RESUMO
Patients with acute myeloid leukaemia (AML) have a five-year survival rate of 28·7%. Natural killer (NK)-cell have anti-leukaemic activity. Here, we report on a series of 13 patients with high-risk R/R AML, treated with repeated infusions of double-bright (CD56bright /CD16bright ) expanded NK cells at an academic centre in Brazil. NK cells from HLA-haploidentical donors were expanded using K562 feeder cells, modified to express membrane-bound interleukin-21. Patients received FLAG, after which cryopreserved NK cells were thawed and infused thrice weekly for six infusions in three dose cohorts (106 -107 cells/kg/infusion). Primary objectives were safety and feasibility. Secondary endpoints included overall response (OR) and complete response (CR) rates at 28-30 days after the first infusion. Patients received a median of five prior lines of therapy, seven with intermediate or adverse cytogenetics, three with concurrent central nervous system (CNS) leukaemia, and one with concurrent CNS mycetoma. No dose-limiting toxicities, infusion-related fever, or cytokine release syndrome were observed. An OR of 78·6% and CR of 50·0% were observed, including responses in three patients with CNS disease and clearance of a CNS mycetoma. Multiple infusions of expanded, cryopreserved NK cells were safely administered after intensive chemotherapy in high-risk patients with R/R AML and demonstrated encouraging outcomes.
Assuntos
Antígeno CD56/análise , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/terapia , Receptores de IgG/análise , Adolescente , Adulto , Brasil/epidemiologia , Antígeno CD56/imunologia , Criança , Feminino , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/imunologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Receptores de IgG/imunologia , Adulto JovemRESUMO
NK cells have been seen as potential agents in adoptive immunotherapy for cancer. The main challenge for the success of this approach is to obtain a great quantity of activated NK cells for adoptive transfer. The present study had aimed to evaluate the effect of a feeder layer of irradiated MSCs in the in vitro expansion of NK cells. MSCs were obtained from the bone marrow (BM) cells remaining in the bag and filter used in the transplantation of hematopoietic stem cells. NK cells were obtained from peripheral blood (PB) of healthy volunteers. NK expansion and activation were stimulated by culture with artificial antigen-presenting cells (aAPCs) and IL-2, in the presence or absence of BM-MSCs. NK cell proliferation, phenotypic expression and cytotoxic activity were evaluated. Both culture conditions showed high NK purity with predominance of NK CD56brightCD16+ subset post expansion. However, cultures without the presence of MSCs showed higher NK proliferation, expression of activation markers (CD16 and NKG2D) and related cytotoxic activity. In this experimental study, the presence of a feeder layer of irradiated BM-MSCs interfered negatively in the expansion of PB-NKs, limiting their growth and activation. Further investigation is needed to understand the mechanisms of NK-MSC interaction and its implications.
Assuntos
Células Apresentadoras de Antígenos/citologia , Células Matadoras Naturais/citologia , Leucócitos Mononucleares/citologia , Células-Tronco Mesenquimais/citologia , Células Apresentadoras de Antígenos/imunologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Voluntários Saudáveis , Humanos , Interleucina-2/metabolismo , Células K562 , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Células-Tronco Mesenquimais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de IgG/metabolismoRESUMO
BACKGROUND: Hematopoietic stem cell transplantation is a curative treatment for many patients with hematological disorders. Donor-recipient genetic disparity, especially involving the human leukocyte antigen system is a critical factor for transplant outcome. OBJECTIVE: To evaluate retrospectively donor characteristics and correlations with the occurrence of acute and chronic graft-versus-host disease, disease-free survival and overall survival in a Brazilian population submitted to allogeneic hematopoietic stem cell transplantation between 1994 and 2012 in a single center. RESULTS: Three hundred and forty-seven consecutive transplantations were included. Related transplants (81.2%) were significantly more common than unrelated transplants (18.7%); donor and recipient median ages were 34 (range: 1-61) and 33 (range: 3-65) years respectively with donor HLAs being matched for 333 (95.9%) patients. Donor gender, cytomegalovirus status and ABO incompatibility did not influence the five-year overall survival. In univariate analyses, overall survival was negatively influenced by the presence of acute graft-versus-host disease (33% vs. 47%, respectively; p-value = 0.04), unrelated transplant (41.5% vs. 50.9%, respectively; p-value = 0.045) and donors aged over 40 years (41% vs. 52%, respectively; p-value = 0.03). Older donors were associated with a higher rate of acute (52% vs. 65.8%; p-value = 0.03) and chronic graft-versus-host disease (60% vs. 43%, respectively; p-value = 0.015). In multivariate analyses, acute graft-versus-host disease [relative risk (RR): 1.8; 95% confidence interval (CI): 1.1-29; p-value = 0.008] and older donors (RR: 1.6; 95% CI 1.11-2.24; p-value = 0.013) were associated with higher transplant-related mortality. CONCLUSIONS: In transplant patients, to have a donor older than 40 years of age seems to significantly increase the incidence of acute and chronic graft-versus-host disease and transplant-related mortality with no impact on disease-free survival and overall survival. In spite of the rather small cohort of patients, these findings are similar to what is described in the literature suggesting that a younger donor should be chosen whenever possible.
