RESUMO
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
Assuntos
Apoptose/efeitos dos fármacos , Dexametasona/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vincristina/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Metilação de DNA , Proteínas de Ligação a DNA/fisiologia , Sinergismo Farmacológico , Feminino , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Indóis , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Panobinostat , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infiltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/sangue , Anemia/epidemiologia , Anemia/etiologia , Anemia/fisiopatologia , Anemia/psicologia , Anemia Hemolítica Autoimune/etiologia , Terapia Combinada , Darbepoetina alfa , Método Duplo-Cego , Eritropoetina/administração & dosagem , Eritropoetina/análogos & derivados , Eritropoetina/sangue , Humanos , Hiperesplenismo/etiologia , Hiperesplenismo/radioterapia , Hiperesplenismo/cirurgia , Incidência , Leucemia Linfocítica Crônica de Células B/complicações , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Esplenectomia , Esplenomegalia/tratamento farmacológico , Esplenomegalia/etiologia , Esplenomegalia/radioterapia , Esplenomegalia/cirurgia , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
La anemia es una complicación frecuente de la leucemia linfática crónica, que con frecuencia condiciona el pronóstico y la calidad de vida de estos pacientes. Distintos mecanismos fi siopatológicos conducen a este estado, entre ellos la infi ltración medular, el hiperesplenismo, la hemólisis inmune o la toxicidad de los tratamientos. El tratamiento con eritropoyetina humana recombinante se ha mostrado efi caz para el tratamiento de la anemia asociada a distintos síndromes linfoproliferativos. En este trabajo se analizan las evidencias disponibles sobre el tratamiento con eritropoyetina en la leucemia linfática crónica. Se revisan las distintas opciones posológicas, los posibles factores predictores de respuesta como los niveles de eritropoyetina endógena y el papel de la darbopoietina alfa
Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infi ltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed
Assuntos
Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Anemia/tratamento farmacológico , Eritropoetina/administração & dosagem , Transtornos Linfoproliferativos/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/complicações , Anemia/etiologiaRESUMO
In the second half of the XX century, the transplant of hemopoietic progenitors ceased to be a desperate treatment with a high incidence of complications implying a high mortality, and became a curative treatment for thousands of patients with hematological neoplasias and other diseases. Since then understanding of the hemopoietic stem cells has increased, peripheral blood has replaced bone marrow as a source of progenitors, cord blood has been established as a viable source of progenitors and the realisation of unrelated transplants is a reality for many patients. The improvement of conditioning regimes and the introduction of new non-myeloablative treatments have reduced relapses. The new diagnostic techniques and the new anti-microbial treatments have reduced infectious complications and their mortality. There has been an advance in knowledge in determining minimal residual disease and the anti-tumour effect of the lymphocytes of the donor, which has made it possible to widen the indications. Besides, new understanding of the immunobiology of the transplant has, on the one hand, improved the options for controlling one of the principal complications, the graft-versus-host disease, and, on the other, a better use is made of the immunotherapeutic effect of the transplant.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Efeito Enxerto vs Tumor , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adulto , Fatores Etários , Idoso , Animais , Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Cães , Previsões , Efeito Enxerto vs Leucemia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/história , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Leucemia/terapia , Pessoa de Meia-Idade , Neoplasias/terapia , Transplante de Células-Tronco de Sangue Periférico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Ratos , Espanha , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
The advances in the manipulation of human tissues, the development of cryobiology, paediatric cardiac surgery, the impossibility of obtaining an ideal prosthetic cardiac valve and the surgical treatment of cardiovascular infections have revived interest in the use of homografts. The donors of these homografts can be: a) Live donors: aortic and pulmonary valve of the recipient of a heart transplant; b) Multiorgan donors with a diagnosis of death according to neurological criteria, whose heart is rejected for heart transplant; c) Cadaver donors with asystolia of less than 8 hours. Homograft cardiac valves are the substitute of choice in aortic valve endocarditis, patients with counter-indications for anticoagulation, reconstruction of the outflow tract of the right ventricle, aortic valve replacement in children and young adults through the Ross operation, and an optional indication is the aortic valve and/or rising aorta replacement in patients over 60 years of age. Although there are not sufficiently broad series of homogratfs with arterial substitutes, with respect to the number of patients and time of evolution, the results suggest that this can benefit patients with vascular infection, immunodepressed patients or complex patients whose technique during the operation might require a homograft.
