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1.
Ann Hematol ; 101(10): 2263-2270, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35997804

ABSTRACT

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.


Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Pyridazines , Antineoplastic Agents/adverse effects , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/genetics , Humans , Imidazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors/adverse effects , Pyrazoles , Pyridazines/adverse effects , Retrospective Studies
2.
Ann Oncol ; 33(3): 259-275, 2022 03.
Article in English | MEDLINE | ID: mdl-34923107

ABSTRACT

BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.


Subject(s)
Hematology , Receptors, Chimeric Antigen , Accreditation , Adult , Bone Marrow , Humans , Immunotherapy, Adoptive , Receptors, Antigen, T-Cell
5.
Leuk Res ; 39(8): 828-34, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26009156

ABSTRACT

The impact of donor age in patients with acute myeloid leukemia and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplant (HSCT) remains unclear. In the current study, we evaluate 179 consecutive patients who received an HSCT, from January 2000 to January 2013, in our Institution. Most of the HSCT (91%) were HLA-matched. Patient and donor median age were 51 years (18-69) and 47 years (12-75) respectively, and 81 donors (45%) were older than 50 years. The median follow-up was 38 months (range 1-138), Kaplan-Meier estimated 3-year overall survival (OS) was 63% and disease free survival (DFS) was 56%. Interestingly, patients who received an HSCT from a donor older age (>50 y) showed a poorer OS (51% vs 73%; p=0.01), as well as a higher TRM (20% vs 8%; p=0.038) and higher relapse rate (28% vs 39%; p=0.03). In a stratified subanalysis, 3-year estimated OS was significantly lower among patients undergoing an HSCT from >50 years sibling donors compared to those receiving an HSCT from <50 years unrelated donor (54% vs 72%; p<0.001). In summary, we can conclude that receiving an HSCT from a donor over 50 years old is associated with poorer outcome in patients diagnosed with MDS and AML, and this information may be incorporated into the complex process of donor selection.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Unrelated Donors/statistics & numerical data , Adolescent , Adult , Age Factors , Aged , Child , Female , Hematopoietic Stem Cell Transplantation/mortality , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Myelodysplastic Syndromes/mortality , Survival Analysis , Transplantation, Homologous , Treatment Outcome , Young Adult
6.
Leuk Res ; 39(3): 296-306, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25601157

ABSTRACT

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Remission Induction , Retrospective Studies , Survival Rate , Treatment Outcome , Validation Studies as Topic
7.
Trauma (Majadahonda) ; 25(3): 127-135, jul.-sept. 2014. ilus, tab
Article in Spanish | IBECS | ID: ibc-128353

ABSTRACT

Objetivo: Evaluar la presencia de células mesenquimales en el núcleo pulposo de disco intervertebral cervical y caracterizarlas comparativamente con las obtenidas de médula ósea de los mismos sujetos. Pacientes y metodología: Hemos realizado un estudio descriptivo con 14 pacientes que precisaron cirugía de artrodesis cervical. Se analizó la presencia de células mesenquimales (CSM) en el núcleo pulposo (NP) del disco, comparándolas cualitativamente con las de médula ósea (MO) de los mismos pacientes. Se aislaron y expandieron CSM, tanto de NP como de MO. Se realizaron los estudios de diferenciación multilineal in vitro de las células mesenquimales de ambas fuentes, hacia osteoblasto y adipocito, y caracterización inmunofenotípica por citometría de flujo. Resultados: Las células de ambos orígenes se diferencian in vitro hacia ambos tipos celulares, si bien la diferenciación adipocítica de las células procedentes del disco fue menor que las procedentes de MO. Tampoco se han demostrado diferencias en los marcadores inmunofenotípicos. Las células de ambas fuentes poseen los marcadores inmunofenotípicos característicos de las células mesenquimales. Conclusión: El NP de disco vertebral cervical degenerado contiene células troncales mesenquimales. Estas células son similares a las células de MO, con la excepción de su capacidad disminuida de diferenciación adipogénica (AU)


