RESUMO
BACKGROUND: Development of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS. METHODS AND RESULTS: Among 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35. CONCLUSIONS: This study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.
Assuntos
Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Carcinoma Adrenocortical/sangue , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Criança , Neoplasias do Plexo Corióideo/sangue , Neoplasias do Plexo Corióideo/genética , Neoplasias do Plexo Corióideo/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Síndrome de Li-Fraumeni/sangue , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Mosaicismo , Proteína Supressora de Tumor p53/sangue , Adulto JovemRESUMO
STUDY OBJECTIVE: To describe our 10 years of experience with childhood choroid plexus tumors (CPTs). DESIGN: Retrospective chart analysis. SETTING: Operating room and pediatric intensive care unit (PICU) of a university hospital. PATIENTS: 18 infants and children undergoing CPT surgery from 1995 to 2004, 11 of whom were younger than 12 months. MEASUREMENTS: Perioperative hematologic and coagulation data were measured as well as estimated red cell volume variations (as a reliable index of blood loss) in the perioperative period, together with coagulation parameters. RESULTS: Greater blood loss was recorded in the infant group vs older children (percentage of estimated red cell volume loss, 1.31 +/- 1.79% vs 0.20 +/- 0.17% [P < 0.01] and 1.50 +/- 1.86% vs 0.29 +/- 0.21% [P < 0.01] on PICU admission and after 72 hours, respectively). Platelet count decrease was similarly noted (51.60 +/- 28.06 vs 27.57 +/- 11.98, P < 0.05, as percentage of preoperative count). Patients operated on in the neonatal period showed the highest blood loss and related coagulation impairment. CONCLUSION: Younger CPT surgery patients present an increased risk versus their older counterparts of massive bleeding resulting in hemodynamic instability and coagulative impairment.
Assuntos
Perda Sanguínea Cirúrgica , Transfusão de Sangue , Neoplasias do Plexo Corióideo/cirurgia , Anestesia Geral , Pesquisa Biomédica , Pré-Escolar , Neoplasias do Plexo Corióideo/sangue , Feminino , Hemostasia Cirúrgica , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Monitorização Fisiológica , Avaliação de Resultados em Cuidados de Saúde , Assistência Perioperatória , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.