Assuntos
Vasos Sanguíneos/transplante , Valvas Cardíacas/transplante , Adulto , Valva Aórtica/transplante , Cadáver , Criança , Criopreservação , Endocardite/cirurgia , Cardiopatias Congênitas/cirurgia , Doenças das Valvas Cardíacas/cirurgia , Humanos , Lactente , Doadores Vivos , Pessoa de Meia-Idade , Seleção de Pacientes , Bancos de Tecidos , Doadores de Tecidos , Transplante Homólogo , Obstrução do Fluxo Ventricular Externo/cirurgiaRESUMO
En la segunda mitad del siglo XX el trasplante de progenitores hemopoyéticos ha pasado de ser un tratamiento desesperado con una alta incidencia de complicaciones que implicaba una elevada mortalidad, a ser un tratamiento curativo para miles de pacientes con neoplasias hematológicas y otras enfermedades. Desde entonces se han ampliado los conocimientos sobre las células madre hemopoyéticas, la sangre periférica ha sustituido a la médula ósea como fuente de progenitores, la sangre de cordón se ha establecido como fuente viable de progenitores, la realización de trasplantes no emparentados es una realidad para muchos pacientes. La mejora en los regímenes de acondicionamiento y la introducción de los regímenes no mieloablativos han disminuido las recaídas. Las nuevas técnicas diagnósticas y los nuevos tratamientos antimicrobianos han disminuido las complicaciones infecciosas y su mortalidad. Se han desarrollado los conocimientos en determinación de enfermedad mínima residual y el efecto antitumoral de los linfocitos del donante lo que ha permitido ampliar las indicaciones. Además, los nuevos conocimientos en la inmunobiología del trasplante han mejorado por un lado las opciones de controlar una de las principales complicaciones como es la enfermedad injerto contra huésped, y por otro un mejor aprovechamiento del efecto inmunoterápico del trasplante
In the second half of the XX century, the transplant of hemopoietic progenitors ceased to be a desperate treatment with a high incidence of complications implying a high mortality, and became a curative treatment for thousands of patients with hematological neoplasias and other diseases. Since then understanding of the hemopoietic stem cells has increased, peripheral blood has replaced bone marrow as a source of progenitors, cord blood has been established as a viable source of progenitors and the realisation of unrelated transplants is a reality for many patients. The improvement of conditioning regimes and the introduction of new non-myeloablative treatments have reduced relapses. The new diagnostic techniques and the new anti-microbial treatments have reduced infectious complications and their mortality. There has been an advance in knowledge in determining minimal residual disease and the anti-tumour effect of the lymphocytes of the donor, which has made it possible to widen the indications. Besides, new understanding of the immunobiology of the transplant has, on the one hand, improved the options for controlling one of the principal complications, the graft-versus-host disease, and, on the other, a better use is made of the immunotherapeutic effect of the transplant
Assuntos
Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante/métodos , Complicações Pós-OperatóriasRESUMO
