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1.
Transpl Infect Dis ; 21(4): e13095, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993823

RESUMO

BACKGROUND: Viral infections are a significant cause of morbidity and mortality in pediatric transplant populations. We analyzed the epidemiology of viral infections in pediatric hematopoietic stem cell transplant (HSCT) patients, including their incidence, associated risk factors, and outcome. METHODS: In a prospective study from September 2011 to September 2015, blood, urine, and stool specimens were monitored weekly from transplantation to day 100 or after if clinically suspected, by use of real-time polymerase chain reaction. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyomavirus (BKV), Herpes simplex virus-1,2, Varicella zoster virus, Human herpes virus-6,7, and Adenovirus infections were monitored. All children and adolescents who underwent HSCT received long-term follow up in the regular outpatient clinics (range 2-48 months). RESULTS: A total of 192 HSCTs (autologous/allogeneic: 53/139) were performed in 165 subjects (median age: 5.6 years). Viruses most commonly isolated were CMV (46.1%), BKV (25.9%) and EBV (22.6%) and were more frequent in allogeneic versus autologous transplants (P < 0.05). Almost all high-risk allogeneic recipients developed EBV infections post-HSCT. EBV-PTLD was the only cause of death among those who developed viral disease. The factors significantly associated with the development of viral infections were recipient's advanced age, unrelated donor, mismatched graft and use of peripheral blood stem cells grafts. CONCLUSIONS: Viral infections were common among our pediatric recipients. Data suggest that monitoring of viral load may be significant to the prevention of viral disease. Particular demographic and transplantation characteristics were associated with the development of viral infections post-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Viroses/epidemiologia , Infecções por Adenoviridae/epidemiologia , Adolescente , Criança , Pré-Escolar , Infecções por Citomegalovirus/epidemiologia , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Fatores de Risco , Transplante Homólogo/efeitos adversos , Carga Viral , Ativação Viral
2.
Clin Infect Dis ; 65(11): 1819-1828, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-29020364

RESUMO

BACKGROUND: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). METHODS: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas ß-lactams (noncarbapenems), carbapenems, and multidrug resistance. RESULTS: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and ß-lactam/ß-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on ß-lactam/ß-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. CONCLUSIONS: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. CLINICAL TRIALS REGISTRATION: NCT02257931.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/microbiologia , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/microbiologia , Transplante de Células-Tronco Hematopoéticas , Transplantados , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/epidemiologia , Humanos , Lactente , Internacionalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Transplantados/estatística & dados numéricos , Adulto Jovem
3.
Pediatr Transplant ; 17(2): E41-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23216973

RESUMO

ADEM is a rare inflammatory demyelinating disease of the CNS, which usually presents after a viral infection or a vaccination. We report a 15-yr-old boy who was diagnosed with ADEM after an HLA-identical sibling allogeneic BMT for transfusion-dependent PRCA. His course was complicated with GVHD affecting the skin and lungs. Five months post-BMT, he developed neurological symptoms including sudden mental status alteration, dysarthria, facial nerve palsy, and acute paraplegia. The MRI revealed multifocal hyperintense lesions mainly in the subcortical white matter of the cerebrum, the brainstem, the basal ganglia, and the thalami. CSF examination was normal. There was no laboratory evidence of infection. The typical MRI findings and an acute monophasic clinical course were consistent with the diagnosis of ADEM. Clinical and radiological improvement was observed after treatment with high-dose steroids and IVIG. Complete neurologic recovery was achieved six months after the onset of symptoms. We present a rare case of ADEM post-BMT and review of the literature.


