[Lung function changes after haematopoietic stem cell transplantation]. / Alteraciones de la función pulmonar tras el trasplante de progenitores hematopoyéticos.

OBJECTIVE: To evaluate lung function abnormalities in children who underwent haematopoietic stem cell transplantation (HSCT) and to compare these abnormalities between autologous and allogenic transplantation. PATIENTS AND METHODS: Prospective observational study from 1996 to 2005. Ninety-three children receiving HSCT, 47 autologous and 46 allogenic, were included. Lung function tests were performed before transplantation and at 2, 6, 12 and 24 months afterwards. The following indices were determined: forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLCO). Paired Student's t-test was used for statistical analysis of data. RESULTS: Before HSCT, 6.8% of the children had FEV1<80%, 1% FEV1/FVC<80%, 7.8% TLC<80% and 13.5% DLCO<70%. At 2 months, FEV1/FVC, TLC and DLCO were significantly reduced, when compared to pre-transplantation values (p=0.05, 0.011 and p<0.001, respectively). Lung function gradually improved from 6 months post-transplantation, but did not reach pre-transplantation values at 24 months. No significant differences were found when comparing allogenic and autologous transplantation, apart from a lower FEV1/FVC value at 6 months (p=0.02) in the first group. CONCLUSIONS: An important proportion of children who undergo HSCT have early pulmonary abnormalities (at 2 and 6 months after transplantation) with partial recovery at 24 months.

El trasplante de células progenitoras hematopoyéticas de sangre de cordón en hemato-oncología pediátrica / Transplant of hematopoietic stem cells form the cord blood in pediatric hemato-oncology

El cordón umbilical se ha convertido en una fuente alternativa válida para el trasplante alogénico de progenitores hematopoyéticos. La experiencia clínica demuestra que es efectiva en niños con determinadas patologías hematológicas malignas y no malignas. Sin embargo, debido al gran impacto de la dosis de células infundidas y su repercusión en la mortalidad relacionada con el trasplante y la supervivencia, su uso como fuente de progenitores hematopoyéticos se ha extendido más en niños y es menor en adultos. Debido a esto, se están investigando nuevas estrategias para superar el obstáculo de la baja celularidad, como es el uso del doble trasplante de cordón (AU)

The umbilical cord has become a valid alternative source for allogeneic transplant of hematopoietic stem cells. Clinical experience shows that it is effective in children with certain malignant and non-malignant hematological diseases. However, due to the great impact of the infused cell dose ant its repercussion in transplant related mortality and survival, its use as a source of hematopoietic stem cells has become more extended in children and less in adults. Due to this, new strategies are being investigated to overcome the obstacle of low cellularity, such as the use of double cord blood transplant (AU)

[Twenty years of treating childhood acute lymphoblastic leukemia]. / Veinte años de experiencia en el tratamiento de la leucemia linfoblástica aguda.

BACKGROUND: Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments. OBJECTIVES: To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL. PATIENTS AND METHOD: We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols. RESULTS: Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively. CONCLUSIONS: A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses.

Veinte años de experiencia en el tratamiento de la leucemia linfoblástica aguda / Twenty years of treating childhood acute lymphoblastic leukemia

