[Ionizing radiation received by patients with osteosarcoma during intra-arterial chemotherapy treatment]. / Radiación ionizante recibida por pruebas de radiología intervencionista durante el tratamiento con quimioterapia intraarterial en pacientes afectos de osteosarcoma.

BACKGROUND: Osteosarcoma paediatric patients are usually treated with intra-arterial chemotherapy (QTia) which is admi-nistered directly to the tumour. This procedure exposes patients to ionizing radiation. Paediatric patients are especially sensitive to this exposure. METHODS: The total amount of ionizing radiation received from QTia administration was quantified in a group of 16 osteo-sarcoma paediatric patients from the Clínica Universidad de Navarra. RESULTS: The median of the total radiation received per patient was 33.4 Gy·cm2 (IQR: 43.33 Gy·cm2), and the median number of procedures performed per subject was 10 (IQR: 6.5). CONCLUSIONS: The study highlights the importance of quantifying the radiation received by a group of children and adoles-cents affected by osteosarcoma during treatment with QTia. Long-term side effects of this radiation should be considered in pae-diatric patients. Currently, there are no previous studies that provide data of the amount of ionizing radiation received through this procedure.

Radiación ionizante recibida por pruebas de radiología intervencionista durante el tratamiento con quimioterapia intraarterial en pacientes afectos de osteosarcoma / Ionizing radiation received by patients with osteosarcoma during intra-arterial chemotherapy treatment

Fundamento: Los pacientes afectos de osteosarcoma reciben tratamiento con quimioterapia administrada por vía intraarterial (QTia)3 directamente al tumor y son expuestos a radiación ionizante durante el mismo. Los pacientes pediátricos son especialmente vulnerables a esta exposición. Material y métodos: Se registró la cantidad de radiación ionizante recibida por 16 pacientes pediátricos afectos de osteosarcoma durante la administración de QTia en la Clínica Universidad de Navarra. Resultados: La mediana de radiación total recibida fue de 33,4 Gy·cm2 (IQR 43,33 Gy·cm2) y la mediana de número de pruebas por paciente de 10 (IQR: 6.5). Conclusión: El estudio resalta la importancia de cuantificar la radiación recibida por un grupo de niños y adolescentes afectos de osteosarcoma durante el tratamiento con QTia ya que no conviene olvidar los potenciales efectos adversos a largo plazo de esta exposición. Actualmente, no existen estudios previos que aporten datos acerca de la cantidad de radiación ionizante recibida a través de este procedimiento (AU)

Background: Osteosarcoma paediatric patients are usually treated with intra-arterial chemotherapy (QTia) which is administered directly to the tumour. This procedure exposes patients to ionizing radiation. Paediatric patients are especially sensitive to this exposure. Methods: The total amount of ionizing radiation received from QTia administration was quantified in a group of 16 osteosarcoma paediatric patients from the Clínica Universidad de Navarra. Results: The median of the total radiation received per patient was 33.4 Gy·cm2 (IQR: 43.33 Gy·cm2), and the median number of procedures performed per subject was 10 (IQR: 6.5). Conclusions: The study highlights the importance of quantifying the radiation received by a group of children and adolescents affected by osteosarcoma during treatment with QTia. Long-term side effects of this radiation should be considered in paediatric patients. Currently, there are no previous studies that provide data of the amount of ionizing radiation received through this procedure (AU)

Papillon-Lefèvre syndrome: a case report and review of the literature

Describimos el caso clínico de un niño de 9 años y medio afecto de periodontitis e hiperqueratosis desde los 5 años de edad. Queremos destacar la afectación generalizada de toda la dentición, las alteraciones inmunológicas encontradas y la discreta afectación dermatológica, siendo el cuadro estomatológico el que identifica en su mayor parte la enfermedad. El tratamiento precoz con acitretino puede mejorar tanto la evolución de las lesiones dérmicas como de la periodontitis

We report the case of a nine-and-a-half-year-old boy who had had periodontitis and hyperkeratosis since the age of five. We describe the involvement of the entire dentition, the associated immunological disorders, and the discrete cutaneous findings. This disease is chiefly identified by its stomatologic features. Early treatment with acitretin can improve the outcome of both the skin lesions and the periodontitis

[The cytogenetic assay as a measure of genetic instability induced by genotoxic agents]. / El ensayo de micronúcleos como medida de inestabilidad genética inducida por agentes genotóxicos.