Los progresos en la manipulación de los tejidos humanos, el desarrollo de la criobiología, la cirugía cardiaca pediátrica, la imposibilidad de conseguir una prótesis valvular cardiaca ideal y el tratamiento quirúrgico de las infecciones cardiovasculares, han reintroducido el interés para utilizar los homoinjertos. Los donantes de estos homoinjertos pueden ser: a) Donantes vivos: válvula aórtica y pulmonar del receptor de trasplante cardiaco; b) Donantes multiorgánicos con el diagnóstico de muerte según criterios neurológicos, cuyo corazón es rechazado para trasplante cardiaco; c) Donantes cadáveres con asistolia inferior a 8 horas. Los homoinjertos valvulares cardiacos son el sustituto de elección en las endocarditis valvulares aórticas, pacientes con contraindicación para la anticoagulación, reconstrucción del tracto de salida de ventrículo derecho, sustitución valvular aórtica en niños o adultos jóvenes mediante la operación de Ross y es una indicación opcional la sustitución valvular aórtica y/o la aorta ascendente en los pacientes con edad superior a 60 años. Aunque no hay series suficientemente amplias de homoinjertos como sustitutos arteriales, en cuanto a número de pacientes y tiempo de evolución, los resultados sugieren que se pueden beneficiar los pacientes con infección vascular, inmunodeprimidos o los pacientes complejos cuya técnica durante la intervención puede requerir la necesidad de un homoinjerto
The advances in the manipulation of human tissues, the development of cryobiology, paediatric cardiac surgery, the impossibility of obtaining an ideal prosthetic cardiac valve and the surgical treatment of cardiovascular infections have revived interest in the use of homografts. The donors of these homografts can be: a) Live donors: aortic and pulmonary valve of the recipient of a heart transplant; b) Multiorgan donors with a diagnosis of death according to neurological criteria, whose heart is rejected for heart transplant; c) Cadaver donors with asystolia of less than 8 hours. Homograft cardiac valves are the substitute of choice in aortic valve endocarditis, patients with counter-indications for anticoagulation, reconstruction of the outflow tract of the right ventricle, aortic valve replacement in children and young adults through the Ross operation, and an optional indication is the aortic valve and/or rising aorta replacement in patients over 60 years of age. Although there are not sufficiently broad series of homogratfs with arterial substitutes, with respect to the number of patients and time of evolution, the results suggest that this can benefit patients with vascular infection, immunodepressed patients or complex patients whose technique during the operation might require a homograft
Assuntos
Humanos , Transplante Homólogo/métodos , Valvas Cardíacas/transplante , Artérias/transplante , Doadores de Tecidos/provisão & distribuição , Seleção de Pacientes , Bancos de Tecidos , Preservação de Órgãos/métodos , Cardiopatias Congênitas/cirurgiaAssuntos
Neoplasias da Mama/tratamento farmacológico , Hiperamonemia/induzido quimicamente , Alanina Transaminase/sangue , Aminoácidos/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Aspartato Aminotransferases/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Trastuzumab , Resultado do TratamentoRESUMO
PURPOSE: To analyse outcome and prognostic factors for overall survival (OS) and time to treatment failure (TTF) in 357 patients with Hodgkin's lymphoma (HL) undergoing an autologous stem cell transplantation (ASCT) after a first relapse and reported to the The Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea (GEL/TAMO) Cooperative Group. METHODS: Two hundred and twenty males and 137 females with a median age of 29 years were autografted in second remission (n=181), first sensitive relapse (n=148) and first resistant relapse (n=28). RESULTS: Five-year actuarial TTF and OS were of 49% +/- 3% and 57% +/- 3%. Advanced stage at diagnosis, complementary radiotherapy before ASCT, a short first complete response (CR) and detectable disease at ASCT adversely influenced TTF. Year of transplant < or =1995, bulky disease at diagnosis, a short first CR, detectable disease at ASCT and > or =1 extranodal areas involved at ASCT were adverse factors for OS. CONCLUSIONS: ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.