Assuntos
Transplante de Medula Óssea , Encefalomielite Aguda Disseminada/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Aplasia Pura de Série Vermelha/cirurgia , Adolescente , Encefalomielite Aguda Disseminada/etiologia , Humanos , Masculino
4.
Transfus Apher Sci ; 46(2): 173-80, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22036202

RESUMO

The Hellenic experience regarding the efficacy of extracorporeal photopheresis (ECP) in the treatment of 58 patients with chronic graft-versus-host disease (cGVHD) is presented in this article. All 58, except one patient, had failed at least one line of immunosuppressive treatment including steroids. Thirty-three out of 58 patients showed an objective overall response to ECP in a median time of 10 weeks after the onset of treatment. The cumulative incidence of overall response was 65.1%. In multivariate analysis, the presence of severe chronic GVHD was the only parameter associated with a significantly lower probability of response to treatment (RR=0.4, CI 95% 0.2-0.9, p=0.03). Responders to treatment with ECP were more likely to discontinue immunosuppression, had a lower probability of non-relapse mortality (RR=0.2, CI 95% 0.1-0.5, p=0.002), and a higher probability of overall survival (RR=7.8, CI 95% 3-20, p<0.001) in comparison with non-responders. Eight out of 58 patients experienced relapse of the original disease. The cumulative incidence of relapse in the group of responders to ECP was 6%, while it was 25% in the group of non-responders to ECP. In multivariate analysis, response to treatment with ECP was the only parameter statistically associated with a significantly decreased hazard of relapse (RR=0.1, CI 95% 0.1-0.7, p=0.02). ECP should be tested as first-line treatment in patients with cGVHD with the aim to minimize the duration of immunosuppression and the rate of relapse of the malignant disease.


Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Fotoferese/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Hematologia , Humanos , Terapia de Imunossupressão/métodos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/terapia , Estudos Retrospectivos , Sociedades Médicas , Taxa de Sobrevida
5.
J Cell Mol Med ; 15(9): 1983-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20731745

RESUMO

Current clinical protocols used for isolation and purification of mesenchymal stem cells (MSC) are based on long-term cultures starting with bone marrow (BM) mononuclear cells. Using a commercially available immunoselection kit for enrichment of MSC, we investigated whether culture of enriched BM-CD105(+) cells could provide an adequate number of pure MSC in a short time for clinical use in the context of graft versus host disease and graft failure/rejection. We isolated a mean of 5.4 × 10(5) ± 0.9 × 10(5) CD105(+) cells from 10 small volume (10-25 ml) BM samples achieving an enrichment >100-fold in MSC. Seeding 2 × 10(3) immunoselected cells/cm(2) we were able to produce 2.5 × 10(8) ± 0.7 × 10(8) MSC from cultures with autologous serum enriched medium within 3 weeks. Neither haematopoietic nor endothelial cells were detectable even in the primary culture cell product. Expanded cells fulfilled both phenotypic and functional current criteria for MSC; they were CD29(+), CD90(+), CD73(+), CD105(+), CD45(-); they suppressed allogeneic T-cell reaction in mixed lymphocyte cultures and retained in vitro differentiation potential. Moreover, comparative genomic hybridization analysis revealed chromosomal stability of the cultured MSC. Our data indicate that adequate numbers of pure MSC suitable for clinical applications can be generated within a short time using enriched BM-CD105(+) cells.


Assuntos
Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Técnicas de Cultura de Células/métodos , Imunofenotipagem/métodos , Células-Tronco Mesenquimais/citologia , Receptores de Superfície Celular/metabolismo , Adulto , Diferenciação Celular , Proliferação de Células , Separação Celular , Células Cultivadas , Criança , Hibridização Genômica Comparativa , Endoglina , Humanos , Teste de Cultura Mista de Linfócitos , Linfócitos/citologia , Células-Tronco Mesenquimais/metabolismo , Adulto Jovem
6.
Biol Blood Marrow Transplant ; 17(7): 1058-66, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21073975

