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BACKGROUND: Bilateral retinoblastoma (Rb) treatment remains a challenge for ophthalmologists and pediatric oncologists despite new therapeutic strategies for eye preservation. The purpose of this work is to evaluate treatment outcomes in patients who underwent eye salvage treatment at a single-center prior to the chemotherapy in situ era. PROCEDURE: We followed a cohort of 88 consecutive Rb patients diagnosed at Hospital Infantil de México between November 2000 and June 2014. Eye salvage treatment consisted of systemic chemotherapy plus focal therapy planned by a multidisciplinary team. Unresponsive tumors were treated with episcleral brachytherapy and external beam radiotherapy (EBRT). RESULTS: A total of 96 eyes underwent eye salvaging therapy. Seventy-eight eyes (81%) were salvaged. Seven patients (8%) required brachytherapy and 34 patients (39%) underwent EBRT. Thirty-three of 78 preserved eyes (42%) achieved normal visual acuity: 5/27 (20%) in radiated patients and 28/51 (61%) in nonradiated patients. Eight patients developed secondary primary malignancies; however, those treated with EBRT did not have a significantly increased risk when compared with nonirradiated patients (OR: 1.66; P = 0.492). The overall survival rate was 86% (95% CI, 76%-92%) after a mean follow-up of 10 years. CONCLUSIONS: Eye preservation, long-term tumor control, and functional visual acuity could be maintained in many child and adolescent Rb survivors. Our data suggest that ocular radiotherapy can be used as consolidation treatment when other recently developed therapies with potentially fewer side effects are not available. Multidisciplinary management of Rb is mandatory to obtain cancer control during eye salvage treatment.

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Background: Penetrating keratoplasty (PK) is a challenging surgical ocular procedure indicated for some pediatric patients with vision-threatening corneal disease damage. Pediatric PK is reserved for cases with advanced pathology or dysfunction as rejection and failure rates greatly supersede the rates of adult PK. The objective was to identify factors associated with graft rejection and failure amongst Mexican children undergoing primary PK for different indications. Methods: A retrospective review of consecutive pediatric PK medical records was conducted between 2001 and 2015 at the Hospital Infantil de México Federico Gómez. Graft survival was calculated using the Kaplan-Meier survival method. Results: During the 15 years of study, 67 eyes of 57 patients underwent PK. The mean age at the time of surgery was 11 years. The mean follow-up duration was 44 months. Keratoconus was the most common indication for PK (61%) followed by herpetic keratitis (15%) and other corneal dystrophies (10%). Mean graft survival time was 45.6 months (95% confidence interval 31.8-58.4 months, standard deviation = 0.069), with a survival rate of 70% at 1 year. Univariate Cox proportional hazard showed that being < 9 years of age at the time of the surgery (p = 0.023) and corneal dystrophies (p = 0.04) were prognostic factors for corneal rejection. Five eyes of five patients developed graft failure. Conclusions: Pediatric PK patients commonly experience graft rejection, which need to be promptly diagnosed and treated to minimize permanent damage. The age at the time of surgery and congenital corneal opacities is factors associated with a higher risk of rejection and failure.

Introducción: La queratoplastia penetrante (QP) es un procedimiento quirúrgico indicado en algunos pacientes pediátricos con daño corneal con riesgo de fracaso que amenaza la visión. El objetivo del presente trabajo fue identificar los factores asociados a rechazo y fallo del injerto corneal en niños sometidos a QP. Métodos: Serie de casos de pacientes sometidos a QP en el Hospital Infantil de México Federico Gómez entre 2001 y 2015. La sobrevida del injerto fue calculada por el método de estimación de la función de supervivencia Kaplan­Meier. Resultados: Durante 15 años de estudio, 67 ojos de 57 pacientes fueron sometidos a QP. El promedio de edad de los pacientes al tiempo de la cirugía fue de 11 años. El seguimiento promedio fue de 44 meses. El queratocono fue la indicación más común de QP (61%), seguido de queratitis herpética (15%) y otras distrofias corneales (10%). El tiempo promedio de sobrevida fue 45.6% (intervalo de confianza [IC] 95%: 31.8-58.4 meses, desviación estándar [DS] = 0.069), con una tasa de sobrevida del 70% a 1 año. El riesgo proporcional de Cox univariado mostró que una edad < 9 años al momento de la cirugía (p = 0.023) y distrofias corneales (p = 0.04) son factores pronóstico para el rechazo corneal. Cinco ojos de cinco pacientes desarrollaron falla del injerto. Conclusiones: El rechazo del injerto en QP en pacientes pediátricos es común y puede ser resuelto satisfactoriamente en casi todos los casos con diagnóstico y tratamiento. La edad al momento de la cirugía y las opacidades corneales congénitas son factores asociados con el rechazo y fallo.