Assuntos
Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Doença de Hodgkin/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Transplante de Células-Tronco/estatística & dados numéricos , Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Here we evaluate the results of high-dose chemotherapy and autologous stem-cell transplantation (HDC/ASCT) in 114 patients included in the GEL/TAMO registry between January 1990 and December 1999 with diffuse large B-cell lymphoma who failed to achieve complete remission (CR) with front-line conventional chemotherapy. PATIENTS AND METHODS: Sixty-eight per cent had a partial response (PR) and 32% failed to respond to front-line therapy. At transplant, 35% were chemoresistant and 29% had two to three adjusted International Prognostic Index (a-IPI) risk factors. RESULTS: After HDC/ASCT, 57 (54%) of 105 patients evaluable for response achieved a CR, 16 (15%) a PR and 32 (30%) failed. Nine patients were not assessed for response because of early death due to toxicity. With a median follow-up of 29 months for alive patients, the survival at 5 years is 43%, with a disease-free survival for complete responders of 63%. The lethal toxicity was 8%. Multivariate analysis revealed a-IPI and chemoresistance to be predicting factors. CONCLUSIONS: Our results show that one-third of patients who do not obtain a CR to front-line chemotherapy may be cured of their disease with HDC/ASCT. However, most chemoresistant patients pretransplant failed this therapy. For this population, as well as for those who presented with adverse factors of the a-IPI, pretransplant novel therapeutic modalities need to be tested.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Linfoma de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoRESUMO
Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standard-dose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III-IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (i.v.) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 microg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34+ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells x 10(6)/l; P=0.01) and on the fifth (25 vs 58 cells x 10(6)/l; P=0.003), as it was the number of CD34+ cells collected per apheresis (1.3 vs 3.5 x 10(6)/l; P<0.0005). The toxic effect of a single course of BCNU-cisplatin CT led to significant impairment of the filgrastim-induced mobilization response.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/administração & dosagem , Cisplatino/efeitos adversos , Glioma/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Adulto , Antígenos CD34/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Cinética , Pessoa de Meia-IdadeRESUMO
BACKGROUND: T-cell immunophenotype constitutes an unfavorable prognostic factor in aggressive non-Hodgkin's lymphomas. High-dose chemotherapy with autologous stem-cell rescue (HDC/ASCT) is the best salvage therapy for patients with aggressive B-cell lymphomas. However, results with this therapy in peripheral T-cell lymphoma (PTCL) are not well defined. PATIENTS AND METHODS: From January 1990 to December 1999, 115 patients with PTCL underwent HDC/ASCT inside the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) registry. At diagnosis the median age was 41 years and 60% of patients presented with two or three risk factors from the adjusted International Prognostic Index (a-IPI). Thirty-two per cent of patients were transplanted in first complete response (CR), 62% in chemosensitive disease and 5% in refractory disease. RESULTS: Eighty-six per cent of the patients attained a CR and 5% a partial response (PR). With a median follow-up of 37 months (range 1-133), overall survival (OS), time-to-treatment failure (TTF) and disease-free survival (DFS) at 5 years was 56%, 51% and 60%, respectively; for the 37 patients transplanted in first CR, OS and DFS at 5 years were 80% and 79%, respectively. Lactase dehydrogenase (LDH), a-IPI and disease status pre-transplant were associated with outcome. CONCLUSIONS: More than half of patients with chemosensitive disease who were transplanted are expected to be alive at 5 years. We confirm the utility of the pre-transplant IPI system in predicting outcome. Salvage treatment results with HDC/ASCT in PTCL are similar to those found in corresponding aggressive B-cell lymphomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carmustina/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação , Transplante Autólogo , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
BACKGROUND: Patients with primary refractory Hodgkin's disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO). PATIENTS AND METHODS: Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13-55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols. RESULTS: One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92-3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90-4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69-9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29-6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95-5.27, P = 0.06) adversely influenced OS. CONCLUSIONS: In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be investigated in this group of patients to improve the outcome.
