Neuroblastoma: validation of the INRG classification system in a small series.

PURPOSE: In 2009, the International Neuroblastoma Risk Group (INRG) published a new classification system of the childhood neuroblastic tumors. In this work, we present the results of the application of this new classification system in our patients. METHODS/PATIENTS: We conducted a retrospective analysis of the patients diagnosed with a neuroblastic tumor in our center in the last 20 years. We classified them according to the new classification and performed a survival analysis based on the Kaplan-Meier method and Mantel-Cox test. RESULTS: The five-year event-free survival (5-year EFS) was 95.8, 80.8, 50 and 45.9% for the very low, low, intermediate and high-risk groups. Mantel-Cox test showed statistically significant differences between these risk groups (p = 0.002). CONCLUSION: The 5-year EFS for the different risk groups was similar to the expected by the INRG. Therefore, this classification allows us to predict the evolution of this tumor and apply the correct intensity of treatment.

Análisis en áreas pequeñas del cáncer pediátrico en el municipio de Murcia / Analysis of small areas of pediatric cancer in the municipality of Murcia (Spain)

INTRODUCCIÓN: Ocasionalmente, los pediatras, sobre todo los de Atención Primaria, alertan de la presencia de pequeños agrupamientos de casos de cáncer pediátrico (CP) y con frecuencia sus expectativas se ven frustradas al aplicar los métodos estadísticos. El estudio de áreas pequeñas en epidemiología espacial ha permitido realizar algunos avances en la identificación de clústeres y de los factores de riesgo medioambientales implicados. El objetivo de este trabajo es describir la incidencia del CP y la distribución espacial a nivel de sección censal, así como presentar el primer mapa urbano municipal de CP de España. MATERIAL Y MÉTODOS: Estudio descriptivo de base poblacional, por sexo, grupos de edad, subperiodos y tipo tumoral de los casos de CP diagnosticados en menores de 15 años, entre 1998 y 2013 en el municipio de Murcia. Georreferenciación de casos en el momento del diagnóstico y análisis de clústeres espaciales y espacio-temporales a nivel de sección censal mediante los estadísticos FleXScan y SatScan. RESULTADOS: Un total de 155 casos fueron diagnosticados. La incidencia global (138 por millón de niños menores de 15 años) y por tipos tumorales está dentro de los márgenes de referencia del área europea. Identificación de un clúster espacio-temporal de linfomas de Hodgkin. CONCLUSIONES: El análisis de áreas pequeñas de los casos diagnosticados de CP es una herramienta útil para identificar clústeres de casos que permita plantear hipótesis sobre las causas que originan la enfermedad y desarrollar modelos urbanos de vigilancia ambiental del cáncer infantil

INTRODUCTION: Occasionally, primary care pediatricians notice the presence of small clusters of pediatric cancer (PC), but are often frustrated by the findings after statistical analysis. The study of small areas in spatial epidemiology has led to advances in identifying clusters and the environmental risk factors involved. The purpose of this study was to describe the PC incidence and the spatial distribution at the minimum level of disaggregation possible in Murcia, presenting the first urban municipality map of PC in Spain. MATERIALS AND METHODS: A population-based descriptive study was conducted on the PC cases diagnosed in children younger than 15 years, between 1998 and 2013 in the municipality of Murcia. Cases were classified by sex, age group, and tumor type. Coordinates of home addresses at the time of diagnosis were assigned to each case, and spatial and spatio-temporal analyses were carried out at the level of census tracts, using FleXScan and SatScan. RESULTS: A total of 155 cases of PC were diagnosed during this period. The overall incidence of PC (138/106 of children under the age of 15) and the incidence for individual tumor types were within the expected ranges for Europe. A spatio-temporal cluster of Hodgkin lymphoma was identified. CONCLUSIONS: Small area analysis of PC cases may be a useful tool for the identification of PC clusters, which would allow for the generation of hypotheses regarding disease etiology, as well as developing urban models for environmental surveillance of PC

[Analysis of small areas of pediatric cancer in the municipality of Murcia (Spain)]. / Análisis en áreas pequeñas del cáncer pediátrico en el municipio de Murcia.