RESUMO

The aim of the present study was to identify factors associated with the risk of development of gastrointestinal acute graft-versus-host disease (GI-aGVHD), as well as to evaluate the impact of various baseline parameters on response to treatment, nonrelapse mortality (NRM), and overall survival (OS) in pediatric patients with GI-aGVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT). We retrospectively analyzed 300 pediatric patients who underwent allo-SCT from HLA-matched related or volunteer unrelated donors in our institution. GI tract involvement was observed in 46 out of 133 patients with aGVHD grade II-IV. Severe aGVHD (grade III-IV) was more frequently observed among patients with GI-aGVHD in comparison with patients without GI involvement (P < .001). Treatment with steroids resulted in durable responses in 22/46 patients; 14 additional patients responded to salvage therapy, whereas 10 were refractory to all treatments administered. Using Cox regression analysis, we observed that serum albumin level ≥ 3 mg/dL on day 5 after the initiation of therapy with steroids was statistically significantly associated with decreased hazard of NRM and improved OS (P = .021 and P = .026, respectively). In our study, serum albumin level, early (+ day 5) after the onset of steroids in patients with GI-aGVHD, was a predictor of treatment outcome. Prospective randomized trials need to be performed to verify the predictive significance of serum albumin and the need for early intensification of immunosuppressive treatment.


Assuntos
Albuminúria/etiologia , Gastroenteropatias/etiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Aguda , Adolescente , Albuminúria/urina , Anemia Aplástica/cirurgia , Biomarcadores , Transplante de Medula Óssea/efeitos adversos , Causas de Morte , Criança , Pré-Escolar , Diarreia/tratamento farmacológico , Diarreia/etiologia , Diarreia/imunologia , Diarreia/prevenção & controle , Diarreia/urina , Feminino , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/imunologia , Gastroenteropatias/prevenção & controle , Gastroenteropatias/urina , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/urina , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Lactente , Estimativa de Kaplan-Meier , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Neoplasias/cirurgia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto Jovem
7.
Blood Cells Mol Dis ; 46(2): 177-81, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21095146

RESUMO

Directed sibling cord blood banking is indicated in women delivering healthy babies who already have a sibling with a disease that is potentially treatable with an allogeneic cord blood transplant. We evaluated the effectiveness of a national directed cord blood banking program in sibling HLA-identical stem cell transplantation for hematological malignancies and the factors influencing the usage rate of the stored cord blood units. Fifty families were enrolled from which, 48 cord blood units were successfully collected and 2 collections failed due to damaged cord/placenta at delivery. Among enrolled families 4 children needed transplantation; however, only one was successfully transplanted using the collected cord blood unit containing 2×10(7) nucleated cells/kg in conjunction with a small volume of bone marrow from the same HLA-identical donor. Two children received grafts from matched unrelated donors because their sibling cord blood was HLA-haploidentical, while the fourth one received bone marrow from his HLA-identical brother, since cord blood could not be collected due to damaged cord/placenta at delivery. With a median follow-up of 6 years (range, 2-12) for the 9 remaining HLA-matched cord blood units, none from the prospective recipients needed transplantation. The low utilization rate of sibling cord blood in the setting of hematopoietic stem cell transplantation for pediatric hematological malignant diseases necessitates the development of directed cord blood banking programs that limit long-term storage for banked cord blood units with low probability of usage such as non-HLA-identical or identical to patients who are in long-term complete remission.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Bancos de Sangue , Criança , Família , Feminino , Sangue Fetal , Feto , Grécia , Antígenos HLA/imunologia , Neoplasias Hematológicas/terapia , Histocompatibilidade/imunologia , Humanos , Lactente , Masculino , Gravidez , Irmãos , Doadores de Tecidos/estatística & dados numéricos
8.
Pediatr Blood Cancer ; 57(2): 345-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21438130

RESUMO

We report successful bone marrow transplantation in an 11-year-old male with chronic myeloid leukemia from his HLA-identical sibling selected by preimplantation HLA testing. Because collection of cord blood failed, the transplantation was performed when the donor reached the age of 19 months, and sufficient bone marrow could be harvested safely. The patient was BCR/ABL negative at the time of transplantation after complete molecular response to imatinib. Currently, 16 months post-transplantation he is well and in complete molecular remission. This report describes preimplantation HLA-genotyping to deliver a matched sibling donor for successful transplantation of a malignant disorder.


