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)

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.

Clinical and molecular features of Ewing sarcoma in a patient with triple-X syndrome.

A case of Ewing sarcoma in a 16-year-old girl with 47 XXXc karyotype is reported.