INTRODUCTION: Occasionally, primary care pediatricians notice the presence of small clusters of pediatric cancer (PC), but are often frustrated by the findings after statistical analysis. The study of small areas in spatial epidemiology has led to advances in identifying clusters and the environmental risk factors involved. The purpose of this study was to describe the PC incidence and the spatial distribution at the minimum level of disaggregation possible in Murcia, presenting the first urban municipality map of PC in Spain. MATERIALS AND METHODS: A population-based descriptive study was conducted on the PC cases diagnosed in children younger than 15 years, between 1998 and 2013 in the municipality of Murcia. Cases were classified by sex, age group, and tumor type. Coordinates of home addresses at the time of diagnosis were assigned to each case, and spatial and spatio-temporal analyses were carried out at the level of census tracts, using FleXScan and SatScan. RESULTS: A total of 155 cases of PC were diagnosed during this period. The overall incidence of PC (138/10(6) of children under the age of 15) and the incidence for individual tumor types were within the expected ranges for Europe. A spatio-temporal cluster of Hodgkin lymphoma was identified. CONCLUSIONS: Small area analysis of PC cases may be a useful tool for the identification of PC clusters, which would allow for the generation of hypotheses regarding disease etiology, as well as developing urban models for environmental surveillance of PC.

Programa de largo seguimiento de supervivientes de cáncer pediátrico en la Región de Murcia: preferencias y actitudes de los profesionales de Atención Primaria / Long-term follow up of childhood cancer survivors in the Murcia Region: preferences and attitudes of Primary Care professionals

OBJETIVO: Evaluar actitudes, creencias y conocimientos de los profesionales médicos de Atención Primaria acerca del seguimiento de los supervivientes de cáncer pediátrico (SCP) y divulgar el Programa de Largo Seguimiento de Supervivientes de Cáncer Pediátrico en la Región de Murcia (PLASESCAP-MUR). MATERIAL Y MÉTODOS: Estudio transversal descriptivo mediante cuestionario estructurado y autocumplimentado. Se enviaron cuestionarios a todos los profesionales médicos de Atención Primaria del Área de Salud 1 del Servicio Murciano de Salud. RESULTADOS: Tasa de respuesta del 58% (100/172). El 71 y el 22% eran médicos de familia y pediatras, respectivamente. El 49% atendió algún SCP en los últimos 5 años. El 84% refiere que nunca o pocas veces recibió un informe detallado de evaluación global del superviviente. Más del 75% encuentran bastante o muy útiles el acceso a información detallada de largo seguimiento. El 95% prefiere atender a los supervivientes conjuntamente con consulta de largo seguimiento. Un 80% considera que mejorando la calidad ambiental del entorno podría disminuir la morbimortalidad de los supervivientes. Se encontró una relación estadísticamente significativa entre años practicando medicina y percepción de importancia de algunos factores medioambientales. CONCLUSIONES: Para el largo seguimiento de los SCP parece importante aumentar la capacitación de los profesionales sanitarios de Atención Primaria y la información detallada a través de un plan personalizado de largo seguimiento de cada superviviente. PLASESCAP-MUR proporciona un seguimiento integrativo a los supervivientes de cáncer pediátrico en un modelo de atención compartida entre la Unidad de Largo Seguimiento y Atención Primaria

