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1.
PLoS One ; 14(6): e0217572, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188842

RESUMO

Steroid-resistant GvHD is one of the most significant causes of mortality following allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Treatment with mesenchymal stromal cells (MSC) seems to be a promising solution, however the results from clinical studies are still equivocal. Better selection of candidate patients and improving monitoring of patients following MSC administration can increase treatment effectiveness. In order to determine which characteristics can be used to predict a good response and better monitoring of patients, blood samples were taken prior to therapy, one week and one month after therapy, from 26 allogeneic HSCT patients whom contracted GvHD and were treated with MSCs. Samples were examined for differential blood counts, bilirubin levels and cell surface markers. Serum cytokine levels were also measured. We found that the level of lymphocytes, in particular T and NK cells, may predict a good response to therapy. A better response was observed among patients who expressed low levels of IL-6 and IL-22, Th17 related cytokines, prior to therapy. Patients with high levels of bilirubin prior to therapy showed a poorer response. The results of this study may facilitate early prediction of success or failure of the treatment, and subsequently, will improve selection of patients for MSC therapy.

2.
Int J Mol Sci ; 20(3)2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30720730

RESUMO

Cannabinoids, the biologically active constituents of Cannabis, have potent neuronal and immunological effects. However, the basic and medical research dedicated to medical cannabis and cannabinoids is limited. The influence of these treatments on hematologic reconstitution and on the development of graft versus host disease (GVHD) after bone marrow transplantation (BMT) is largely unknown. In this research, we compared the influence of D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on lymphocyte activation in vitro and in murine BMT models. Our in vitro results demonstrate that these treatments decrease activated lymphocyte proliferation and affect cytokine secretion. We also discovered that CBD and THC utilize different receptors to mediate these effects. In vivo, in a syngeneic transplantation model, we demonstrate that all treatments inhibit lymphocyte reconstitution and show the inhibitory role of the cannabinoid receptor type 2 (CB2) on lymphocyte recovery. Although pure cannabinoids exhibited a superior effect in vitro, in an allogeneic (C57BL/6 to BALB/c) BMT mouse model, THC-high and CBD-high cannabis extracts treatment reduced the severity of GVHD and improved survival significantly better than the pure cannabinoids. Our results highlights the complexity of using cannabinoids-based treatments and the need for additional comparative scientific results.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Canabidiol/farmacologia , Dronabinol/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Inflamação/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Animais , Canabidiol/uso terapêutico , Modelos Animais de Doenças , Dronabinol/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Resultado do Tratamento
3.
Leuk Lymphoma ; : 1-8, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30277100

RESUMO

Myeloablative doses of busulfan (Bu) with fludarabine (Flu) have reduced toxicity, however, limited by an increased relapse rate. We aimed to improve outcome of Flu-Bu regimen by augmentation with thiotepa (TT) (10 mg/kg). Eighty-nine patients with AML, 44 patients conditioned with Flu-Bu (group 1), and 45 patients augmented with TT (Flu-Bu-TT, group 2), were retrospectively analyzed. Primary objectives were toxicity and outcomes. Major toxicities were comparable: mucositis (p = 1.0), sepsis (p = .7), severe venocclusive disease of liver (VOD) (p = 1.0), and non-relapse mortality (NRM) (22 vs. 22%, p = .7). Five-year disease-free survival was significantly better in group 2 compared to group 1 (62 vs. 38%, p = .02). Five-year overall survival (OS) showed trend toward benefit in group 2 (62 vs. 42%, p = .06). Lower relapse rate in group 2 (14 vs. 46%, p = .005) contributed to better outcomes. Augmented regimen has better disease-free survival (DFS) (mainly due to reduced relapse rate) and similar toxicities as compared to Flu-Bu. Key points  Assessing the addition of TT to myeloablative conditioning (Flu, Bu) in patients undergoing allogeneic stem cell transplant for acute myeloid leukemia with regard to relapse rate, disease-free survival and toxicity.  Addition of thiotepa improves disease-free survival and shows trend toward benefit in overall survival, by reducing relapses without additional toxicity.

