Corioide/patologia , Enucleação Ocular/métodos , Nervo Óptico/patologia , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
This is the first of a two-part review that aims to report the current knowledge of retinoblastoma (Rb) and its implications in Mexico (including the authors' experience at the leading Rb centers), identify the gaps in practice, and propose solutions to improve diagnosis, treatment, and patient uptake. In this first part, general knowledge of Rb diagnosis and management is summarized with a focus on the latest advances in chemotherapy. A general review of peer-reviewed literature of Rb was conducted on PubMed. Key findings were summarized. Provided there is early detection and referral of patients followed by appropriate conservative management, Rb is curable. In developed countries, the primary treatment outcome is ocular salvage with sight preservation. Advanced chemotherapeutic options such as intra-arterial and intravitreal chemotherapy can now save even the most advanced tumors. Advances in Rb therapy are generally limited to developed countries. The implications in Mexico, of the findings from this review will be discussed in Part 2, which will be a comprehensive situational analysis of the state of Rb programming in Mexico, including a review of current demographic data available from hospitals that have Rb programs or treat Rb.
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Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK-p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ-41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies.
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Raios gama/efeitos adversos , Sistema de Sinalização das MAP Quinases , Ácido Quínico/análogos & derivados , Lesões Experimentais por Radiação , Retina , Doenças Retinianas , Vasos Retinianos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Humanos , Molécula 1 de Adesão Intercelular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Camundongos , Ácido Quínico/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/enzimologia , Lesões Experimentais por Radiação/patologia , Retina/enzimologia , Retina/patologia , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/enzimologia , Doenças Retinianas/patologia , Vasos Retinianos/enzimologia , Vasos Retinianos/patologia , Proteína Supressora de Tumor p53 , Células U937RESUMO
BACKGROUND: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma. MATERIALS AND METHODS: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated. RESULTS: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y). CONCLUSIONS: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.
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Quimioterapia Adjuvante/métodos , Enucleação Ocular , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/cirurgia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Medição de Risco/métodos , Teniposídeo/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Since its original description in 1908, Coats disease has been recognized as an idiopathic cause of severe vision loss with a remarkable diversity in clinical presentation and morphology. Key clinical and imaging variables are helpful in differentiating Coats disease from life-threatening malignancies, and proper management revolves around a thorough knowledge of the differential diagnosis. Despite significant advancement in scientific understanding of the disease process and clinical spectrum, the underlying etiology remains obscure, and both primary and secondary forms are recognized. With the development of anti-VEGF therapy, vitreoretinal specialists have a new, effective adjunct to the clinical management of exudates, macular edema, and serous retinal detachment. We highlight the history, diagnostic challenges, evolving clinical spectrum, and current management of Coats disease.
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Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/terapia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Crioterapia , Diagnóstico Diferencial , Angiofluoresceinografia , Humanos , Fotocoagulação a Laser , Imageamento por Ressonância Magnética , Telangiectasia Retiniana/etiologia , Tomografia de Coerência Óptica , Ultrassonografia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
IMPORTANCE: We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects. OBJECTIVE: To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model. DESIGN: Comparative interventional case series. SETTING: Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee. PARTICIPANTS: Six adult male rhesus macaques (Macacca mulatta). INTERVENTIONS: The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves. MAIN OUTCOME MEASURES: Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs. RESULTS: We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal. CONCLUSIONS AND RELEVANCE: Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.
