Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood.

Background: Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time. Material and methods: Multicenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020). Results: Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3-18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2-24 years]. Six patients died, the median age was 13 years [range, 6-24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6-32 years]. None of them have developed myeloblastic syndrome or cancer. Conclusions: DC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.

Post-hematopoietic stem cell transplant squamous cell carcinoma in patients with Fanconi anemia: a dreadful enemy.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with Fanconi anemia (FA) and hematological manifestations but it does not prevent solid tumors, especially squamous cell carcinomas (SCC). METHODS: Retrospective study in 22 FA patients who had received HSCT and had been followed up beyond 2 years after HSCT. RESULTS: The median follow-up was 15 years. Six patients developed head-and-neck SCC after transplantation. The cumulative incidence of SCC at 15 and 30 years from the HSCT was 14.2% and 71.2%, respectively. One patient was diagnosed in stage IV and the rest, who were being followed up in cancer screening programs, in stage I. Treatment of SCC consisted of surgery in all patients; radiotherapy and chemotherapy were used in two patients and were poorly tolerated. CONCLUSION: FA patients have high risk of head-and-neck SCC. Multi-disciplinary programs for early cancer detection are of special relevance in these patients.

Survival and toxicity outcomes of hematopoietic stem cell transplantation for pediatric patients with Fanconi anemia: a unified multicentric national study from the Spanish Working Group for Bone Marrow Transplantation in Children.

Hematopoietic stem cell transplantation (HSCT) is currently the only curative option for hematological manifestations in patients with Fanconi anemia (FA). We report the outcome of 34 patients with FA inside a collaborative multicenter national study based on recommendations of Spanish Working Group for Bone Marrow Transplantation in Children (GETMON) between 2009 and 2016. Fludarabine-based conditioning regimen was carried out in all patients, with low dose total body irradiation in unrelated transplants. Disease status before HSCT was bone marrow failure (BMF) in 30 patients and myelodysplastic syndrome (MDS) in four. Donors were matched siblings donors (MSD) in 18, matched unrelated donors (MUD) in 15, and one haploidentical donor. All except one patient engrafted. Cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) was 29% and 11% for chronic GVHD. Median follow-up after HSCT was 6.5 years. Seven patients (21%) died due to transplant-related causes, two (6%) because of MDS relapse, and one (3%) after a squamous cell carcinoma. Overall survival (OS) was 73% at 5 years post-transplant, with no differences between MSD and MUD transplants. OS for patients with BMF was 80% while for MDS was 25%. Our data suggest HSCT can cure hematologic manifestations of most FA patients with BMF.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.

INTRODUCTION: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. METHODS: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. RESULTS: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. CONCLUSIONS: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Landscape of early clinical trials for childhood and adolescence cancer in Spain

Purpose: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. Methods: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. Results: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. Conclusions: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer (AU)

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Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Análisis de la supervivencia de los niños con inmunodeficiencias primarias que han recibido un trasplante de progenitores hematopoyéticos en Espana / Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain

INTRODUCCIÓN: Los niños afectados de inmunodeficiencias primarias presentan infecciones graves y mayor prevalencia de manifestaciones autoinmunitarias, alergias y enfermedad linfoproliferativa. El trasplante alogénico de precursores hematopoyéticos ha sido el único tratamiento curativo durante décadas. PACIENTES Y MÉTODOS: Pacientes con inmunodeficiencias primarias que recibieron trasplante alogénico de precursores hematopoyéticos desde 1985 hasta 2011, recogidos en el Registro Nacional del Grupo Español para Trasplante de Médula Ósea en Niños. RESULTADOS: Ciento cincuenta y nueve niños recibieron un total de 173 trasplantes, 97 por inmunodeficiencia combinada grave, 30 por enfermedades de disregulación inmunitaria, 25 por síndrome de Wiskott-Aldrich y 21 por defectos de número y/o función de los fagocitos. La mediana de edad al diagnóstico fue de 6 meses (17 días-168 meses) y de 12 meses (1 mes-189 meses) al trasplante. Los donantes fueron hermano HLA idéntico en 30 (19%), donante familiar alternativo en 40 (25%) y donante no emparentado en 89 (56%). La fuente de progenitores fue médula ósea en 68 (43%), sangre de cordón umbilical en 52 (33%) y sangre periférica en 39 (24%). Permanecen vivos 98 niños (61,6%), 57 (35,9%) fallecieron. La supervivencia libre de enfermedad a los 10 años fue del 63, el 90% para los pacientes trasplantados de hermano HLA idéntico, el 36% para los trasplantados de un donante familiar alternativo y el 66 para los trasplantados de donante no emparentado

