Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies. METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies. RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Efficacy of interleukin 10 gene hydrofection in pig liver vascular isolated 'in vivo' by surgical procedure with interest in liver transplantation.

AIM: Liver transplantation is the only curative strategy for final stage liver diseases. Despite the great advances achieved during the last 20 years, the recipient immune response after transplantation is not entirely controlled. This results in high rates of acute cell rejection and, approximately, 10% of early mortality. Therapeutic treatment could be improved by efficiently transfecting genes that encode natural immunosuppressant proteins, employing safe procedures that could be transferred to clinical setting. In this sense, interleukin 10 plays a central role in immune tolerance response by acting at different levels. METHODS: hIL10 gene was hydrofected by retrograde hydrodynamic injection in pig liver with complete vascular exclusion mediated by an 'in vivo' surgical procedure. Levels of IL10 DNA, RNA and protein were determined within liver tissue 1 and 10 days after the injection and, more frequently, also the interleukin-10 protein in peripheral blood. RESULTS: The procedure was safe for the animals and neither hemodynamic parameters nor liver function determinations showed relevant alterations. The hIL10 hydrofection in watertight liver mediated efficient gene transfer and this was transcribed and translated to protein, achieving up to 110 pg/ml of IL10 in peripheral blood. This value is close to that considered able to reduce the activity of TNFα by half (IL10 IC50 for TNFα = 124 pg/ml). CONCLUSIONS: Results of this work suggest that IL10 liver hydrofection with vascular exclusion in vivo is a safe and transferable procedure that mediates plasma protein levels with potential clinical interest in immune modulation after transplantation.

Ensayos clínicos precoces en oncología pediátrica en España: una perspectiva nacional / Early clinical trials in paediatric oncology in Spain: a nationwide perspective

Introducción: El cáncer es la primera causa de muerte por enfermedad entre el primer año de vida y la adolescencia. Algunos tipos de enfermedad siguen constituyendo un reto en términos de curación. Existe por tanto una necesidad imperiosa de nuevos fármacos. Algunos descubrimientos recientes en la biología del cáncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia. Esto se ha traducido en resultados prometedores sobre todo en oncología de adultos, y en menor medida todavía en niños. Presentamos la actividad en ensayos clínicos precoces (fase I-II) en oncología pediátrica en España. Material y métodos: A través de la Sociedad Española de Oncología y Hematología Pediátrica (SEHOP) contactamos a sus miembros para identificar los ensayos fase I-II en cáncer pediátrico abiertos entre 2005 y 2015. Resultados: En este periodo se abrieron 30 ensayos: 21 (70%) en tumores sólidos y 9 (30%) en hemopatías malignas y se incluyó a 212 pacientes. La mayoría están promovidos por la industria farmacéutica (53%). Desde 2010, 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en cáncer infantil. Esto ha permitido ampliar el abanico de posibilidades terapéuticas. Los resultados de ensayos clínicos terminados muestran la contribución de los investigadores españoles, la introducción de terapias dirigidas y sus beneficios. Conclusiones: La actividad en ensayos clínicos precoces ha aumentado en estos años. La SEHOP está comprometida a desarrollar y participar en ensayos clínicos académicos colaborativos, que favorezcan el avance en las terapias frente al cáncer infantil (AU)

Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer (AU)

[Early clinical trials in paediatric oncology in Spain: a nationwide perspective]. / Ensayos clínicos precoces en oncología pediátrica en España: una perspectiva nacional.

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.

La oncología pediátrica: pasado, presente y futuro / Paediatric oncology: Past, present and future

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Leucemia linfoblástica aguda T pediátrica: análisis de supervivencia y factores pronósticos en 4 protocolos consecutivos del grupo cooperativo multicéntrico SHOP / T-cell pediatric acute lymphoblastic leukemia: analysis of survival and prognostic factors in 4 consecutive protocols of the Spanish cooperative study group SHOP

