Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients.

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

[Bone mineral density determination by osteosonography in healthy children and adolescents: normal values]. / Estudio de la densidad mineral ósea mediante osteosonografía en niños y adolescentes sanos: valores de normalidad.

BACKGROUND: Osteoporosis is a frequent health problem in adults. Optimization of bone mass acquisition during childhood and adolescence may play a major role in the prevention of this disease. Osteosonography is a recent technique for measuring bone mineralization without exposing the patient to radiation. OBJECTIVES: To measure bone mineral density using osteosonography in healthy Spanish Caucasian children and adolescents in order to determine normal values. METHODS: We performed a cross sectional study of 829 healthy child and adolescent volunteers (360 girls and 469 boys) randomly selected from the urban area of Pamplona in Navarre (Spain). Ages ranged from 6 to 18 years. ADBM Sonic 1200 ultrasound densitometer from IGEA was used. Daily calcium dietary intake and amount of physical activity were recorded. RESULTS: Cross sectional standards for Ad-SOS are presented. Ad-SOS did not significantly change between the ages of 6 and 9 years in girls or until the age of 10 years in boys. From the ages of 10 to 14 years, Ad-SOS values were higher in girls than in boys. After the age of 14 years, no significant differences were found. No correlation was found between calcium dietary intake, amount of physical exercise or bone mineralization values. CONCLUSIONS: Measurement of Ad-SOS by osteosonography is an easy, fast and inexpensive method for measuring bone mineral density in children and adolescents without exposing them to radiation. It can be used in the pediatric population to detect early alterations in bone mineralization.

Estudio de la densidad mineral ósea mediante osteosonografía en niños y adolescentes sanos: valores de normalidad / Measurement of bone mineral desity by osteosonography in healthy children and adolescents: determination of normal values

Antecedentes: La osteoporosis es una enfermedad frecuente en adultos. La adquisición de una masa ósea óptima durante la infancia y adolescencia es importante en la prevención de la enfermedad. La osteosonografía permite valorar la mineralización ósea sin radiación. Objetivos: Determinar la mineralización ósea mediante osteosonografía en niños y adolescentes caucásicos españoles para proporcionar valores normales. Métodos: Estudio transversal en 829 niños y adolescentes voluntarios sanos de edades comprendidas entre los 6 y los 18 años (360 mujeres y 469 varones) seleccionados al azar del área urbana de Pamplona (Navarra). Se utilizó un densitómetro DBM Sonic 1200 de IGEA(r). Se registraron la ingesta diaria de calcio y el grado de ejercicio físico. Resultados: Se presentan los valores de normalidad para la velocidad del sonido (a través del hueso) dependiente de la amplitud (Ad-SOS). La Ad-SOS no cambia de manera significativa desde los 6 a los 9 años en las niñas y hasta los 10 años en los niños. Los valores de la Ad-SOS son más altos en las niñas que en los niños desde los 10 a los 14 años. A partir de esa edad no se encontraron diferencias significativas. No se encontró ninguna correlación entre la ingesta diaria de calcio, el grado de ejercicio físico y la mineralización ósea. Conclusiones: La medida de la Ad-SOS mediante osteosonografía es un método carente de radiación, fácil, rápido y económico para medir la mineralización ósea en niños y adolescentes. Es un método que puede utilizarse en la población pediátrica para la detección precoz de alteraciones en la mineralización ósea (AU)

p21WAF1 mutation is not a predominant alteration in pediatric bone tumors.

The molecular events leading to the development of pediatric bone tumors are not clear to date, but abnormal cell cycle progression has been reported in a wide variety of human tumors due to the alteration of several tumor suppressor genes. We have analyzed 55 bone sarcoma samples from pediatric patients to test the possibility that they harbor mutations in the p21WAF1 tumor suppressor gene. Mutation analysis was performed through denaturing gradient gel electrophoresis analysis of exon 2 of the gene and consequent cycle sequencing of the altered fragments. No mutations affecting the coding regions of the p21WAF1 were found. Nevertheless, we found genetic polymorphisms in nine of the samples analyzed. We conclude that p21WAF1 mutations do not play an important role in the development of this kind of pediatric malignancy.

[Molecular analysis of tumor suppressor genes p16INK4 and TP53 of osteosarcomas in Spanish children]. / Análisis molecular de los genes supresores tumorales p16INK4 y TP53 en osteosarcomas pediátricos en pacientes españoles.

OBJECTIVE: Alterations affecting tumor suppressor genes, specifically p16INK4 and TP53, have been shown to be involved in the development of human cancer due to their important role in the control of normal cell cycle progression. As the genetic events leading to the development of pediatric osteosarcoma remain partially unclear, we have tested the possibility that a significant number of pediatric osteosarcoma patients harbor mutations in these genes. PATIENTS AND METHODS: We have analyzed 64 samples (fresh tissues, paraffin embedded biopsies and peripheral blood lymphocytes) corresponding to 38 pediatric osteosarcoma patients. TP53 mutations were analyzed by DGGE (Denaturing Gradient Gel Electrophoresis) analysis of exons 5 through 8. We searched for deletions in the p16INK4 gene by PCR (Polymerase Chain Reaction) analysis and point mutations were screened by means of SSCP (Single Strand Conformation Polymorphisms). RESULTS: Our analysis showed that 18.4% of the samples harbored mutations in the coding region of TP53 and that 7% had a homozygous deletion of the p16INK4 gene. Our results suggest that p16INK4 deletions may constitute a bad prognostic factor and that TP53 alterations may be correlated, although not statistically, with reduced survival time. CONCLUSIONS: Mutations of the TP53 and deletion of p16INK4 tumor suppressor genes seem to be involved in the development of pediatric osteosarcoma. Moreover, alterations of these genes may constitute a prognostic factor related with poor prognosis or decreased survival time.

[Experience with the use of a subcutaneous venous access system in 57 pediatric patients]. / Experiencia con el uso de un sistema de acceso venoso subcutáneo en 57 pacientes pediátricos.

Since May of 1983 to December of 1988, 62 subcutaneous venous reservoires were implanted in 57 pediatric patients; 29 were boys and the remaining 28 were girls between the ages of 2 and 18 years. Fifty-one patients had malignant illnesses and seven other pathologies. The reservoir was used for the endovenous administration of cytotoxic chemotherapy and antibiotics, hidration, nutrition, the transfusion of blood product and the extraction of samples for laboratory tests. In our experience the most important complication was the infection of the system, on the average 0.06 episodes of infections occurred for every 100 days per reservoir. Other complications observed were less frequent. In our opinion the subcutaneous reservoir represents an useful tool for the care of the pediatric patients who require a central venous catheter for long periods of time.