RESUMO
PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Azatioprina/efeitos adversos , Mercaptopurina/efeitos adversos , Metiltransferases/deficiência , Metiltransferases/genética , Polimorfismo de Fragmento de Restrição , Trombocitopenia/induzido quimicamente , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Hospitalização , Humanos , Lactente , Masculino , Metiltransferases/metabolismo , Neoplasias/tratamento farmacológico , Fenótipo , Transfusão de Plaquetas , Fatores de Risco , Trombocitopenia/genéticaRESUMO
The purpose of this report is to describe the tolerability and activity of the combination of high-dose cytosine arabinoside (Ara-C) given at the maximum tolerated dose of 36 g/m2, together with high doses of etoposide in relapsed and refractory childhood acute leukemias. Eighteen children with relapsed or refractory acute leukemia were treated with Ara-C 3 g/m2 every 12 h on days 1-6, followed by etoposide 400 mg/m2 on days 7-9 (HDAC/VP-16). Eight children with refractory disease received HDAC/VP-16 as salvage induction therapy after failing conventional induction regimens; four of five refractory ANLL patients (80%) had a complete response (CR) after HDAC/VP-16 therapy. Ten patients received HDAC/VP-16 as post-remission intensification therapy; five patients (four ANLL, one relapsed ALL) remain in second CR at 56, 26, 9, 5 and 2 months. Toxicities were primarily hematologic and dermatologic. Seven patients (39%) developed bacterial or fungal infections; four patients developed grade 3 or 4 acral erythema. No patient died of therapy-related toxicity. The combination of 36 g/m2 cytosine arabinoside and 1200 mg/m2 etoposide is an effective regimen for children with relapsed or refractory acute nonlymphocytic leukemia, with tolerable toxicities; the absence of anthracyclines makes this regimen suitable for patients who have previously received maximal doses of anthracyclines or who have evidence of cardiac dysfunction. Further evaluation of this regimen in acute nonlymphocytic leukemia is presently being investigated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças da Medula Óssea/induzido quimicamente , Criança , Pré-Escolar , Contraindicações , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Lactente , Infecções/etiologia , Leucemia Mieloide/mortalidade , Masculino , Terapia de Salvação , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adolescente , Antibióticos Antineoplásicos , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Evolução Fatal , Fluoruracila/administração & dosagem , Humanos , Masculino , Estreptozocina/administração & dosagem , Vincristina/administração & dosagemRESUMO
PURPOSE: Seven children with newly diagnosed acquired severe aplastic anemia (SAA) were treated with a combination of long-term granulocyte-macrophage colony-stimulating factor (GM-CSF) and immunosuppression to assess the potential for GM-CSF to induce sustained neutrophil recovery, reduce the incidence of infection, and enhance the therapeutic efficacy of immunosuppression. METHODS: Patients received a 14-day course of i.v. antithymocyte globulin 15 mg/kg/day with oral prednisone 1 mg/kg/day, long-term daily oral cyclosporine A 10 mg/kg/day, and long-term daily s.c. GM-CSF 5 micrograms/kg/day. RESULTS: All seven children recovered an absolute neutrophil count of > 1.0 x 10(9)/L within 3.5 months of diagnosis (mean 60 days). Of the six children followed throughout their entire illness (follow-up 10-27 months), five are platelet and red cell transfusion independent (three off-therapy, two on tapering therapy) and one continues on therapy with a diminishing transfusion requirement. Compared with seven children treated previously with immunosuppression alone, children who received GM-CSF spent fewer days in the hospital and were less likely to develop infection. CONCLUSIONS: The addition of GM-CSF to immunosuppressive therapy appears to be beneficial in the treatment of children with acquired SAA with GM-CSF stimulating granulopoiesis. The children are better protected from infectious complications while immunosuppressive agents achieve full therapeutic potential.
Assuntos
Anemia Aplástica/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Imunossupressores/uso terapêutico , Adolescente , Soro Antilinfocitário/uso terapêutico , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Lactente , Masculino , Prednisona/uso terapêuticoRESUMO
The factor IX gene has a G + C content of approximately 40% in all mammalian species examined. In human factor IX, C----T and G----A transitions at the dinucleotide CpG are elevated at least 24-fold relative to other transitions. Can the G + C content be explained solely by this hot spot of mutation? Using our mathematical model, we show that the elevation of mutation at CpG cannot alone lower the G + C content below 45%. To search for other hot spots of mutation that might contribute to the reduction of G + C content, we assessed the relative rates of base substitution in our sample of 160 families with hemophilia B. Seventeen independent single-base substitutions are reported herein for a total of 96 independent point mutations in our sample. The following conclusions emerge from the analysis of our data and, where appropriate, the data of others: (1) Transversions at CpG are elevated an estimated 7.7-fold relative to other transversions. (2) The mutation rates at non-CpG dinucleotides are remarkably uniform; none of the observed rates are either more than twofold above the median for transitions or more than threefold above the median for transversions. (3) The pattern of recent mutation is compatible with the pattern during mammalian evolution that has maintained the G + C content of the factor IX gene at approximately 40%.
