EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma.

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.

Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome.

BACKGROUND: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is <15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES. PATIENTS AND METHODS: We carried out a pharmacogenetic study of 384 single-nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe. RESULTS: We identified associations with OS (P < 0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette subfamily C member 6 (ABCC6) gene [discovery: hazard ratio (HR) = 14.30, 95% confidence interval (CI) = 1.53-134, P = 0.020; replication: HR = 9.28, 95% CI = 2.20-39.2, P = 0.0024] and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette subfamily B member 1 (ABCB1) gene (discovery: HR = 2.96, 95% CI = 1.08-8.10, P = 0.034; replication: HR = 1.60, 95% CI = 1.05-2.44, P = 0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR = 2.49, 95% CI = 1.06-5.87, P = 0.037; replication: HR = 1.77, 95% CI = 1.06-2.96, P = 0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated. CONCLUSION: Using an integrated pathway-based approach, we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.

Aspectos inmunológicos de la leucemia mieloblástica aguda / An immunological approach to acute myeloid leukaemia

INTRODUCCIÓN: La leucemia mieloblástica aguda (LMA) constituye la segunda hemopatía maligna en la población pediátrica y una de las principales causas de mortalidad por cáncer infantil. La supervivencia se sitúa alrededor del 60% sin haber mejorado en las últimas décadas, por lo que son necesarios nuevos enfoques terapéuticos. El efecto antileucémico ejercido por los linfocitos y las células natural killer (NK) del sistema inmunológico está bien establecido en el trasplante de células madre hematopoyéticas pero también como estrategia de inmunoterapia adoptiva tras la quimioterapia de consolidación. PACIENTES Y MÉTODOS: De manera retrospectiva, se analizan las características clínicas de los pacientes diagnosticados de LMA en nuestro centro durante el período 1996-2014. Además en 10 leucemias agudas, 5 linfoides y 5 mieloides, se analizaron la intensidad media de fluorescencia de HLA-I, MICA-B, ULBP1-4, ligandos para los receptores de las células NK. RESULTADOS: Un total de 67 pacientes formaron parte de este análisis. La supervivencia libre de eventos con una mediana de seguimiento de 25 meses fue del 62% (IC del 95%, 55-67). Las LMA con menor supervivencia fueron las secundarias, las no M3 y las carentes de marcadores citogenéticos favorables. La probabilidad de recaída fue del 38% (IC del 95%, 31-45). La expresión de HLA-I y ULBP-4 fue significativamente menor en los blastos mieloides que en los linfoides. CONCLUSIONES: Nuestros resultados clínicos son similares a los descritos en la literatura. No se ha modificado significativamente la supervivencia en las últimas décadas y la probabilidad de recaída sigue siendo elevada. Los blastos mieloides podrían ser más susceptibles a las células NK al expresar menos HLA-I, por lo que estrategias de terapia celular podrían ser eficaces tal y como reportan otros grupos

INTRODUCTION: Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. PATIENTS AND METHODS: A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. RESULTS: A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. CONCLUSIONS: Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups

[An immunological approach to acute myeloid leukaemia]. / Aspectos inmunológicos de la leucemia mieloblástica aguda.

INTRODUCTION: Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. PATIENTS AND METHODS: A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. RESULTS: A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. CONCLUSIONS: Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups.

Mortalidad infantil en un hospital de nivel terciario. Limitación de esfuerzo terapéutico, correspondencia clínico-patológica y precisión diagnóstica / Infant mortality in a third level paediatric hospital. therapeutic effort limitation, clinical-pathological agreement and diagnostic accuracy