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Antineoplásicos Alquilantes/toxicidade , Carboplatina/toxicidade , Endotélio Vascular/ultraestrutura , Infusões Intra-Arteriais/efeitos adversos , Leucostasia/patologia , Melfalan/toxicidade , Artéria Oftálmica/efeitos dos fármacos , Oclusão da Artéria Retiniana/patologia , Animais , Arteríolas , Biomarcadores/metabolismo , Corioidite/induzido quimicamente , Corioidite/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Técnicas Imunoenzimáticas , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Leucostasia/induzido quimicamente , Macaca mulatta , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Artéria Oftálmica/ultraestrutura , Oclusão da Artéria Retiniana/induzido quimicamente , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologiaRESUMO
PURPOSE: To compare wrapped and polymer-coated hydroxyapatite implants in children undergoing primary enucleation with no adjuvant therapies. DESIGN: Retrospective, interventional cohort study. PARTICIPANTS: All children undergoing primary enucleation without adjuvant therapies between 1999 and 2009 at a tertiary pediatric cancer hospital. METHODS: Review and analysis of patient records. MAIN OUTCOME MEASURES: Implant exposure, extrusion and migration, socket contracture, and formation of pyogenic granuloma. RESULTS: Sixty consecutive patients undergoing primary enucleation with no adjuvant chemotherapy or radiation with follow-up of at least 12 months were included. Retinoblastoma was the diagnosis in 59 eyes (98.3%). Median follow-up was 3.6 years (range, 1.0-9.3 years). Two implant sizes were used: 20 mm in 47 patients (78.3%) and 18 mm in 13 patients (21.7%). Overall, 52 patients (86.7%) had an event-free recovery. Polymer-coated hydroxyapatite implants (43/60, 71.7%), when compared with wrapped ones (17/60, 28.3%), had a trend toward greater event-free recovery (odds ratio [OR], 1.6; 95% confidence interval [CI], 0.3-7.7) and lower exposure rate (OR, 2.1; 95% CI, 0.4-10.5). CONCLUSIONS: The use of polymer-coated hydroxyapatite implants is associated with favorable outcomes in the pediatric population. Despite observed complications, long-term implant retention is possible in most children. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Derme Acelular , Anoftalmia/cirurgia , Materiais Revestidos Biocompatíveis , Durapatita , Enucleação Ocular , Órbita/cirurgia , Implantes Orbitários , Poliglactina 910 , Feminino , Seguimentos , Humanos , Complicações Intraoperatórias , Masculino , Complicações Pós-Operatórias , Neoplasias da Retina/cirurgia , Retinoblastoma/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
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Antineoplásicos/administração & dosagem , Angiografia por Ressonância Magnética , Neoplasias Experimentais/tratamento farmacológico , Artéria Oftálmica/patologia , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Tomografia Computadorizada por Raios X , Animais , Injeções Intra-Arteriais , Macaca mulatta , Masculino , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Artéria Oftálmica/diagnóstico por imagem , Reprodutibilidade dos Testes , Neoplasias da Retina/diagnóstico por imagem , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Resultado do TratamentoRESUMO
PURPOSE: To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma. METHODS AND MATERIALS: We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT. RESULTS: Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worse eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289). CONCLUSIONS: Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.
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Glioma do Nervo Óptico/radioterapia , Radioterapia Conformacional/métodos , Acuidade Visual/efeitos da radiação , Adolescente , Algoritmos , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Glioma do Nervo Óptico/tratamento farmacológico , Glioma do Nervo Óptico/fisiopatologia , Glioma do Nervo Óptico/cirurgia , Dosagem Radioterapêutica , Resultado do Tratamento , Carga Tumoral , Acuidade Visual/efeitos dos fármacos , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: New, effective chemotherapeutic agents are needed for intraocular retinoblastoma. METHODS: This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m(2) /day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients <12 months of age and 1.5 mg/m(2) for those >12 months of age at diagnosis. RESULTS: From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7-22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%-96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony-stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life. CONCLUSIONS: The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony-stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0-3, 3-6, 6-9, 9-12, and >12 months of age are specified.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Lactente , Masculino , Neutropenia/induzido quimicamente , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