Assuntos
Transplante de Medula Óssea , Antígenos HLA/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Diagnóstico Pré-Implantação , Irmãos , Doadores de Tecidos , Criança , Feminino , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Gravidez
9.
Biol Blood Marrow Transplant ; 16(3): 344-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19835970

RESUMO

We report 2 children with X-linked chronic granulomatous disease (X-CGD) who underwent hematopoietic stem cell transplantation (HSCT) using grafts from their siblings selected before implantation to be both unaffected and HLA-matched donors. Preimplantation genetic diagnosis (PGD) along with HLA-typing were performed on preimplantation embryos by single-cell multiplex polymerase chain reaction using informative short tandem repeat markers in the HLA locus together with the gene region containing the mutations. Two singleton pregnancies resulted from the intrauterine transfer of selected embryos; these developed to term, producing 1 healthy female and 1 X-CGD carrier female, which are HLA-identical siblings to the 2 affected children. Combined grafts of umbilical cord blood (UCB) and bone marrow (BM) stem cells were administered to the recipients after myeloablative (MA) conditioning at the ages of 4.5 years and 4 years, respectively. Both patients are well, with complete donor hematopoietic and immunologic reconstitution, at 18 and 13 months posttransplantation, respectively. This report demonstrates that HSCT with HLA-matched sibling donors created by PGD/HLA typing of in vitro fertilized embryos is a realistic therapeutic option and should be presented as such to families with children who require a non-urgent HSCT but lack an HLA-genoidentical donor.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Diagnóstico Pré-Implantação , Irmãos , Plaquetas/citologia , Células da Medula Óssea/citologia , Contagem de Células , Pré-Escolar , Embrião de Mamíferos/imunologia , Feminino , Fertilização in vitro , Sangue Fetal/citologia , Sobrevivência de Enxerto , Doença Granulomatosa Crônica/genética , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutação de Sentido Incorreto/genética , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Explosão Respiratória/efeitos dos fármacos , Superóxidos/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Quimeras de Transplante/genética , Quimeras de Transplante/metabolismo , Resultado do Tratamento
10.
Blood Cells Mol Dis ; 44(2): 107-10, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19931473

RESUMO

Several cord blood banks store cord blood units from healthy siblings of patients, who are candidates for stem cell transplantation. We analyzed the quality characteristics of 50 cord blood units collected from families with beta-thalassemia major and the outcome of subsequent stem cell transplantations during a 15-year period. All cord blood units were found suitable for banking based on a minimum net volume of 40 ml. The mean volume of the units was 98.9 ml; the mean total nucleated cell count (NC) was 7.8 x 10(8) and the mean CD34+ cell count was 2.8 x 10(6). Eight out of twelve HLA matched collections were released for transplantation. All but one recipient belonged to Pesaro II-III risk classes. Three patients received a cord blood graft with >5 x 10(7) NC/kg . One of them with Pesaro class I disease engrafted, whereas the other two who failed to engraft, were re-transplanted with bone marrow from the same donor later. Cord blood grafts containing NCs <4 x 10(7)/kg combined with reduced volume bone marrow from the same donor were used in all 5 remaining cases and stable engraftment was achieved. All patients survived, 7/8 thalassemia-free. Cord blood banking from healthy siblings of children with beta-thalassemia major can result in a successful transplantation in cases in which there is HLA compatibility. However, in high-risk patients, the use of combined cord blood and bone marrow grafts seems necessary in order to ensure stable engraftment, especially when cord blood unit cell counts are low.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Antígenos HLA/imunologia , Talassemia beta/terapia , Adolescente , Bancos de Sangue , Criança , Pré-Escolar , Grécia , Humanos , Irmãos , Doadores de Tecidos , Resultado do Tratamento , Talassemia beta/cirurgia
11.
Clin Chem Lab Med ; 48(2): 199-203, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20001441