INTRODUCTION: Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option. PATIENTS AND METHODS: Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children. RESULTS: One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors. CONCLUSIONS: The best results have been obtained with identical siblings, but other options may be considered

[Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain]. / Análisis de la supervivencia de los niños con inmunodeficiencias primarias que han recibido un trasplante de progenitores hematopoyéticos en España.

INTRODUCTION: Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option. PATIENTS AND METHODS: Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children. RESULTS: One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors. CONCLUSIONS: The best results have been obtained with identical siblings, but other options may be considered.

Long-term outcome and prognostic factors of unrelated cord blood transplantation in children with haematological malignancies: a retrospective study using the Spanish Working Party for BMT in Children (GETMON) database.

Outcomes of unrelated cord blood transplants (UCBT) were assessed in 172 consecutive children, median age 5 years (range: 0.5-18), with haematological malignancies treated at nine Spanish hospitals between February 1996 and April 2009. Data were collected from the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) database. ALL was diagnosed in 125 patients, AML in 43 and myelodysplastic syndrome in 4. Myeloid engraftment (ANC⩾0.5 × 10(9)/L) occurred in 87.2% at a median of 22 days and was associated with the total nucleated cell (TNC) dose infused and use of a TT-containing conditioning regimen. Cumulative incidence of relapse was 20% at 1 year post transplant and 29% at 3 years, being higher in patients with a diagnosis of ALL, very high risk disease and GVHD grades 0-1. Cumulative incidence of non-relapse mortality (NRM) was 19% at 100 days post transplant and 39% at 1 year. BU-FLU-TT-ATG-conditioned patients had lower NRM. Disease-free survival (DFS) was 40% at 2 years post transplant (for patients transplanted since 2006). On multivariate analysis, TNC dose infused, AML and BU-FLU-TT-ATG-conditioning regimen increased the probability of DFS. It is of paramount importance to select cord blood units with the highest cell dose. As the BU-FLU-TT-ATG-conditioning regimen was associated with better DFS owing to lower NRM, further prospective studies testing this regimen are warranted.

Resultados del trasplante de progenitores hematopoyéticos en hemoglobinopatías: talasemia maior y enfermedad drepanocítica / Results of hematopoietic stem cell transplantation in hemoglobinopathies: Thalassemia major and sickle cell disease

