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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(8): 854-859, 2021 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34511177

RESUMO

Haploidentical hematopoietic stem cell transplantation is a recommended alternative therapy for children with severe aplastic anemia who lack a human leukocyte antigen (HLA)-identical sibling donor and do not respond well to immunosuppressive therapy; however, due to non-identical HLA, the patients may have donor-specific anti-HLA antibody, which may lead to a relatively high incidence rate of poor graft function. Compared with HLA-identical transplantation, conditioning regimen for haploidentical transplantation still needs to be explored. This article reviews the detection and treatment of donor-specific anti-HLA antibody, the selection of conditioning regimen, and the mechanism and treatment of poor graft function in haploidentical hematopoietic stem cell transplantation.


Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/terapia , Criança , Humanos , Condicionamento Pré-Transplante , Transplante Homólogo
2.
Trials ; 22(1): 611, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503552

RESUMO

BACKGROUND: Increasingly, it is argued that clinical trials struggle to recruit participants because they do not respond to key questions or study treatments that patients will be willing or able to use. This study explores how elicitation of patient-preferences can help designers of randomized controlled trials (RCTs) understand the impact of changing modifiable aspects of treatments or trial design on recruitment. METHODS: Focus groups and a discrete choice experiment (DCE) survey were used to elicit preferences of people with scleroderma for autologous hematopoietic stem cell transplant (AHSCT) treatment interventions. Preferences for seven attributes of treatment (effectiveness, immediate and long-term risk, care team composition and experience, cost, travel distance) were estimated using a mixed-logit model and used to predict participation in RCTs. RESULTS: Two hundred seventy-eight people with scleroderma answered the survey. All AHSCT treatment attributes significantly influenced preferences. Treatment effectiveness and risk of late complications contributed the most to participants' choices, but modifiable factors of distance to treatment center and cost also affected preferences. Predicted recruitment rates calibrated with participation in a recent trial (33%) and suggest offering a treatment closer to home, at lower patient cost, and with holistic, multidisciplinary care could increase participation to 51%. CONCLUSIONS: Through a patient engaged approach to preference elicitation for different features of AHSCT treatment options, we were able to predict what drives the decisions of people with scleroderma to participate in RCTs. Knowledge regarding concerns and the trade-offs people are willing to make can inform clinical study design, improving recruitment rates and potential uptake of the treatment of interest.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Preferência do Paciente , Comportamento de Escolha , Grupos Focais , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e Questionários
3.
Rinsho Ketsueki ; 62(8): 1256-1264, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497214

RESUMO

Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after hematopoietic cell transplantation (HCT). Despite its relatively low incidence and the spontaneous resolution of most SOS/VOD cases, severe SOS/VOD evolved to multi-organ failure with an >80% mortality rate and represents one of the major clinical problems after HCT. The sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen in these patients. Several risk factors have been identified for SOS/VOD development. Although defibrotide is recommended for both prevention and treatment, no satisfactory therapy exists for managing severe SOS/VOD. Thus, this review describes the new definition of SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation. Furthermore, it describes the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Células Endoteliais , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , Condicionamento Pré-Transplante
4.
Rinsho Ketsueki ; 62(8): 1265-1274, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497215

RESUMO

Graft versus host disease (GVHD) prophylaxis using antithymocyte globulin (ATG) has been shown for chronic GVHD inhibition effect by a series of randomized control trials in unrelated hematopoietic or peripheral blood stem cell transplantation (PBSCT). Lower doses of ATG have been used in recent studies, although the optimal dose of ATG remains undefined. Consequently, a multicenter phase II study of low-dose ATG (2 mg/kg Thymoglobulin®) was conducted in patients undergoing human leukocyte antigen-matched PBSCT, showing the safety and efficacy for the prevention of both acute and chronic GVHD. In a nationwide retrospective study for ATG in unrelated PBSCT, the ATG group had a significantly lower incidence of chronic GVHD and a higher probability of GVHD- and relapse-free survival compared with the non-ATG group, although the dose of ATG used was low (1.0-3.0 mg/kg of Thymoglobulin®). Regarding absolute lymphocyte count (ALC) before the administration of ATG, the incidences of grades III-IV acute GVHD and moderate-to-severe chronic GVHD were significantly higher in patients with high ALC before ATG. Conversely, the relapse rate was significantly higher in patients with low ALC before ATG, suggesting a strategy to individualize ATG dosing by modulating ATG doses according to ALC before ATG.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Estudos Retrospectivos , Condicionamento Pré-Transplante
5.
Rinsho Ketsueki ; 62(8): 1275-1280, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497216