RESUMO

BACKGROUND: Exercise in humans augments the mobilization of circulating hematopoietic progenitor cells (CD34(+)) from the bone marrow. We investigated the effect of inflammation on erythroid marrow activity by mobilization of erythroid progenitor cells (EPs) along with soluble markers of erythropoiesis. METHODS: Ten healthy athletes who participated in an ultradistance foot race participated in the study. Peripheral blood mononuclear cells were isolated, before (phase I), at the end (phase II), and at 48 h post-race (phase III). EPs were detected as burst colony forming units (BFU-e) and colonies were scored at day 14. Markers of inflammation (C-reactive protein, serum amyloid-A, interleukin-6, ferritin and S100B) and bone marrow activity (erythropoietin, soluble transferrin receptor and lipocalin-2) were assessed. RESULTS: An approximately three-fold decrease in BFU-e number was observed at phase II. sTfR concentrations were also decreased at phase II and remained decreased at phase III. However, EPO and lipocalin-2 concentrations reached a maximum value at phase II, with a tendency to decrease at phase III. CONCLUSIONS: These findings indicate that exercise-induced inflammation modulates bone marrow homeostasis leading to an increase in leukocyte turnover and a decrease in erythroid compartment. It appears that lipocalin-2 is the main factor that regulates the production and mobilization of EPs.


Assuntos
Biomarcadores/sangue , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/patologia , Eritropoese/fisiologia , Inflamação/sangue , Esforço Físico/fisiologia , Corrida/lesões , Proteínas de Fase Aguda/imunologia , Proteínas de Fase Aguda/metabolismo , Atletas , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Precursoras Eritroides/imunologia , Eritropoese/imunologia , Eritropoetina/sangue , Ferritinas/sangue , Humanos , Inflamação/etiologia , Inflamação/imunologia , Lipocalina-2 , Lipocalinas/imunologia , Lipocalinas/metabolismo , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores da Transferrina/sangue , Fatores de Tempo
12.
Eur J Echocardiogr ; 11(5): 440-5, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20308191

RESUMO

AIMS: We sought to evaluate the efficacy of intracoronary infusion of selected bone marrow stem cells (BMSCs) in patients with remote, anterior non-viable MI by the use of tissue Doppler imaging. METHODS AND RESULTS: We infused selected CD133+ and CD133-CD34+ BMSCs in 10 patients enrolled in the study. Peak systolic strain rate, maximum strain during the cardiac cycle (epsilon(max)), strain during ejection time (epsilon(et)), and post-systolic strain (epsilon(ps)) were measured. Peak systolic strain rate (-0.69 +/- 0.2 vs. -1.15 +/- 0.27, P = 0.001), epsilon(max) (-9.87 +/- 3.30 vs. -15.57 +/- 5, P = 0.006), and epsilon(et) (-7.45+/-2.86 vs. -10.92 +/- 4.45, P = 0.015) improved significantly during the rest study 6 months after cell infusion. Low-dose inotropic challenge also showed significant improvement of longitudinal deformation indices in the follow-up study. Global ejection fraction did not improve significantly after cell therapy. CONCLUSION: Intracoronary infusion of selected BMSCs in patients with remote, anterior, non-viable myocardial infarction is safe and leads to improvement of longitudinal deformation indices 6 months after the infusion.


Assuntos
Transplante de Medula Óssea , Infarto do Miocárdio/terapia , Miocárdio/patologia , Antígeno AC133 , Adulto , Antígenos CD , Antígenos CD34 , Intervalos de Confiança , Ecocardiografia , Feminino , Glicoproteínas , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Peptídeos , Estatística como Assunto , Estatísticas não Paramétricas , Volume Sistólico , Sístole , Transplante Autólogo , Ultrassonografia Doppler , Função Ventricular Esquerda
13.
Bone Marrow Transplant ; 55(10): 1946-1954, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157246

RESUMO

We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient-donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) or busulfan-cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II-IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 ± 4%. GRFS was 62 ± 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 ± 4% in 10/10 group vs. 75 ± 10% in 9-8/10 (p = 0.042); GRFS was 69 ± 9% vs. 50 ± 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease.