OBJECTIVE: To assess attitudes, beliefs and knowledge of primary medical care professionals as regards the follow-up of Childhood Cancer Survivors (CCS) and the introduction of a Long-Term Follow-Up Program for Childhood Cancer Survivors in the Region of Murcia (PLASESCAP-MUR). MATERIAL AND METHODS: Descriptive cross-sectional study using a structured, self-administered questionnaire. These questionnaires were sent to all primary medical care professionals in Murcia Health District 1. RESULTS: Response rate of 58% (100/172), with 71% and 22% being family physicians and pediatricians, respectively, of whom 49% provided medical care to a CCS in the last 5 years, with 84% reporting that they never or rarely received a detailed report of overall assessment of the survivor. More than 75% found that access to detailed follow-up information was quite or very useful; 95% prefer to consult experts when providing medical care to survivors, and 80% believe that improving the quality of the environment may decrease the morbidity and mortality of the survivors. A statistically significant relationship was found between the length of practicing medicine and the perception of the importance of environmental factors. CONCLUSIONS: It seems to be important to increase the training of primary care professionals for the long-term follow-up of CCS, as well as having the detailed information through a personalized long-term follow-up of each survivor. PLASESCAP-MUR offers an integrated follow-up to CCS in a model of shared care between Long Term Monitoring Units and Primary Care Units

[Long-term follow up of childhood cancer survivors in the Murcia Region: preferences and attitudes of Primary Care professionals]. / Programa de largo seguimiento de supervivientes de cáncer pediátrico en la Región de Murcia: preferencias y actitudes de los profesionales de Atención Primaria.

OBJECTIVE: To assess attitudes, beliefs and knowledge of primary medical care professionals as regards the follow-up of Childhood Cancer Survivors (CCS) and the introduction of a Long-Term Follow-Up Program for Childhood Cancer Survivors in the Region of Murcia (PLASESCAP-MUR). MATERIAL AND METHODS: Descriptive cross-sectional study using a structured, self-administered questionnaire. These questionnaires were sent to all primary medical care professionals in Murcia Health District 1. RESULTS: Response rate of 58% (100/172), with 71% and 22% being family physicians and pediatricians, respectively, of whom 49% provided medical care to a CCS in the last 5 years, with 84% reporting that they never or rarely received a detailed report of overall assessment of the survivor. More than 75% found that access to detailed follow-up information was quite or very useful; 95% prefer to consult experts when providing medical care to survivors, and 80% believe that improving the quality of the environment may decrease the morbidity and mortality of the survivors. A statistically significant relationship was found between the length of practicing medicine and the perception of the importance of environmental factors. CONCLUSIONS: It seems to be important to increase the training of primary care professionals for the long-term follow-up of CCS, as well as having the detailed information through a personalized long-term follow-up of each survivor. PLASESCAP-MUR offers an integrated follow-up to CCS in a model of shared care between Long Term Monitoring Units and Primary Care Units.

Los trastornos de la secreción lisosomal en la sinapsis inmune y otros tejidos / Secretory lysosome disorders in the immune synapse and other tissues

Introducción: El síndrome hemofagocítico (SH) constituye una manifestación común a una serie de anomalías congénitas que afectan a la excreción lisosomal, interrumpiendo la vía citolítica gránulodependiente y desencadenando una disfunción de la sinapsis inmunológica. La presencia de manifestaciones características en otros tejidos puede orientar el diagnóstico etiológico. Pacientes y métodos: Presentamos los hallazgos clínicos y biológicos de dos hermanos diagnosticados de linfohistiocitosis hemofagocítica familiar tipo 3 (FHL-3), dos pacientes con síndrome de Griscelli tipo 2 (GS-2), y un síndrome de Chédiak-Higashi (CHS). Resultados: Los pacientes de FHL-3 aportaron un resultado positivo en el estudio mutacional de UNC13D indicado por un SH precoz en el primero de ellos. El primer diagnóstico de SG-2 se confirmó por la presencia de una mutación en el gen Rab27A en una paciente con SH en la que había un llamativo trastorno de la pigmentación. La misma mutación se detectó en una prima afecta también de trastornos de la pigmentación. El diagnóstico de SCH se realizó en un paciente que presentaba un SH con trastornos de la pigmentación y granulación atípica en células hematopoyéticas. El hallazgo de una mutación en el gen LYST confirmó el diagnóstico. Conclusiones: En los pacientes con SH primario es preciso atender a manifestaciones extra-inmunológicas características de ciertos trastornos de la secreción lisosomal. La curiosa relación entre albinismo e inmunidad ha jugado recientemente un papel decisivo en la identificación de los mecanismos moleculares involucrados en estos procesos(AU)