4.
Pediatr Blood Cancer ; 65(11): e27312, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30070020

RESUMO

INTRODUCTION: Thalassemia major (TM) is an inherited disorder caused by ineffective erythropoiesis. At the present time, allogeneic stem cell transplantation (allo-SCT) is a curative option. Conventional busulfan and cyclophosphamide based myeloablative conditioning regimens are limited by increased toxicity, especially in high-risk patients. Replacement of cyclophosphamide with fludarabine has reduced toxicity and nonrelapse mortality (NRM), thus improving outcomes. We analyzed long-term data of our fludarabine-based myeloablative, reduced toxicity protocol, specifically in high-risk patients. METHODS: We retrospectively analyzed a cohort of 47 consecutive patients with TM undergoing allo-SCT from matched donors, using the fludarabine-based regimen (reduced toxicity regimen). The median age of the cohort was 10 years. Thirty-eight patients (80%) were in the high-risk and nine patients (20%) were in the low-risk category. The primary aim of this analysis was thalassemia-free survival (TFS). RESULTS: The rejection rate was 11% within high-risk patients with NRM of 2%. With a median follow-up period of 7 years (1-15 years), the 10-year TFS in the entire cohort was 87%, and the overall survival (OS) was 97%. The 10-year TFS and OS among the low-risk and high-risk groups were 90% versus 84%, respectively (P = 0.45) and 100% versus 96%, respectively (P = 0.5), and both subsets of patients did equally well. CONCLUSION: In conclusion, replacement of high-dose cyclophosphamide with fludarabine is well tolerated with minimal regimen-related toxicity and acceptable rejection rates, especially in high-risk patients.

5.
Br J Haematol ; 183(1): 110-118, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29984823

RESUMO

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.

6.
Clin Case Rep ; 6(5): 867-870, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29744075

RESUMO

A few cases of thyroid eye disease following alemtuzumab therapy have been described in patients with multiple sclerosis. Our patient is the first case of Graves' orbitopathy after alemtuzumab conditioning for hematopoietic stem cell transplantation.

7.
Clin Lymphoma Myeloma Leuk ; 18(4): 272-279, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29500148

RESUMO

BACKGROUND: High-dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for relapsed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Conditioning regimens with high-dose carmustine have been associated with idiopathic pneumonitis syndrome. We, therefore, created a modified alternative TECAM conditioning regimen, consisting of etoposide, thiotepa, cytarabine, cyclophosphamide, and melphalan. PATIENTS AND METHODS: We retrospectively analyzed our cohort of 212 NHL and HL patients, who had undergone ASCT with the TECAM conditioning regimen from 2000 to 2013. Although toxicity and engraftment were analyzed for all 212 patients, the survival analysis was performed for the 2 largest groups of patients, those with diffuse large B-cell lymphoma (DLBCL) and those with HL (n = 127) to minimize heterogeneity. RESULTS: The 3-year overall survival among the DLBCL and HL patients was 0.618 (95% confidence interval [CI], 0.490-0.722) and 0.828 (95% CI, 0.701-0.904), respectively. Stage IV disease at transplantation was a statistically significant poor prognostic factor. Higher Eastern Cooperative Oncology Group performance status and progressive disease at transplantation were found to be borderline significant. No idiopathic pneumonitis syndrome cases were reported in our cohort. Six patients died of treatment-related toxicity during the first 100 days. The 3-year progression-free survival was 0.5 (95% CI, 0.37-0.61) for HL patients and 0.49 (95% CI, 0.36-0.60) for DLBCL patients. CONCLUSION: Our results are encouraging and justify evaluation of TECAM versus BEAM (carmustine, etoposide, cytarabine, melphalan) in a prospective multicenter study in a large homogenous patient population.