Assuntos
Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Transplante de Células-Tronco/estatística & dados numéricos , Adolescente , Adulto , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Estatísticas não Paramétricas , Taxa de Sobrevida , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this study was to analyse the results and prognostic factors influencing overall survival (OS) and disease-free survival (DFS) in 452 patients diagnosed with diffuse large cell lymphomas (DLCL) treated with high-dose therapy (HDT) included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry. PATIENTS AND METHODS: At transplantation, median age was 42 years (range 15-73), 146 patients (32%) were transplanted in first complete remission (1st CR), 19% in second CR (2nd CR) and 47% had active disease: sensitive disease in 157 (35%) patients [95 were in first partial remission (1st PR) and 62 in second PR (2nd PR)] and refractory disease in 55 (12%) patients. Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 51 patients (12%). Conditioning regimen consisted of BEAM (carmustine, etoposide, cytarabine and melphalan) in 39% of patients, BEAC (carmustine, etoposide, cytarabine and cyclophosphamide) in 33%, CBV (carmustine, etoposide and cyclophosphamide) in 10% and cyclophosphamide plus total body irradiation (TBI) in 12%. RESULTS: Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 53% and 43%, respectively. The transplant-related mortality was 11% (53 cases). By multivariate analysis three variables significantly influenced OS and DFS: number of protocols to reach 1st CR, disease status at transplant and TBI in the conditioning regimen. Age-adjusted IPI at transplantation also influenced OS. CONCLUSIONS: Prolonged OS and DFS can be achieved in patients with DLCL after HDT and our results suggest that the best line of chemotherapy should be used up-front in patients considered as candidates for HDT in order to obtain an early CR. Resistant patients are not good candidates for HDT and they should be offered newer strategies. Finally, polichemotherapy conditioning regimens offer better results compared with TBI.
Assuntos
Biomarcadores Tumorais/análise , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Carmustina , Terapia Combinada , Ciclofosfamida , Citarabina , Citocinas , Doxorrubicina , Etoposídeo , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Melfalan , Pessoa de Meia-Idade , Podofilotoxina , Prednisona , Prognóstico , Radioterapia Adjuvante , Indução de Remissão , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento , VincristinaRESUMO
La posibilidad de utilizar células madre en el tratamiento de diversas enfermedades humanas como la diabetes, la enfermedad de Parkinson, la cardiopatía isquémica constituye uno de los retos mas importantes de la medicina moderna. Sin embargo, antes de que los resultados de los estudios con células madre se traduzcan clínicamente existen múltiples problemas que deben ser resueltos. A continuación trataremos de exponer algunos conceptos relacionados con las células madre y su potencial, centrándonos principalmente en las células madre adultas tal como han sido recientemente descritas por el grupo de Catherine Verfaillie. Además presentaremos resultados de alguno de los primeros estudios clínicos realizados con células madre adultas como forma de terapia regenerativa cardíaca. En dichos trabajos se han empleado células madre de músculo (células satélite) autólogas en pacientes con infarto de miocardio, inyectándose directamente dichas células en la periferia de la cicatriz secundaria al infarto (AU)
One of the most important challenges in modern medicine is the use of stem cells for the treatment of human disease such as diabetes, Parkinson´s disease or isquemic cardiomyopathy. A number of problems need to be solved before stem cells can be applied clinically. In this paper we will review some concepts related to the potential of stem cells, focusing on adult stem cells as they have recently been described by the group of Catherine Verfaillie. We will also present our initial clinical results using adult stem cells for cardiac regenerative therapy. In the studies mentioned above, autologous muscle stem cells (satelite cells) were infused directly in the periphery of the scar tissue of the infarct. We describe the technique for ex vivo expansion and purification of muscle stem cells (AU)
Assuntos
Humanos , Masculino , Feminino , Células-Tronco/fisiologia , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências , Infarto do Miocárdio/reabilitação , Infarto do Miocárdio/terapia , Citometria de Fluxo/métodos , Citometria de Fluxo , Autorrenovação Celular/fisiologia , Mioblastos/fisiologia , Mioblastos Cardíacos/fisiologia , Mioblastos Cardíacos/ultraestruturaRESUMO