Introduction: Haemophagocytic syndrome (HS) is a common manifestation of several congenital disorders characterised by a disruption of lysosomal secretion, interrupting the cytolytic pathway and triggering a dysfunction in the immune synapse. In this situation, the recognition of certain extra-immunological manifestations may help in the diagnostic process. Patients and methods: We describe the clinical and biological features present in two brothers with familial haemophagocytic lymphohistiocytosis type 3 (FHL-3), two patients with Griscelli syndrome type 2 (GS-2) and one patient with Chédiak-Higashi syndrome (CHS). Results: Mutational assays at UNC13D were carried out on two brothers after diagnosing an early onset HS in the first one, yielding a positive result in both cases with a consequent diagnosis of FHL-3. The diagnosis of GS-2 was supported by positive results of mutational Rab27A studies in one patient with HS and abnormal pigmentation, and in her cousin who was affected by a similar abnormal pigmentation. The diagnosis of CHS was established in one patient with HS, abnormal pigmentation and atypical granules on cytological examination of a bone marrow smear. Diagnosis was confirmed in this patient by the finding of a homozygous LYST mutation. Conclusions: We point out the importance of recognising the presence of typical extra-immunological manifestations of certain congenital disorders of lysosome secretion in patients diagnosed with HS. The association of albinism and immunodeficiency has played a critical role in the recent identification of the molecular mechanism involved in these disorders(AU)

Análisis de GATA1 en los trastornos mieloproliferativos asociados a la trisomía 21 / GATA1 analysis in myeloproliferative disorders associated to trisomy 21

Introducción: La enfermedad mieloproliferativa transitoria neonatal y la leucemia aguda megacarioblástica del síndrome de Down se consideran manifestaciones distintas de la misma enfermedad. La mayoría de casos de enfermedad mieloproliferativa transitoria no requiere tratamiento mientras que la leucemia aguda megacarioblástica del síndrome de Down se caracteriza por una elevada sensibilidad a la quimioterapia, lo que ha llevado a la reducción en la intensidad de dosis de tratamiento administrada. Ambas entidades comparten mutaciones específicas en los exones 2 y 3,1 del factor de transcripción GATA1. Pacientes y métodos: Hemos analizado los hallazgos biológicos incluyendo la presencia de mutaciones de GATA1 en cuatro pacientes con enfermedad mieloproliferativa transitoria neonatal (2) y leucemia aguda megacarioblástica (2) incluyendo un paciente fenotípicamente normal portador de un mosaicismo para la trisomía 21. Resultados: En los cuatro casos hemos encontrado la presencia de una clona GATA1 mutante y en tres de ellos se describe una mutación puntual en el exón 2 de dicho gen. Dada la heterogeneidad fenotípica de los blastos megacariocíticos y el bajo porcentaje de estos elementos, la detección de mutaciones en GATA1 resultó de gran utilidad para establecer el diagnóstico. Además, sucesivos resultados normales del análisis mutacional de GATA1 permitieron establecer la remisión molecular en 2 pacientes. Conclusiones: Concluimos que el análisis mutacional de GATA1 es una herramienta útil para el diagnóstico y manejo de los trastornos mieloproliferativos asociados a la trisomía 21 (AU)