Assuntos
Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Anemia Falciforme/terapia , Criança , Europa (Continente) , Humanos , Condicionamento Pré-Transplante
14.
Blood Cells Mol Dis ; 42(3): 294-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19233694

RESUMO

Endothelial progenitor cells (EPCs) and the recently described circulating fibrocytes (CFs) are strongly associated with tissue repair. We investigated the kinetics of both "repair" progenitor cells in healthy athletes who participated in the "Spartahlon" ultradistance foot race (246 km continuous running exercise), which provides a unique model of inducing dramatic systemic inflammatory changes. Peripheral blood mononuclear cells (PBMCs) were isolated from 10 volunteer athletes, who completed successfully the race, before, at the end, and at 48 h post-race. EPCs and CFs were detected as endothelial colony-forming units (CFU-ECs) and as the number of adherent with a spindle-shaped morphology Collagen I(+) cells detected after 6-day culture of PBMCs, respectively. The marked increase of plasma levels of CRP, IL-6, SAA, MCP-1, IL-8, sVCAM-1, sICAM-1, thrombomodulin (sTM) and NT-pro-BNP at the end of race established acute inflammation and tissue injury. EPCs increased by nearly eleven-fold in peripheral blood at the end of the race from 44.5+/-2.5/ml to 494.6+/-27.9/ml and remained increased 428.5+/-31.5/ml at 48 h post-race (p<0.0001). The number of the fibrocytes cultured from PBMCs obtained before, at the end, and 48 h post-race did not reveal any significant difference. These findings indicate that bone marrow responses to acute inflammatory damage, induced by exhausting exercise, with a rapid release of EPCs but not CFs into circulation. Given the ability of EPCs to promote angiogenesis and vascular regeneration, we may suggest that this kind of cell mobilization may serve as a physiologic repair mechanism in acute inflammatory tissue injury.


Assuntos
Inflamação/sangue , Células-Tronco Mesenquimais/fisiologia , Regeneração/fisiologia , Corrida/lesões , Adulto , Antígenos de Diferenciação/análise , Biomarcadores , Contagem de Células Sanguíneas , Medula Óssea/fisiopatologia , Moléculas de Adesão Celular/sangue , Diferenciação Celular , Ensaio de Unidades Formadoras de Colônias , Células Endoteliais/patologia , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Mediadores da Inflamação/sangue , Masculino , Células-Tronco Mesenquimais/química , Pessoa de Meia-Idade , Monócitos/patologia , Miosite/sangue , Miosite/etiologia , Miosite/fisiopatologia , Neovascularização Fisiológica , Corrida/fisiologia
16.
Eur J Cancer ; 67: 183-190, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27677054

RESUMO

AIM: To assess trends in survival and geographic disparities among children (0-14 years) with chronic myeloid leukaemia (CML) before and after the introduction of molecular therapy, namely tyrosine kinase inhibitors (TKIs) in Southern-Eastern European (SEE) countries and the USA. METHODS: We calculated survival among children with CML, acute lymphoblastic (ALL) and acute myeloid leukaemia (AML) in 14 SEE (1990-2014) cancer registries and the U.S. Surveillance, Epidemiology and End Results Program (SEER, 1990-2012). We used Kaplan-Meier curves and multivariate Cox regression models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 369 CML cases, substantial improvements were noted in 2-year survival during the post-TKI (range: 81-89%) compared to pre-TKI period (49-66%; HR: 0.37, 95% CI: 0.23-0.60). Risk of death was three times higher for <5-year-old children versus those aged 10-14 years (HR: 3.03, 95% CI: 1.85-4.94) and 56% higher for those living in SEE versus SEER (HR: 1.56, 95% CI: 1.01-2.42). Regardless of geographic area and period of TKI administration, however, age seems to be a significant determinant of CML prognosis (pre-TKI period, HR0-4y: 2.71, 95% CI: 1.53-4.79; post-TKI period, HR0-4y: 3.38, 95% CI: 1.29-8.85). Noticeably, post-TKI survival in CML overall approximates that for ALL, whereas therapeutic advancements for AML remain modest. CONCLUSION: Registry data show that introduction of molecular therapies coincides with revolutionised therapeutic outcomes in childhood CML entailing dramatically improved survival which is now similar to that in ALL. Given that age disparities in survival remain substantial, offering optimal therapy to entire populations is an urgent priority.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Sistema de Registros , Taxa de Sobrevida/tendências , Adolescente , Fatores Etários , Criança , Pré-Escolar , Europa (Continente) , Europa Oriental , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Terapia de Alvo Molecular , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Programa de SEER , Estados Unidos
17.
Cell Reprogram ; 16(6): 447-55, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25354259