Objetivo: Analizar la mortalidad en un hospital infantil de tercer nivel y alta complejidad. Material y métodos: Se revisaron los fallecidos en el Hospital Infantil La Paz durante los años 2007, 2008 y 2009. Se analizaron datos epidemiológicos, diagnósticos clínicos y de autopsia y su correspondencia, y si se llegaba a un diagnóstico etiológico definitivo. La limitación del esfuerzo terapéutico y la previsibilidad del fallecimiento también fueron recogidas. Las variables fueron prospectivamente definidas al inicio. Resultados: Se estudiaron 253 fallecimientos (6,08 por mil ingresos). El 43,4% eran menores de 1 mes y el 63,9% menores de un año. La patología neonatal y la hemato-oncológica fueron las causas más frecuentes. Fallecieron en las tres unidades de cuidado intensivo el 87%. Se practicó autopsia a 53% de los fallecidos y se detectó un 7,8% de nuevos hallazgos significativos, aunque solo en un caso podría el tratamiento haber modificado el pronóstico. Limitación de esfuerzo terapéutico y cuidado paliativo se instauró en el 41,9%. El fallecimiento era esperado al inicio del proceso en 83,9%, En 92% se consideró que existía un diagnóstico definitivo y en 86,4% un diagnóstico etiológico de los procesos que condujeron al fallecimiento. Conclusiones: El análisis de la mortalidad hospitalaria permite evaluar la calidad de la asistencia pediátrica y detectar resultados adversos. La autopsia continúa proporcionando información relevante. La limitación de esfuerzo terapéutico y cuidado paliativo es una medida cada vez más frecuente en la edad pediátrica. El número de niños que muere sin diagnóstico etiológico sigue siendo alto(AU)

Objective: To study infant and child mortality in a third level children's hospital treating highly complex patients. Patients and methods: All children dying in the period 2007- 2009 at La Paz Children's Hospital were evaluated. Epidemiological data, autopsy rate, clinical and autopsy diagnoses and their correspondence and the number of, patients with precise final diagnoses were analysed. Therapeutic effort limitation and palliative care were also evaluated as well as if the final result was expected according to the initial disease or clinical condition of the patients. All the variables were prospectively defined at the start of the study period. Results: A total of 253 cases (6.08‰ admissions) were analysed. The two leading causes of death were disorders related to prematurity and low birth weight, and haematology oncology malignant diseases. Most patients (87%) died in an intensive care unit (neonatal or paediatric). During the study period 134 autopsies (53%) were performed, and new clinically significant findings were observed in 12 of these (7.8%) but in only one case the treatment could have possibly modified the prognosis (class I discrepancy). Therapeutic effort limitation and palliative care were implemented in 41.9%. Death was initially expected in 83.9% of cases. An accurate final diagnosis was defined in 92%, and the aetiology of the disease was considered to be identified in 86.4% of all deaths. Conclusions: Hospital mortality analysis is useful to evaluate the quality of the paediatric care and to detect adverse results that could be corrected. Paediatric autopsy continues to provide clinically significant data for paediatricians and families. Therapeutic effort limitation and palliative care is increasingly applied in paediatric end of life care. The number of infants and children dying without a final aetiological diagnosis is still considerably high(AU)

[Infant mortality in a third level paediatric hospital. therapeutic effort limitation, clinical-pathological agreement and diagnostic accuracy]. / Mortalidad infantil en un hospital de nivel terciario. Limitación de esfuerzo terapéutico, correspondencia clínico-patológica y precisión diagnóstica.

OBJECTIVE: To study infant and child mortality in a third level children's hospital treating highly complex patients. PATIENTS AND METHODS: All children dying in the period 2007- 2009 at La Paz Children's Hospital were evaluated. Epidemiological data, autopsy rate, clinical and autopsy diagnoses and their correspondence and the number of, patients with precise final diagnoses were analysed. Therapeutic effort limitation and palliative care were also evaluated as well as if the final result was expected according to the initial disease or clinical condition of the patients. All the variables were prospectively defined at the start of the study period. RESULTS: A total of 253 cases (6.08‰ admissions) were analysed. The two leading causes of death were disorders related to prematurity and low birth weight, and haematology oncology malignant diseases. Most patients (87%) died in an intensive care unit (neonatal or paediatric). During the study period 134 autopsies (53%) were performed, and new clinically significant findings were observed in 12 of these (7.8%) but in only one case the treatment could have possibly modified the prognosis (class I discrepancy). Therapeutic effort limitation and palliative care were implemented in 41.9%. Death was initially expected in 83.9% of cases. An accurate final diagnosis was defined in 92%, and the aetiology of the disease was considered to be identified in 86.4% of all deaths. CONCLUSIONS: Hospital mortality analysis is useful to evaluate the quality of the paediatric care and to detect adverse results that could be corrected. Paediatric autopsy continues to provide clinically significant data for paediatricians and families. Therapeutic effort limitation and palliative care is increasingly applied in paediatric end of life care. The number of infants and children dying without a final aetiological diagnosis is still considerably high.