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Abstract Background: Penetrating keratoplasty (PK) is a challenging surgical ocular procedure indicated for some pediatric patients with vision-threatening corneal disease damage. Pediatric PK is reserved for cases with advanced pathology or dysfunction as rejection and failure rates greatly supersede the rates of adult PK. The objective was to identify factors associated with graft rejection and failure amongst Mexican children undergoing primary PK for different indications. Methods: A retrospective review of consecutive pediatric PK medical records was conducted between 2001 and 2015 at the Hospital Infantil de México Federico Gómez. Graft survival was calculated using the Kaplan–Meier survival method. Results: During the 15 years of study, 67 eyes of 57 patients underwent PK. The mean age at the time of surgery was 11 years. The mean follow-up duration was 44 months. Keratoconus was the most common indication for PK (61%) followed by herpetic keratitis (15%) and other corneal dystrophies (10%). Mean graft survival time was 45.6 months (95% confidence interval 31.8-58.4 months, standard deviation = 0.069), with a survival rate of 70% at 1 year. Univariate Cox proportional hazard showed that being < 9 years of age at the time of the surgery (p = 0.023) and corneal dystrophies (p = 0.04) were prognostic factors for corneal rejection. Five eyes of five patients developed graft failure. Conclusions: Pediatric PK patients commonly experience graft rejection, which need to be promptly diagnosed and treated to minimize permanent damage. The age at the time of surgery and congenital corneal opacities is factors associated with a higher risk of rejection and failure.

Resumen Introducción: La queratoplastia penetrante (QP) es un procedimiento quirúrgico indicado en algunos pacientes pediátricos con daño corneal con riesgo de fracaso que amenaza la visión. El objetivo del presente trabajo fue identificar los factores asociados a rechazo y fallo del injerto corneal en niños sometidos a QP. Métodos: Serie de casos de pacientes sometidos a QP en el Hospital Infantil de México Federico Gómez entre 2001 y 2015. La sobrevida del injerto fue calculada por el método de estimación de la función de supervivencia Kaplan–Meier. Resultados: Durante 15 años de estudio, 67 ojos de 57 pacientes fueron sometidos a QP. El promedio de edad de los pacientes al tiempo de la cirugía fue de 11 años. El seguimiento promedio fue de 44 meses. El queratocono fue la indicación más común de QP (61%), seguido de queratitis herpética (15%) y otras distrofias corneales (10%). El tiempo promedio de sobrevida fue 45.6% (intervalo de confianza [IC] 95%: 31.8-58.4 meses, desviación estándar [DS] = 0.069), con una tasa de sobrevida del 70% a 1 año. El riesgo proporcional de Cox univariado mostró que una edad < 9 años al momento de la cirugía (p = 0.023) y distrofias corneales (p = 0.04) son factores pronóstico para el rechazo corneal. Cinco ojos de cinco pacientes desarrollaron falla del injerto. Conclusiones: El rechazo del injerto en QP en pacientes pediátricos es común y puede ser resuelto satisfactoriamente en casi todos los casos con diagnóstico y tratamiento. La edad al momento de la cirugía y las opacidades corneales congénitas son factores asociados con el rechazo y fallo.

