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.

Micofenolato mofetilo como alternativa de tratamiento de la anemia hemolítica autoinmunitaria crónica corticodependiente / Mycophenolate mofetil: An alternative treatment for refractory autoimmune hemolytic anemia in children

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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)

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

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.

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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Translation of the recommendations for the diagnosis of diabetes mellitus into daily clinical practice in a primary health care setting.

AIMS: to assess the implementation of 1985 recommendations for the diagnosis of diabetes (World Health Organization [WHO]) in a primary care setting, and the physician's attitude toward the diagnosis of diabetes mellitus (DM). MATERIAL AND METHODS: Subjects with a fasting plasma glucose (FPG)>6.1 mmol/l (> or =110 mg/dl) and with previously unknown glucose tolerance status were identified retrospectively in a primary health care center during a 45-month period. The following variables were evaluated: anthropometric parameters, fasting plasma glucose and oral glucose tolerance test (OGTT) values, registration of a diagnosis of diabetes in clinical records, smoking status, lipid profile and blood pressure. RESULTS: 1181 subjects with a FPG>6.1 mmol/l were identified (target population): 171 with a FPG>7.8 mmol/l and 1010 with a FPG between 6.1 and 7.7 mmol/l. In the latter group, an OGTT was performed in 553 subjects (54.8%) (173 yielded a diagnosis of diabetes). During the study period, diabetes was diagnosed in 29.1% (n=344) of the target population. Following the 1985 WHO recommendations, a confirmatory diagnostic test was repeated in 92 (69.7%) subjects with a FPG between 7.8 and 11.0 mmol/l, and in 132 subjects (23.87%) who had already received an initial OGTT. The analysis of the diagnostic process followed by the different physicians revealed a high interindividual variability in terms of: proportion of cases diagnosed as diabetes by an OGTT (from 35.7 to 65.2), percentage of subjects with a FPG 6.1-7.7 mmol/l without an OGTT (7.33-70.27%), proportion of confirmatory OGTTs (0-57.89%), and percentage of misdiagnosed cases (1.16-6.34%). The percentage of subjects misdiagnosed was negatively correlated with the proportion of OGTT repetitions. CONCLUSIONS: 1985 WHO recommendations for the diagnosis of diabetes are only partially followed at a primary health care level. There is a high interindividual variability among physicians in the implementation of these recommendations that is associated with the misdiagnosis of diabetes.

Estudio diana. Depresión con insomnio y ansiedad: nueva aproximación / DIANA study. Depression with Insomnia and Anxiety: New Approach

El estudio DIANA (Depresión con Insomnio y Ansiedad: Nueva Aproximación) es un estudio multicéntrico, observacional, abierto, no controlado, de fase IV y diseñado con el objetivo principal de evaluar la eficacia de mirtazapina en el control de la ansiedad asociada a la depresión. De forma secundaria, se recogió la eficacia de mirtazapina en los trastornos del sueño también asociados a la depresión, así como la tolerabilidad del fármaco.La población sujeta a estudio estuvo constituida por pacientes ambulatorios diagnosticados de depresión con un grado importante de ansiedad asociada. Se recogió a un total de 891 pacientes, de los que se incluyeron los análisis presentados a 885, realizándose evaluaciones en los días 0, 14 y 28 mediante la escala de Hamilton de depresión de 17 ítems (HAMD17), la escala de Hamilton de ansiedad (HAS) y la escala de Impresión Clínica Global (ICG).El análisis de eficacia puso de manifiesto una reducción significativa (p < 0,001) de la escala de Hamilton para la depresión desde el primer control (media inicial, 21,69; media final, 8,58), así como una reducción significativa de la HAS (p < 0,001) desde su primer control (media inicial, 23,38; media final, 8,82), también es evidente al analizar los cambios en la escala ICG y los porcentajes de las reducciones superiores al 50 por ciento de la puntuación basal de la HAS.La seguridad y la tolerancia observadas fueron muy favorables, mejor que las encontradas en otros estudios.En nuestra muestra, representativa por su tamaño y características de la población general de pacientes depresivos y con ansiedad de nuestro país, la mirtazapina ha evidenciado su eficacia en el tratamiento de la ansiedad asociada a la depresión, e incluso en el subanálisis que se ha realizado comparando dos grupos de tratamiento distintos, mirtazapina ha demostrado una eficacia totalmente equiparable a las benzodiazepinas en el tratamiento de la ansiedad (AU)

Fluvastatin and low-density lipoprotein oxidation in hypercholesterolemic renal transplant patients.

