RESUMO
BACKGROUND: Retrospective studies in hematological unit have suggested that single red blood cell (1-RBC) unit transfusion policy may reduce the number of RBC used without negative clinical impact. METHOD: Acute leukemia patients requiring intensive chemotherapy or patients receiving autologous or allogeneic transplantation were randomly assigned to receive either single RBC (1-RBC arm) or double RBC (2-RBC arm) per transfusion with a hemoglobin trigger of 8 g/dL. The primary composite endpoint was the percentage of patients experiencing serious complications, such as a non-hematological adverse event grade ≥ 3 or intensive care admission or death. FINDINGS: A total of 981 and 592 RBC transfusions were required in the 1-RBC arm (n = 125) and the 2-RBC arm (n = 120), respectively. The mean pre-transfusion hemoglobin levels were 7.49 ± 0.83 g/dL in the 1-RBC arm and 7.46 ± 0.67 g/dL in the 2-RBC arm (p = 0.275). The predefined non-inferiority criteria was achieved with 28/125 patients reaching the primary endpoint in the 1-RBC arm (22.4 %) and 28/120 patients in the 2-RBC arm (23.3 %) (Risk difference 0.009; 95 %, Confidence interval [-0.0791 to 0.0978], p = 0.021). The median (IQR) of RBC units transfused per patient was 7 (4-12) in the 1-RBC arm and 8 (4-12) in 2-RBC arm. Hemoglobin levels at discharge were also comparable in both arms. INTERPRETATION: The results of this trial indicate that a single RBC transfusion policy is not inferior to a double RBC transfusion policy for patients receiving a bone marrow transplant or intensive chemotherapy in a hematological intensive care unit. However, the single RBC transfusion policy did not reduce the number of RBC units transfused per stay. FUNDING: This trial was funded by a grant from the French Ministry of Health.
Assuntos
Doenças Hematológicas , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Transfusão de Eritrócitos/efeitos adversos , Hemoglobinas , Leucemia Mieloide Aguda/etiologia , Doença AgudaRESUMO
INTRODUCTION: Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: In the setting of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. RESULTS: The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×109/L neutrophils and 20 × 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. CONCLUSION: In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Sociedades Médicas , Idoso , Idoso de 80 Anos ou mais , Transplante de Medula Óssea , Terapia Baseada em Transplante de Células e Tecidos , Intervalo Livre de Doença , Feminino , Seguimentos , França/epidemiologia , Humanos , Incidência , Linfoma não Hodgkin/epidemiologia , Masculino , Prevalência , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
OBJECTIVE: This multicenter phase III study compared the MEMID regimen (mitoxantrone, VP16, methylglyoxal, ifosfamide and dexamethasone) with CEOP, a CHOP-like regimen (cyclophosphamide, epirubicin, vincristine and prednisone), in elderly patients (> or =65 years) with aggressive non-Hodgkin's lymphoma (NHL). METHODS: One hundred and forty-nine patients were eligible, 72 in the MEMID arm and 77 in the CEOP arm. The primary endpoint was to compare overall survival (OS) between groups, and secondary endpoints were event-free survival (EFS), response rate and toxicity. RESULTS: Neutropenia (p < 10(-5)), anemia (p < 10(-5)) and thrombocytopenia (p = 0.0006) were significantly more frequent in patients who received MEMID. We observed an objective response rate of 55.5% in the MEMID arm and 64.9% in the CEOP arm (p = 0.24). The median OS and EFS were 15.4 and 8.5 months in the MEMID arm, and 20.3 and 10.5 months in the CEOP arm (p = 0.59 and 0.47), respectively. The median EFS was 15.4 months in the MEMID arm and 20.3 months in the CEOP arm (p = 0.59). CONCLUSION: The increased toxicity without survival benefit confirms the superiority of CHOP and CHOP-like regimens for elderly patient with aggressive NHL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Epirubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Linfoma não Hodgkin/patologia , Masculino , Mitoxantrona/administração & dosagem , Neutropenia/induzido quimicamente , Prednisona/administração & dosagem , Estudos Prospectivos , Aldeído Pirúvico/administração & dosagem , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Monofosfato de Citidina/análogos & derivados , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Arabinonucleotídeos/administração & dosagem , Monofosfato de Citidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide de Fase Crônica/mortalidade , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Recombinantes , Fatores de Risco , Taxa de SobrevidaRESUMO
The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Recidiva , Tretinoína/administração & dosagemRESUMO
PURPOSE: Hydroxyurea is a treatment of myeloproliferative syndromes. Its cutaneous side-effects are underestimated, because they are usually benign. We undertook a prospective study to evaluate their frequency. METHODS: During a 2-year period, all patients taking hydroxyurea for more than 6 months who had consultations at the dermatology department were systematically examined, regarding cutaneous side effects. RESULTS: Twenty-six patients were examined. All but one had cutaneous side-effects, including dryness (n = 16), moderate alopecia (n = 2), increased skin pigmentation (n = 5), melanonychia, single (n = 1) or multiple (n = 7), cutaneous atrophy (n = 4), leg ulcers (n = 8), plantar keratoderma (n = 3), pseudodermatomyositis (n = 1), lichen planus-like eruption on the dorsum of the hands (n = 2), actinic keratosis (n = 8), squamous cell carcinomas (n = 2), and mouth ulcerations (n = 1). CONCLUSION: This study shows that the frequency of hydroxyurea cutaneous side-effects diagnosed in 95% of studied patients is underestimated. They are usually benign, but some of them, in particular leg ulcers and squamous cell carcinomas, lead to modification of the treatment (39% of studied patients).