RESUMO

Allogeneic hematopoietic cell transplantation (allo-HCT) plays an important role as the most potent therapeutic option for refractory acute lymphoblastic leukemia (ALL). However, advances of supporting therapy have enabled more intensive chemotherapy, and severe late complication of allo-HCT has been recognized, thus, indication of allo-HCT is now limited to carefully selected population with highest risk for relapse, based on assessment by minimal residual disease status. Furthermore, especially for B-cell precursor ALL, we should re-establish a role of allo-HCT in the entire of therapeutic strategy, including novel options, such as small molecular agents and immunotherapy. We are now required to maximize safety and efficacy of allo-HCT for selected high-risk ALL.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Transplante Homólogo
6.
Rinsho Ketsueki ; 62(8): 1281-1287, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497217

RESUMO

Graft-versus-host disease (GVHD) is a major complication that occurs after allogeneic hematopoietic stem cell transplantation (HSCT). While the allogeneic immune response may cause GVHD, it also plays essential roles in the resultant antitumor effects and in engraftment facilitation. Therefore, the application of necessary and sufficient immune control at an appropriate time according to the condition of each individual patient is the key to successful HSCT. Recently, the landscape of HSCT has changed drastically due to the diversification of transplanted grafts and the emergence of novel immunosuppressive methods and immune-modulatory agents. In this review, we first describe the current understanding of the immune pathogenesis of acute and chronic GVHD, and then, we discuss the characterization and therapeutic intervention for GVHD after diversified HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores , Transplante Homólogo
7.
Rinsho Ketsueki ; 62(8): 1288-1295, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497218

RESUMO

Respiratory viral infection is a common disease even among immunocompetent individuals. Moreover, approximately 40% of the hematopoietic cell transplantation (HCT) recipients suffer from a respiratory infection within 100 days after HCT. New respiratory viruses have been continuously identified in the past 20 years, such as new strains of coronaviruses (CoV), human metapneumovirus (HMPV), and human bocavirus (BoV). In 2019, severe acute respiratory syndrome coronavirus (SARS-CoV)-2 that caused the coronavirus disease (COVID)-19 pandemic was identified. The 30-day overall survival after lower respiratory tract disease (LRTD) due to CoV, including SARS-CoV-2 or HMPV, was 60-70%, which is similar to that after LRTD due to influenza or respiratory syncytial virus. However, whether BoV is a pathogen of LRTD remains unclear. Moreover, corticosteroid has been reported as an efficient drug for LRTD due to SARS-CoV-2. Antiviral drug (remdesivir), anti-IL-6 receptor antibody (tocilizumab), and JAK inhibitor (ruxolitinib) are also expected to be efficient for the treatment of COVID-19. Thus, managing respiratory viruses in HCT recipients needs to be learned based on experiences from the COVID-19 pandemic.


Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Vírus , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pandemias , SARS-CoV-2
8.
Rinsho Ketsueki ; 62(8): 1327-1333, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497223

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are caused by genetic mutations at loci associated with DNA repair, telomere maintenance, and ribosome function. Hematopoietic stem cell transplantation (HSCT) can result in a permanent cure in transfusion-dependent patients if reduced-intensity conditioning and long-term screening for relapse can be successfully implemented. Primary immunodeficiency diseases (PIDs) arise from inborn errors of the host immune system and affected patients must protect themselves against intractable infections and immune system dysregulation. HSCT is curative in many pediatric patients; however, specific immunomodulatory therapies are now available for controlling autoimmune and/or autoinflammatory diseases. Advanced clinical sequencing technologies have continued to identify novel monogenic diseases that share the phenotype of hematological and immunological abnormalities, along with adult cases of IBMFS and/or PIDs. Importantly, genetic counseling is required for carrier detection while selecting sibling donors for HSCT. Here, we describe treatment strategies for IBMFS and/or PIDs and associated pitfalls.


