RESUMO
PURPOSE: The purpose of this study was twofold: (1) to provide a population-based estimate of neuroblastoma incidence, disease stage and age distribution, and survival and mortality rates in North America; and (2) to compare these figures in the province of Quebec at a time shortly before the institution of province-wide screening with those in a population-based control group, the Greater Delaware Valley (GDV) Pediatric Tumor Registry. MATERIALS AND METHODS: In Quebec, the four major pediatric teaching hospital records were searched for children with a diagnosis of neuroblastoma. Tumor board registry data and information supplied to the Division of Vital Statistics were also reviewed. Birth statistics were obtained from the population registry. The GDV Pediatric Tumor Registry is a population-based registry of pediatric cancer covering all of Delaware and parts of New Jersey, Pennsylvania, and Maryland. Age, stage of disease, and follow-up data were obtained through December 31, 1989, with Evans neuroblastoma staging data used for all comparisons. RESULTS: One hundred thirty children with neuroblastoma were identified in Quebec and 165 in the GDV, in a combined population of 3,178,736 children. The annual incidence of neuroblastoma was 10.95/10(6) under the age of 15 years and 27.75/10(6) between the ages of 0 and 4 years. The annual mortality rate due to neuroblastoma was 4.89/10(6) and 9.10/10(6) for the age groups 0 to 14 and 0 to 4, respectively. The overall 10-year survival rate for the 295 cases of neuroblastoma was 55%. The 10-year survival rates for patients with Evans stage I-IV and IVS disease were 88%, 90%, 63%, 21%, and 81%. There was no significant difference observed in the incidence, mortality, or survival in the two populations. CONCLUSION: These data represent the first large, population-based description of the clinical presentation and outcome of patients with neuroblastoma in North America, with no significant differences noted between Quebec patients and the GDV patients.
Assuntos
Neuroblastoma/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Programas de Rastreamento , Mid-Atlantic Region/epidemiologia , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Quebeque/epidemiologia , Sistema de Registros , Taxa de SobrevidaRESUMO
PURPOSE: To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was > or = 1,500 microL after the time of the expected ANC nadir. RESULTS: A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewing's sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades > or = 3 was rare and consisted of nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). CONCLUSION: The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewing's sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Neuroblastoma/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Topotecan/administração & dosagemRESUMO
Lymphoblasts from children with B-progenitor cell acute lymphoblastic leukemia (BpALL) with chromosomal hyperdiploidy and with translocations affecting chromosome 12p11-13, accumulate high and low levels of methotrexate polyglutamates (MTXPGs), respectively. Recently a cryptic translocation, t(12;21) (p13;q22), has been demonstrated by molecular and fluorescence in situ hybridization techniques in this disease. The chimeric TEL-AML1 transcript, which has been associated with this translocation, can be detected in up to 25% of children with BpALL. We detected the TEL-AML1 and/or the AML1-TEL transcript in 30 (33%) of 91 patients studied. Levels of lymphoblast MTXPGs were lower in those with than in those without the TEL-AML1 translocation (P = 0.004). Hyperdiploidy was rare in lymphoblasts with the TEL-AML1 translocation (P = 0.047). Both ploidy (P= 0.0015) and TEL-AML1 status (P= 0.0043) were independently and significantly correlated with the log of the lymphoblast MTXPG level. However, the presence of TEL-AML1 or of hyperdiploidy accounted for only 22% of the variation of this value. Our results imply that each of 1.16 > or = DI and the presence of the TEL-AML1 translocation confers a 50% decrease in lymphoblast MTXPG level. When planning reduction of therapy for either of the two excellent outcome categories of hyperdiploid or TEL-AML1 BpALL, one should consider the difference between these two subgroups in the ability of lymphoblasts to accumulate MTXPGs.
Assuntos
Linfócitos/metabolismo , Metotrexato/metabolismo , Proteínas de Fusão Oncogênica/genética , Ploidias , Ácido Poliglutâmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Humanos , Lactente , Masculino , Metotrexato/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismoRESUMO
Children with B-progenitor cell acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) appear to have a good prognosis. This has been attributed to increased sensitivity of their blast cells to MTX. However, the proportion of children who are cured of B-progenitor cell acute lymphoblastic leukemia exceeds the number whose lymphoblasts accumulate high MTXPG levels. We report that lymphoblasts from patients with < 50 chromosomes who have translocations that involve the short arm of chromosome 12 accumulate low levels of MTXPGs. These patients appear to have an excellent survival because none of 14 patients with translocations affecting 12p has relapsed, 26-79 months following diagnosis.
Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Cromossomos Humanos Par 12 , Metotrexato/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Repressoras , Translocação Genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-ets , Fatores de Transcrição/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
The increasing success of antineoplastic therapy has resulted in a growing number of long-term survivors. These people are at risk for complications of the therapy itself. Among these induced acute nonlymphoid leukemia (ANLL) has been both common and often lethal. We reviewed 72 recently reported patients under 30 years of age at the time of initial diagnosis who developed a secondary, karyotypically defined leukemia. Fifty-eight patients contracted ANLL a mean of 4 1/2 years from the initial diagnosis. In 25 patients, this was preceded by a preleukemic phase characterized by a hypercellular bone marrow with abnormal precursors, often accompanied by peripheral pancytopenia, that lasted a mean of 6 months. Three additional patients died in this preleukemic phase. In all 61, the most common chromosomal abnormalities were numerical errors. Twenty-four patients had a hypodiploid karyotype, most often in those in whom the primary diagnosis was lymphoma (22 of 43). The most common chromosomes missing in whole or in part were number 7 (18 patients), number 5 (8 patients), number 17 (5 patients), and number 21 (4 patients). The anomalies were frequently multiple and complex. Monosomy 7 figured particularly strongly and may be similar to a karyotypically identical myeloproliferative disorder characterized by micromegakaryocytes, giant platelets, and abnormal granulocyte function arising de novo in children. These findings are similar to those in older patients with ANLL induced by environmental carcinogens or antineoplastic therapy. They are different from the karyotypic changes seen in de novo ANLL in children and young adults, suggesting a different etiology. Also, they reinforce the need to find less leukemogenic treatment programs.
Assuntos
Leucemia/genética , Doença Aguda , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Células da Medula Óssea , Divisão Celular , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 7 , Feminino , Doença de Hodgkin/complicações , Doença de Hodgkin/tratamento farmacológico , Humanos , Cariotipagem , Leucemia Linfoide/complicações , Leucemia Linfoide/tratamento farmacológico , Masculino , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/etiologiaRESUMO
PURPOSE: Although infections associated with indwelling urinary catheters are common, costly, and morbid, the use of these catheters is unnecessary in more than one-third of patients. We sought to assess whether attending physicians, medical residents, and medical students are aware if their hospitalized patients have an indwelling urinary catheter, and whether physician awareness is associated with appropriate use of these catheters. METHODS: The physicians and medical students responsible for patients admitted to the medical services at four university-affiliated hospitals were given a list of the patients on their service. For each patient, the provider was asked: "As of yesterday afternoon, did this patient have an indwelling urethral catheter?" Respondents' answers were compared with the results of examining the patient. RESULTS: Among 288 physicians and students on 56 medical teams, 256 (89%) completed the survey. Of 469 patients, 117 (25%) had an indwelling catheter. There were a total of 319 provider-patient observations among these 117 patients. Overall, providers were unaware of catheterization for 88 (28%) of the 319 provider-patient observations. Unawareness rates by level of training were 21% for students, 22% for interns, 27% for residents, and 38% for attending physicians (P = 0.06). Catheter use was inappropriate in 36 (31%) of the 117 patients with a catheter. Providers were unaware of catheter use for 44 (41%) of the 108 provider-patient observations of patients who were inappropriately catheterized. Catheterization was more likely to be appropriate if respondents were aware of the catheter (odds ratio = 3.7; 95% confidence interval, 2.1 to 6.7, P <0.001). CONCLUSION: Physicians are commonly unaware that their patients have an indwelling urinary catheter. Inappropriate catheters are more often "forgotten" than appropriate ones. System-wide interventions aimed at discontinuing unnecessary catheterization seem warranted.