Human genetic integrity is compromised by the intense industrial activity, which emphasizes the importance to determine an "acceptable" genetic damage level and to carry out routine genotoxicity assays in the populations at risk. Micronuclei are cytoplasmatic bodies of nuclear origin which correspond to genetic material that is not correctly incorporated in the daughter cells in the cellular division; they reflect the existence of chromosomal aberrations and are originated by chromosomal breaks, replication errors followed by cellular division of the DNA and/or exposure to genotoxic agents. There are several factors able to modify the number of micronuclei present in a given cell, among them are age, gender, vitamins, medical treatments, daily exposure to genotoxic agents, etc. The cytogenetic assay for the detection of micronuclei (CBMN: cytokinesis-block micronucleus) is based on the use of a chemical agent, cytochalasin-B, which is able to block cytocinesis but allowing the nuclear division, therefore yielding binucleated and monodivided cells. The micronuclei scoring is performed on 1000 binucleated cells and the starting sample may vary, although most studies are performed on peripheral blood lymphocytes. The micronuclei assay is considered a practical, universally validated and technically feasible protocol which is useful to evaluate the genetic instability induced by genotoxic agents.

El ensayo de micronúcleos como medida de inestabilidad genética inducida por agentes genotóxicos / The cytogenetic assay as a measure of genetic instability induced by genotoxic agents

La integridad genética de la población humana se encuentra comprometida por la gran actividad industrial; por lo que es importante determinar qué se conoce como un nivel “aceptable” de daño genético y realizar ensayos de genotoxicidad de manera rutinaria en poblaciones de riesgo. Los micronúcleos son cuerpos citoplasmáticos de naturaleza nuclear, se corresponden con material genético no incorporado correctamente a las células hijas durante la división celular, reflejan aberraciones cromosómicas y se originan por roturas cromosómicas, por errores durante la replicación y posterior división celular del ADN y/o por la exposición a agentes genotóxicas. Existen factores capaces de influir o modificar el número de micronúcleos presentes en una célula (edad, género, vitaminas, tratamientos médicos, exposición diaria a agentes genotóxicos, etc.).El ensayo citogenético para la detección de micronúcleos (CBMN: cytokinesis-block micronucleus) se basa en la utilización de un agente químico, denominado citocalasina-B capaz de impedir la citocinesis permitiendo la división nuclear proporcionando a las células un aspecto de células binucleadas monodivididas. El recuento de micronúcleos se realiza sobre 1.000 células binucleadas y la muestra de partida puede variar aunque lo óptimo es el uso de linfocitos aislados de sangre periférica.El ensayo de micronúcleos está considerado como un ensayo práctico, universalmente validado y accesible tecnológicamente, útil para evaluar la inestabilidad genética inducida por agentes genotóxicos

Human genetic integrity is compromised by the intense industrial activity, which emphasizes the importance to determine an “acceptable” genetic damage level and to carry out routine genotoxicity assays in the populations at risk. ;;Micronuclei are cytoplasmatic bodies of nuclear origin which correspond to genetic material that is not correctly incorporated in the daughter cells in the cellular division; they reflect the existence of chromosomal aberrations and are originated by chromosomal breaks, replication errors followed by cellular division of the DNA and/or exposure to genotoxic agents. There are several factors able to modify the number of micronuclei present in a given cell, among them are age, gender, vitamins, medical treatments, daily exposure to genotoxic agents, etc. ;;The cytogenetic assay for the detection of micronuclei (CBMN: cytokinesis-block micronucleus) is based on the use of a chemical agent, cytochalasin-B, which is able to block cytocinesis but allowing the nuclear division, therefore yielding binucleated and monodivided cells. The micronuclei scoring is performed on 1000 binucleated cells and the starting sample may vary, although most studies are performed on peripheral blood lymphocytes. ;;The micronuclei assay is considered a practical, universally validated and technically feasible protocol which is useful to evaluate the genetic instability induced by genotoxic agents

TNF-alpha promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic-onset juvenile idiopathic arthritis.