Introducción: La prevalencia de las hemoglobinopatías en nuestro medio ha aumentado como consecuencia de los flujos migratorios. La talasemia mayor cursa con anemia hemolítica crónica y necesidad de transfusiones regulares desde el año de vida. La enfermedad drepanocítica cursa con anemia, vasculopatía y daño orgánico progresivo. En ambas, la esperanza de vida está disminuida. El trasplante alogénico de progenitores hematopoyéticos es una opción de curación para estos pacientes. Pacientes: Diecisiete pacientes recibieron un trasplante alogénico de progenitores hematopoyéticos: 14 afectados de talasemia maior y 3 de enfermedad drepanocítica. Resultados: Los donantes fueron en los pacientes con talasemia mayor 9 hermanos HLA-idénticos, 2 progenitores con una diferencia antigénica HLA y 3 donantes no emparentados, y en aquellos con enfermedad drepanocítica, 3 hermanos HLA-idénticos. La fuente fue la médula ósea en todos, excepto uno. La media de edad al trasplante de progenitores hematopoyéticos fue de 6 años (intervalo: 1-16) en los niños con talasemia mayor y doce años (intervalo: 8-15) en los niños con enfermedad drepanocítica. Se confirmó injerto medular en todos los pacientes. Dos con talasemia mayor presentaron fallo de injerto secundario, precisando nuevamente soporte transfusional. Trece pacientes presentaron quimerismo completo y 2 quimerismo mixto, todos con normalización de la cifra de hemoglobina y sin requerimiento de transfusiones. Los pacientes con enfermedad drepanocítica no presentaron más episodios vasooclusivos y la funciones pulmonar y cerebral en aquellos pacientes que presentaban afectación en el momento del trasplante se estabilizaron. Tres pacientes con talasemia mayor desarrollaron enfermedad injerto contra huésped crónica y 5, hipogonadismo hipogonadotropo. Conclusiones: Nuestra experiencia confirma que el trasplante alogénico de progenitores hematopoyéticos de hermano HLA idéntico es una buena opción en el tratamiento de la talasemia mayor y la enfermedad drepanocítica. En el caso de la talasemia mayor, el trasplante de donante no emparentado es una opción terapéutica en centros especializados, ya que, a pesar de los buenos resultados presentados, la morbimortalidad de este procedimiento puede ser elevada, frente a la alternativa de un tratamiento médico no curativo pero con expectativas de supervivencia prolongada. En el caso de la enfermedad drepanocítica, el trasplante de donante no emparentado todavía está en fases preliminares de investigación (AU)

Background: The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Patients: Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. Results: In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1–16) in the thalassemia group, and twelve years (range: 8–15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. Conclusions: We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival. Despite good results, morbidity and mortality associated with transplantation from unrelated donors is a risk that might be considered, in contrast to a non-curative medical treatment that offers a long term survival. For thalassemia major groups it could be an option, but not for sickle cell disease, which is still in the investigational phase (AU)

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease]. / Resultados del trasplante de progenitores hematopoyéticos en hemoglobinopatías: talasemia maior y enfermedad drepanocítica.

BACKGROUND: The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. PATIENTS: Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. RESULTS: In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. CONCLUSIONS: We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival. Despite good results, morbidity and mortality associated with transplantation from unrelated donors is a risk that might be considered, in contrast to a non-curative medical treatment that offers a long term survival. For thalassemia major groups it could be an option, but not for sickle cell disease, which is still in the investigational phase.

Shock séptico en el niño oncohematológico / Septic shock in the oncohematologic child

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Neutropenia congénita grave: análisis de las características clínicas, estudios diagnósticos, tratamiento y seguimiento a largo plazo / Severe congenital neutropenia: analysis of clinical features, diagnostic methods, treatment and long-term outcome

Introducción: La NCG es una entidad heterogénea que se manifiesta en edades precoces de la vida y se caracteriza por un fallo primario en la mielopoyesis con un RAN < 0,5 x 109/l, infecciones graves y riesgo de transformación leucémica. Objetivo: Conocer el curso evolutivo a largo plazo de los pacientes diagnosticados de NCG. Material y métodos: Se analizaron las características clínicas, los métodos diagnósticos, el tratamiento y la evolución de 11 pacientes afectados de NCG. Resultados: La mediana de edad al diagnóstico fue de 4 meses (rango: 3 días-12 años). Clínica inicial en todos los casos: infección grave. Mediana de RAN al diagnóstico: 0,2 x 109/l (rango: 0-0,37). El aspirado de médula ósea mostró en todos los casos stop madurativo a nivel de promielocito. El estudio genético mostró en 3 mutaciones, 2 que afectaban al gen ELA2 y una en el gen G6PC3. El G-CSF fue el tratamiento de elección en 9 pacientes. Seis presentaron una buena respuesta a las dosis de entre 5-15 μg/kg/día administrado de 3 a 7días por semana. Tres no respondieron a G-CSF, indicándose un TPH alogénico. En 2 pacientes el TPH fue el tratamiento de primera elección. Mediana de seguimiento de 5 años (rango: 1-10), con una supervivencia del 100% sin ningún caso de transformación leucémica. Conclusiones: A la vista de los datos podemos concluir que el estudio genético de la NCG es útil para establecer una correlación entre genotipo y fenotipo. El tratamiento de elección es la administración G-CSF por vía subcutánea, al que responden las dos terceras partes de los pacientes, indicándose el TPH para los casos de mala respuesta o en aquellos que evolucionan a SMD o leucemia, por lo que el seguimiento de esta entidad es fundamental (AU)