Fundamento y objetivo: La leucemia linfoblástica aguda (LLA) es el cáncer más frecuente en la edad pediátrica, con tasas de curación del 80-85%. En la LLA de fenotipo T (LLA-T, 15% de casos) los factores pronósticos no están bien definidos. Nuestro objetivo es analizar la supervivencia y los factores pronósticos clínicos en una serie de pacientes con LLA-T. Pacientes y método: Se analizaron los niños con LLA-T (1-18 años) tratados según los protocolos SHOP/LLA-89/LLA-94/LLA-99/LLA-2005 (desde febrero de 1989 hasta noviembre de 2009) en 37 instituciones. Resultados: Se incluyeron 218 pacientes con LLA-T sobre un total de 1.652 LLA pediátricas. De ellos, 164 (75%) eran varones. La edad mediana fue de 7,8 años (extremos 1,3-18,6). La mediana de leucocitos fue 78,2×109/l (extremos 0,8-930). Quince niños (6,8%) tuvieron infiltración del sistema nervioso central (SNC). En cuanto a la respuesta al tratamiento de inducción, 150 (75%) pacientes tenían menos de 5% de blastos en médula ósea del día +14 y 199 alcanzaron la remisión completa. La supervivencia global (SG) media (DE) a 60 meses para los protocolos SHOP/LLA-89, LLA-94 y LLA-99 fue del 48 (8), 49 (6) y 70 (6) %, respectivamente, y la SG a 48 meses para el protocolo SHOP/LLA-05 (protocolo en curso) del 74 (8) %. La mediana de seguimiento fue de 206, 152, 74 y 17 meses, respectivamente. El análisis de factores pronósticos no mostró diferencias significativas en cuanto a sexo ni edad. Resultaron significativos la cifra de leucocitos mayor o igual a 200×109/l (p=0,024), la infiltración del SNC al diagnóstico (p<0,006), la respuesta al tratamiento (médula ósea día +14) (p=0,005) y la remisión completa al final de la inducción (p=0,0000). Conclusiones: Los resultados obtenidos en la LLA-T con los protocolos SHOP/LLA-89 y SHOP/LLA-94 fueron inferiores a otros protocolos contemporáneos, pero la supervivencia mejoró en los 2 últimos protocolos. En concordancia con otras series de LLA-T, la respuesta al tratamiento fue el principal factor pronóstico (AU)

Background and objectives: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. Patients and methods: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. Results: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (109/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×109/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). Conclusions:Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact (AU)

[T-cell pediatric acute lymphoblastic leukemia: analysis of survival and prognostic factors in 4 consecutive protocols of the Spanish cooperative study group SHOP]. / Leucemia linfoblástica aguda T pediátrica: análisis de supervivencia y factores pronósticos en 4 protocolos consecutivos del grupo cooperativo multicéntrico SHOP.

BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. PATIENTS AND METHODS: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. RESULTS: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (10(9)/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×10(9)/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). CONCLUSIONS: Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact.

Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005.

Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6·8years, range, 1·2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow-up of 109 and 39months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29·6% and 78·7%, respectively (P=0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.

Immunohistochemical study as a tool in differential diagnosis of pediatric malignant rhabdoid tumor.

Malignant rhabdoid tumors (MRTs) are aggressive childhood neoplasms, occurring mainly in the kidney and brain. We describe 2 unusual cases of extrarenal and noncranial location (liver and soft tissue with dissemination) mimicking hepatoblastoma, neuroblastoma or Ewing sarcoma. Both cases revealed a polyphenotypic profile, combined with cytokeratin, vimentin, and CD99 expression. INI1/BAF-47 showed negative protein nuclear expression in both cases, suggesting a diagnosis of MRT. An extensive immunohistochemical panel was performed to exclude pediatric tumors reminiscent of MRT. The genetic studies failed to detected MYCN amplification, 11q23 deletion, and EWS break-apart positivity. No alterations of 22q integrity were demonstrated with the probes used for the study (N25 Di George/22q11.2, 22qter, and EWS/22q12). We discuss the differential diagnosis in pediatric polyphenotypic tumors (Wilms tumor, neuroblastoma, desmoplastic small round cell tumor, and Ewing sarcoma). Analysis of INI1/BAF-47 expression can offer important clues in the diagnosis of pediatric tumors with rhabdoid phenotype. The integration of clinical, morphologic, immunohistochemical, and genetic data is required to approach a correct diagnosis of pediatric tumor in unusual location with atypical or undifferentiated morphology.

Allogeneic stem cell transplantation for myelodysplastic syndromes in children: a report from the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON).

INTRODUCTION: Experience with the use of allogeneic hemopoietic stem transplantation (AHSCT) in pediatric myelodisplastic syndrome (MDS) in Spain is reviewed. METHODS AND PATIENTS: Twenty-four children with MDS were analyzed retrospectively. Median age of the patients was 10 years. Twenty patients received a bone marrow graft and 4 an unrelated cord blood (UCB) transplant; 12 bone marrow grafts were from a matched related donor (MRD) and 8 from a matched unrelated donor (MUD). Conditioning regimen consisted of chemotherapy alone in 17 patients (busulfan and cyclophosphamide +/- melfalan) Seven patients received TBI and cyclophosphamide. RESULTS: Ten patients died from transplant-related toxicity and 4 had relapse or disease progression post-AHSCT. Nine patients are alive and event-free with a median follow-up of 120 months. EFS rate in the MRD group was 0.48 (SE 0.13) versus 0.25 (SE 0.12) in the MUD/UCB group (p = .07). Lansky score in survivors is >or=90%. CONCLUSIONS: In this historical series of children with MDS, in spite of severe transplant-related toxicity, encouraging EFS outcomes have been achieved after AHSCT with good quality of life.