OBJECTIVE: To explore the possible association/s of the first reported tumour necrosis factor (TNF-alphaTNF-) alpha promoter gene polymorphisms -308, -238, -376 and -163 (G-->A) with systemic (SoJIA) and oligoarticular subtypes of juvenile idiopathic arthritis (JIA); and to test the association between these polymorphisms and the class I/class II HLA alleles in our population. METHODS: The patient group comprised 29 oligoarticular and 26 systemic Caucasian Spanish children with JIA; 68 healthy volunteers from the same ethnic group and geographical region served as controls. HLA alleles were determined using low-resolution polymerase chain reaction (PCR). TNF-alpha promoter gene polymorphisms were screened using PCR denaturing gradient gel electrophoresis (PCR-DGGE), followed, if positive, by restriction fragment length polymorphism (RFLP) analysis for identification. RESULTS: No statistical association was found between the four polymorphisms studied and JIA. However, the -308 G-->A polymorphism (TNF A2) tended to be more frequent in patients with SoJIA than in the oligoarticular group. TNF A2 was strongly associated with the extended haplotype A1B8DR3 (p = 0.003), and the tandem polymorphism -238/-376 in the presence of B18 and DR3. CONCLUSION: The TNF A2 allele was more frequent in SoJIA than in the oligoarticular group. TNF A2 can help to create a more inflammatory milieu in this JIA subtype, in combination with other polymorphisms involved in regulatory sequences of key molecules in the inflammatory response. The association of the -308 and -238/-376 polymorphisms with specific alleles of the HLA is reconfirmed.

[Vascular malformations as syndromic markers]. / Malformaciones vasculares como marcadores sindrómicos.

Vascular malformations are static lesions, generally present at the moment of birth, formed by displasic vessels that grow in proportion to the growth of the child. They show normal cell replacements that constitute genuine mistakes of morphogenesis. The absence of regression of these malformations implies that they remain throughout the lifetime. The terminology describing this type of lesions gave rise to confusion in the medical literature until the International Society for the Study of Vascular Anomalies adopted a classification based on the dominant vessel of the malformation in 1996. This classification distinguishes between simple and complex forms depending on whether they affect one or several types of vessel. Vascular malformations can show themselves as isolated lesions or can be associated with other lesions, constituting the guide sign or being the principal marker of some syndromic complexes. This paper describes the principal signs and symptoms of those syndromes in which a vascular malformation is the key that raises suspicion about the existence of other associated lesions.

Current role for resection of thoracic metastases in children and young adults--do we need different strategies for this population?

UNLABELLED: A retrospective review of surgical interventions for pulmonary metastases found 44 surgical metastasectomies in patients 20 years old or younger. OBJECTIVE: Indications for pulmonary metastasectomy are well established in adults, but are not so clear when we are dealing with a younger population. PATIENTS AND METHODS: A retrospective review of surgical interventions for pulmonary metastases (from December 1996 to October 2001) found 44 surgical metastasectomies in patients considered pediatric or young adults (20 years old or younger). Initial primary tumor, disease-free interval (DFI), previous thoracotomies, tumor histology, number of metastases, surgery performed, postoperative complications, other treatments received, and outcomes were recorded. RESULTS: Median age was 16.3 years (range 5 to 20 years) with 27 male and 17 female patients. Primary tumors were sarcoma (n = 31), Ewing's tumor (n = 8), Wilms' tumor (n = 3), and testicular carcinoma (n = 2). 27 patients had undergone previous resection of pulmonary metastases. Approaches were posterolateral thoracotomy (n = 18), clamshell incision (n = 8), VATS (n = 7), axillary thoracotomy (n = 9), and others (n = 2). Wedge resections were the procedure of choice (n = 35). In very select cases 1 pneumonectomy, 3 lobectomies, 2 chest wall resections, and 1 spinal surgery (vertebrectomy) were performed. Intra-operative radiotherapy (IORT) was employed in 2 patients. Cardiopulmonary bypass was necessary in 1 patient in order to resect an intra-atrial tumor thrombus. There was no operative mortality. Morbidity was related to prolonged air leaks (3 patients), hemothorax (2 patients), cerebrospinal fluid leak (1 patient), atelectasia (1 patient), peritoneal pain (1 patient), and postoperative fever syndrome (1 patient). Patterns of failure were thoracic (lung-pleura-chest wall) (n = 20), distant (n = 3) and thoracic + distant (n = 6). CONCLUSION: A close collaboration between oncologists, radiotherapists, and surgeons is mandatory in order to obtain good results. IORT is an interesting option. Better results are obtained if there is a long DFI and probably justifies a more aggressive approach in these specific cases.