Antecedentes Los factores pronósticos en el tratamiento de la leucemia linfoblástica aguda (LLA) son la base del tratamiento adaptado al grupo de riesgo. Objetivos Analizar los factores de riesgo convencionales y establecer un modelo predictivo de recaída en nuestra serie, tras 20 años de experiencia en el tratamiento de la LLA. Pacientes y método Realizamos un análisis multivariante de los factores pronósticos convencionales en el tratamiento de la LLA y los comparamos con los grupos de riesgo del protocolo de tratamiento Berlín-Frankfurt-Münster (LLA-BFM), en nuestra unidad. Resultados Entre 1984 y 2004, un total de 232 niños fueron diagnosticados de LLA y tratados siguiendo el protocolo BFM en sus diferentes versiones (BFM83, BFM86, BFM90 y BFM95). La supervivencia libre de episodios de la serie fue de 79,4 % (IC 95 %: 72,7-85,4). La supervivencia global de los pacientes que recayeron fue de 10,72 % (IC 95 %: 6-27,3). La única variable predictora en el análisis multivariante fue el número de leucocitos al diagnóstico mayor de 80.000/ml (hazard ratio [HR]: 4,63; IC 95 %: 1,61-13,3; p 5 0,004). La sensibilidad y especificidad del número de leucocitos al diagnóstico mayor de 80.000/ml para predecir la recaída fue en nuestra serie de 31,4 y 87,5, respectivamente. La sensibilidad y especificidad de los grupos de riesgo BFM para predecir la recaída fue de 25 y 85,9, respectivamente. Conclusiones El número de leucocitos al diagnóstico mayor de 80.000/ml o los grupos de tratamiento adaptados al riesgo según las variables convencionales no tienen suficiente sensibilidad y especificidad para identificar las recaídas

Background Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments. Objectives To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL. Patients and method We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols. Results Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively. Conclusions A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses

[Obstructive lung disease after allogenic stem cell transplantation in children]. / Enfermedad pulmonar obstructiva tras trasplante alogénico de progenitores hematopoyéticos en niños.

INTRODUCTION: Bronchiolitis obliterans is recognized as a life-threatening pulmonary complication that can develop 3 months after bone marrow transplantation. OBJECTIVE: To determine the incidence and clinical progression of obstructive lung disease (OLD) in a population of children who had undergone allogenic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: We examined a sequential sample of 110 patients who received allogeneic HSCT between January 1992 and June 2002. The incidence of OLD in the 77 children who survived for more than 100 days after transplantation was analyzed. The diagnosis of OLD was based on clinical findings with no evidence of infection, pulmonary function test (FEV1/FVC less than 80 % and FEV1 less than 80 % of predicted value) and computed tomography scan. RESULTS: Eight patients (10.4 %) developed OLD at a median time of onset of 184 days after allogenic HSCT (range: 100-1735 days). All patients with OLD had respiratory symptoms. In six out of eight patients airflow obstruction was diagnosed within 1 year of transplantation. All patients showed chronic graft-versus-host disease (GVHD) (p < 0.01). The incidence of OLD in the 23 patients with chronic GVHD was 34.8 %. Two patients (25 %) had a complete response to intensified treatment of chronic GVHD with immunosuppressant therapy. FEV1 declined rapidly in three patients (37.5 %) who died of respiratory failure. Two patients (25 %) had partial reversal but pulmonary function continued below normal values. In one patient (12.5 %) severe obstructive disease was stable. CONCLUSIONS: The time of onset and form of progression of OLD after HSCT may vary. OLD is strongly associated with chronic GVHD and its incidence depends on the number of patients with chronic GVHD.

[High-dose chemotherapy with autologous stem cell rescue in children with high-risk and recurrent brain tumors]. / Trasplante autólogo con progenitores hematopoyéticos de sangre periférica en niños con tumores del sistema nervioso central de alto riesgo.

BACKGROUND: In the last few years, survival in children with central nervous system (CNS) tumors has slightly improved, especially in children with tumors such as medulloblastoma and those in which complete surgical resection is achieved. However, outcome remains poor in patients with incomplete surgical resection, neuroaxial dissemination, metastatic or recurrent tumors and in very young children. OBJECTIVES: To improve prognosis in patients with high-risk and recurrent tumors, new therapeutic strategies such as high-dose chemotherapy with autologous stem cell rescue (ASCR) have been developed. METHODS: We retrospectively studied patients with high-risk and recurrent CNS tumors who underwent ASCR between September 1995 and December 2002 in our unit. RESULTS: Thirty-five patients underwent ASCR. Seven patients died of treatment-related toxicities (20 %). Thirteen (37 %) are event-free survivors at a median post-ASCR follow-up of 18 months (range: 5-63 months). The 2-year Kaplan-Meier estimates of event-free survival was 37.64 +/- 8.7 % in all patients, 57 +/- 15 % in the group of patients with high-risk medulloblastoma/supratentorial primitive neuroectodermal tumor (stPNET) and 71.43 +/- 17 % in patients aged less than 4 years with medulloblastoma/stPNET. CONCLUSIONS: In our experience, ASCR may be effective in the treatment of malignant tumors of the central nervous system in patients with controlled disease, in certain histologic groups and chemosensitive tumors (medulloblastoma, malignant astrocytoma), as well as in very young children in whom cranial radiotherapy is contraindicated.