Assuntos
Composição de Bases/genética , Fosfatos de Dinucleosídeos/genética , Fator IX/genética , Hemofilia B/genética , Mutação/genética , Evolução Biológica , Citosina/análise , Guanina/análise , Haplótipos , Humanos , Modelos Genéticos , Modelos TeóricosRESUMO
The molecular defect responsible for moderate and severe hemophilia A has been identified for two unrelated patients with the CRM-positive form of this disorder (factor VIII activity of 0.02 and 0.05 U/mL with factor VIII antigen of 0.87 and 2.20 U/mL). In both cases, the immunopurified dysfunctional factor VIII protein is abnormal, in that the 80 Kd light chain is not cleaved by thrombin at arginine-1689. The basis for this failure was identified by polymerase chain reaction amplification of exon 14 of the variant factor VIII genes and direct sequencing of the amplified products. In both cases, a single base substitution (C to T) was identified that produces an arginine to cysteine substitution at amino acid residue 1689. These data identify the molecular defects of the two identical factor VIII variant proteins. The dysfunctional factor VIII has been designated "Factor VIII-East Hartford," the residence of the patient in whom the defect was first identified.
Assuntos
Fator VIII/genética , Hemofilia A/genética , Arginina , Sequência de Bases , Reações Cruzadas , Fator VIII/imunologia , Humanos , Técnicas de Imunoadsorção , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase , Trombina/metabolismoRESUMO
Disorders that predispose children to venous thrombosis include inherited abnormalities of antithrombin III, protein S, protein C, fibrinogen, and plasminogen. Arterial thrombosis may result from disorders that produce endothelial damage, abnormal vascular flow, or increased platelet aggregation. We present here a case of a child who had recurrent thromboses and discuss the evaluation and management of such patients.
Assuntos
Deficiência de Antitrombina III , Transtornos da Coagulação Sanguínea/sangue , Adulto , Transtornos da Coagulação Sanguínea/genética , Infarto Cerebral/sangue , Infarto Cerebral/genética , Criança , Saúde da Família , Feminino , Glicoproteínas/deficiência , Humanos , Masculino , Linhagem , Deficiência de Proteína C , Proteína S , Embolia Pulmonar/sangue , Embolia Pulmonar/genética , Recidiva , Tromboflebite/sangue , Tromboflebite/genéticaRESUMO
Many bleeding episodes in hemophilia are thought to be related to ambient stress. The evidence in support of this hypothesis comes from a variety of anecdotal and clinical reports. Whether or not stress leads to bleeding has had little direct study in a prospective way, however, and methodological problems affect most of the studies in this field. This paper examines the evidence in support of this hypothesis and suggests ways to improve research relating stress to bleeding.
Assuntos
Hemofilia A/complicações , Hemorragia/etiologia , Estresse Psicológico/complicações , Criança , Hemofilia A/psicologia , Hemofilia B/complicações , Hemofilia B/psicologia , Humanos , Masculino , Relações Pais-FilhoRESUMO
Systemic metastases from central nervous system germinomas are exceedingly rare, and when they occur lead to fatal outcomes. The authors report the case of a 10-year-old girl who presented with metastatic involvement of the rib and pelvis 2.5 years after surgical resection and radiation therapy for a suprasellar dysgerminoma. After combination chemotherapy, the patient remains disease-free 30 months after relapse. This case provides evidence that chemotherapy can be an effective therapeutic alternative to the use of radiation in the treatment of children with extracranial germinomas.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias Encefálicas/patologia , Disgerminoma/patologia , Neoplasias Encefálicas/terapia , Criança , Disgerminoma/secundário , Disgerminoma/terapia , Feminino , Humanos , Ílio , CostelasRESUMO
Critical to providing cancer therapy to children in rural areas is finding dependable sources of therapy near the patients' homes. In this study, comparison was made of 668 visits by 24 patients to nearby private practitioners, who carried out 70% of the therapy, with 712 visits by 22 other patients for whom all care was managed by pediatric hematologist-oncologists. There was no significant difference by Wilcoxon rank sum test between the two groups in the accuracy with which protocol rules were followed, in the incidence of neutropenia, infection, fever, thrombocytopenia, drug toxicity, or the proportion of days hospitalized. The findings indicate that the private practitioners participating in a shared-management system were a dependable resource for providing 70% of the total cancer therapy to these patients.