BACKGROUND: Hyperlipidemia contributes to the development and progression of vascular disease in organ transplant patients. Oxidative modification of low-density lipoproteins (LDLs) has been suggested as a key event in early atherogenesis. METHODS: We conducted a pilot study in renal transplanted patients with persistent hypercholesterolemia above 6.5 mmol/liter. We studied the LDL oxidation before and after one year of fluvastatin treatment. Twenty patients (12 males and 8 females, 46 +/- 10 years old) who received a kidney transplant 24 +/- 18 months before the study were treated with fluvastatin (20 mg/day for 12 weeks). Patients with a total cholesterol under 6.3 mmol/liter continued to receive 20 mg/day for another 40 weeks (group I, N = 10). Nine patients with a total cholesterol above 6.3 mmol/liter received 40 mg/day for a further 40 weeks (group II). RESULTS: Cyclosporine levels did not experience a significant variation. Total and LDL cholesterol decreased significantly in both groups (21.7 and 27.9% in group I, 18.3 and 27.2% in group II, respectively). The lag-phase time, which was significantly enlarged before fluvastatin treatment in the patients with respect to the controls (N = 18, 82 +/- 45 vs. 50 +/- 8 min) was shortened after one year of fluvastatin treatment (64 +/- 24 vs. 50 +/- 8 min, P = 0.04). Fluvastatin was stopped in only one patient because of nausea and vomiting. Transaminases and creatin-phospho-kinase were not altered. All of the patients maintained a functioning graft during the study period. CONCLUSIONS: Fluvastatin significantly reduced total and LDL cholesterol, without interferences with cyclosporine A through levels. Fluvastatin has not demonstrated an antioxidant effect in our renal hypercholesterolemic transplant patients.

[Hypovitaminosis D: its high prevalence in elderly outpatients in Barcelona. Associated factors]. / Hipovitaminosis D: alta prevalencia en ancianos de Barcelona atendidos ambulatoriamente. Factores asociados.

BACKGROUND: Hypovitaminosis D is a frequent finding in the elderly of northern countries. In Spain because of high sun irradiation it has been traditionally considered that hypovitaminosis D is not a frequent problem. In this study we have evaluated the prevalence of hypovitaminosis D in the elderly and the associated factors. SUBJECTS AND METHODS: All individuals older than 65 years attending a primary care unit (november 1995-march 1996) and without any disease modifying vitamin D status were included. The following data were recorded: age, gender, height, weight, white and red cell counts, glycaemia, serum ions, albuminemia, plasma creatinine, creatinine clearance, urinary creatinine and calcium, parathyroid hormone (PTHi), calcidiol and calcitriol. Sun exposure and fish ingestion was also determined by questionnaire. RESULTS: 127 individuals were evaluated (age: mean [SD] 74.8 [6.4] years; 47 men, 37.0%). Forty-four subjects (34.6%; CI 95%: 26.3-42.9%) had calcidiol levels < or = 10 ng/ml, 15 (11.8%; CI 95%: 6.2-17.4%) low values of calcidiol, and 13 (10.2%; CI 95%: 4.9-15.5%) high PTHi values. Subjects with hypovitaminosis D (calcidiol levels < or = 10 ng/ml) were mainly women, older, short stature, had a lower values of body surface, albuminemia, phosphatemia, creatinine clearance, sun exposure and fish intake and higher PTHi levels. In the logistic regression model, hypovitaminosis D was positively associated with age and negatively with sun exposure, albuminemia, height and phosphoremia. CONCLUSIONS: Hypovitaminosis D is a very frequent finding in Spanish elderly people. Its presence is independently associated with age (positively) and sun exposure, serum albumin, height and phosphoremia (negatively).

Soluble extracts from a lymphoblastoid cell line modulate simian immunodeficiency syndrome (SAIDS) evolution.

Nineteen Macaca fascicularis monkeys were injected with SIV. They were subsequently divided into 5 groups. Four groups of 4 animals were injected with dialysable extracts (DLE) from a lymphoblastoid cell line which had been previously induced with DLE obtained either from the total lymphocyte population, or from the CD4 or CD8 subpopulations of mice immunized with SIV virus. The other three animals which constituted the control group received saline injections. The animals were kept under observation for a 108-day period, and the values of several biological parameters were compared in a multivariant statistical analysis. On the 108th day, the control group was significantly different from the other groups in the multivariant analysis. Furthermore, the CD4/CD8 ratio and the platelets and CD4 cell counts varied significantly between the groups in the univariant analysis. It is thus surmised that DLE obtained from CD8 cells or the total lymphocyte population of immunized animals may exert a modulating effect on the evolution of SAIDS.