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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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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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IMPORTANCE: Fatal metastatic relapse may occur in children with retinoblastoma and high-risk pathologic features (HRPFs). Minimal dissemination (MD) may be an additional tool for risk estimation. The use of cone-rod homeobox (CRX) transcription factor messenger RNA for MD evaluation in metastatic retinoblastoma was previously reported, but no data in nonmetastatic cases with HRPFs are available. OBJECTIVES: To evaluate whether MD is detectable in patients with nonmetastatic retinoblastoma and to assess its prognostic effect on disease-free survival (DFS). DESIGN, SETTING, AND PARTICIPANTS: This single-institution cohort study of patients with nonmetastatic retinoblastoma and HRPFs used prospectively defined inclusion criteria and a sampling strategy to procure bone marrow (BM) and cerebrospinal fluid (CSF) samples from May 1, 2007, through October 31, 2013. Median follow-up was 38 months (range, 8-89 months). Survival analysis was closed in December 2015, and no further updates were made after that point. INTERVENTIONS: The study evaluated CRX messenger RNA by quantitative polymerase chain reaction in BM and CSF at diagnosis and follow-up. In 14 patients, GD2 synthase was used instead of CRX for CSF evaluation. Patients were treated under uniform guidelines. MAIN OUTCOMES AND MEASURES: Metastatic relapse. RESULTS: The study included 96 children (median age at study inclusion, 26 months; range, 1-168 months; 46 male [47.9%]; 50 female [52.1%]) with nonmetastatic retinoblastoma and HRPFs (isolated massive choroidal invasion in 14, postlaminar optic nerve invasion in 51 [26 with concomitant massive choroidal and 13 with scleral invasion], 12 with scleral invasion without postlaminar optic nerve invasion, and 7 with tumor at the resection margin of the optic nerve) were evaluated at the time of primary or secondary enucleation. Minimal dissemination was detected in 9 patients (7 BM samples and 2 CSF samples) and was associated with extension beyond the resection margin of the optic nerve and scleral involvement, but only the former was independently associated (adjusted odds ratio, 57.0; 95% CI, 4.8-678.2; P = .001). In addition, MD occurred in 8 of the 43 International Intraocular Retinoblastoma Classification group E eyes with glaucoma (18.6%) and in 8 of 80 (10%) and 1 of 16 children (6.3%) who underwent primary or secondary enucleation, respectively. Children with MD had a 3-year DFS of 0.78 compared with 0.98 in those without MD (95% CI for the difference in DFS, 0.17-0.23; P = .004). CONCLUSIONS AND RELEVANCE: These findings identified a high-risk population of children with retinoblastoma and HRPFs with MD. Because the number of events was small, these results, which suggest that children with International Intraocular Retinoblastoma Classification group E retinoblastoma and glaucoma have a higher risk of MD at diagnosis, should not be considered definitive at this time.

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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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To describe the characteristics of infants with bilateral Stage 4b or 5 ROP (i.e. with subtotal or total retinal detachment) who presented to eye departments in two major cities in Mexico, to identify reasons why they may have become blind in order to recommend how programs could be improved. A large case-series of infants with Stage 4b or 5 ROP in both eyes confirmed by ultrasound who attended the ROP Clinic, Hospital Civil de Guadalajara from September 2010 to November 2012, and the Department of Ophthalmology, Hospital Infantil de Mexico Federico Gomez from December 2011 to December 2012 were identified from the diagnostic databases of each hospital. Mothers of infants in Guadalajara had a telephone interview. 89/94 eligible infants were included in the study, 48 in Guadalajara and 41 in Mexico City. Cases came from 22 of the 32 states in Mexico. Half of the infants attending Guadalajara 24/48 (50 %) had been cared for in NICUs without ROP screening programs and were not examined. Among the 24 infants cared for in NICUs with ROP programs, 7/24 (29.1 %) mothers reported that their infant had not been examined while in the NICU, and a further 9/24 (37.5 %) were either not referred for screening after discharge or they did not attend. Two infants had failed laser treatment. Strategies and resources to prevent end stage ROP have not been firmly established in Mexico. There is an urgent need to expand the coverage and quality of ROP programs, to ensure that existing screening guidelines are better adhered to, and to improve communication with parents.

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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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El aumento en la sobrevida de los recién nacidos prematuros, las características del cuidado neonatal y la escasez de programas para la prevención, detección y tratamiento de la retinopatía del prematuro provocan que esta enfermedad sea la principal causa de ceguera infantil prevenible en México. El advenimiento de agentes antiangiogénicos de uso oncológico, y su uso -no autorizado, aunque con buenos resultados- en el tratamiento de enfermedades vaso proliferativas en la retina del paciente adulto, así como la presencia de reportes anecdóticos en la literatura y series de casos con serias fallas metodológicas han sugerido su utilización en el tratamiento de la retinopatía del prematuro. Desafortunadamente, estos agentes, utilizados indiscriminadamente, presentan absorción sistémica y causan efectos secundarios en el organismo del paciente prematuro. Además, no existen estudios de seguimiento a largo plazo que garanticen la seguridad de su uso en esta población. El presente artículo describe la situación en nuestro país y advierte sobre los riesgos de estos medicamentos en la población de pacientes prematuros.

The increase in survival rates among preterm infants, characteristics of neonatal care for such infants and a lack of suitable programs for preventing, detecting and treating retinopathy of prematurity (ROP) are factors that have made this disease the main cause of preventable blindness among children in Mexico. The advent of antiangiogenic agents in cancer treatment and their off-label use with favorable results in the treatment of proliferative vessel disease of the retina among adult patients, as well as anecdotal reports in the literature and a series of cases showing serious methodological flaws, have prompted their use in the treatment of retinopathy of prematurity. Unfortunately, these agents used indiscriminately in our country have a systemic absorption and secondary effects on the preterm patient's body. There are no long-term monitoring studies that guarantee their safe use in this segment of the population. This article describes the situation in our country and warns of the risks posed by the use of this type of drug on the preterm infant population.