RESUMO
ABSTRACT Background: Hematopoietic stem cell transplantation is a curative treatment for many patients with hematological disorders. Donor-recipient genetic disparity, especially involving the human leukocyte antigen system is a critical factor for transplant outcome. Objective: To evaluate retrospectively donor characteristics and correlations with the occurrence of acute and chronic graft-versus-host disease, disease-free survival and overall survival in a Brazilian population submitted to allogeneic hematopoietic stem cell transplantation between 1994 and 2012 in a single center. Results: Three hundred and forty-seven consecutive transplantations were included. Related transplants (81.2%) were significantly more common than unrelated transplants (18.7%); donor and recipient median ages were 34 (range: 1-61) and 33 (range: 3-65) years respectively with donor HLAs being matched for 333 (95.9%) patients. Donor gender, cytomegalovirus status and ABO incompatibility did not influence the five-year overall survival. In univariate analyses, overall survival was negatively influenced by the presence of acute graft-versus-host disease (33% vs. 47%, respectively; p-value = 0.04), unrelated transplant (41.5% vs. 50.9%, respectively; p-value = 0.045) and donors aged over 40 years (41% vs. 52%, respectively; p-value = 0.03). Older donors were associated with a higher rate of acute (52% vs. 65.8%; p-value = 0.03) and chronic graft-versus-host disease (60% vs. 43%, respectively; p-value = 0.015). In multivariate analyses, acute graft-versus-host disease [relative risk (RR): 1.8; 95% confidence interval (CI): 1.1-29; p-value = 0.008] and older donors (RR: 1.6; 95% CI 1.11-2.24; p-value = 0.013) were associated with higher transplant-related mortality. Conclusions: In transplant patients, to have a donor older than 40 years of age seems to significantly increase the incidence of acute and chronic graft-versus-host disease and transplant-related mortality with no impact on disease-free survival and overall survival. In spite of the rather small cohort of patients, these findings are similar to what is described in the literature suggesting that a younger donor should be chosen whenever possible.
Assuntos
Humanos , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-HospedeiroRESUMO
Mesenchymal stem cells (MSC) are considered multipotent stromal, non-hematopoietic cells with properties of self-renovation and differentiation. Optimal conditions for culture of MSC have been under investigation. The oxygen tension used for cultivation has been studied and appears to play an important role in biological behavior of mesenchymal cells. The aim is characterize MSC in hypoxia and normoxia conditions comparing their morphological and functional characteristics. Bone marrow-derived mesenchymal stem cells obtained from 15 healthy donors and cultured. MSC obtained from each donor were separated into two cultivation conditions normoxia (21% O2 ) and hypoxia (three donors at 1%, three donors at 2%, five donors at 3%, and four donors at 4% O2 ) up to second passage. MSC were evaluated for proliferation, differentiation, immunophenotyping, size and cell complexity, oxidative stress, mitochondrial activity, and autophagy. Culture conditions applied did not seem to affect immunophenotypic features and cellular plasticity. However, cells subjected to hypoxia showed smaller size and greater cellular complexity, besides lower proliferation (P < 0.002). Furthermore, cells cultured in low O2 tension had lower mitochondrial activity (P < 0.03) and a reduced tendency to autophagy, although oxidative stress did not vary among groups (P < 0.39). Oxygen tension seems to be a key regulator of cellular adaptation in vitro, and metabolic effects underlying this variable remain undescribed. Heterogeneity or even lack of results on the impact of oxygen concentration used for expanding MSC highlights the need for further research, in order to optimize conditions of cultivation and expansion and achieve greater safety and therapeutic efficacy. J. Cell. Biochem. 118: 3072-3079, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Células da Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Consumo de Oxigênio , Células da Medula Óssea/citologia , Técnicas de Cultura de Células , Hipóxia Celular , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Fatores de TempoRESUMO
Pressure ulcers (PU) may increase the incidence of hospital complications, and one should prevent this damage. The Braden Scale stands out as a tool to assess the risk of PU. The study aimed to identify changes in the score of the Braden subscales are associated with the risk of developing PCU. Logistic regression was used in a retrospective cohort study conducted in Hospital de Clínicas de Porto Alegre in adults hospitalized in surgical clinical units from October 2005 to June 2006. We evaluated the records database of 1503 patients with a mean aged 55.5 +/- 16 years, 52.7% female. The incidence of PU was 1.8% and was associated with diabetes and heart failure. There was a higher PU in patients worst in sensory perception, mobility, and activity and the presence of moisture. No association was found between nutrition and PU. Except nutrition, the other Braden sub-scales shown to be predictive of PU.