8.
Bone Marrow Transplant ; 53(8): 1001-1009, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29463854

RESUMO

The purpose of this retrospective registry study was to investigate the outcome of autoSCT for primary mediastinal B-cell lymphoma (PMBCL) in the rituximab era, including the effects of eventual post-transplant radiotherapy (RT) consolidation. Patients with PMBCL aged between 18 and 70 years who were treated with a first autoSCT between 2000 and 2012 and registered with the EBMT were eligible. Eighty-six patients with confirmed PMBCL and the full data set required for this analysis were evaluable. Sixteen patients underwent autoSCT in remission after first-line therapy (CR/PR1), 44 patients were transplanted with chemosensitive relapsed or primary refractory disease (CR/PR >1), and 24 patients were chemorefractory at the time of autoSCT. With a median follow-up of 5 years, 3-year estimates of relapse incidence, progression-free survival, and overall survival were 6%, 94%, and 100% for CR/PR1; 31%, 64%, and 85% for CR/PR >1; and 52%, 39%, and 41% for REF, respectively. Whilst there was no significant benefit of post-transplant RT in the CR/PR >1 group, RT could completely prevent disease recurrence post d100 in the refractory group. In conclusion, autoSCT with or without consolidating RT is associated with excellent outcome in chemoimmunotherapy-sensitive PMBCL, whereas its benefits seem to be limited in chemoimmunotherapy-refractory disease.

9.
Front Immunol ; 9: 3053, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30622539

RESUMO

Background: Bone marrow mesenchymal stem cells (bmMSC) may play a role in the regulation of maturation, proliferation, and functional activation of lymphocytes, though the exact mechanisms are unknown. MSC-derived exosomes induce a regulatory response in the function of B, T, and monocyte-derived dendritic cells. Here, we evaluated the specific inhibition of human lymphocytes by bmMSC-derived exosomes and the effects on B-cell function. Methods: Exosomes were isolated from culture media of bmMSC obtained from several healthy donors. The effect of purified bmMSC-derived exosomes on activated peripheral blood mononuclear cells (PBMCs) and isolated B and T lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester assay. Using the Illumina sequencing platform, mRNA profiling was performed on B-lymphocytes activated in the presence or absence of exosomes. Ingenuity® pathway analysis software was applied to analyze pathway networks, and biological functions of the differentially expressed genes. Validation by RT-PCR was performed. The effect of bmMSC-derived exosomes on antibody secretion was measured by ELISA. Results: Proliferation of activated PBMCs or isolated T and B cells co-cultured with MSC-derived exosomes decreased by 37, 23, and 18%, respectively, compared to controls. mRNA profiling of activated B-lymphocytes revealed 186 genes that were differentially expressed between exosome-treated and control cells. We observed down- and up-regulation of genes that are involved in cell trafficking, development, hemostasis, and immune cell function. RNA-Seq results were validated by real time PCR analysis for the expression of CXCL8 (IL8) and MZB1 genes that are known to have an important role in immune modulation. Functional alterations were confirmed by decreased IgM production levels. Consistent results were demonstrated among a wide variety of healthy human bmMSC donors. Conclusion: Our data show that exosomes may play an important role in immune regulation. They inhibit proliferation of several types of immune cells. In B-lymphocytes they modulate cell function by exerting differential expression of the mRNA of relevant genes. The results of this study help elucidate the mechanisms by which exosomes induce immune regulation and may contribute to the development of newer and safer therapeutic strategies.

10.
Oncotarget ; 8(32): 53563-53580, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881832

RESUMO

Sphingolipid derivatives play key roles in immune cell migration and function. Synthetic sphingolipid analogues are used as therapeutics to intervene various inflammatory and malignant conditions. We hypothesize that different analogs have different effects on immune cells and therefore can be used as treatment for specific diseases. This study examines the properties of the novel synthetic sphingolipid analog, AD2900, and its effects on immune cell activation and lymphocyte localization in homeostasis. AD2900 is an antagonist for all sphingosine-1-phosphate (S1P) receptors. It demonstrates a significant inhibitory effect on the proliferation of activated human peripheral blood mononuclear cells, which is dependent on cAMP reduction and calcium signal transduction but not on phospholipase C activation. AD2900 causes a significant but reversible downregulation of S1P1 expression on the cell surface. AD2900 administration to C57BL/6J mice leads to the accumulation of T cells in the blood and spleen and in turn reduces T-cell number in the lymph nodes. Moreover, AD2900 treatment shows significant effects on the localization of T-cell subpopulations. These results demonstrate the key roles of S1P in T-cell trafficking in a steady state and suggest a potential clinical application for AD2900. Notably, this sphingolipid analog does not cause a severe lymphopenia. The clinical effect of AD2900 in hemato-oncologic diseases and immune-related diseases needs further investigation.