Assuntos
Doenças da Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Criança , Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Doadores de Tecidos , Condicionamento Pré-Transplante
9.
Rinsho Ketsueki ; 62(8): 1334-1342, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497224

RESUMO

Viral infections are one of the leading causes of death in hematopoietic cell transplantation (HCT) and are a problem that should be resolved. For post-HCT viral infections, reduction of antiviral treatment or immunosuppressive drug dose is generally performed; however, the effect of antiviral drug is sometimes limited, and reduction of immunosuppressive treatment might worsen the graft-versus-host disease. Therefore, appropriate infection preventive measures and early diagnosis and therapeutic intervention for viral infections are important. In addition, virus-specific T-cell (VST) therapy is attracting attention as a new treatment method for intractable and refractory post-HCT viral infections. Various methods have been developed to establish VSTs, from a single- to multiple-virus targeting and from related- to third-party-derived donors. Its safety and efficacy have already been reported in clinical trials, and thereby, it is expected to be established as one of the important treatments for post-HCT viral infections.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Viroses , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfócitos T , Transplante Homólogo , Viroses/terapia
10.
Rinsho Ketsueki ; 62(8): 922-930, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497232

RESUMO

Treatments of aplastic anemia comprise supportive therapy and aplastic anemia-specific therapy to recover from hematopoiesis. Supportive therapy includes transfusion, granulocyte colony-stimulating factor, and iron chelation therapy in addition to symptomatic treatment. Aplastic anemia-specific treatments that aim to achieve hematopoietic recovery are immunosuppressive therapy, thrombopoietin receptor agonist (TPO-RA) treatment, allogeneic hematopoietic stem cell transplantation, and anabolic hormone therapy. Although the transplantation achieves complete recovery of hematopoiesis (healing), there is a risk of death from transplant-related complications. The most effective drug therapy is the combination of TPO-RA and the immunotherapy combined with anti-thymocyte globulin and cyclosporine. This treatment is also effective against secondary, drug-induced, or hepatitis-associated aplastic anemia. In the treatment of aplastic anemia, the treatment choice is made based on the disease severity and patient ages.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Soro Antilinfocitário/uso terapêutico , Ciclosporina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos , Humanos
11.
Rinsho Ketsueki ; 62(8): 954-966, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497236

RESUMO

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Tirosina Quinase 3 Semelhante a fms/genética
12.
Rinsho Ketsueki ; 62(8): 978-987, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497238

RESUMO

Recurrence in acute myeloid leukemia (AML) is a major barrier in patients who achieve complete remission after induction of remission and consolidation therapy and desire long-term survival. Allogeneic hematopoietic stem cell transplantation lowers recurrence risk in patients; however, recurrence is common even after transplantation. Many maintenance therapies for AML aim to lower recurrence risk; therefore, research has focused on identifying drugs with a tolerable adverse-effect profile. Thus far, many trials of cytotoxic anticancer drugs used in maintenance therapy have showed no improvement in survival rates. In contrast, recent studies on immunomodulation, epigenetics, molecular-targeted drugs, etc. have demonstrated promising results. Therefore, we plan to review various maintenance therapies, such as immunotherapy, demethylating agents, and targeted therapies (including fms-like tyrosine kinase 3 inhibitors in particular) based on the current evidence. Moreover, we describe a new strategy that incorporates the assessment of measurable minimal residual disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Preparações Farmacêuticas , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Uso Off-Label , Indução de Remissão
13.
Rev Esc Enferm USP ; 55: e20200270, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34477195

RESUMO

OBJECTIVE: To assess the domains of quality of life related to hematologic cancer patient health in the first three years from autologous and allogeneic hematopoietic stem cell transplantation. METHOD: A prospective cohort from September 2013 to February 2019 at a reference service in Latin America with 55 patients. The instruments Quality of Life Questionnaire Core C30 and Functional Assessment Cancer Therapy - Bone Marrow Transplantation were used. For data analysis, Generalized Linear Mixed Model was used. RESULTS: The domains global and overall quality of life presented the lowest scores in the pancytopenia phase: 59.3 and 91.4 in autologous, 55.3 and 90.3 in allogeneic. The mixed method analysis has shown that there was a significant change in scores between the phases throughout the treatment (p< 0.05). CONCLUSION: Health-related quality of life presented significant changes in the domains between the phases throughout time. Understanding these results enables nursing interventions directed at the domains which were damaged during treatment.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Transplante de Medula Óssea , Humanos , Estudos Prospectivos , Qualidade de Vida
14.
BMC Res Notes ; 14(1): 346, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34481515