Serotonergic polymorphisms and psychotic disorders in populations from North Spain.

There is strong biological evidence relating alterations in the serotonergic system with mental disorders. These alterations may be originated at the DNA level by sequence mutations that alter the functioning of serotonin receptors and transporter. To test this hypothesis we investigated three genetic variants of the 5-HT2A receptor (-1438G/A, 102T/C and His452Tyr) and two variants of the serotonin transporter (a VNTR in the second intron and a 44 bp insertion/delition in the promoter region of the gene) in a clinical sample recruited in a human isolate and in surrounding areas in Northern Spain (N = 257) and in ethnically matched controls (N = 334). No clear association was found between 5-HT2A variants and psychosis. However, marginal associations were observed between the 5-HTT LPR and VNTR variants and psychosis (P < or = 0.05) indicating a minor contribution to psychosis of genetic alterations in this gene.

Malformaciones vasculares como marcadores sindrómicos / Vascular malformations as syndromic markers

Las malformaciones vasculares son lesiones estáticas, generalmente presentes en el momento del nacimiento, formadas por vasos displásicos que crecen de forma proporcional al crecimiento del niño. Presentan un recambio celular normal que constituyen verdaderos errores de la morfogénesis. La ausencia de regresión de estas malformaciones implica que permanezcan toda la vida. La terminología que describe este tipo de lesiones ha sido motivo de confusión en la literatura médica hasta que en 1996 la Sociedad Internacional para el Estudio de las Anomalías Vasculares adoptó una clasificación basada en el vaso dominante de la malformación. Esta clasificación distingue entre formas simples y complejas según se afecte un tipo de vaso o varios. Las malformaciones vasculares pueden presentarse como lesiones aisladas o bien asociarse a otras lesiones, constituyendo el signo guía o ser el marcador principal de algunos complejos sindrómicos. En este trabajo se describen los principales signos y síntomas de aquellos síndromes en los que una malformación vascular es la clave que hace sospechar la existencia de otras lesiones asociadas (AU)

Bone metastases from osteosarcoma.

Bony metastases in patients with osteosarcoma are unusual and normally appear late in the course of the disease. We report our experience with eight such patients, four with solitary and four with multiple metastases. Those with solitary metastases were treated as new tumours with neoadjuvant chemotherapy and surgery. Three remain alive with no evidence of disease at 5, 7 and 8 years follow-up respectively. Histology and response to neoadjuvant chemotherapy was similar in both the primary and metastatic lesions and is a predictive factor of outcome. Those with multiple metastases were treated by palliative measures, and none survived. We conclude that resection of solitary metastases from osteosarcoma after neoadjuvant chemotherapy can be curative.

Transient posterior encephalopathy induced by chemotherapy in children.

The cases of three children, 16, 12, and 12 years of age, who suffered sudden confusional state and cortical blindness lasting 12 to 30 minutes while under treatment with high-dose methotrexate, cyclophosphamide, and dactinomycin for a lower limb osteosarcoma are reported. Transient neuropsychologic deficits arose after the acute phase of treatment: left hemispatial neglect and constructive apraxia (Patient 1); constructive apraxia (Patient 2); and constructive apraxia and alexia without aphasia (Patient 3). The three patients recovered completely from all their deficits within the time frame of 3 hours to 2 weeks. Arterial hypertension and hypomagnesemia were found during the acute phase in all patients. In Patients 2 and 3, magnetic resonance imaging revealed increased parieto-occipital T(2) signal involving gray and white matter. In Patients 1 and 2, HmPAO-SPECT revealed parieto-occipital hypoperfusion that resolved a few days later. The alterations detected by neuroimaging were concurrent with the appearance and disappearance of the clinical symptoms. Such transient acute episodes have been named occipital-parietal encephalopathy. On the basis of our clinical, laboratory, and neuroimaging findings, an explanation for the origin of this syndrome, a migrainelike mechanism, triggered by chemotherapy-induced hypomagnesemia, is proposed.