Long-term results of two consecutive trials in childhood acute lymphoblastic leukaemia performed by the Spanish Cooperative Group for Childhood Acute Lymphoblastic Leukemia Group (SHOP) from 1989 to 1998.

INTRODUCTION: The first multi-centric protocol for childhood acute lymphoblastic leukaemia (ALL) treatment in Spain started in 1989 and was conducted by the Spanish Pediatric Hematology and Oncology Societies. MATERIALS AND METHODS: A total of 673 patients were included in two consecutive trials, SHOP-89 (1989-1993) and SHOP- 94 (1994-1998). Approximately 67% of the children diagnosed with ALL in Spain during this period were enrolled in these trials. The 250 eligible patients enrolled in the SHOP- 89 study were stratified to either a standard or a high-risk group. Therapy schedule was based on the central nervous system (CNS) therapy designed by St Jude CRH and the Children's Cancer Group, and the post-induction intensification developed by the BFM group. In the SHOP-94 study, a further high-risk group was included in the stratification of the 423 enrolled patients. The therapeutic protocol was characterised by intensification of systemic chemotherapy and the administration of cranial radiotherapy only to patients at high risk of relapse or with CNS involvement at diagnosis. RESULTS: Event-free survival (EFS) increased from 0.57+/- 0.03 at 15 years in SHOP-89, to 0.68+/-0.03 at 11 years in SHOP-94 (p=0.01). Relapse rate decreased from SHOP-89 to SHOP-94: 0.38 vs. 0.25 (p=0.01). CNS relapse rate was 9.1% in SHOP-89 and 4.6% in SHOP-94 (p=0.001). EFS in patients with T-immunophenotype was 0.40+/-0.08 in SHOP-89 and 0.44+/-0.06 in SHOP-94 (p=ns). CONCLUSIONS: Our therapeutic results evidence a significant improvement in EFS and systemic and CNS relapse rates among the two consecutive trials after modification of patient stratification and intensification of systemic chemotherapy.

[Results of the SHOP LNHB98 (LMB89) trial in pediatric patients with B-cell non-Hodgkin's lymphoma]. / Resultados del protocolo SHOP LNHB98 (LMB89) en pacientes de edad pediátrica afectados de linfoma no hodgkiniano de células B.

BACKGROUND AND OBJECTIVE: After the good results obtained by the Société Française d'Oncologie Pédiatrique (SFOP) regarding the pediatric B-type non-Hodgkin's (Burkitt and large B-cell) lymphoma and L3 leukemia, the Sociedad Española de Hematología y Oncología Pediátricas (SHOP) decided to use the same treatment protocol. PATIENTS AND METHOD: Pediatric patients diagnosed with B-type non-Hodgkin's lymphoma without a previous history of malignant diseases were eligible for this study. They were classified in 3 groups of risk: group A (resected stage I and abdominal stage II), group B (not eligible for groups A or C), and group C (with central nervous system involvement and L3 leukemia). All received treatment according to the SFOP's LMB89 protocol. RESULTS: A total of 153 patients were considered in this multicenter, prospective and non-randomized trial (1997-2005). The global and event-free survival (EFS) were found to be of 88% (0.88; 95% confidence interval [CI], 0.83-0.93) and 85% (0.85; 95% CI, 0.79-0.90), respectively. The EFS was 100% for the group A (n = 16), 86% (0.86; 95% CI, 0.79-0.92) for the group B (n = 113), and 68% (0.68; 95% CI, 0.49-0.86) for the group C (n = 24). CONCLUSIONS: The results confirm the good efficiency of the LMB89 protocol for treating B-cell lymphoma and L3 leukemia, despite having diminished the treatment intensity in the less risk groups. The worst prognostic factor was found to be a central nervous system involvement, whereas being younger than 10 years was confirmed to be a favorable prognostic factor. In addition, no differences were evidenced between Burkitt and large B-cell lymphoma.