RESUMO

Synthetic modified mRNA molecules encoding pluripotency transcription factors have been used successfully in reprogramming human fibroblasts to induced pluripotent stem cells (iPSCs). We have applied this method on bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from a patient with ß-thalassemia (ß-thal) with the aim to generate trangene-free ß-thal-iPSCs. Transfection of 10(4) BM-MSCs by lipofection with mRNA encoding the reprogramming factors Oct4, Klf4, Sox2, cMyc, and Lin28 resulted in formation of five iPSC colonies, from which three were picked up and expanded in ß-thal-iPSC lines. After 10 serial passages in vitro, ß-thal-iPSCs maintain genetic stability as shown by array comparative genomic hybridization (aCGH) and are capable of forming embryoid bodies in vitro and teratomas in vivo. Their gene expression profile compared to human embryonic stem cells (ESCs) and BM-MSCs seems to be similar to that of ESCs, whereas it differs from the profile of the parental BM-MSCs. Differentiation cultures toward a hematopoietic lineage showed the generation of CD34(+) progenitors up to 10%, but with a decreased hematopoietic colony-forming capability. In conclusion, we report herein the generation of transgene-free ß-thal-iPSCs that could be widely used for disease modeling and gene therapy applications. Moreover, it was demonstrated that the mRNA-based reprogramming method, used mainly in fibroblasts, is also suitable for reprogramming of human BM-MSCs.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , RNA Mensageiro/genética , Fatores de Transcrição/genética , Talassemia beta , Diferenciação Celular , Linhagem Celular , Hibridização Genômica Comparativa , Fibroblastos/citologia , Humanos , Fator 4 Semelhante a Kruppel
18.
Hum Gene Ther ; 23(1): 15-31, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21875313

RESUMO

To address how low titer, variable expression, and gene silencing affect gene therapy vectors for hemoglobinopathies, in a previous study we successfully used the HPFH (hereditary persistence of fetal hemoglobin)-2 enhancer in a series of oncoretroviral vectors. On the basis of these data, we generated a novel insulated self-inactivating (SIN) lentiviral vector, termed GGHI, carrying the (A)γ-globin gene with the -117 HPFH point mutation and the HPFH-2 enhancer and exhibiting a pancellular pattern of (A)γ-globin gene expression in MEL-585 clones. To assess the eventual clinical feasibility of this vector, GGHI was tested on CD34(+) hematopoietic stem cells from nonmobilized peripheral blood or bone marrow from 20 patients with ß-thalassemia. Our results show that GGHI increased the production of γ-globin by 32.9% as measured by high-performance liquid chromatography (p=0.001), with a mean vector copy number per cell of 1.1 and a mean transduction efficiency of 40.3%. Transduced populations also exhibited a lower rate of apoptosis and resulted in improvement of erythropoiesis with a higher percentage of orthochromatic erythroblasts. This is the first report of a locus control region (LCR)-free SIN insulated lentiviral vector that can be used to efficiently produce the anticipated therapeutic levels of γ-globin protein in the erythroid progeny of primary human thalassemic hematopoietic stem cells in vitro.