High-risk hepatoblastoma: results in a pediatric liver transplantation center.

AIM: Aim of the study was assess the results of the treatment of High-Risk Hepatoblastoma (HRH) in a tertiary center where all liver surgery facilities, including pediatric transplantation (LT), are available. METHODS: 91 primary liver tumors treated between 1991 and 2009 were retrospectively reviewed. HRHs as defined by the SIOP criteria (PRETEXT IV or any stage with venous involvement, extrahepatic disease, tumor rupture and <100 ng/ml serum AFP) were identified and imaging and biopsies were reviewed. The treatment consisted of total removal of the tumor, involving extended hepatectomies and LT if necessary, together with SIOPEL-guided chemotherapy. RESULTS: 23/57 hepatoblastomas were HRH (11F/12M). 17 were considered unresectable by standard techniques, 3 had extrahepatic disease, and 3 fulfilled both criteria. Mean age at diagnosis was 2.3 ± 2.4 years. 3 children (referred after chemotherapy) died without surgery. 4 had resections (2 left and 2 right trisegmentectomies). Primary LT was required in 15 children (7 cadaveric donors and 8 living related donor transplantations (LRDT), 2 of them with retrohepatic vena cava replacement), and 1 patient had rescue LT after recurrence. Mean follow-up was 4.8 ± 2.9 years. 2 children who had undergone liver resection developed pulmonary metastases at 1.7 and 1.6 years postoperatively and survived after surgical treatment. 2 children with LT developed EBV-related lymphoma and leukemia respectively but survived. Event-free survival (EFS) at 1, 5, and 10 years was 78.3 ± 8.6%, 63.1 ± 10.5%, and 63.1 ± 10.5%, respectively. 6 children died (3 without surgery, 1 after liver resection, 1 after primary LT and 1 after rescue LT). Overall survival at 1, 5 and 10 years was 78.3 ± 21.7%, 73.2 ± 26.8% and 73.2 ± 26.8%. Of those with primary LT, survival at 1, 5 and 10 years was 93.3 ± 6.4%, 93.3 ± 6.4% and 93.3 ± 6.4%. CONCLUSIONS: Outstanding results in the treatment of HRH are possible in tertiary centers when referral is early (preferably at diagnosis) and specialized liver surgery and transplantation facilities are available.

Long-term results of the Spanish Protocol SO-95 for the treatment of non-metastatic high-grade osteosarcoma of the extremities in children

INTRODUCTION: The long-term results of the Spanish Study Protocol SEOP-SO-95 for treatment of localised osteosarcoma of the extremities in children were evaluated. PATIENTS AND METHODS: One hundred consecutive patients under 18 years of age from 22 institutions were enrolled from January 1995 to December 2000. Immunohistochemical expression of p53, HER/erbB-2 and P-glycoprotein were retrospectively studied in 27 patients. Treatment consisted of: preoperative chemotherapy with doxorubicin, cisplatin, high-dose methotrexate with leucovorin rescue and ifosfamide for 14 weeks; surgery of primary tumour in week 16; postoperative chemotherapy with the above-mentioned drugs for 25 weeks. RESULTS: With a median follow-up of 124 months (range 84-158 months), 69 patients (69%) were continuously event-free survivors; the 10-year probability of event-free survival (EFS) was 62%. Conservative surgery was performed in 85% of patients. Twenty-six patients had local recurrence or distant relapse. The median time to recurrence/ relapse was 27 months (range 17-93 months). The local recurrence rate was 7% (7 of the 100 patients); 4 had wide surgical margins, 2 marginal and 1 intralesional. Four patients died as a result of chemotherapy-related toxicity and 1 developed a second neoplasia (acute myeloid leukaemia). p53 expression and HER2/erbB-2 expression showed no effect on survival or EFS. CONCLUSIONS: This therapeutic protocol achieved good oncologic and orthopaedic results. We observed a significant treatment-related toxicity (AU)