Trasplante autólogo con progenitores hematopoyéticos de sangre periférica en niños con tumores del sistema nervioso central de alto riesgo / High-dose chemotherapy with autologous stem cell rescue in children with high-risk and recurrent brain tumors

Antecedentes. En los últimos años ha mejorado discretamente la supervivencia de los niños con tumores del sistema nervioso central (SNC). Especialmente en tumores como el meduloblastoma y en aquellos en los que se consigue una resección quirúrgica completa. En cambio, los pacientes con resecciones quirúrgicas incompletas, tumores diseminados por el neuroeje, metastásicos, recurrentes o en los pacientes de menor edad, el pronóstico resulta muy pobre. Objetivos. Con intención de mejorar el pronóstico de los pacientes de alto riesgo y con enfermedad recurrente, se han desarrollado nuevas estrategias terapéuticas como el trasplante autólogo de progenitores hematopoyéticos (TAPH). Métodos. Revisión retrospectiva de los pacientes con tumores de alto riesgo del SNC y recurrentes sometidos a TAPH entre los meses de septiembre de 1995 y diciembre de 2002 en nuestra unidad. Resultados. Un total de 35 pacientes fueron trasplantados. Fallecieron 7 pacientes (20 por ciento) por toxicidad del procedimiento y 15 pacientes (42 por ciento) por enfermedad progresiva, 13 pacientes se encuentran vivos, con una mediana de seguimiento tras el trasplante de 18 meses (5-63 meses). La supervivencia libre de enfermedad (SLE) estimada mediante el método de Kaplan-Meier con una mediana de 2 años fue de 37,64 +/- 8,7 por ciento, en todos los pacientes; de 57 +/- 15 por ciento en los pacientes con meduloblastoma/tumor primitivo neuroectodérmico supratentorial (MB/stPNET) de alto riesgo, y de 71,43 +/- 17 por ciento en los pacientes con MB/stPNET menores de 4 años. Conclusiones. En nuestra experiencia el TAPH podría ser efectivo en el tratamiento de los tumores malignos del SNC en pacientes con enfermedad controlada y en determinados grupos histológicos, tumores quimiosensibles (meduloblastoma, astrocitoma anaplásico), así como en los niños de menor edad donde la radioterapia craneal está contraindicada (AU)

Altas dosis de quimioterapia y soporte hematopoyético en el tratamiento de niños con meduloblastoma y tumor neuroectodérmico primitivo supratentorial de alto riesgo / High-dose chemotherapy with hemopoietic support for the treatment of children with medulloblastoma and high risk supratentorial primitive neuroectodermal tumor