OBJECTIVE: With the aim of obtaining monoclonal antibodies (mAbs) against mouse endothelial surface antigens, immunization of rats with a mouse-derived endothelial cell line (PY4.1) and subsequent hybridoma production were performed. MATERIALS AND METHODS: One of the mAbs produced by hybridoma EOL5F5 was selected for its surface binding to endothelial cell lines, and identification of the mAb-recognized antigen was performed by immunoprecipitation. Experiments were performed to analyze the effects of EOL5F5 on systemic administration to mice. RESULTS: EOL5F5-recognized antigen was a single band of 35 kDa under reducing and nonreducing conditions, features that do not match other known differentiation antigens with comparable tissue distribution. In vivo administration of purified EOL5F5 mAb to mice (n = 20) induced intense cutaneous purpura as well as severe but transient thrombocytopenia. Expression of EOL5F5-recognized antigen was detected on platelets from which it immunoprecipitated a moiety of identical electrophoretic pattern in SDS-PAGE, as the one recognized on endothelial cells. Immunohistochemically, EOL5F5-recognized antigen (p35) also was expressed on dermal capillaries, suggesting that, in addition to thrombocytopenia, damaging effects of the antibody on endothelial cells also might cause the observed purpura. CONCLUSIONS: Our results show induction of thrombocytopenic purpura in mice with an mAb against a single antigenic determinant expressed on both platelets and endothelium. EOL5F5 mAb injection sets the stage for useful experimental models that resemble immune thrombocytopenic purpura.
Assuntos
Anticorpos Monoclonais/toxicidade , Antígenos de Diferenciação/imunologia , Antígenos de Superfície/imunologia , Plaquetas/imunologia , Endotélio Vascular/imunologia , Púrpura Trombocitopênica/etiologia , Animais , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Hibridomas/imunologia , Imunização , Camundongos , Camundongos Nus , Púrpura Trombocitopênica/imunologia , Ratos , Ratos Wistar , Pele/irrigação sanguínea , Trombocitopenia/etiologiaRESUMO
PURPOSE: To analyze clinical outcome and significant prognostic factors for overall (OS) and time to treatment failure (TTF) in a group of 494 patients with Hodgkin's disease (HD) undergoing autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Detailed records from the Grupo Español de Linfomas/Transplante Autólogo de Médula Osea Spanish Cooperative Group Database on 494 HD patients who received an ASCT between January 1984 and May 1998 were reviewed. Two hundred ninety-eight males and 196 females with a median age of 27 years (range, 1 to 63 years) received autografts while in complete remission (n = 203) or when they had sensitive disease (n = 206) or resistant disease (n = 75) at a median time of 26 months (range, 4 to 259 months) after diagnosis. Most patients received high-dose chemotherapy without radiation for conditioning (n = 443). The graft consisted of bone marrow (n = 244) or peripheral blood (n = 250). RESULTS: The 100-day mortality rate was 9%. The 5-year actuarial TTF and OS rates were 45.0% (95% confidence interval [CI], 39.5% to 50.5%) and 54.5% (95% CI, 48.4% to 60.6%), respectively. In multivariate analysis, the presence of active disease at transplantation, transplantation before 1992, and two or more lines of therapy before transplantation were adverse prognostic factors for outcome. Sixteen patients developed a secondary malignancy (5-year cumulative incidence of 4.3%) after transplantation. Adjuvant radiotherapy before transplantation, the use of total-body irradiation (TBI) in the conditioning regimen, and age > or = 40 years were found to be predictive factors for the development of second cancers after ASCT. CONCLUSION: ASCT achieves long-term disease-free survival in HD patients. Disease status before ASCT is the most important prognostic factor for final outcome; thus, transplantation should be considered in early stages of the disease. TBI must be avoided in the conditioning regimen because of a significantly higher rate of late complications, including secondary malignancies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Doença de Hodgkin/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
No disponible
Assuntos
Idoso , Masculino , Humanos , Invasividade Neoplásica , Próstata , Linfoma não HodgkinRESUMO
INTRODUCTION: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insufficiency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. MATERIALS AND METHODS: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were defined: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. RESULTS AND CONCLUSION: Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).