Introduction: Severe congenital neutropenia (SCN), a heterogeneous condition with onset at early ages, is characterised by primary myelopoiesis failure with an absolute neutrophil count (ANC) < 0.5 x109/L, severe infections and risk of leukaemic transformation. Objective: The aim of the study was to ascertain the long term outcome of patients with SCN. Material and methods: The clinical features, diagnostic methods, treatment and outcome of 11 patients with SCN were analysed. Results: The median age at diagnosis was 4 months (range: 3 days-12 years). The primary clinical manifestation was severe infection. Median ANC at diagnosis: 0.2 x 109/L (range: 0-0.37). Bone marrow aspirate showed maturation arrest at promyelocyte stage in all cases. Genetic studies revealed 3 mutations, two in ELA-2 gene and 1 in G6PC3 gene, showing a correlation between genotype and phenotype. Granulocyte Colony Stimulating Factor (G-CSF) was the first-line treatment in 9 patients; six of whom showed a good response at doses between 5 and 15 μg/kg/day for 3-7 days/week. The remaining 3 patients failed to respond to G-CSF and allogeneic stem cell transplantation (SCT) was indicated. Furthermore, SCT was the treatment of choice in two cases. Median follow-up of the cohort was 5 years (range: 1-10 years) with 100% survival and no cases of leukaemic transformation. Conclusions: We conclude that genetic study is useful for establishing a correlation between genotype and phenotype. The treatment of choice for SCN is G-CSF to which 2/3 of patients should respond; while SCT is reserved for cases of poor response or those evolving to myelodysplastic syndrome (MDS) or leukaemia; thus close follow-up of this condition is essential (AU)

[Severe congenital neutropenia: analysis of clinical features, diagnostic methods, treatment and long-term outcome]. / Neutropenia congénita grave: análisis de las características clínicas, estudios diagnósticos, tratamiento y seguimiento a largo plazo.

INTRODUCTION: Severe congenital neutropenia (SCN), a heterogeneous condition with onset at early ages, is characterised by primary myelopoiesis failure with an absolute neutrophil count (ANC) < 0.5 x10(9)/L, severe infections and risk of leukaemic transformation. OBJECTIVE: The aim of the study was to ascertain the long term outcome of patients with SCN. MATERIAL AND METHODS: The clinical features, diagnostic methods, treatment and outcome of 11 patients with SCN were analysed. RESULTS: The median age at diagnosis was 4 months (range: 3 days-12 years). The primary clinical manifestation was severe infection. Median ANC at diagnosis: 0.2 x 10(9)/L (range: 0-0.37). Bone marrow aspirate showed maturation arrest at promyelocyte stage in all cases. Genetic studies revealed 3 mutations, two in ELA-2 gene and 1 in G6PC3 gene, showing a correlation between genotype and phenotype. Granulocyte Colony Stimulating Factor (G-CSF) was the first-line treatment in 9 patients; six of whom showed a good response at doses between 5 and 15 µg/kg/day for 3-7 days/week. The remaining 3 patients failed to respond to G-CSF and allogeneic stem cell transplantation (SCT) was indicated. Furthermore, SCT was the treatment of choice in two cases. Median follow-up of the cohort was 5 years (range: 1-10 years) with 100% survival and no cases of leukaemic transformation. CONCLUSIONS: We conclude that genetic study is useful for establishing a correlation between genotype and phenotype. The treatment of choice for SCN is G-CSF to which 2/3 of patients should respond; while SCT is reserved for cases of poor response or those evolving to myelodysplastic syndrome (MDS) or leukaemia; thus close follow-up of this condition is essential.