Assuntos
Antineoplásicos/efeitos adversos , Hidroxiureia/efeitos adversos , Dermatopatias/induzido quimicamente , Carcinoma de Células Escamosas/induzido quimicamente , Humanos , Úlcera da Perna/induzido quimicamente , Transtornos Mieloproliferativos/tratamento farmacológicoRESUMO
PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 microg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 x 10(9)/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P <.001) and after ICC 2 (20 v 28 days, P <.001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P <.001; 29 v 34 days after ICC 2, P <. 001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Amsacrina/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Filgrastim , Hospitalização , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Neutropenia/prevenção & controle , Proteínas Recombinantes , Indução de Remissão , Resultado do TratamentoRESUMO
In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bussulfano/administração & dosagem , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Neutrófilos/citologia , Condicionamento Pré-TransplanteRESUMO
INTRODUCTION: The association between diffuse normolipemic plane xanthomatosis and monoclonal dysglobulinemia is well known. The presence of cutaneous xanthomas with normal serum lipid levels is due to the antibetalipoproteic activity of the monoclonal immunoglobulin. METHODS: A 51-year-old female patient had generalized polyadenopathy and diffuse normolipemic plane xanthomatosis of 3 years duration. The clinical status of the patient was fluctuating. Lipids levels were in the normal range. Weight loss and new nodal enlargements revealed high-grade malignant non-Hodgkin's lymphoma. CONCLUSION: This case illustrates the development of diffuse normolipemic plane xanthomatosis in association with dysglobulinemia revealing non Hodgkin's lymphoma. The association has not been reported earlier in the literature.
Assuntos
Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/diagnóstico , Paraproteinemias/complicações , Paraproteinemias/diagnóstico , Xantomatose/etiologia , Biópsia , Feminino , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Redução de PesoRESUMO
The purpose of this work was to study the effects of chronic lymphoid leukemia (CLL) and its treatments on bone mineral density (BMD). Lumbar and femoral BMD was measured by X-ray absorptiometry in 50 (32 M, 18 F, median age 65, range age: 47-87 yr) CLL patients. In order to gauge the respective effects of CLL and corticoids on bone mass, 31 CLL patients under treatment were compared with 31 controls on cortisone. Nineteen untreated patients with CLL were compared with controls devoid of osteopenia risk factor. There was no significant difference regarding lumbar and femoral BMD between the untreated patients with CLL and the healthy controls. An increase in lumbar and femoral BMD was noted in the treated CLL group compared with the controls on cortisone (lum BMD: 1.018 vs. 0.861 g/cm2, p=6.10(-4); fem BMD: 0.773 vs. 0.699 g/cm2, p=0.037). This increase was observed only in patients who had received chlorambucil (lum BMD: 1.066 vs. 0.861 g/cm2, p=0.10(-4); fem BMD: 0.806 vs. 0.699 g/cm2, p=4.10(-3)), whereas there was no difference between the CLL patients treated without chlorambucil and the controls on cortisone. Multiple linear regression analysis confirmed the marked effect of chlorambucil (r=0.3715, p<10(-3)) on BMD increase in the course of CLL.