11.
Clin Cancer Res ; 23(22): 6790-6801, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28835380

RESUMO

Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019).Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immunodeficient mice.Results: BL-8040 was found safe and well tolerated at all doses tested (0.5-1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/µL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34+ cells/kg collected were 11.6 × 106 cells/kg. The graft composition was rich in immune cells.Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790-801. ©2017 AACR.


Assuntos
Antígenos CD34/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Peptídeos/administração & dosagem , Receptores CXCR4/antagonistas & inibidores , Animais , Biomarcadores , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Voluntários Saudáveis , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Imunofenotipagem , Leucaférese , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Animais , Transplante Homólogo
12.
Am J Hematol ; 92(10): 997-1003, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28614903

RESUMO

The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa-based conditioning (n = 180) with those receiving Cy/TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Agonistas Mieloablativos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total , Adolescente , Adulto , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
13.
Hematol Oncol ; 35(4): 797-803, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27338621

RESUMO

The probability of achieving long term remission for patients with refractory acute leukaemia is very low. Allogeneic stem cell transplantation (SCT) is offered to these patients in order to improve their dismal outcome. We retrospectively analyzed 361 acute leukaemia patients, who underwent allogeneic SCT in the Hadassah's bone marrow transplantation department between the years 2005 and 2012 and identified 84 patients with active leukaemia at transplantation. Median age was 34 years. Sixty four patients were diagnosed with acute myeloid leukaemia (AML), 18 patients with acute lymphoblastic leukaemia and two with biphenotypic leukaemia. The majority of patients were diagnosed with de-novo AML and transplanted at relapse. In the surviving patients, median follow up was 15 months. One year OS was 20%. At time of last follow up, 13 patients were alive (15.5%): ten patients with AML and two patients with acute lymphoblastic leukaemia. In the univariate analysis, factors associated with significantly better overall survival were as follows: matched unrelated donor (p = 0.006), matched donor (p = 0.014) and occurrence of acute graft-versus-host disease (aGVHD) (p = 0.019). Karnofsky performance score at SCT and occurrence of cGVHD were found to be borderline significant. Only matched unrelated donor and aGVHD were found to affect overall survival significantly in the multivariate analysis. Other than performance score at SCT, none of the pretransplant patients' characteristics were found to influence survival. In conclusion, as none of the pretransplant characteristics were found to influence the ability to select the patients that will benefit from HSC transplantation, this work supports offering HSCT to all active leukaemia eligible patients with reasonable performance status. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Am J Hematol ; 92(1): 18-22, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27673280

RESUMO

In this study, we analyzed a thiotepa-based conditioning regimen for allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia, using the EBMT database. A total of 323 patients were identified. The median age was 43 years. Disease status at transplant was first complete remission (CR1) in 48.9%, CR2 in 21.7%, CR3 in 6.2%, while 23.2% of the patients had an active disease at the time of transplant. This was performed from a HLA-matched sibling (49.8%) or a matched-unrelated donor (51.2%). The incidence of acute graft-vs.-host disease (GvHD) (grade > II) was 26.6%, while chronic GvHD occurred in 35.9% of the patients at 1 year (24.6% with extensive disease). With a median follow-up of 16.8 months, the nonrelapse mortality was 12.4 and 25.3% at 100 days and 1 year, respectively. The relapse incidence at 1 year was 33.3% with no difference for patients in CR1 (27%). The one-year leukemia-free survival (LFS) and overall survival (OS) were 57 and 66%, respectively for the entire cohort and 50 and 66%, respectively in patients in CR1. Thiotepa/busulfan ± melphalan (n = 213) in comparison to thiotepa/other (n = 110) conditioning regimen resulted in higher relapse incidence at 1 year (34.9 vs. 30.3%, P = 0.016) and lower LFS (38.8 vs. 45.9%, P = 0.0203), while nonrelapse mortality (23.8 vs. 26.3%, n.s.) and OS (59.6 vs. 51.1%, P = 0.109) did not differ. This large study suggests that a thiotepa-based conditioning for allogeneic transplantation in acute lymphoblastic leukemia is feasible and effective, with the main outcomes being comparable to those achieved with other regimens. Am. J. Hematol. 92:18-22, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Tiotepa/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Tiotepa/administração & dosagem , Transplante Homólogo , Adulto Jovem
15.
Oncotarget ; 7(37): 58975-58994, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27449294

