RESUMO
A prospective randomised phase III study in patients < or =65 years old with previously untreated multiple myeloma (MM), intensive chemotherapy followed by myeloablative chemotherapy and autologous stem-cell rescue was compared with intensive chemotherapy alone. This economic evaluation was based on detailed data from patient charts and hospital information systems. In the intention-to-treat analysis, mean total treatment and follow-up costs of the myeloablative treatment arm were 81,643 euros compared to 68,802 euros for the chemotherapy arm (P=0.09). Costs per quality-adjusted life year were 51,357 euros versus 37,328 euros. In the clinical study, no significant differences were found in overall survival after a median follow-up of 33 months from randomisation. Intensive chemotherapy is regarded as standard therapy for younger patients with previously untreated MM. Cost-effectiveness of myeloma therapy after 3 years of follow up seems not to be favoured by myeloablative treatment with autologous stem-cell rescue.
Assuntos
Antineoplásicos Alquilantes/economia , Ciclofosfamida/economia , Transplante de Células-Tronco Hematopoéticas/economia , Melfalan/economia , Mieloma Múltiplo/economia , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Análise Custo-Benefício , Custos e Análise de Custo , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Estudos Prospectivos , Transplante AutólogoRESUMO
The treatment of Multiple Myeloma (MM), a malignant plasma cell disorder has changed considerably over the past decade. It has been convincingly shown that intensive treatment supported by autologous stem cell reinfusion is superior to conventional chemotherapy with alkylating agents or vincristine, doxorubicin and dexamethasone (VAD) alone in terms of a more rapid response and a longer disease-free survival. However, cure is not achieved in the majority of patients. Several trials have therefore focussed on repeated intensive treatments in order to improve the survival of these patients. Other approaches are aimed at identifying patients on the basis of prognostic factors, who may benefit from high-dose therapy. This review discusses the recent developments in intensive therapy for multiple myeloma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Antineoplásicos Alquilantes/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Humanos , Melfalan/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , RecidivaRESUMO
Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.
Assuntos
Processamento Alternativo , Neoplasias Hematológicas/metabolismo , Receptores de Glucocorticoides/biossíntese , Animais , Medula Óssea/metabolismo , Células CHO , Células COS , Cricetinae , Células HeLa , Neoplasias Hematológicas/genética , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Células Tumorais CultivadasRESUMO
Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2-3 were observed more often with VAD + cyclosporin A than with VAD only: nausea (30% versus 8%, P = 0.015), mucositis (18% versus 5%, P = 0.13), infection (45% versus 35%, P = 0.50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (-18.5%, 26.9%)]. The median progression-free survival (PFS) was 8.6 months (VAD + cyclosporin A) versus 5.8 months (VAD): [log rank P = 0.16, hazard ratio = 0.71, 95% CI (0.44, 1.15)], and median overall survival was 13 months versus 14.6 months [log rank P = 0.89, hazard ratio = 0.96, 95% CI (0.62, 1.72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp-positive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclosporina/administração & dosagem , Resistência a Múltiplos Medicamentos , Mieloma Múltiplo/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Idoso , Distribuição de Qui-Quadrado , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
PURPOSE: To report the endovascular treatment of a symptomatic extracranial internal carotid artery (ICA) aneurysm that was complicated by heparin-induced thrombocytopenia and thrombosis. METHODS AND RESULTS: After undergoing a coronary artery bypass graft procedure, a patient was diagnosed with a symptomatic, 3.5-cm ICA aneurysm by computed tomography and angiography. Via a semiclosed access, an Enduring vascular graft was inserted under controlled back bleeding from the ICA. The patient was recovering uneventfully when routine duplex scanning on the fifth postoperative day suggested multiple thrombi within the graft, which was confirmed by arteriography. Thrombectomy and local fibrinolysis were performed; however, the graft occluded the next day without causing neurological symptoms. Heparin-induced thrombocytopenia was diagnosed by enzyme-linked immunosorbent assay. CONCLUSIONS: Endovascular repair of high cervical extracranial ICA aneurysms is feasible, and protection against intracerebral embolization can be achieved using a semiclosed technique with controlled back bleeding from the ICA during endograft deployment. However, multiple thrombi or thrombotic occlusion during the postoperative period, particularly in a patient already sensitized to heparin, should direct attention toward possible heparin-induced thrombocytopenia.