Assuntos
Densidade Óssea/efeitos dos fármacos , Clorambucila/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Absorciometria de Fóton , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cortisona/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A 17-year-old male patient complaining of intense pain in his right hip was found to be suffering from chronic myelogenous leukaemia. Preliminary X-rays and bone scintigraphy did not suggest avascular necrosis of the femoral head. Magnetic resonance imaging (MRI) did, however, reveal leukaemic infiltration of the femoral neck and generalised ischeamia in the femoral head. Further, MRI carried out 4 months later disclosed typical signs of osteonecrosis, despite previous indications of an improvement under chemotherapy. Flattening of the head of the femur appeared in radiographs taken in the 9th month. In the 12th month, recurrence of pain made it necessary to perform a total hip arthroplasty. Anatomo-pathological investigation confirmed both the necrosis and the leukaemic invasion.
Assuntos
Necrose da Cabeça do Fêmur/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Adolescente , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/diagnóstico , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , RadiografiaRESUMO
From December 1987 to June 1992, 251 patients aged 50-65 with de novo acute myelogenous leukaemia (AML) were recruited to a multi-institutional randomized clinical trial. Induction therapy consisted of Ara-C (200 mg/ m2, continuous infusion, days 1-7) with either zorubicin (ZRB) (200 mg/m2, i.v., days 1-4) or idarubicin (IDR) (8 mg/ m2, i.v., days 1-5). Consolidation therapy consisted of a single course of intensive chemotherapy with high-dose Ara-C (3 g/m2, 3 h infusion, q 12 h, days 1-4) and m-Amsa (100 mg/m2/d, i.v., days 5-7). The complete remission (CR) rate was (73%) with Ara-C/ IDR versus (60%) with Ara-C/ZRB (P = 0.033). In multivariate analysis, factors found to be significant in predicting CR were normal karyotype and treatment with IDR. With a median follow-up of 73 months, the median disease-free survival (DFS) duration of all CR patients and the probability of CR at 6 years were 17 months and 29%. In multivariate analysis the only factor associated with an increased DFS duration was a normal karyotype. The median event-free survival (EFS) duration for all evaluable patients and the median overall survival duration for all eligible patients were respectively 7 and 12 months without any difference between induction arms. The study shows that in patients aged 50-65 idarabicin is more effective than zorubicin for remission induction. However, the type of anthracycline did not influence overall survival duration. Using a unique consolidation course, we observed a prolonged DFS which compares favourably with results obtained with more prolonged consolidation therapy or maintenance treatment.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Daunorrubicina/análogos & derivados , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Daunorrubicina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Análise de Sobrevida , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Terapia Combinada , Tolerância a Medicamentos , França , Humanos , Hidroxiureia/administração & dosagem , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Pessoa de Meia-Idade , Proteínas RecombinantesRESUMO
Confocal microspectrofluorometry allows the analysis of fluorescent molecules such as anthracylines in isolated living cells. An optical microscope fitted with a phase-contrast 100 X water-immersion objective enables simultaneous observation of the sample, focusing of the laser beam on the selected cell fraction (nucleus) and collection of the fluorescence emitted from the sample. The resulting intranuclear spectra are interpreted according to a quantitative model of the fluorescence spectra of both free and DNA-bound anthracycline. The intranuclear drug concentration can thus be determined. This technique has been applied to blast cells collected in patients with acute leukemia. Leukemic cells are aspirated from bone marrow, separated by Ficoll sedimentation and resuspended in RPMI-1640 containing 10% fetal calf serum and 200 nM tetrahydropyranyl-doxorubicin (THP-DOX). After one hour, 20 cells are analyzed and the mean nuclear drug content is determined (C1). Cells are then resuspended in the same medium but without anthracycline for 3 hours and the mean intranuclear drug concentration is then also determined (C3). From C1 and C3 the retention rate (RR) is calculated. Firstly, the accuracy of the method was checked. In 4 AML patients, two different samples aspirated on the same day were divided into two portions. Thus, two measurements were made on each one (4 values per patient). Coefficients of variation were satisfactory (4, 6, 12, and 12%). Secondly, blast cells collected in patients with AML and ALL at diagnosis or in relapse were studied. P-glycoprotein (P-gp) and CD34 expression was also studied using respectively immunohistochemistry land flow cytometry. Results obtained from the first 21 patients showed that there was no correlation between RR and either P-gp or CD34 expression. This could result from the efflux of THP-DOX by other mechanisms and/or low sensitivity of the staining technique.