Nuevos fármacos en oncología pediátrica / New drugs in pediatric oncology

Actualmente el 75-80% de los niños que padecen una neoplasia conseguirán sobrevivir. El resto de pacientes fallecerán a causa del cáncer, la gran mayoría a causa de la progresión de su tumor. A pesar de los grandes avances en los tratamientos antineoplásicos desarrollados en las últimas décadas, aún existen tumores que por su histología, localización o bien por su extensión al diagnóstico, resultan muy difíciles de curar. También tumores inicialmente sensibles a la quimioterapia se hacen resistentes y progresan a pesar de todo tipo de tratamiento. Es indudable que se necesitan más armas terapéuticas para luchar contra estos casos de mal pronóstico. Aunque el desarrollo de nuevos antineoplásicos para tumores infantiles es más lento que en los adultos, varios medicamentos ofrecen resultados preliminares muy esperanzadores: anticuerpos monoclonales, como rituximab y gemtuzumab, ozogamicin en neoplasias hematológicas; inhibidores de la topoisomerasa I, como topotecan e irinotecan en los tumores sólidos; y los antiangiogénicos, en estudio para todo tipo de tumores son algunos ejemplos. Existen muchas drogas en desarrollo, aún en fases muy preliminares. Es de esperar que en no mucho tiempo, gracias a ellas, mejore el pronóstico de los tumores en los que aún nos e consigue una buena supervivencia (AU)

Currently, 75%-80% of children who suffer a neoplasm survive it. The rest of the patients will die because of the cancer, most because of tumor progression. Tumors still exist in spite of the great advances inantineoplastic treatment developed in recent decades. However, these are very difficult to cure due to their histology, location or extension on diagnoses. In addition, tumors that are initially sensitive to chemotherapy become resistant and progress in spite of all the different types of treatment. Undoubtedly, more therapeutic armamentarium is needed to fight against these cases having poor prognosis. Although the development of new antioneoplastics for childhood tumors is slower than in the adults, several drugs offer very encouraging preliminary results. A few examples are monoclonal antibodies such as Rituximab and Gemtuzumab Ozogamicin in blood neoplasms; Topoisomerase I inhibitors such as Topotecan and Irinotecan in solid tumors, and antigenic ones, under study for all types of tumors. There are many drugs still being developed, although in very preliminary phases. It is expected that thanks to them, the prognoses of the tumors for which good survival rate has not been achieved as of yet will improve in a short time (AU)

Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma.

Ewing's sarcoma (ES) is characterized by specific chromosome translocations, the most common being t(11;22)(q24;q12). Additionally, other type of genetic abnormalities may occur and be relevant for explaining the variable tumour biology and clinical outcome. We have carried out a high-resolution array CGH and expression profiling on 25 ES tumour samples to characterize the DNA copy number aberrations (CNA) occurring in these tumours and determine their association with gene-expression profiles and clinical outcome. CNA were observed in 84% of the cases. We observed a median number of three aberrations per case. Besides numerical chromosome changes, smaller aberrations were found and defined at chromosomes 5p, 7q and 9p. All CNA were compiled to define the smallest overlapping regions of imbalance (SORI). A total of 35 SORI were delimited. Bioinformatics analyses were conducted to identify subgroups according to the pattern of genomic instability. Unsupervised and supervised clustering analysis (using SORI as variables) segregated the tumours in two distinct groups: one genomically stable (< or =3 CNA) and other genomically unstable (>3 CNA). The genomic unstable group showed a statistically significant shorter overall survival and was more refractory to chemotherapy. Expression profile analysis revealed significant differences between both groups. Genes related with chromosome segregation, DNA repair pathways and cell-cycle control were upregulated in the genomically unstable group. This report elucidates, for the first time, data about genomic instability in ES, based on CNA and expression profiling, and shows that a genomically unstable group of Ewing's tumours is correlated with a significant poor prognosis.