Recomendaciones de la Sociedad Española de Infectología Pediátrica sobre diagnóstico y tratamiento de la candidiasis invasiva / The Spanish Society of Paediatric Infectious Diseases (SEIP) recommendations on the diagnosis and management of invasive candidiasis

Las levaduras del género Candida son comensales ubicuos, que pueden causar infección oportunista en cualquier localización del organismo; la fuente de infección puede ser tanto endógena como exógena. La candidiasis invasiva engloba entidades distintas que van desde la candidemia o invasión limitada al torrente circulatorio a la candidiasis diseminada o infección multiorgánica. La candidemia constituye la tercera causa de infección del torrente circulatorio en la IN y la cuarta de todas las infecciones. También constituye la IFI más frecuente en el paciente crítico no neutropénico, habiendo sufrido un incremento muy notable en los últimos 20 años, debido tanto a una mayor supervivencia de los pacientes críticamente enfermos como a una mayor complejidad de los procedimientos diagnóstico terapéuticos y quirúrgicos. Su incidencia en lactantes, según revisiones recientes, se sitúa en 38,8 casos/100.000 menores de 1 año. La especie más frecuentemente implicada en infecciones invasoras sigue siendo Candida albicans, aunque en los últimos años existe un incremento de infecciones causadas por especies distintas: es relevante la aparición de Candida kruseiy Candida glabrata y el incremento de candidemia por Candida parapsilosis asociada principalmente al manejo de catéteres intravenosos centrales, especialmente en unidades neonatales. La mortalidad global de la candidiasis invasiva es elevada, llegando a cifras del 20 al 44% a los 30 días en determinadas series que incluyen a pacientes pediátricos. Este documento recoge una revisión actualizada sobre incidencia, epidemiología, diagnóstico, tratamiento y evolución, de la infección invasiva por Candida spp. en el paciente pediátrico (AU)

Candida yeasts are ubiquitous commensals, which can cause opportunistic infection in any location of the body. The source of infection may be both endogenous and exogenous. Invasive candidiasis encompasses different entities ranging from invasive candidiasis to disseminated multiorgan infection. Invasive candidiasis is the third leading cause of nosocomial bloodstream infection and the fourth of all nosocomial infections. It is also the most common invasive fungal infection in non-neutropenic critically ill patients, with a remarkable increase in the last 20 years owing to the increased survival of these patients and to more complex diagnostic, therapeutic and surgical procedures. Its incidence in infants, according to recent reviews, stands at 38.8 cases/100,000 children younger than 1 year. Candida albicans remains the most frequent isolate in invasive infections, although infections caused by other species have risen in the last years, such as C. kruzsei, C. glabrata and C. parapsilosis; the latter causing invasive candidiasis mainly associated with central venous catheter management, especially in neonatal units. The overall mortality of invasive candidiasis is high, with 30-day mortality reaching20-44% in some series involving paediatric patients. This report provides an update on incidence, epidemiology, clinical presentation, diagnosis, treatment and outcome of invasive infection by Candida spp. in the paediatric patient (AU)

[The Spanish Society of Paediatric Infectious Diseases (SEIP) recommendations on the diagnosis and management of invasive candidiasis]. / Recomendaciones de la Sociedad Española de Infectología Pediátrica sobre diagnóstico y tratamiento de la candidiasis invasiva.