Assuntos
Medula Óssea/metabolismo , Resistência a Múltiplos Medicamentos/genética , Leucemia Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacocinética , Antígenos CD34/genética , Transporte Biológico , Medula Óssea/patologia , Núcleo Celular/metabolismo , Criança , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide/patologia , Microscopia Confocal/métodos , Microespectrofotometria/métodos , Pessoa de Meia-Idade , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Microspectrofluorometry allows the analysis of fluorescent molecules such as anthracyclines in the nucleus of isolated living cells. Using this technique, we confirmed that the amount of doxorubicin or THP-doxorubicin incorporated into the nucleus was related to the resistant or sensitive character of K562 cells. It was then extended to the study of fresh leukemic cells and kinetic studies were performed allowing the calculation of the retention rate (RR) of anthracycline (THP-doxorubicin) into the cell nucleus. A reproducibility study confirmed the accuracy of the method. Blast cells collected in patients with acute myeloid (n = 22) or lymphoid (n = 8) leukemia, at diagnosis (n = 26), or in relapse (n = 4) have been studied. RR varied from 8 to 98% independently of the type of leukemia or the clinical status. RR did not correlate either with P-glycoprotein or with CD34 expression although this latter result should be confirmed on a higher number of subjects. Among 18 patients presenting with AML at diagnosis, 14 have been treated with intensive chemotherapy including anthracyclines; the only one who had resistant disease had the lowest RR value. In conclusion, the results obtained here show that microspectrofluorometry allows the performance of kinetic studies on fresh leukemic cells in order to quantify chemo-resistance phenomena related to drug transport.
Assuntos
Doxorrubicina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Microscopia Confocal/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Transporte Biológico , Compartimento Celular , Núcleo Celular/metabolismo , Doxorrubicina/metabolismo , Resistência a Medicamentos , Humanos , Técnicas In Vitro , Espectrometria de Fluorescência/métodos , Células Tumorais CultivadasRESUMO
Erythrocyte aggregation is a physiological phenomenon and constitutes one of the most important factors accounting for the non-Newtonian properties of normal human blood. Pathological aspects have also been described and therapy aimed at reducing hyperaggregability has been proposed. The object of this study was to establish normal values of erythrocyte aggregation parameters as measured by laser light backscattering and to study the influence of various physiological factors. Normal values were determined from a reference population. Sex and age induce variations in erythrocyte aggregation which are neither fibrinogen nor haematocrit dependent and there is a general trend towards stronger aggregation in women, although neither hormonal state nor oestroprogestative treatment appear to influence the female aggregation parameters. In elderly people stronger aggregation is also observed but this effect is of lower magnitude. In vivo, the plasma fibrinogen level is the most important factor influencing erythrocyte aggregation, while variations in haematocrit play a lesser role and mean corpuscular volume, red cell distribution width and white blood cell and platelet counts have no effect. Finally, no difference is noted in cigarette smokers.
Assuntos
Envelhecimento/sangue , Agregação Eritrocítica/fisiologia , Hormônios/sangue , Caracteres Sexuais , Fumar/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Estrogênios/uso terapêutico , Feminino , Testes Hematológicos , Hormônios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Progestinas/uso terapêutico , Valores de ReferênciaRESUMO
A prospective study was carried out in 44 patients treated by intensive chemotherapy inducing a prolonged neutropenia (granulocytes less than 0.5.10(9)/l). All the patients were isolated in protected rooms, received a pathogen-free diet and nonabsorbable oral antibiotics. After double-blind randomization, 22 patients received 2 g of Ceftriaxone (Cef) in a daily infusion beginning on the first day of chemotherapy; and 22 patients received 2 g of placebo (P) under the same conditions. Prophylaxis was continued until the neutropenia resolved (granulocytes greater than 0.5.10(9)/l) or until the onset of infectious symptoms. 19 patients in each group developed febrile episodes, occurring significantly later in the Cef group (16.6 days versus 10.6 days in the P group). No Cef-resistant organism was isolated. Finally, the time at which apyrexia was obtained after the beginning of curative antibiotherapy was the same in both groups. The routine intravenous administration of Cef in combination with nonabsorbable antibiotics is a useful approach in reducing the risk of infection in the neutropenic host.