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.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Células Endoteliais/efeitos dos fármacos , Melfalan/toxicidade , Artéria Oftálmica/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carboplatina/toxicidade , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Macaca mulatta , Neutrófilos/metabolismo , RNA Mensageiro/metabolismoRESUMO
PURPOSE: Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin. PATIENTS AND METHODS: We reviewed the audiologic test results of 60 patients with retinoblastoma who received front-line treatment with systemic carboplatin and vincristine according to the St Jude RET-3 protocol (n = 23) or best clinical management (n = 37). Ototoxicity was evaluated by three different grading systems. RESULTS: Twelve patients (20%) developed ototoxicity at some time after treatment initiation; however, ototoxicity resolved in two patients, and thus,10 patients (17%) had sustained hearing loss as documented at their most recent audiologic evaluation. Nine of these 10 patients had grade 3 or 4 ototoxicity, and nine patients were less than 6 months of age at the start of chemotherapy. Age at the start of chemotherapy was the only risk factor identified as a significant predictor of sustained hearing loss. Younger age was associated with an increased incidence of hearing loss. The different ototoxicity grading systems showed good overall agreement in the identification of patients with ototoxicity. Agreement was greatest between the Brock and Children's Cancer Group systems. CONCLUSION: We found that young patients with retinoblastoma who were treated with systemic carboplatin had a higher incidence of ototoxicity than previously reported. Younger patients (< 6 months of age at the start of treatment) were more likely to have ototoxicity than were older patients. Children treated with carboplatin should routinely undergo thorough, long-term audiologic monitoring.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Perda Auditiva/induzido quimicamente , Audição/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Perda Auditiva/epidemiologia , Testes Auditivos , Humanos , Incidência , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Vincristina/administração & dosagemRESUMO
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.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Carboplatina/toxicidade , Quimioterapia do Câncer por Perfusão Regional , Melfalan/toxicidade , Artéria Oftálmica/efeitos dos fármacos , Oftalmoscopia , Doenças Retinianas/induzido quimicamente , Angiografia , Animais , Antineoplásicos Alquilantes/administração & dosagem , Carboplatina/administração & dosagem , Angiofluoresceinografia , Fluoroscopia , Macaca mulatta , Masculino , Melfalan/administração & dosagem , Doenças Retinianas/diagnósticoAssuntos
Antineoplásicos Alquilantes/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Melfalan/administração & dosagem , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Antineoplásicos Alquilantes/farmacocinética , Humanos , Injeções Intra-Arteriais , Melfalan/farmacocinética , Artéria OftálmicaRESUMO
PURPOSE: To determine the impact of chemotherapy or external beam radiotherapy (EBRT) on pediatric anophthalmic sockets. DESIGN: A retrospective, nonrandomized, interventional cohort study. PARTICIPANTS: A total of 135 sockets of 133 children undergoing enucleation from late 1999 to early 2009 at the St. Jude Children's Research Hospital were included. METHODS: A retrospective chart review of outcomes after enucleation in patients treated with systemic chemotherapy or orbital EBRT either before or after removal of the eye compared with patients who received no other treatment. MAIN OUTCOME MEASURES: Incidence of implant exposure, migration, extrusion, socket contracture, and pyogenic granuloma formation. RESULTS: Retinoblastoma was the primary diagnosis in 128 eyes (95%). Median follow-up was 3.6 years (range, 0.1-9.3 years). Event-free course was observed in 94 sockets (69.6%). Complications included implant exposure (n = 28, 20.7%), socket contracture (n = 16, 11.9%), pyogenic granuloma (n = 9, 6.7%), implant extrusion (n = 3, 2.2%), and migration (n = 2, 1.5%). Exposure resolved in 21 sockets (77.8%) and improved in 2 sockets (11.1%); 1 patient with exposure died. Use of prior, adjuvant, or subsequent chemotherapy increased the long-term risk of exposure (odds ratio [OR] = 3.7; 95% confidence interval [CI], 1.4-9.4), and contracture (OR could not be calculated, P<0.0001). External beam radiotherapy greatly increased the risk of contracture (OR 24.0; 95% CI, 6.9-82.8) and exposure (OR 2.89; 95% CI, 1.1-7.9). CONCLUSIONS: In this unique pediatric population with cancer, chemotherapy and EBRT had an additive effect, significantly increasing the incidence of exposure and socket contracture. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.