RESUMO

Acute Radiation Syndrome (ARS) may lead to cancer and death and has few effective countermeasures. Efficacy of synthetic PIF treatment was demonstrated in preclinical autoimmune and transplantation models. PIF protected against inflammation and mortality following lethal irradiation in allogeneic bone marrow transplant (BMT) model. Herein, we demonstrate that PIF imparts comprehensive local and systemic protection against lethal and sub-lethal ARS in murine models. PIF treatment 2 h after lethal irradiation led to 100% survival and global hematopoietic recovery at 2 weeks after therapy. At 24 h after irradiation PIF restored hematopoiesis in a semi-allogeneic BMT model. PIF-preconditioning provided improved long-term engraftment. The direct effect of PIF on bone marrow cells was also demonstrated in vitro: PIF promoted pre-B cell differentiation and increased immunoregulatory properties of BM-derived mesenchymal stromal cells. PIF treatment also improved hematopoietic recovery and reduced systemic inflammatory cytokine production after sub-lethal radiation exposure. Here, PIF also prevented colonic crypt and basal membrane damage coupled with reduced nitric oxide synthetase (iNOS) and increased (B7h1) expression. Global upper GI gene pathway analysis revealed PIF's involvement in protein-RNA interactions, mitochondrial oxidative pathways, and responses to cellular stress. Some effects may be attributed to PIF's influence on macrophage differentiation and function. PIF demonstrated a regulatory effect on irradiated macrophages and on classically activated M1 macrophages, reducing inflammatory gene expression (iNOS, Cox2), promoting protective (Arg1) gene expression and inducing pro-tolerance cytokine secretion. Notably, synthetic PIF is stable for long-term field use. Overall, clinical investigation of PIF for comprehensive ARS protection is warranted.


Assuntos
Síndrome Aguda da Radiação/prevenção & controle , Transplante de Medula Óssea , Proteoglicanas/uso terapêutico , Protetores contra Radiação/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Sobrevivência de Enxerto , Hematopoese/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Condicionamento Pré-Transplante , Transplante Homólogo , Irradiação Corporal Total
16.
Immunobiology ; 221(7): 778-93, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26944449

RESUMO

Secreted by viable embryos, PIF is expressed by the placenta and found in maternal circulation. It promotes implantation and trophoblast invasion, achieving systemic immune homeostasis. Synthetic PIF successfully transposes endogenous PIF features to non-pregnant immune and transplant models. PIF affects innate and activated PBMC cytokines and genes expression. We report that PIF targets similar proteins in CD14+, CD4+ and CD8+ cells instigating integrated immune regulation. PIF-affinity chromatography followed by mass-spectrometry, pathway and heatmap analysis reveals that SET-apoptosis inhibitor, vimentin, myosin-9 and calmodulin are pivotal for immune regulation. PIF acts on macrophages down-stream of LPS (lipopolysaccharide-bacterial antigen) CD14/TLR4/MD2 complex, targeting myosin-9, thymosin-α1 and 14-3-3eta. PIF mainly targets platelet aggregation in CD4+, and skeletal proteins in CD8+ cells. Pathway analysis demonstrates that PIF targets and regulates SET, tubulin, actin-b, and S100 genes expression. PIF targets systemic immunity and has a short circulating half-life. Collectively, PIF targets identified; protective, immune regulatory and cytoskeleton proteins reveal mechanisms involved in the observed efficacy against immune disorders.