[Characteristics and value of chromosome aberrations induced by antitumor treatments in pediatric patients with cancer]. / Características y valor de las aberraciones cromosómicas inducidas por los tratamientos antitumorales en pacientes pediátricos con cáncer.

Cytogenetic studies were performed on 80 pediatric cancer patients to test the chromosomal damage induced by the chemotherapy treatments. G-banded karyotypes were performed on peripheral blood lymphocytes (PBL) (n = 127) obtained at diagnosis, during treatment, at remission and at relapse. We detected a significant increase in the number of altered karyotypes in the samples during treatment, lowering to similar values to those at diagnosis at two-year remission. Most of the chromosomal aberrations (CA) detected during chemotherapy were unbalanced (75%) and affected most frequently chromosomes 1, 3, 5, 6, 11, 12, 16 and 17. There was also a marked increase of CA in samples at relapse, with similar features (type and distribution) to those detected during treatment. There was an outstanding correlation between the chromosomal breakpoints in our series and fragile sites (58%), oncogene (75%) and tumour suppressor gene (33%) loci described in the literature. The results obtained suggest that the cytostatic drugs induce a transient increase in chromosome fragility that focuses to several cancer-associated breakpoints.

Nonclonal chromosomal aberrations induced by anti-tumoral regimens in childhood cancer: relationship with cancer-related genes and fragile sites.

Cytogenetic studies were performed on 80 pediatric cancer patients to observe the chromosomal damage, both quantitative and qualitative, induced by chemotherapy. Peripheral blood lymphocytes (PBL) (n = 127) were obtained at diagnosis, during treatment, at remission, and at relapse, and chromosome analysis performed utilizing G-banding standard procedures. The results show a significant increase in the number of altered karyotypes (P = 0.03) in the samples during treatment, returning to values that were similar to those at diagnosis at 2-year remission. Most of the chromosomal aberrations (CA) detected during the chemotherapy regimens were nonclonal, unbalanced (75%), and involved chromosomes 1, 3, 5, 6, 11, 12, 16, and 17 most frequently. There was also a marked increase of CA in samples at relapse with very similar features (type and distribution) to those detected during treatment. There was a good correlation between the chromosomal breakpoints in our series and fragile sites (58%), oncogene (75%), and tumor suppressor gene (33%) loci described in the literature. The results obtained suggest that cytostatic drugs induce a transient increase in chromosome fragility occurring at several cancer-associated breakpoints.

Características y valor de las aberraciones cromosómicas inducidas por los tratamientos antitumorales en pacientes pediátricos con cáncer / characterization and value of the chromosomal aberrations induced by the antitumoral treatments in oncology pediatric patients

Con el fin de determinar el número y tipo de alteraciones cromosómicas inducidas por las drogas citostáticas, analizamos, mediante cariotipo convencional, muestras de sangre periférica (n=127) de pacientes pedátricos con tumores (n=80) que fueron obtenidas al diagnóstico, durante el tratamiento, en remisión clínica y en recidiva tumoral. Los resultados obtenidos muestran un incremento significativo del número de cariotipos alterados en las muestras recogidas durante el tratamiento y en recidivas tumorales, reduciéndose a valores próximos a los obtenidos al diagnóstico en las muestras de pacientes que llevaban, al menos, dos años en remisión clínica. La mayoría de las aberraciones cromosómicas (AC) eran de tipo no equilibrado (75 por ciento) y afectaban principalmente a los cromosomas 1, 3, 5, 6,11,12,16y17.Existe una destacable coincidencia entre los puntos de rotura detectados en nuestra serie y lugares cromosómicos que han sido descritos como loci para oncogenes (75 por ciento), genes de supresión tumoral (33 por ciento) y puntos frágiles (58 por ciento).Los resultados obtenidos sugieren que las drogas citostáticas inducen un incremento temporal en la fragilidad cromosómica que no se distribuye al azar si no que coincide con lugares genéticos implicados en la aparición y progresión de determinados tumores (AU)