Assuntos
Conscientização , Controle de Infecções , Médicos/estatística & dados numéricos , Cateterismo Urinário/estatística & dados numéricos , Idoso , Cateteres de Demora , Competência Clínica , Feminino , Médicos Hospitalares/estatística & dados numéricos , Hospitais Universitários/estatística & dados numéricos , Hospitais de Veteranos/estatística & dados numéricos , Humanos , Internato e Residência/estatística & dados numéricos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Estudos Prospectivos , Estudantes de Medicina/estatística & dados numéricos , Cateterismo Urinário/métodosRESUMO
Deep venous thrombosis is a frequent, well-recognized complication of spinal cord injury. Patients with myelomeningocele often have similar weakness of the lower extremities. Following orthopedic surgery, they may also be immobilized at a time when they are hypercoagulable. In addition, as with patients with spinal cord injury, patients with myelomeningocele are prone to urinary tract infection, which may cause local inflammation in the pelvic veins. For the first time, three patients with myelomeningocele complicated by deep venous thrombosis are described. The differential diagnosis (deep venous thrombosis vs osteomyelitis vs fracture) is also discussed in a child with myelomeningocele and a warm, swollen leg, as are the diagnostic methods available. Finally, the issue of antithrombotic prophylaxis in patients with myelomeningocele who are to undergo extensive orthopedic surgery is discussed.
Assuntos
Meningomielocele/complicações , Tromboflebite/etiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Osteomielite/complicações , Complicações Pós-Operatórias , Cintilografia , Fusão Vertebral/efeitos adversos , Tromboflebite/diagnóstico por imagem , Tromboflebite/terapiaRESUMO
OBJECTIVE: To compare how parents and physicians value potential clinical outcomes in young children who have a fever but no focus of bacterial infection. METHODS: Cross-sectional study of 100 parents of well children aged 3 to 24 months, 61 parents of febrile children aged 3 to 24 months, and 56 attending staff physicians working in a children's hospital emergency department. A pretested visual analog scale was used to assess values on a 0-to-1 scale (where 0 is the value of the worst possible outcome, and 1 is the value for the best) for 22 scenarios, grouped in three categories according to severity. Based on the three or four common attributes comprising the scenarios in a given group, each respondent's value function was estimated statistically based on multiattribute utility theory. RESULTS: For outcomes in group 1 (rapidly resolving viral infection with one or more diagnostic tests), no significant group differences were observed. For outcomes in groups 2 (acute infections without long-term sequelae) and 3 (long-term sequelae of urinary tract infection or bacterial meningitis), parents of well children and parents of febrile children had values that were similar to each other but significantly lower than physicians' values for pneumonia with delayed diagnosis, false-positive diagnosis of urinary tract infection, viral meningitis, and unilateral hearing loss. For bacterial meningitis with or without delay, however, the reverse pattern was observed; physicians' values were lower than parents'. In arriving at their judgment for group 2 and 3 scenarios, parents gave significantly greater weight to attributes involving the pain and discomfort of diagnostic tests and to diagnostic error, whereas physicians gave significantly greater weight to attributes involving both short- and long-term morbidity and long-term worry and inconvenience. Parents were significantly more likely to be risk-seeking in the way they weighted the attributes comprising group 2 and 3 scenarios than physicians, ie, they were more willing to risk rare but severe morbidity to avoid the short-term adverse effects of testing. CONCLUSIONS: Parents and physicians show fundamental value differences concerning diagnostic testing, diagnostic error, and short- and long-term morbidity; these differences have important implications for diagnostic decision making in the young febrile child.
Assuntos
Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Infecções Bacterianas/diagnóstico , Febre/etiologia , Corpo Clínico Hospitalar/psicologia , Avaliação de Resultados em Cuidados de Saúde , Pais/psicologia , Infecções Bacterianas/complicações , Pré-Escolar , Estudos Transversais , Técnicas de Apoio para a Decisão , Erros de Diagnóstico , Serviço Hospitalar de Emergência , Reações Falso-Positivas , Febre/terapia , Hospitais Pediátricos , Humanos , Lactente , Quebeque , Viroses/complicações , Viroses/diagnósticoRESUMO
We describe a female patient with multiple anomalies suggestive of a new syndrome. Manifestations include: VSD and ASD, mild developmental delay, conductive hearing loss, minor facial anomalies, thrombocytopenia, and radiological findings (including carpal fusion). Some of these manifestations may be present in the Keutel syndrome, IVIC syndrome, and the 10qter deletion syndrome. However, none of these syndromes can explain the spectrum of anomalies seen in our patient.