Assuntos
Hemoglobina Fetal/metabolismo , Terapia Genética/métodos , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/metabolismo , Inativação de Vírus , Talassemia beta/terapia , Antígenos CD34/metabolismo , Apoptose , Cromatografia Líquida de Alta Pressão , Clonagem Molecular , Elementos Facilitadores Genéticos , Células Eritroides/metabolismo , Eritropoese , Hemoglobina Fetal/genética , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Células HEK293 , Células-Tronco Hematopoéticas/patologia , Humanos , Lentivirus/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Plasmídeos/genética , Plasmídeos/metabolismo , Mutação Puntual , Regiões Promotoras Genéticas , Transfecção , Vírus da Estomatite Vesicular Indiana/genética , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , gama-Globinas/genética , gama-Globinas/metabolismo
19.
Cell Mol Immunol ; 8(3): 276-80, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21358669

RESUMO

Various polymorphisms in cytokine genes have recently been investigated as candidate risk factors in allogeneic hematopoetic stem cell transplantation (allo-HSCT). We retrospectively analyzed specific polymorphisms in genes for interleukin (IL)-10, IL-6, tumor-necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in a pediatric cohort of 57 histocompatibility leucocyte antigen (HLA)-identical sibling myeloablative transplants. Both recipient and donor genotypes were tested for association with graft-versus-host disease (GVHD) by statistical methods including Cox regression analysis. We found a significant association between the IL-10 promoter haplotype polymorphisms at positions -1082, -819 and -592 with the occurrence of severe (grades III-IV) acute GVHD (aGVHD). Recipients with the haplotype GCC had a statistically significant decreased risk of severe aGVHD (hazard risk (HR)=0.20, 95% confidence interval (CI): 0.06-0.67) in comparison with patients with other IL-10 haplotypes (P=0.008). Transplant-related mortality at 1 year was significantly lower in recipients with this haplotype (HR=0.17, 95% CI: 0.012-0.320) versus other IL-10 haplotypes (P=0.03), whereas overall survival was not influenced by IL-10 haplotype polymorphisms. In multivariate analysis, the presence of the IL-10 GCC haplotype was found as the only variable associated with a statistically significant decreased hazard of severe aGVHD development (P=0.02, HR=0.21, 95% CI: 0.05-0.78). These results suggest that pediatric patients possessing the IL-10 GCC haplotype may be protected from the occurrence of severe aGVHD in the setting of matched sibling HSCT.


Assuntos
Citocinas/metabolismo , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Criança , Pré-Escolar , Citocinas/genética , Citocinas/imunologia , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro/mortalidade , Grécia , Haplótipos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Lactente , Polimorfismo Genético , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante
20.
Stem Cells Dev ; 19(9): 1285-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20001597

RESUMO

Abstract The origin (recipient/donor) of the myofibroblasts mediating fibrosis in sclerodermatous chronic graft-versus-host disease (cGvHD) was investigated. Sclerodermatous specimens obtained from a patient with extensive cGvHD after an HLA-identical sibling bone marrow transplantation were cultured in order to derive tissue myofibroblasts. All proliferating a-SMA+ fibroblastoid cells revealed recipient origin as examined by variable number tandem repeat (VNTR)-PCR. This case report shows that fibrosis in sclerodermatous lesions results from the activation and proliferation of locally-derived recipient fibroblasts rather than from donor-derived fibroblasts or circulating fibrocytes.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Miofibroblastos/patologia , Miofibroblastos/fisiologia , Dermatopatias/etiologia , Dermatopatias/patologia , Técnicas de Cultura de Células , Proliferação de Células , Células Cultivadas , Doença Crônica , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Esclerose , Irmãos , Dermatopatias/imunologia , Doadores de Tecidos , Transplante Homólogo
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