Objective: To evaluate the presence of mesenchymal cells in the nucleus pulposus (NP) of cervical discs and characterize them in comparison ot those obtained from the bone marrow of the same subjects. Patients and methods: We have performed a descriptive study with 14 patients requiring cervical fusion surgery. The presence of mesenchymal stem cells (MSCs) were analyzed in the NP from the disk and compared qualitatively with the bone marrow (BM) of the same patients. MSC were isolated and expanded for both NP and MO. We performed in vitro differentiation studies of mesenchymal cells from both sources, into osteogenic and adipogenic lines, and flow cytometric immunophenotyping. Results: We got differentiation towards both cell types, although adipocyte differentiation of disc-derived cells was decreased compared to those from BM. There were no differences in immunophenotypic markers. Cells from both sources have immunophenotypic markers characteristic of mesenchymal cells. Conclusion: The NP of degenerated cervical disc contains mesenchymal stem cells. These cells are quite similar to BM cells, with the exception of a diminished adipogenic differentiation capacity (AU)


Subject(s)
Humans , Male , Female , Stem Cells , Intervertebral Disc/pathology , Intervertebral Disc/surgery , Intervertebral Disc , Cell- and Tissue-Based Therapy/methods , Cell- and Tissue-Based Therapy , Intervertebral Disc Degeneration/complications , Intervertebral Disc Degeneration/diagnosis , Intervertebral Disc Degeneration/surgery , Arthrodesis/methods , Arthrodesis/trends , Arthrodesis , Cell- and Tissue-Based Therapy/instrumentation , Cell- and Tissue-Based Therapy/trends , Intervertebral Disc Degeneration/physiopathology , Intervertebral Disc Degeneration/rehabilitation , Intervertebral Disc Degeneration
8.
Bone Marrow Transplant ; 49(5): 684-90, 2014 May.
Article in English | MEDLINE | ID: mdl-24566710

ABSTRACT

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.


Subject(s)
Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Methotrexate/administration & dosage , Sirolimus/administration & dosage , Tacrolimus/administration & dosage , Thrombotic Microangiopathies/etiology , Adult , Aged , Drug Therapy, Combination , Female , Graft vs Host Disease/drug therapy , Graft vs Host Disease/epidemiology , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Incidence , Male , Methotrexate/blood , Middle Aged , Multivariate Analysis , Prognosis , Retrospective Studies , Risk Factors , Sirolimus/blood , Tacrolimus/blood , Thrombotic Microangiopathies/epidemiology , Transplantation, Homologous , Young Adult
9.
Cell Transplant ; 22(7): 1171-83, 2013.
Article in English | MEDLINE | ID: mdl-23031585

ABSTRACT

Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood (UCB) progenitors is increasingly being used. One of the problems that may arise after UCB transplantation is an impaired engraftment. Either intrabone (IB) injection of hematopoietic progenitors or mesenchymal stem cell (MSC) coadministration has been proposed among the strategies to improve engraftment. In the current study, we have assessed the effects of both approaches. Thus, NOD/SCID recipients were transplanted with human UCB CD34+ cells administered either intravenously (IV) or IB, receiving or not bone marrow (BM)-derived MSCs also IV or IB (in the right femur). Human HSC engraftment was measured 3 and 6 weeks after transplantation. Injected MSCs were tracked weekly by bioluminescence. Also, lodgment within the BM niche was assessed at the latter time point by immuno-fluorescence. Our study shows regarding HSC engraftment that the number of BM human CD45+ cells detected 3 weeks after transplantation was significantly higher in mice cotransplanted with human MSCs. Moreover, these mice had a higher myeloid (CD13+) engraftment and a faster B-cell (CD19+) chimerism. At the late time point evaluated (6 weeks), human engraftment was higher in the group in which both strategies were employed (IB injection of HSC and MSC coadministration). When assessing human MSC administration route, we were able to track MSCs only in the injected femurs, whereas they lost their signal in the contralateral bones. These human MSCs were mainly located around blood vessels in the subendosteal region. In summary, our study shows that MSC coadministration can enhance HSC engraftment in our xenogenic transplantation model, as well as IB administration of the CD34+ cells does. The combination of both strategies seems to be synergistic. Interestingly, MSCs were detected only where they were IB injected contributing to the vascular niche.


Subject(s)
Fetal Blood/cytology , Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cell Transplantation , Adult , Animals , Antigens, CD34/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Bone and Bones/physiology , Chimerism , Female , Graft Survival/immunology , HEK293 Cells , Hematopoietic Stem Cells/cytology , Humans , Leukocyte Common Antigens/metabolism , Male , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Transplantation, Heterologous
10.
Transfus Med ; 22(2): 122-7, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22296109