Assuntos
Anormalidades Múltiplas , Comunicação Interatrial , Comunicação Interventricular , Trombocitopenia/congênito , Ossos do Carpo/anormalidades , Criança , Deficiências do Desenvolvimento , Feminino , Humanos , Coluna Vertebral/anormalidades , SíndromeRESUMO
Previous studies of the value of the complete blood count (CBC) in distinguishing viral from bacterial infection in young febrile children have failed to exclude children with clinically evident bacterial infection and thus have inflated the positive predictive value of the test for occult focal infection. We prospectively studied 2492 children 3-24 months of age who presented to a children's hospital emergency department between March 1989 and August 1990 with fever (> or = 38.0 degrees C) of acute (< or = 4 days) onset but no evident bacterial focus of infection, 433 (17.4%) of whom received a CBC. We also carried out an 8-year retrospective analysis to estimate prior, or pre-test, probabilities (prevalences) and examine CBC results for rare occult bacterial infections (meningitis, osteomyelitis, and septic arthritis). Estimated prior probabilities for the four most common categories of infection that can be diagnosed at the initial visit were: non-pneumonitic viral infection, 88.6% in boys and 86.0% in girls; pneumonia, 8.5% in both sexes; urinary tract infection (UTI), 3.0% in boys and 5.5% in girls; and bacterial meningitis, 0.0066% in both sexes. The likelihood (sensitivity) of a total white blood cell (WBC) count > or = 15,000/mm3 was 25.5, 64.5, 62.5, and 50.0% for viral infection, pneumonia, UTI, and meningitis, respectively. Among children with a high total white blood cell count, neither a total polymorphonuclear count > or = 10,000/mm3 nor a band count > or = 500/mm3 was associated with significantly elevated likelihoods for occult pneumonia or UTI, a finding confirmed by multiple logistic regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Infecções Bacterianas/diagnóstico , Contagem de Células Sanguíneas , Febre/diagnóstico , Infecção Focal/diagnóstico , Fatores Etários , Infecções Bacterianas/sangue , Infecções Bacterianas/epidemiologia , Pré-Escolar , Estudos de Coortes , Intervalos de Confiança , Diagnóstico Diferencial , Feminino , Febre/sangue , Febre/epidemiologia , Infecção Focal/sangue , Infecção Focal/epidemiologia , Humanos , Lactente , Masculino , Prevalência , Viroses/diagnósticoRESUMO
The purpose of this study was to determine the correlation between different intervals in the 12-min walk test, to determine which of the intervals best correlated with maximal oxygen intake (VO2max) and maximal CO2 expelled (VCO2max) and to determine the degree of correlation between changes in the VO2max and changes in the walk test and spirometry. Nine elderly (age, 67 +/- 4 years) patients with moderate COPD (FEV1, 1.32 +/- 0.28 L) who were ventilatory limited were seen 6 times over a 14-week period. At each visit they performed spirometry, a 12-min walk, and a symptom-limited maximal exercise test. During the 12-min walk the distances traversed in each 2-min interval were recorded. A Borg score was obtained at the end of each 2 min. The distances that the patients walked in each 2-min interval were very similar, but the mean Borg score became higher the longer the patient walked. The Borg score after 2 min was 1.64 +/- 1.15, while the Borg score after 12 min was 5.70 +/- 3.59. The correlation coefficients between the distance walked at various intervals and the oxygen consumption (VO2)/kg (approximately 0.65) and the VCO2/kg (approximately 0.52) were very similar. However, changes in the VO2/kg were more closely correlated with changes in the 12-min walk (r = 0.72), than with changes in the 6-min walk (r = 0.64), the 4-min walk (r = 0.59), or the 2-min walk (r = 0.53). This latter observation suggests that the 12-min walk may be preferable to tests in which the patient walks 4 or 6 min for documenting changes in the exercise capabilities.