Candida yeasts are ubiquitous commensals, which can cause opportunistic infection in any location of the body. The source of infection may be both endogenous and exogenous. Invasive candidiasis encompasses different entities ranging from invasive candidiasis to disseminated multiorgan infection. Invasive candidiasis is the third leading cause of nosocomial bloodstream infection and the fourth of all nosocomial infections. It is also the most common invasive fungal infection in non-neutropenic critically ill patients, with a remarkable increase in the last 20 years owing to the increased survival of these patients and to more complex diagnostic, therapeutic and surgical procedures. Its incidence in infants, according to recent reviews, stands at 38.8 cases/100,000 children younger than 1 year. Candida albicans remains the most frequent isolate in invasive infections, although infections caused by other species have risen in the last years, such as C. kruzsei, C. glabrata and C. parapsilosis; the latter causing invasive candidiasis mainly associated with central venous catheter management, especially in neonatal units. The overall mortality of invasive candidiasis is high, with 30-day mortality reaching 20-44% in some series involving paediatric patients. This report provides an update on incidence, epidemiology, clinical presentation, diagnosis, treatment and outcome of invasive infection by Candida spp. in the paediatric patient.

[Severe acquired aplastic anemia: historical outcome of patients treated by allogeneic bone marrow transplantation from matched sibling donors. A study by the Spanish Group for Bone Marrow Transplantation in Children (GETMON)]. / Aplasia medular grave adquirida: evolución histórica de los resultados obtenidos con trasplante de progenitores hematopoyéticos de donante familiar. Estudio del Grupo Español para el Trasplante de Médula Osea en Niños (GETMON).

INTRODUCTION: Allogeneic haematopoietic stem-cell transplantation is the treatment of choice for acquired aplastic anaemia in children. Experience with this approach from Spanish Working Party for Bone Marrow Transplantation in Children in two sequential time periods (1982-1990 and 1991-2004) is reported. PATIENTS AND METHODS: Sixty two consecutive patients with a median age of 10 years were transplanted; 18 in the 1982-1990 period and 44 in the 1991-2004 period. Conditioning regimen consisted mainly of irradiation and cyclophosphamide in the first period (72 % of patients) and cyclophosphamide +/- anti-thymocyte globulin (62 %) in the second. Graft versus host disease prophylaxis consisted of cyclosporine in most patients (57/62). RESULTS: Fifty one patients are alive and disease-free at a median follow-up of 127 months. Five years probability of event-free survival is 82 %. The survival increased from 61 % to 91 % during the two time periods. Eleven patients died from graft failure or rejection (3), acute or chronic graft versus host disease and infection (4) or multi-organ failure (4). Univariate analysis identified two significant prognostic factors: interval diagnostic/transplant and time period of transplant (for both p = 0.03). CONCLUSIONS: This experience corroborates that allogeneic haematopoietic stem-cell transplantation is the best treatment for severe acquired aplastic anaemia, with a current disease-free survival of 90 % of patients.

[Spanish multidisciplinary consensus on the prevention of respiratory syncytial virus infection in children]. / Consenso multidisciplinar español sobre la profilaxis de la infección respiratoria pediátrica por virus respiratorio sincitialConsenso.

BACKGROUND: A certain degree of feasibility exists in Spanish clinical practice with respect to interventions performed to prevent paediatric respiratory infection by RSV, including hygienic measures and intramuscular immunoprophylaxis with palivizumab. This task involves different paediatric specialties that may have a different perception of the magnitude of the problem and different professional criteria regarding the most appropriate actions. OBJECTIVES: To develop Spanish multidisciplinary consensus on preventing infection by RSV with the participation of the paediatric scientific societies involved (SNS, SSPC, SSPP and SSHPO). METHODS: Delphi Consensus modified in two rounds was used. The study was conducted in four phases: 1) constitution of a multidisciplinary Scientific Committee at the recommendation of the scientific entities participating in the study, for bibliographic review and submission of the recommendations to discussion; 2) constitution of an Expert Panel with 77 speciality representatives; 3) postal survey organised in two rounds and intermediate processing of opinions and issuing of a report for the panellists, and 4) discussion of the results in a meeting of the Scientific Committee. RESULTS: Consensus was reached on 48 of the 57 preventive recommendations analysed. With respect to the 9 remaining issues, no consensus was reached, due to differences in professional opinion and the absence of established criteria among the majority of the experts. Only in 3 recommendations was the opinion of the experts associated with the speciality of origin. CONCLUSIONS: A list of anti-RSV prophylactic recommendations was submitted, rated in accordance with the degree of professional consensus on which they were based. These can be considered valid until such time as new scientific information emerges that warrants a review thereof.