Assuntos
Úlcera por Pressão/epidemiologia , Índice de Gravidade de Doença , Idoso , Comorbidade , Demência/epidemiologia , Complicações do Diabetes/epidemiologia , Suscetibilidade a Doenças , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Umidade , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Atividade Motora , Neoplasias/epidemiologia , Estado Nutricional , Valor Preditivo dos Testes , Úlcera por Pressão/etiologia , Úlcera por Pressão/enfermagem , Fatores de Risco , Transtornos de Sensação/epidemiologiaRESUMO
Úlceras por pressão (UP) podem aumentar a incidência de complicações hospitalares, devendo-se prevenir este dano. A Escala de Braden destaca-se como instrumento para avaliar o risco de UP. O estudo objetivou identificar quais alterações, na pontuação das subescalas de Braden, estão associadas com o risco do desenvolvimento de UP. Empregou-se regressão logística em uma coorte retrospectiva realizada no Hospital de Clínicas de Porto Alegre, em adultos hospitalizados em unidades clínicas e cirúrgicas, de outubro de 2005 a junho de 2006. Foram avaliados os registros de banco de dados de 1503 pacientes, com idade de 55,5±16 anos, sendo 52,7% do sexo feminino. A incidência de UP foi de 1,8%, e foi associada com diabetes e insuficiência cardíaca. Houve mais UP em pacientes com pior percepção sensorial, mobilidade, atividade e na presença de umidade. Não houve associação entre nutrição e UP. Exceto nutrição, as demais subescalas de Braden mostraram-se preditivas de UP.
Pressure ulcers (PU) may increase the incidence of hospital complications, and one should prevent this damage. The Braden Scale stands out as a tool to assess the risk of PU. The study aimed to identify changes in the score of the Braden subscales are associated with the risk of developing PU. Logistic regression was used in a retrospective cohort study conducted in Hospital de Clínicas de Porto Alegre in adults hospitalized in surgical clinical units from October 2005 to June 2006. We evaluated the records database of 1503 patients with a mean aged 55.5±16 years, 52.7% female. The incidence of PU was 1.8% and was associated with diabetes and heart failure. There was a higher PU in patients worst in sensory perception, mobility, and activity and the presence of moisture. No association was found between nutrition and PU. Except nutrition, the other Braden sub-scales shown to be predictive of PU.
Úlceras por presión (UPP) pueden aumentar la incidencia de complicaciones hospitalarias, y se debe evitar este daño. La Escala de Braden se destaca como una herramienta para evaluar el riesgo de UPP. El objetivo fue identificar como los cambios en las subescalas se asocian con el riesgo de desarrollar UPP. Regresión logística fue utilizada en estudio de corte retrospectivo realizado en Hospital de Clínicas de Porto Alegre en adultos hospitalizados en unidades clínicas quirúrgicas de octubre 2005 a junio 2006. Se evaluó la base de datos de 1503 pacientes con edad de 55,5±16 años, 52,7% mujeres. La incidencia de UPP fue un 1,8% y se asoció con diabetes e insuficiencia cardiaca. Hubo mayor UPP en pacientes con peor percepción sensorial, movilidad y actividad y presencia de humedad. No se encontró asociación entre nutrición y la ocurrencia de UPP. Excepto nutrición, las otras subescalas de Braden demostraron ser predictivo de UPP.