- Propósito: las altas dosis de quimioterapia (ADQ) y el rescate con progenitores hematopoyéticos autólogos ha demostrado mejorar la supervivencia en pacientes con meduloblastoma (MB) y tumor neuroectodérmico primitivo supratentorial (stPNET) recurrente y de alto riesgo.- Material y métodos: presentamos 19 pacientes tratados con ADQ, 13 de alto riesgo y 6 con enfermedad recurrente. Los pacientes fueron movilizados con factores estimulantes de colonias granulocíticas (G-CSF) a dosis de 12 µg/kg/12h durante 4 días. El acondicionamiento consistió en busulfán-melfalán. Tres pacientes recibieron de manera adicional tiotepa y cuatro pacientes topotecán. Los progenitores hematopoyéticos fueron reinfundidos 48h tras finalizar la quimioterapia.- Resultados: con una mediana de seguimiento de 18 meses (rango 5-63) tras el trasplante, 9 pacientes (47 por ciento) están vivos (8 en remisión completa y 1 en remisión parcial). Fallecieron 3 pacientes (15 por ciento) por toxicidad del procedimiento y 7 por enfermedad progresiva (36 por ciento). La supervivencia libre de eventos, según el método de Kaplan-Meier, es del 37,67ñ14 por ciento en todos los pacientes y un 57ñ15 por ciento en los pacientes de alto riesgo.- Conclusiones: en nuestra experiencia las ADQ, aunque es un procedimiento tóxico, puede mejorar la supervivencia especialmente en pacientes con MB o stPNET de alto riesgo (AU)

Topotecán en el tratamiento de niños con tumores sólidos refractarios o recidivantes / Topotecan for pediatric patients with resistant and recurrent solid tumors

Antecedentes: Topotecán es un quimioterápico alcaloide derivado de la planta Camptotheca acuminata (originaria de China) con capacidad de inhibir la enzima topoisomerasa I y de reciente uso en el tratamiento del cáncer pediátrico. Objetivos: Evaluar nuestra experiencia preliminar con el topotecán en el tratamiento de segunda línea de tumores sólidos refractarios en la edad pediátrica.Pacientes y métodos Estudio retrospectivo de 10 pacientes con tumores sólidos refractarios o recidivantes a la primera línea de tratamiento que reciben topotecán en monoterapia o en asociación con otros agentes quimioterápicos. Resultados: Se incluyeron 10 pacientes con tumores sólidos refractarios o recidivantes al tratamiento convencional (dos neuroblastomas, tres rabdomiosarcomas, dos tumores neuroectodérmicos primitivos (PNET)/Ewing, un astrocitoma anaplásico, un tumor desmoplásico y un sarcoma sinovial). Obtuvieron respuesta favorable 5 pacientes (dos remisiones completas, dos remisiones parciales y un estabilización de la enfermedad). En 5 pacientes no se consiguió ninguna respuesta. Todos los pacientes presentaron toxicidad hematológica de grado III-IV. Conclusiones: En nuestra experiencia, topotecán sería beneficioso en determinados tumores sólidos refractarios o recidivantes, sobre todo neuroblastomas y sarcomas de partes blandas, con una aceptable tolerancia a la toxicidad hematopoyética con el uso de factores estimulantes de colonias granulocíticas. Los pacientes en remisión completa de su enfermedad tras topotecán podrían beneficiarse de una intensificación de quimioterapia con rescate autólogo de progenitores hematopoyéticos (AU)

[Topotecan for pediatric patients with resistant and recurrent solid tumors]. / Topotecán en el tratamiento de niños con tumores sólidos refractarios o recidivantes.

BACKGROUND: Topotecan is a cytotoxic drug isolated from the Camptotheca acuminata tree (from China). It is able to block the enzyme DNA topoisomerase I and has recently been used in the treatment of pediatric cancer. OBJECTIVES: To evaluate our preliminary experience with topotecan in the second line treatment of refractory solid tumors in the pediatric age group. PATIENTS AND MEHTODS: We performed a retrospective study of 10 patients with various recurrent solid tumors resistant to first line treatment who were treated with topotecan alone or in association with other chemotherapeutic agents. RESULTS: Ten patients with recurrent solid tumors or tumors that were refractory to conventional treatment (two neuroblastomas, three rhabdomyosarcoma, two PNET/Ewing's sarcoma, one anaplastic astrocytoma, one soft tissue sarcoma and one synovial sarcoma) were included. Five patients showed favorable responses (two had complete responses, two had partial responses and one had stable disease). Five patients showed no response. All patients showed grade II-IV hematological toxicity. CONCLUSIONS: In our experience, topotecan is beneficial in some refractory or recurrent solid tumors, especially neuroblastomas and soft tissue sarcomas. Myelosuppression was tolerable with the use of granulocyte colony-stimulating factors. Patients with a complete response to topotecan could benefit from high-dose chemotherapy and autologous stem cell rescue therapy.