Aplasia medular grave adquirida: evolución histórica de los resultados obtenidos con trasplante de progenitores hematopoyéticos de donante familiar. Estudio del Grupo Español para el Trasplante de Médula Ósea en Niños (GETMON) / Severe acquired aplastic anemia: historical outcome of patients treated by allogeneic bone marrow transplantation from matched sibling donors. A study by the Spanish Group for Bone Marrow Transplantation in Children (GETMON)

Introducción: El trasplante de progenitores hematopoyéticos (TPH) de donante familiar compatible es el tratamiento de elección en la aplasia medular adquirida (AMA) grave en la infancia. Se presenta la experiencia de Grupo Español para el Trasplante de Médula Ósea en Niños en esta enfermedad a lo largo del período cronológico 1982-2004. Pacientes y métodos: Recibieron un trasplante 62 pacientes con una mediana de edad de 10 años. En el período 1982-1990 lo recibieron 18 pacientes y en el período 1991-2004, 44. El régimen de acondicionamiento varió según el período cronológico; en el primero se utilizó preferentemente la asociación de radioterapia y ciclofosfamida (72 % de los casos) y en el segundo ciclofosfamida con o sin globulina antitimocitaria (62 %). La profilaxis de enfermedad injerto contra huésped más utilizada fue la ciclosporina (57/62 pacientes). Resultados: Un total de 51 pacientes están vivos y en remisión completa de su aplasia con períodos de observación de entre 24 y 289 meses (mediana de 127 meses). La probabilidad de supervivencia actuarial libre de eventos a 5 años es del 82 %. Dicha supervivencia se incrementó del 61 al 90 % entre los dos períodos analizados. Un total de 11 pacientes fallecieron por fracaso o pérdida del injerto (3), enfermedad injerto contra huésped aguda o crónica asociada a infecciones (4) o fallo multiorgánico (4). El análisis univariante evidenció dos factores con valor predictivo para la supervivencia: el intervalo diagnóstico/trasplante y el período cronológico en que se efectuó (en ambos, p = 0,03). Conclusiones: Esta experiencia confirma que el trasplante de progenitores hematopoyéticos de donante familiar compatible es el tratamiento de elección para la aplasia medular grave adquirida, con un porcentaje de supervivencia libre de episodios del 90 % en la actualidad (AU)

Allogeneic haematopoietic stem-cell transplantation is the treatment of choice for acquired aplastic anaemia in children. Experience with this approach from Spanish Working Party for Bone Marrow Transplantation in Children in two sequential time periods (1982-1990 and 1991-2004) is reported. Patients and methods: Sixty two consecutive patients with a median age of 10 years were transplanted; 18 in the 1982-1990 period and 44 in the 1991-2004 period. Conditioning regimen consisted mainly of irradiation and cyclophosphamide in the first period (72 % of patients) and cyclophosphamide ± anti-thymocyte globulin (62 %) in the second. Graft versus host disease prophylaxis consisted of cyclosporine in most patients (57/62). Results: Fifty one patients are alive and disease-free at a median follow-up of 127 months. Five years probability of event-free survival is 82 %. The survival increased from 61 % to 91 % during the two time periods. Eleven patients died from graft failure or rejection (3), acute or chronic graft versus host disease and infection (4) or multi-organ failure (4). Univariate analysis identified two significant prognostic factors: interval diagnostic/transplant and time period of transplant (for both p = 0.03). Conclusions: This experience corroborates that allogeneic haematopoietic stem-cell transplantation is the best treatment for severe acquired aplastic anaemia, with a current disease - free survival of 90 % of patients (AU)