Assuntos
Citoesqueleto/metabolismo , Leucócitos Mononucleares/imunologia , Proteínas da Gravidez/metabolismo , Calmodulina/metabolismo , Células Cultivadas , Biologia Computacional , Feminino , Humanos , Imunidade Humoral , Imunomodulação , Proteínas Motores Moleculares/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Gravidez , Proteínas da Gravidez/genética , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Vimentina/metabolismo
17.
Pediatr Blood Cancer ; 63(3): 535-40, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26485304

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for infantile malignant osteopetrosis (IMO), but is associated with a high incidence of adverse outcomes. In this study, we present our experience with HSCT for IMO patients comparing different types of conditioning regimens. METHODS: Thirty-eight patients with IMO (aged from 1 month to 6 years, median 0.66 years) who underwent allogeneic HSCT from 1983 in our hospital were included in this retrospective study. Fludarabine-based conditioning regimens were used in 26 patients and 12 patients were transplanted using other conditioning regimens. RESULTS: The overall survival after conditioning with fludarabine was 96% (25/26) versus 58% (7/12) for the alternative regimens (P = 0.004), with significantly fewer adverse effects including hypercalcemia and veno-occlusive disease of liver. All patients who survive are clinically well. CONCLUSIONS: We conclude that fludarabine-based conditioning regimens are safe and effective in patients with IMO, improving morbidity and mortality related to HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Osteopetrose/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Hipercalcemia/etiologia , Lactente , Recém-Nascido , Masculino , Osteopetrose/mortalidade , Complicações Pós-Operatórias , Doadores de Tecidos , Sobrevivência de Tecidos , Resultado do Tratamento , Vidarabina/farmacologia
18.
Eur J Haematol ; 96(1): 90-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25807864

RESUMO

Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total , Adolescente , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Irmãos , Taxa de Sobrevida , Doadores não Relacionados
19.
Mycoses ; 58(12): 694-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26429354

RESUMO

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic-driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non-significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic-driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non-statistically significant, number of IFI in our medical centre.


Assuntos
Antifúngicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Itraconazol/administração & dosagem , Micoses/epidemiologia , Infecções Oportunistas/epidemiologia , Administração Oral , Adolescente , Adulto , Idoso , Quimioprevenção/métodos , Criança , Pré-Escolar , Protocolos Clínicos , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Micoses/diagnóstico , Micoses/prevenção & controle , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/prevenção & controle , Soluções Farmacêuticas/administração & dosagem , Taxa de Sobrevida , Transplante Homólogo/efeitos adversos , Voriconazol/administração & dosagem , Adulto Jovem
20.
Blood ; 126(16): 1885-92; quiz 1970, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26185129

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of severe congenital neutropenia (SCN), but data on outcome are scarce. We report on the outcome of 136 SCN patients who underwent HSCT between 1990 and 2012 in European and Middle East centers. The 3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%. In multivariate analysis, transplants performed under the age of 10 years, in recent years, and from HLA-matched related or unrelated donors were associated with a significantly better OS. Frequency of graft failure was 10%. Cumulative incidence (day +90) of acute graft-versus-host disease (GVHD) grade 2-4 was 21%. In multivariate analysis, HLA-matched related donor and prophylaxis with cyclosporine A and methotrexate were associated with lower occurrence of acute GVHD. Cumulative incidence (1 year) of chronic GVHD was 20%. No secondary malignancies occurred after a median follow-up of 4.6 years. These data show that the outcome of HSCT for SCN from HLA-matched donors, performed in recent years, in patients younger than 10 years is acceptable. Nevertheless, given the TRM, a careful selection of HSCT candidates should be undertaken.


Assuntos
Ciclosporina/administração & dosagem , Rejeição de Enxerto , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Metotrexato/administração & dosagem , Neutropenia , Doadores não Relacionados , Doença Aguda , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Teste de Histocompatibilidade , Humanos , Incidência , Masculino , Oriente Médio , Neutropenia/congênito , Neutropenia/epidemiologia , Neutropenia/terapia , Estudos Retrospectivos , Sociedades Médicas
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