Assuntos
Dióxido de Carbono/metabolismo , Teste de Esforço/métodos , Pneumopatias Obstrutivas/fisiopatologia , Consumo de Oxigênio/fisiologia , Idoso , Limiar Anaeróbio/fisiologia , Tolerância ao Exercício/fisiologia , Volume Expiratório Forçado/fisiologia , Humanos , Pneumopatias Obstrutivas/metabolismo , Masculino , Esforço Físico/fisiologia , Respiração/fisiologia , Espirometria , Fatores de Tempo , Capacidade Vital/fisiologia , CaminhadaRESUMO
CASE: A suspected alteration in ifosfamide (IFF) metabolism and pharmacokinetics was observed in a pediatric patient receiving phenytoin. METHODS: Sequential plasma samples were obtained and analyzed for the concentrations of the enantiomers of IFF and their N-dechloroethylated metabolites (DCE-IFF) using a validated enantioselective gas chromatographic-mass spectrometric method. RESULTS: In the phenytoin-treated patient, the metabolic formation of IFF enantiomers was increased and the metabolic pattern of the N-dechloroethylation altered from non-phenytoin-treated patients: (R)-3-DCE IFF > > (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-2-DCE-IFF (control) vs (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-3-DCE-IFF > > (R)-2-DCE-IFF (patient). CONCLUSIONS: Previous studies have attributed the production of the (S)-2-DCE-IFF and (S)-3-DCE-IFF metabolites to the activity of CYP2B6 and (R)-2-DCE-IFF and (R)-3-DCE-IFF to the activity of CYP3A4. The results suggest that phenytoin induced the activity of CYP2B6 to a greater extent than CYP3A4. In addition, the patient, who was at least partially refractory to several other treatments, went into remission after IFF treatment suggesting that phenytoin pretreatment might increase IFF therapeutic efficacy.
Assuntos
Antineoplásicos Alquilantes/farmacocinética , Ifosfamida/farmacocinética , Fenitoína/farmacologia , Alquilação , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/uso terapêutico , Criança , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Ifosfamida/química , Ifosfamida/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , EstereoisomerismoRESUMO
PURPOSE: WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is a chemoprotective agent that is currently in pediatric clinical trials. It is a prodrug that is dephosphorylated by alkaline phosphatase to the active free thiol form, WR-1065 [S-2-(3-aminopropylamino)ethanethiol]. It is likely that adequate and sustained cellular levels of the drug are necessary for optimum cytoprotection. To date, a method to measure both plasma and cellular levels of WR-2721 and its metabolites in clinical samples has not been available. METHODS: In the study reported here the monobromobimane (mBBr) fluorescent labeling method was used to measure these levels when drug was added in vitro to blood samples from normal volunteers. In addition, we present pharmacokinetic data from a pediatric patient receiving WR-2721 (825 mg/m2 x 2). RESULTS: The results can be summarized as follows: (1) WR-2721 was detected in the patient's plasma with a half-life of about 10 min; (2) the WR-1065 concentration in the blood cellular fraction was similar to that of plasma; (3) both WR-1065 and WR-SS-low molecular weight (WR-SS-LMW) metabolites disappeared from plasma and the cellular fraction by 3.6 h after WR-2721 infusion; (4) a large proportion of WR-1065 was oxidized in plasma to WR-SS protein and WR-SS-LMW; (5) a large proportion of WR-1065 in the cellular fraction was oxidized to WR-SS-protein; (6) the WR-SS-LMW concentration in the cellular fraction was low; and (7) saturation of plasma and cellular protein binding sites was possible. CONCLUSIONS: The pharmacokinetic data that were generated with this technique could guide clinical trials using WR-2721.
Assuntos
Amifostina/análise , Cromatografia Líquida de Alta Pressão/métodos , Pró-Fármacos/análise , Protetores contra Radiação/análise , Amifostina/metabolismo , Compostos Bicíclicos com Pontes , Criança , Feminino , Corantes Fluorescentes , Meia-Vida , Humanos , Mercaptoetilaminas/análise , Pró-Fármacos/metabolismo , Protetores contra Radiação/metabolismoRESUMO
PURPOSE: Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna. METHODS: WR-2721 was administered (15 min intravenous infusion of 825 mg/m(2) per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence. RESULTS: The active metabolite of the drug, WR-1065, peaked at 100 microM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half-life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at approximately 1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by approximately 50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being approximately 36%. CONCLUSIONS: (1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of approximately 16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.