RESUMO

OBJECTIVE: Studies on the genetic background of patients with multiple myeloma (MM) have been increasing; two important factors considered in such works are uncoupling protein-2 (UCP-2) and nuclear receptor subfamily 3 group C member 1 (NR3C1). We aim to reveal the association of MM with NR3C1 and UCP-2 gene polymorphisms. In this prospective study, 200 patients diagnosed between January 2009 and 2018 and 200 healthy individuals were included. For patients who had undergone autologous stem cell transplantation and control subjects, we statistically compared the CC, GC, and GG genotypes and the C and G alleles of the NR3C1 gene, as well as the AA, AG, and GG genotypes and the A and G alleles of the UCP-2 gene. RESULTS: While the AA genotype was significantly more common in the MM group (p = 0.001), the GG genotype was significantly more common in the control group (p = 0.016). Overall survival was found to be significantly shorter in patients with the UCP-2 GG genotype (p = 0.034). It was also found that having the GG genotype of the UCP-2 gene was a 2.48-fold risk factor for mortality. The fact that overall survival is significantly shorter in MM patients with the UCP-2 GG genotype and its definition as a risk factor for mortality have been put forward for the first time in the literature.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Receptores de Glucocorticoides , Proteína Desacopladora 2 , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores de Glucocorticoides/genética , Transplante Autólogo , Resultado do Tratamento , Proteína Desacopladora 2/genética
15.
Blood Adv ; 5(17): 3309-3321, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34473237

RESUMO

Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.


Assuntos
Infecções por Adenoviridae , Transplante de Células-Tronco Hematopoéticas , Infecções por Adenoviridae/terapia , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interferon gama , Transplante de Células-Tronco/efeitos adversos , Linfócitos T
16.
Blood Adv ; 5(17): 3418-3426, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34495311

RESUMO

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based prognosis index defined as creatinine × lactate dehydrogenase/platelets. When measured at pretransplantation evaluation (EASIX-PRE), it predicts allogeneic hematopoietic cell transplantation (alloHCT) mortality. This study explores its ability to predict intensive care unit (ICU) admission and validates EASIX-PRE predictive power for overall survival (OS) and nonrelapse mortality (NRM) in 167 consecutive patients undergoing alloHCT. EASIX-PRE was calculated retrospectively in all patients and transformed into log2 values (log2-EASIX-PRE). Log2-EASIX-PRE predicted ICU admission (hazard ratio [HR], 1.41; P < .001), OS (HR, 1.19; P = .011), and NRM (HR, 1.28; P = .004). The most discriminating EASIX-PRE cutoff value for risk of ICU admission was the 75th percentile (2.795); for OS and NRM, it was the median value (1.703). Patients with EASIX-PRE >2.795 had higher incidence of ICU admission in comparison with patients with lower EASIX-PRE values (day +180, 35.8% vs 12.8%; HR, 2.28; P = .010). Additionally, patients with EASIX-PRE >1.073 had lower OS (2 years, 57.7% vs 68.7%; HR, 1.98; P = .006) and higher NRM (2 years, 38.7% vs 18.5%; HR, 2.92; P = .001) than patients with lower EASIX-PRE results. Log2-EASIX-PRE was not associated with incidence of transplantation-associated microangiopathy, sinusoidal obstruction syndrome, or acute graft-versus-host disease. This study proposes EASIX-PRE as a prognostic tool to identify patients undergoing alloHCT at increased risk of severe organ dysfunction and who would therefore require ICU admission. Early identification of patients at high risk of severe events could contribute to personalized intervention design. Additionally, it validates the association between EASIX-PRE and OS and NRM in those undergoing alloHCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Unidades de Terapia Intensiva , Estudos Retrospectivos , Transplante Homólogo
17.
Blood Adv ; 5(17): 3407-3417, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34495313

RESUMO

Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPα and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPα variants might activate monocytic allorecognition, possibly as the result of non-self SIRPα-CD47 interaction. However, the frequency of SIRPα variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPα allelic mismatches were present in 39% of transplantation pairs. SIRPα variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPα had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPα variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPα variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPα variant matching could provide valuable information for donor selection and risk stratification in HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunidade Inata
18.
Trials ; 22(1): 595, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488845

RESUMO

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Noma , Tecido Adiposo , Animais , Ensaios Clínicos Fase II como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Método Duplo-Cego , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
19.
Nat Commun ; 12(1): 5023, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408144

RESUMO

T cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-µbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αß T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-µbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Células-Tronco Hematopoéticas/citologia , Linfopoese , Doenças da Imunodeficiência Primária/terapia , Linfócitos T/citologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antígenos CD34/genética , Antígenos CD34/imunologia , Proteínas de Ligação ao Cálcio/genética , Linhagem da Célula , Terapia Baseada em Transplante de Células e Tecidos , Células Cultivadas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/imunologia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/transplante
20.
Stem Cell Res Ther ; 12(1): 463, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407875

RESUMO

BACKGROUND: We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS: We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS: We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS: Stem cell transplantation is a valuable supplementary therapy for CD.


Assuntos
Doença de Crohn , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Animais , Doença de Crohn/terapia , Humanos , Camundongos , Ratos
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