Trasplante hepático en tumores malignos en el niño / Liver transplantation for malignant tumors in children

Objetivo. Analizar nuestros resultados con el trasplante hepático (TxH) en tumores primitivos hepáticos malignos irresecables. Discutirlas indicaciones controvertidas en base a nuestra experiencia. Pacientes. Doce niños (edad 6 meses-14 años) con hepatoblastoma (11)y hepatocarcinoma (1) sin cirrosis. El TxH se planteó como tratamiento primario en 10 casos (catalogados como PRETEXT IV o con cualquier grado si tenían extensión a cava retrohepática, a 3 venas hepáticaso a tronco de la porta o sus 2 ramas principales) y como tratamiento de rescate tras recidiva (1) o constancia de persistencia de restos (..) (AU)

Objective. To analyse our results on liver transplantation(LTX) in primitive malignant unresectable liver tumours in children and discussing its controversial indications in order to our experience. Methods/Patients. We report 12 patients with ages ranging from 6 months to 14 years old. They had hepatoblastoma (11) and fibrolamellar hepatocellular carcinoma (1) without cirrhosis. LTX was considered as primary treatment in 10 patients (PRETEXT IV or any grade if extension to retrohepaticcava vein, 3 hepatic veins or porta vein were assessed) and as rescuetherapy after recurrence (1) or persistence of unresectable macroscopicrests (2). One of the patients who underwent a LTX as primary therapy had lung metastases previously resolved with chemotherapy. We usedentire liver (5), left lateral segment from cadaveric donor (3), live related donor (3, 2 segments II-III and 1 right liver) and left lateral segment (..) (AU)

[Liver transplatation for malignant tumors in children]. / Trasplante hepático en tumores malignos en el niño.

OBJECTIVE: To analyse our results on liver transplantation (LTX) in primitive malignant unresectable liver tumours in children and discussing its controversial indications in order to our experience. METHODS/PATIENTS: We report 12 patients with ages ranging from 6 months to 14 years old. They had hepatoblastoma (11) and fibrolamellar hepatocelullar carcinoma (1) without cirrhosis. LTX was considered as primary treatment in 10 patients (PRETEXT IV or any grade if extension to retrohepatic cava vein, 3 hepatic veins or porta vein were assessed) and as rescue therapy after recurrence (1) or persistence of unresectable macroscopic rests (2). One of the patients who underwent a LTX as primary therapy had lung metastases previously resolved with chemotherapy. We used entire liver (5), left lateral segment from cadaveric donor (3), live related donor (3, 2 segments II-III and 1 right liver) and left lateral segment from split (1). All children received chemotherapy prior and post-transplantation following SIOPEL protocol. OUTCOMES ANALYSED: Procedure tolerance, survival, recurrence rate, disease-free period and risk factors for adverse evolution. RESULTS: All patients overcame the LTX and no early loss of the graft was assessed. 2 patients died because of tumoral relapse, 1 after primary LTX and 1 after rescue LTX (survival rate of both groups 90% vs 50%). Graft and patients 1-year, 3-year, 5-year and 14-year survival were 91%, 91%, 82% and 82% respectively. The boy who presented lung metastases developed new ones one year after LTX that were removed and he actually is free of disease. The disease-free period has a probability for 1, 3 and 5 years of 91%, 75% and 75%. Tumoral tissue persistence is the only risk factor for an adverse evolution in our series. CONCLUSIONS: LTX is possible therapeutic approach for unresectable malignant liver tumours. It provides better results as a primary treatment than as a rescue one, being these outcomes comparable to those from resectable tumours. A right staging and referring patients to an expertise centre contribute to optimize results. LTX for patients presenting with lung metastases could be a controversial option. Live-related donor transplantation is an excellent alternative to avoid disease progression during cadaveric waiting list.

Liver transplantation for malignant tumours in children.