Alteraciones genéticas inducidas por los tratamientos antitumorales en pacientes pediátricos con cáncer: carcinogénesis química / Genetic alterations induced by anti-tumour treatments in paediatric patients with cancer: chemical carcinogenesis

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Análisis de la implicación de los genes de supresión tumoral TP53, p16INK4, p21WAF1, RB1 y de las enzimas metabolizadoras de drogas en el desarrollo de tumores óseos en niños / Analysis of the involvement of the tumour suppressor genes TP53, p16INK4, p21WAF1, RB1 and the drugs metabolizing enzymes in the development of bone tumours in children

Fundamento. Los genes de supresión tumoral p16ink4, TP53, RB1 y p21waf1 son algunos de los componentes de la compleja red de regulación del ciclo celular y ejercen un control negativo de la proliferación o positivo de la diferenciación en respuesta al daño en el ADN. Se ha investigado la presencia de mutaciones en estos genes y variaciones en la secuencia codificante de las enzimas metabolizadoras de drogas que pudieran estar asociadas con el desarrollo de tumores óseos pediátricos o con el pronóstico de los mismos. Material y métodos. Mediante técnicas de biología molecular basadas en PCR se han analizado las variaciones en la secuencia de los genes p16ink4, TP53, RB1 y p21waf1 y de las enzimas metabolizadoras de drogas en un grupo de 82 osteosarcomas y 47 sarcomas de Ewing así como en una población control de 115 niños sanos. Resultados. Se detectaron mutaciones del gen TP53 en, aproximadamente, 25 por ciento de las muestras en asociación con tumores de mal pronóstico y supervivencia reducida. El gen p16ink4 estaba delecionado un 18 por ciento de los tumores, asociado igualmente a mal pronóstico y supervivencia reducida. El gen p16 estaba delecionado un 18 por ciento de los tumores, asociado igualmente a mal pronóstico y a subtipos histológicos desfavorables, y el gen RB1 presentaba alteraciones en 21 por ciento de los osteosarcomas. No parece existir relación entre la presencia de polimorfismos en las enzimas metabolizadoras de drogas y mutaciones del gen p21waf1 y el desarrollo de los tumores óseos pediátricos. Conclusiones. La alteración de los genes p16ink4, TP53 y RB1 está implicada en el desarrollo del osteosarcoma de Ewing, y parece constituir un factor de mal pronóstico en este tipo de tumores pediátricos. (AU)

[Analysis of the involvement of the tumour suppressor genes TP53, p16INK4, p21WAF1, RB1 and the drugs metabolizing enzymes in the development of bone tumours in children]. / Análisis de la implicación de los genes de supresión tumoral TP53, p16INK4, p21WAF1, RB1 y de las enzimas metabolizadoras de drogas en el desarrollo de tumores óseos en niños.

BACKGROUND: Several tumor suppressor genes such as p16INK4, TP53, RB1 y p21WAF1 are involved in cell cycle regulation in response to DNA damage and belong to the complex pathway that regulates cell proliferation and/or differentiation. We have investigated the presence of mutations in those genes and polymorphisms of Drug Metabolizing Enzymes that could be involved in the development of pediatric bone tumors or in their outcome. MATERIALS AND METHODS: By means of PCR-based techniques, we have analyzed the presence of variations in the coding sequence of p16INK4, TP53, RB1 y p21WAF1 and of the Drug Metabolizing Enzymes in a group of 82 osteosarcomas and 47 Ewing's sarcomas as well as in a control group of 115 healthy children. RESULTS: We detected mutations of the TP53 gene in about 25% of the samples analyzed, most frequently in association with tumors of poor prognosis or reduced survival. The p16INK4 gene was homozygously deleted in 18% of the osteosarcomas, also associated with poor prognosis and unfavourable histologic subtypes; RB1 was altered in 21% of the osteosarcomas. We did not detect relevant associations between polymorphisms of the Drug Metabolizing Enzymes or mutation of the p21WAF1 and development of pediatric bone tumors. CONCLUSIONS: Alteration of TP53, p16INK4 and p21WAF1 seems to be involved in the development of pediatric bone tumors and to be an unfavourable prognostic factor in this type of tumors.