Sperm dysfunction in subfertile patients with varicocele and marginal semen analysis.

A comparative analysis of potentially functional spermatozoa per ejaculate, progressive motility, hypo-osmotic swelling test, acrosome integrity and sperm viability (24 and 48 h) was carried out in a group of 40 subfertile patients with varicocele and marginal semen analysis and 40 fertile subjects, in order to identify subclinical abnormalities that may explain subfertility. Patients with varicocele had lower numbers of potentially functional spermatozoa per ejaculate, progressive motility, acrosome and membrane integrity and sperm viability. These abnormalities were not related to the grade of varicocele, testicular volume or serum FSH concentration. A positive correlation between the hypo-osmotic swelling test and progressive motility (r = 0.71) and between potentially functional spermatozoa and the hypo-osmotic swelling test (r = 0.69) was found in patients with varicocele. These data suggest that some of the deleterious effects produced by the varicocele might be related to sperm migration and viability in the female genital tract and others to sperm-zona interaction and/or sperm-egg fusion.

[The results of treatment by the Madrid Pediatric Oncology Group according to the BFM protocols in non-Hodgkin's B-cell lymphoma and acute B-cell lymphoblastic leukemia in pediatric patients]. / Resultados del tratamiento según protocolos BFM del linfoma no Hodgkin B y de la leucemia linfoblástica aguda de células B en pacientes pediátricos por el GOPM.

The objective of this report is to present the results of the BFM group in the treatment of 41 children with non-Hodgkin's B cell lymphoma and acute B cell lymphoblastic leukemia according to the BFM 86 and 90 protocols. Forty-one children, between 2 and 16 years of age, were treated from November 1987 to October 1993. Of these, 25 were treated with the BFM 86 protocol (18 non-Hodgkin's B cell lymphomas and 7 acute B cell lymphoblastic leukemias) and the rest with the BFM 90 protocol (15 non-Hodgkin's B cell lymphomas and 1 acute B cell lymphoblastic leukemia). Complete remission was achieved in 97.5% of the patients. A relapse occurred in 12.5% of the cases. Currently, 80.4% remain in continuous complete remission and 17% have died. The 5 year actuarial survival rate of those treated with the BFM 86 and 90 protocols was 79% and 87%, respectively, and event free survival in the same period was 76% and 87%, respectively. There was no statistically significant difference in the results obtained with the two treatment protocols.

[Index of cells obtainable from semen: indicator of fertility?]. / Indice de células recuperables del semen: indicador de fertilidad?

It has been recognized that semen analysis is not a sensible nor a specific tool for detecting infertility in the male. Its predictive value is limited by the subjectivity of manual analysis, a high variability of semen parameters in fertile men and lack of correlation between sperm characteristics and fertility indexes. In this paper we present evidence supporting the concept that calculating an index of potentially fertile cells from data obtained in a regular semen analysis might be useful for predicting fertility in the male.

Evidence that human follicular fluid contains a chemoattractant for spermatozoa.

Considering that information from the literature clearly establishes that human follicular fluid enhances both motility and viability of spermatozoa and that this fluid contains substances with chemotactic activity for leukocytes, we looked to see if follicular fluid might exert any chemical attraction to male germinal cells. In an vitro model using 0.8% agarose plates, it was demonstrated that the number of cells migrating to wells containing follicular fluids from patients in a program for GIFT, classified as mature in accordance to oocyte morphology, was significantly higher than those migrating to control wells. Further studies are needed to confirm these results and to study the possible specificity of the signal.