Resultados del protocolo SHOP LNHB98 (LMB89) en pacientes de edad pediátrica afectados de linfoma no hodgkiniano de células B / Results of the SHOP LNHB98 (LMB89) trial in pediatric patients with B-cell non-Hodgkin's lymphoma

Fundamento y objetivo: Las Sociedades Españolas de Hematología y Oncología Pediátricas (SHOP), ante los buenos resultados obtenidos por la Société Française d'Oncologie Pédiatrique (SFOP) en el tratamiento de los linfomas no hodgkinianos de células B (tipo Burkitt y difuso de células grandes) y de la leucemia aguda linfoblástica tipo 3 en la edad pediátrica, decidieron adoptar la misma línea de tratamiento. Pacientes y método: Se incluyó en el estudio a pacientes pediátricos diagnosticados de novo de linfoma no hodgkiniano de células B y se les clasificó en: grupo A (estadios I completamente resecados y estadios II abdominales); grupo B (no incluidos en A ni en C), y grupo C (afectación del sistema nervioso central o leucemia aguda linfoblástica tipo 3). Recibieron tratamiento según protocolo LMB89 del grupo SFOP. Resultados: Se incluyó a un total de 153 pacientes en este ensayo multicéntrico, prospectivo y no aleatorizado (entre enero de 1997 y abril de 2005). La supervivencia global y la supervivencia libre de eventos (SLE) fueron del 88% (0,88; intervalo de confianza [IC] del 95%, 0,83-0,93) y del 85% (0,85; IC del 95%, 0,79-0,90), respectivamente. La SLE en el grupo A (n = 16) fue del 100%, en el grupo B (n = 113) del 86% (0,86; IC del 95%, 0,79-0,92) y en el grupo C (n = 24) del 68% (0,68; IC del 95%, 0,49-0,86). Conclusiones: Se obtuvieron resultados muy satisfactorios y esperanzadores, a pesar de haber disminuido la intensidad del tratamiento en los grupos de menor riesgo. El peor factor pronóstico fue la afectación del sistema nervioso central en el diagnóstico. La edad menor de 10 años en el momento del diagnóstico fue un claro valor pronóstico favorable. No se observaron diferencias en la SLE entre linfomas tipo Burkitt y difusos de células grandes

Background and objective: After the good results obtained by the Société Française d'Oncologie Pédiatrique (SFOP) regarding the pediatric B-type non-Hodgkin's (Burkitt and large B-cell) lymphoma and L3 leukemia, the Sociedad Española de Hematología y Oncología Pediátricas (SHOP) decided to use the same treatment protocol. Patients and method: Pediatric patients diagnosed with B-type non-Hodgkin's lymphoma without a previous history of malignant diseases were eligible for this study. They were classified in 3 groups of risk: group A (resected stage I and abdominal stage II), group B (not eligible for groups A or C), and group C (with central nervous system involvement and L3 leukemia). All received treatment according to the SFOP's LMB89 protocol. Results: A total of 153 patients were considered in this multicenter, prospective and non-randomized trial (1997-2005). The global and event-free survival (EFS) were found to be of 88% (0.88; 95% confidence interval [CI], 0.83-0.93) and 85% (0.85; 95% CI, 0.79-0.90), respectively. The EFS was 100% for the group A (n = 16), 86% (0.86; 95% CI, 0.79-0.92) for the group B (n = 113), and 68% (0.68; 95% CI, 0.49-0.86) for the group C (n = 24). Conclusions: The results confirm the good efficiency of the LMB89 protocol for treating B-cell lymphoma and L3 leukemia, despite having diminished the treatment intensity in the less risk groups. The worst prognostic factor was found to be a central nervous system involvement, whereas being younger than 10 years was confirmed to be a favorable prognostic factor. In addition, no differences were evidenced between Burkitt and large B-cell lymphoma

Multiple evidence for an early age pro-oxidant state in Down Syndrome patients.

Oxidative stress has been associated with Down syndrome (DS) and with its major phenotypic features, such as early ageing. In order to evaluate an in vivo pro-oxidant state, the following analytes were measured in a group of DS patients aged 2 months to 57 years: (a) leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG); (b) blood glutathione; (c) plasma levels of: glyoxal (Glx) and methylglyoxal (MGlx); some antioxidants (uric acid, UA, ascorbic acid, AA and Vitamin E), and xanthine oxidase (XO) activity. A significant 1.5-fold increase in 8-OHdG levels was observed in 28 DS patients vs. 63 controls, with a sharper increase in DS patients aged up to 30 years. The GSSG:GSH x 100 ratio was significantly higher in young DS patients (< 15 years), in contrast to DS patients aged >or=15 years that showed a significant decrease in the GSSG:GSH x 100 ratio ratio vs. controls of the respective age groups. Plasma Glx levels were significantly higher in young DS patients, whereas no significant difference was detected in DS patients aged >or=15 years. Unlike Glx, the plasma levels of MGlx were found to be significantly lower in DS patients vs. controls. A significant increase was observed in plasma levels of UA in DS patients that could be related to an increased plasma XO activity in DS patients. The plasma concentrations of AA were also increased in young (< 15 years) DS patients, but not in older patients vs. controls in the same age range. The levels of Vitamin E in DS patients did not differ from the values determined in control donors. The evidence for a multiple pro-oxidant state in young DS patients supports the role of oxidative stress in DS phenotype, with relevant distinctions according to patients' ages.