Introduction: Neonatal transient myeloproliferative disorder and acute megakaryoblastic leukaemia of Down syndrome are considered different manifestations of the same disease. In most cases, transient myeloproliferative disorders require no treatment, while acute megakaryoblastic leukaemia of Down's syndrome is characterised by an increased sensitivity to chemotherapy and its treatment should be adapted with a reduction in dose intensity. Both entities share specific mutations at exón 2 of the transcription factor GATA1. Patients and methods: We analysed biological features and GATA1 mutations in 4 patients with transient abnormal myelopoiesis (2) and acute megakaryoblastic leukaemia (2) including one phenotypically normal trisomy 21 mosaicism. We found abnormal GATA1 mutated clones in each case, and a specific point mutation at exón 2 was detected in three cases. Given the heterogeneous phenotype of megakaryoblastic blasts and the low percentage of blasts at presentation, the recognition of GATA1 mutations was helpful for diagnosis. In addition, molecular remission was established in 2 patients after subsequent normal mutational GATA1 analysis. Conclusions: We conclude that GATA1 mutational study is a useful tool for the diagnosis and management of trisomy 21 associated myeloproliferative disorders (AU)

[GATA1 analysis in myeloproliferative disorders associated to trisomy 21]. / Análisis de GATA1 en los trastornos mieloproliferativos asociados a la trisomía 21.

INTRODUCTION: Neonatal transient myeloproliferative disorder and acute megakaryoblastic leukaemia of Down syndrome are considered different manifestations of the same disease. In most cases, transient myeloproliferative disorders require no treatment, while acute megakaryoblastic leukaemia of Down's syndrome is characterised by an increased sensitivity to chemotherapy and its treatment should be adapted with a reduction in dose intensity. Both entities share specific mutations at exón 2 of the transcription factor GATA1. PATIENTS AND METHODS: We analysed biological features and GATA1 mutations in 4 patients with transient abnormal myelopoiesis (2) and acute megakaryoblastic leukaemia (2) including one phenotypically normal trisomy 21 mosaicism. We found abnormal GATA1 mutated clones in each case, and a specific point mutation at exón 2 was detected in three cases. Given the heterogeneous phenotype of megakaryoblastic blasts and the low percentage of blasts at presentation, the recognition of GATA1 mutations was helpful for diagnosis. In addition, molecular remission was established in 2 patients after subsequent normal mutational GATA1 analysis. CONCLUSIONS: We conclude that GATA1 mutational study is a useful tool for the diagnosis and management of trisomy 21 associated myeloproliferative disorders.

Síndrome nefrótico y linfoma de Hodgkin: una asociación infrecuente / Nephrotic syndrome and Hodgkin’s disease, a rare association

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Seudotrombocitopenia dependiente de EDTA / EDTA-dependent pseudothrombocytopenia

Introducción. La seudotrombocitopenia dependiente de etilendiaminotetracetato (EDTA) es un fenómeno conocido consistente en la formación de agregados de plaquetas in vitro en muestras de sangre anticoaguladas con EDTA y que puede conducir a diagnósticos erróneos de trombocitopenia. Es poco frecuente entre la población pediátrica y carece de significación patológica. Su correcta identificación puede evitar estudios innecesarios y tratamientos potencialmente peligrosos. Caso clínico. Niña de 10 años que ingresó en nuestro centro para estudio de trombopenia sin episodios previos ni clínica actual sugestiva de diátesis hemorrágica. El recuento de plaquetas fue de 31 x 109/L. En el examen microscópico de la sangre se observaron frecuentes agregados plaquetarios. Al realizar un hemograma de una muestra anticoagulada con heparina se evidenció un recuento de plaquetas normal, emitiéndose el diagnóstico de seudotrombocitopenia dependiente de EDTA. Discusión. La mayoría de casos de seudotrombopenia dependiente de EDTA obedecen a aglutininas de tipo IgM o IgG con máxima actividad entre 4 y 20 °C. Se desconoce el mecanismo íntimo de interacción con las plaquetas, pero se supone que en presencia de EDTA ocurre un cambio conformacional de la superficie plaquetaria que induce la exposición de un neoantíngeno al que se unirían las aglutininas (AU)

[Central nervous system tumors in children less than three years of age]. / Tumores de sistema nervioso central en niños menores de 3 años.