Assuntos
Amifostina/farmacocinética , Amifostina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Amifostina/administração & dosagem , Células Sanguíneas/metabolismo , Neoplasias Ósseas/sangue , Criança , Ciclofosfamida/administração & dosagem , Cisteína/sangue , Feminino , Humanos , Ifosfamida/administração & dosagem , Infusões Intravenosas , Cinética , Masculino , Mesna/administração & dosagem , Protetores contra Radiação/administração & dosagem , Sarcoma de Ewing/sangue , Compostos de Sulfidrila/sangue , Fatores de TempoRESUMO
A phase I trial of indicine-N-oxide was carried out in 12 children with solid tumors and in 16 with leukemia. Doses of 5, 6, and 7.5 g/m2 were given parenterally as a 15-min infusion every 3 weeks. The maximum tolerated dose in patients with solid tumors was 7.5 g/m2 and the dose-limiting toxicity was myelosuppression. In leukemia, the maximum tolerated dose was 6.0 g/m2 and hepatotoxicity was dose-limiting. Half of the children with leukemia showed elevations in transaminase levels and one child died of massive hepatic necrosis. This hepatotoxicity limits the use of indicine-N-oxide in children with leukemia. Antineoplastic activity was limited to a transient reduction in the numbers of circulating leukemic cells.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Alcaloides de Pirrolizidina/uso terapêutico , Adolescente , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Criança , Pré-Escolar , Esquema de Medicação , Avaliação de Medicamentos , Humanos , Infusões Intravenosas , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Alcaloides de Pirrolizidina/administração & dosagem , Alcaloides de Pirrolizidina/efeitos adversos , Trombocitopenia/induzido quimicamenteRESUMO
Drug development in pediatric oncology has been reviewed, concentrating on overall development issues and COG studies of cytotoxic compounds. A variety of interesting molecules with more specific targeting are becoming available. The challenges that remain include the availability of such compounds for pediatric trial and their study in a timely fashion, and the subsequent incorporation of the new agents into more up-front regimens, with the ultimate shared goal of curing more children with less toxicity.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto/legislação & jurisprudência , Neoplasias/tratamento farmacológico , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos Fase I como Assunto/normas , Desenho de Fármacos , Ética Médica , Controle de Formulários e Registros , Humanos , Lactente , Fígado/efeitos dos fármacos , Fígado/metabolismo , Dose Máxima Tolerável , Estudos Multicêntricos como Assunto , Seleção de Pacientes , Segurança , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos , United States Food and Drug AdministrationRESUMO
This 40-year-old male presented with the signs and the symptoms of acute aortic insufficiency and underwent aortic valve replacement. At surgery a deformed aortic valve with perforation was found. This represents a unique example of a congenitally deformed aortic valve complicated by acute perforation with resultant valvular incompetence.
Assuntos
Insuficiência da Valva Aórtica/etiologia , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/cirurgia , Ecocardiografia , Próteses Valvulares Cardíacas , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
As the dental profession moves toward additional emphasis in detection of disease and sophistication in diagnosis, biopsy is being used with increasing frequency as a diagnostic tool. This article states and elucidates simple ground rules that govern the rationale of surgical sampling of pathologic tissue. The three most common deficiencies that hamper interpretation (tissue artifact, inadequate clinical information, and inappropriate tissue sampling) are discussed, and the biopsy approach to various types of clinical lesions is reviewed.
Assuntos
Biópsia , Doenças da Boca/patologia , Biópsia/métodos , Cistos/patologia , Diagnóstico Diferencial , Fixadores , Congelamento , Humanos , Relações Interprofissionais , Anamnese , Boca/patologia , Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Patologia , PigmentaçãoRESUMO
This paper presents a case report describing the forensic dental investigation that enabled the identification of a decomposed dead body. The body was discovered under such circumstances that there were no known missing persons to account for its occurrence and no clues as to a possible identify. Through teamwork, fragments of nonspecific information were pieced together to point to a possible victim who had disappeared a year earlier and 1,400 miles away. Subtle dental and anthropologic peculiarities were detected and identified on antemortem medical radiographs made 3 years earlier, thus allowing a successful match. The extent of our nation's missing persons and unidentified dead problem is discussed. In a country where almost 40,000 cases of unsolved missing persons are recorded and 2,000 to 10,000 unidentified dead bodies remain anonymous, cooperation among jurisdictions and the use of dental evidence in a computerized form are the likely means of approaching this problem.
Assuntos
Odontologia Legal , Adulto , Registros Odontológicos , Humanos , MasculinoRESUMO
Oral exfoliative cytology can be a powerful tool for early detection of malignant and premalignant lesions as well as for some viral and fungal infections, if the limitations of the method are thoroughly understood and appreciated by the dental clinician. The rationale for oral cytology is developed and documented, and interpretations of the results are explained. Advantages and disadvantages of this technique are given and indications and contraindications for this diagnostic adjunct are discussed. A simple method involving the use of inexpensive equipment in the office is suggested.