Assuntos
Aneurisma/cirurgia , Doenças das Artérias Carótidas/cirurgia , Trombose das Artérias Carótidas/complicações , Artéria Carótida Interna , Heparina/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Trombocitopenia/induzido quimicamente , Procedimentos Cirúrgicos Vasculares/métodos , Idoso , Ponte de Artéria Coronária , Humanos , Masculino , Trombocitopenia/complicaçõesRESUMO
We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mg and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32-65 years; Durie & Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
There are a number of studies dealing with intensive chemotherapy and stem cell transplantation in multiple myeloma. As to autologous transplantation best results have been obtained with younger patients (below 60 years) who had responsive disease and received their transplant within one year after start of treatment. Unfavourable prognostic factors were a high beta 2-microglobulin level and abnormal cytogenetics including any translocation or chromosome 11/13 abnormalities. Only one phase III study has been published, indicating a favourable effect of autologous transplantation. Despite the existence of a so-called 'graft-versus-myeloma effect' the overall outcome of patients after allogeneic transplantation is not better than after autologous transplantation, probably due to the inclusion in the published studies of heavily pretreated and refractory patients responsible for a high treatment related mortality. The ultimate value of intensive treatment of multiple myeloma will become clear in the coming years when more data become available from current phase III studies including the Dutch HOVON multicentre trial in which conventional treatment is compared with intensified therapy including bone marrow ablation and autologous stem cell transplantation.
Assuntos
Mieloma Múltiplo/terapia , Adulto , Idoso , Transplante de Medula Óssea , Ensaios Clínicos como Assunto , Resistência a Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Países Baixos/epidemiologia , Prevalência , Prognóstico , Transplante Autólogo/efeitos adversos , Resultado do Tratamento , Microglobulina beta-2/análiseRESUMO
Spontaneous recurrent hypothermia and hyperhidrosis associated with agenesis of the corpus callosum was first described by Shapiro and Plum in 1967. Since then, several cases with similar symptoms (now known as Shapiro's syndrome or spontaneous periodic hypothermia) have been described. We report another case of this syndrome in a 21-year-old-man, and discuss possible pathogenetic mechanisms and therapeutic approaches.
Assuntos
Agenesia do Corpo Caloso , Hiperidrose/complicações , Hipotermia/complicações , Adulto , Temperatura Corporal , Humanos , Hiperidrose/diagnóstico , Hiperidrose/terapia , Hipotermia/diagnóstico , Hipotermia/terapia , Imageamento por Ressonância Magnética , Masculino , Recidiva , SíndromeAssuntos
Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Leucemia Mieloide Aguda/classificação , Biomarcadores/sangue , Diagnóstico Diferencial , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Imunofenotipagem , Cariotipagem , Leucemia Mieloide Aguda/imunologia , Síndromes Mielodisplásicas/imunologia , Valor Preditivo dos Testes , Prognóstico , Translocação GenéticaRESUMO
In the period from August 1991 to August 1994, the Dutch Slide Review Committee of Adult Leukemias classified 14 leukemias as AML-M0. We reviewed the clinical characteristics and response to therapy of these patients. Eight patients were male. Patients' age ranged from 7 to 77 years (medium age 62 years). There was a striking homogeneity in morphological appearance of the blasts, being small to medium-sized round cells with often an eccentric nucleus with fine chromatin, several distinct nucleoli, and a high nucleo-cytoplasmic ratio. In addition to myeloid-associated markers such as CD13 and CD33, the blasts of all patients were positive for CD34 and HLA-DR, pointing to their immature differentiation stage. TdT was present in the blasts of 71%, CD7 was positive in the blasts of 42% of the patients. No consistent cytogenetic abnormalities were found. With respect to the treatment outcome, four patients achieved a complete remission after remission-induction treatment. The median survival was 4.5 months. Our present study shows AML-M0 to be an immature leukemia, uniform in morphology and immunological phenotype, with no consistent cytogenetic phenotype and with a poor clinical outcome.