OBJECTIVE: Central nervous system (CNS) tumors are the most frequent solid tumors in children. Twelve to twenty percent are diagnosed in patients younger than two years of age and these patient present more morbidity and mortality due to the illness and the treatment itself. PATIENTS AND METHODS: A retrospective study of CNS tumors in children younger than three years of age diagnosed in our hospital between 1985 and 1995 was carried out. RESULTS: We treated 21 patients between 1985 and 1995. There were 10 male and 11 females. The mean age was 20.3 months (range: 0-32 months). The mean time between symptoms and treatment was 2.4 months (range: 0-18 months). The most common symptoms included ataxia, nausea and vomits. The most common locations of the tumor were: infratentorial (57.1%) and supratentorial (38.1%). Complete surgery was performed in 3 patients, subtotal in 10, partial in 5, and a biopsy in 2. The anatomical-pathological diagnosis was: astrocytoma (6), ependinoma (5), meduloblastoma (4), ganglioglioma (1), neuroblastoma (1), and primitive neuroectodermic tumor (1). We could not document the histology in 3 patients. Ten patients received chemotherapy that was well tolerated and 14 received radiotherapy whose sequels were updated. The mean follow-up period was 44.42 months (range: 0-136 months). Overall survival was 42.86%. There were no statistically significant differences in survival between those who were irradiated and those who were not, nor between those with supra-or infratentorial tumors. CONCLUSIONS: CNS tumors in children younger than three years of age have a worse prognosis than in older children. New therapeutic schedule with chemotherapy are being tested to avoid radiotherapy side-effects.

[Down's syndrome and leukemia]. / Síndrome de Down y leucemia.

OBJECTIVE: Children with Down's Syndrome (DS) have a high risk for leukemia and need special clinical management. For this reason we have reviewed our experience. PATIENTS AND METHODS: All children with DS diagnosed a having acute leukemia during a 21-year period were reviewed retrospectively. Treatment was administered according to current protocols in our unit at the time of diagnosis without any initial modification. RESULTS: There were 13 children with DS and acute leukemia [6 ALL, 4 AML and 3 transient leukemias (TL)]. No patient presented CNS leukemia at diagnosis. All children with AML and DS were under three years of age and standard treatments did not achieve satisfactory results. TL regressed in two newborns without developing AMKL later. Five out of six patients with DS and ALL achieved complete remission. Currently, 4 of these children are alive and off therapy. Toxicities related to treatment were observed in almost all of the patients. CONCLUSIONS: Children with DS suffer a higher risk of developing leukemia. They should receive standard protocols, but aggressive supportive care might be provided as they have a higher incidence of treatment related toxicities. Prognosis of these children is similar or even better in some cases than children without DS. TL is a true neoplastic process capable of spontaneous remission and it can progress to AMKL.

[Surgical treatment of pediatric pulmonary metastases]. / Tratamiento quirúrgico de las metástasis pulmonares pediátricas.

OBJECTIVE: We comment and update the surgical treatment for pulmonary metastases (PM) within a multidisciplinary approach for paediatric cancer. MATERIAL AND METHODS: We analyse patients with PM who have been operated between 1976-1996. Scientific literature published in the last 25 years (Cancerlit and Medline) was reviewed. RESULTS: PM from 13 patients were removed. Seven were males and 6 females with a mean age 5 4/12 years (range: 11 months- 12 3/12 years). Diagnoses were Wilms' tumour (7), osteosarcoma (3), Ewing sarcoma (1), rabdomiosarcoma (1), Yolk sac tumour (1). PM were unilateral in 7 cases and bilateral in six cases. PM appeared synchronically in four patients and metacronically in nine cases (3 of these after chemotherapy). All patients received chemotherapy and four of them local radiotherapy. Surgery consisted on radical segmentectomy and only one patient needed lobectomy due to a local relapse. Nowadays five patients (38%) are in complete remission with a mean follow-up from surgery of 11 11/12 years (range: 6 3/12-20 years). CONCLUSIONS: Metastasectomy is an important surgical technique in global treatment of children with PM and for a selected group of patients it can offer the only opportunity for curation.