OBJECTIVE: The object of this study was to analyse our results with liver transplantation (LTX) for primitive malignant unresectable liver tumours in children and to discuss the controversial indications, based on our experience. METHODS/PATIENTS: We report on 12 patients, aged 6 months to 14 years, with hepatic malignant tumours: 11 with hepatoblastoma and 1 with fibrolamellar hepatocelullar carcinoma without cirrhosis. LTX was the primary treatment in 10 patients (PRETEXT IV or any grade, if there was extension to the retrohepatic vena cava, 3 hepatic veins or portal vein) and a rescue therapy after recurrence for 1 and for persistence of unresectable macroscopic residuals in 2 patients. One of the patients who underwent a LTX as primary therapy had lung metastases previously resolved with chemotherapy. We used entire liver (n = 5), left lateral segment from cadaveric donor (n = 3), living related donor (n = 3; 2 segments II-III and 1 right lobe) and left lateral segment from split liver (n = 1). All children received chemotherapy prior and post transplantation following the SIOPEL protocol. We analysed procedure tolerance, survival, recurrence rate, disease-free period and risk factors for adverse evolution. RESULTS: All patients overcame LTX and no early graft loss was recorded. Two cases died because of tumour relapse, 1 after primary LTX and 1 after rescue LTX (survival rate of both groups, 90% and 50%). Graft and patient survival rates at 1 year, 3 years, 5 years and 14 years were 91%, 91%, 82% and 82% respectively. The boy who presented with lung metastases developed new ones one year after LTX that were removed and he is currently free of disease. The disease-free period has a probability at 1, 3 and 5 years of 91%, 75% and 75%, respectively. Tumour tissue persistence was the only risk factor for an adverse clinical course in our series. CONCLUSIONS: LTX is a reasonable therapeutic approach for unresectable malignant liver tumours, providing outcomes comparable to those for resectable tumours. Results obtained with LTX are better when it is used as a primary treatment than when used as a rescue procedure. Proper staging and early referral to centres with enough expertise optimise the results. LTX for patients with lung metastases could be a controversial option. Living related-donor transplantation is an excellent alternative to avoid disease progression while on the waiting list for cadaveric donors.

Lymphoproliferative disorders in paediatric rheumatic diseases. A report of two cases.

Lymphoproliferative disorders (LPD) are reported with a much lower frequency in children with rheumatic diseases than in their adult counterparts. We describe 2 patients who developed a lymphoma during the course of the disease. The first is a 16-year-old girl diagnosed with systemic juvenile idiopathic arthritis 6 years before who developed a mucosa-associated lymphoid tissue (MALT) lymphoma. The second report involves a boy diagnosed with systemic lupus erythematosus at 9 years of age who developed a Hodgkin's lymphoma 9 years after the disease onset. In spite of the low frequency of LPD in children with rheumatic diseases, these processes do occur.

Analysis of factors affecting PBPC collection in low-weight children with malignant disorders.

BACKGROUND: PBPC collection in children weighing

Outcome of high-risk neuroblastoma using a dose intensity approach: improvement in initial but not in long-term results.

BACKGROUND: Stage 4 and MYCN amplified (MNA) neuroblastoma in children have a poor prognosis. Our aim was to increase initial and long-term response in this population. PROCEDURE: High-risk children were studied according to the International Neuroblastoma Staging System, then treated with high-dose cyclophosphamide and high-dose carboplatin, followed by surgery and autologous stem cell transplant or maintenance chemotherapy. RESULTS: From June 1992 to December 1998, 83 children were admitted in the study (72 stage 4> 1 year, 5 stage 4 MNA infants, and 6 MNA stage 3 children); tumor tissue was obtained from 73, MYCN was performed in 65, being amplified in 21 (32%). Induction chemotherapy was administered in the expected time in 35% of patients. Its toxicity was mainly hematologic followed by infections, and there were 3 chemotherapy-related deaths. Delayed surgery was performed on 60 patients with complete or >90% resection in 80% of cases. Chemotherapy plus surgery produced some response in 90% of patients, 53% were in CR/VGPR; 49 children received autologous SCT, and 16 received maintenance chemotherapy for 9 months. Follow-up ranges are 1-87 months, mean 30 months. S and EFS at 4 years are 0.33 (SD 0.02). CONCLUSIONS: High-dose cyclophosphamide and high-dose carboplatin are effective in the initial treatment of neuroblastoma; combined with surgery they produce some response in most patients. Nevertheless, the CR/VGPR rate reaches only 53%. Survival time has also been prolonged but most patients relapse with metastases.

Consentimiento informado en Pediatría. Consentimiento informado para el tratamiento de procesos malignos infantiles / Informed consent in pediatrics. Informed consent for the treatment of infant malignant conditions

No disponible

Ewing's sarcoma of the mandible: radiologic features with emphasis on magnetic resonance appearance.

Ewing's sarcoma is an uncommon malignancy that usually occurs in children. A case of Ewing's sarcoma of the mandible is presented, and the radiologic appearance is described, with special consideration given to the magnetic resonance imaging features.