ABSTRACT

PURPOSE: The aim of this study was to optimise the yield of metaphases in mesenchymal stromal cells (MSC) in vitro cultures and to study the karyotype of MSC expanded in good manufacturing practice (GMP) conditions for clinical use. BACKGROUND: MSC are being increasingly used in clinical trials for a number of diseases. Biosafety demonstration in all cases is mandatory. Unfortunately, current standard karyotyping methods fail to obtain enough number of evaluable metaphases. METHODS AND MATERIALS: In the present work, to optimise the yield of metaphases in MSC expanded in vitro, we have tested several conditions by modifying colcemid concentration (we have tested 0.01, 0.05 and 0.1 µg mL(-1) ) and exposure time (during 5, 15 and 24 h). We further applied these optimised conditions to 61 MSC expansions in GMP conditions for clinical use. RESULTS: Our results show that the highest number of metaphases was obtained when MSC were incubated with 0.05 µg mL(-1) of colcemid overnight (15 h), compared to the remaining experimental conditions. In most cases (59/61 cases) enough number of metaphases was obtained. And what is more relevant, only in one case a karyotypic abnormality was found (trisomy of chromosome 10), and cells were subsequently discarded for clinical use. CONCLUSION: We describe here an optimal method to obtain enough number of metaphases for karyotype analysis of in vitro expanded MSCs, what is essential for their clinical use in cell therapy programmes.


Subject(s)
Karyotyping/methods , Mesenchymal Stem Cells/cytology , Metaphase , Cells, Cultured , Female , Humans , Male
13.
Leukemia ; 23(8): 1515-27, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19357701

ABSTRACT

It is an open question whether in multiple myeloma (MM) bone marrow stromal cells contain genomic alterations, which may contribute to the pathogenesis of the disease. We conducted an array-based comparative genomic hybridization (array-CGH) analysis to compare the extent of unbalanced genomic alterations in mesenchymal stem cells from 21 myeloma patients (MM-MSCs) and 12 normal donors (ND-MSCs) after in vitro culture expansion. Whereas ND-MSCs were devoid of genomic imbalances, several non-recurrent chromosomal gains and losses (>1 Mb size) were detected in MM-MSCs. Using real-time reverse transcription PCR, we found correlative deregulated expression for five genes encoded in regions for which genomic imbalances were detected using array-CGH. In addition, only MM-MSCs showed a specific pattern of 'hot-spot' regions with discrete (<1 Mb) genomic alterations, some of which were confirmed using fluorescence in situ hybridization (FISH). Within MM-MSC samples, unsupervised cluster analysis did not correlate with particular clinicobiological features of MM patients. We also explored whether cytogenetic abnormalities present in myelomatous plasma cells (PCs) were shared by matching MSCs from the same patients using FISH. All MM-MSCs were cytogenetically normal for the tested genomic alterations. Therefore we cannot support a common progenitor for myeloma PCs and MSCs.


Subject(s)
Comparative Genomic Hybridization , Mesenchymal Stem Cells/chemistry , Multiple Myeloma/genetics , Adult , Aged , Aged, 80 and over , Bone Marrow/pathology , Bone Marrow Cells/chemistry , Cell Lineage , Cells, Cultured/chemistry , Cluster Analysis , Female , Gene Dosage , Gene Expression Regulation, Neoplastic , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multiple Myeloma/pathology , Neoplastic Stem Cells/chemistry , Oligonucleotide Array Sequence Analysis , Plasma Cells/chemistry , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured/chemistry
14.
Leukemia ; 23(4): 664-72, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19151777

ABSTRACT

The presence of cytogenetic aberrations on mesenchymal stem cells (MSC) from myelodysplastic syndrome (MDS) patients is controversial. The aim of the study is to characterize bone marrow (BM) derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridization (FISH) and genetic changes by array-based comparative genomic hybridization (array-CGH). In all 36 cases of untreated MDS were studied. MDS-MSC achieved confluence at a significantly slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic. These results were confirmed by FISH. To confirm that genomic changes were also present in freshly obtained MSCs they were enriched by sorting BM cells with the following phenotype: CD45(-)/CD73(++)/CD34(-)/CD271(++). They also showed genomic changes that were confirmed by FISH. To analyze the relationship of these aberrations with clinical-biological data an unsupervised hierarchical cluster analysis was performed, two clusters were identified: the first one included the 5q- syndrome patients, whereas the other incorporated other MDS. Our results show, for the first time that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to a particular MDS subtype, the 5q- syndrome.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Mesenchymal Stem Cells/pathology , Myelodysplastic Syndromes/pathology , Adult , Aged , Aged, 80 and over , Bone Marrow Cells/pathology , Bone Marrow Examination , Chromosome Aberrations , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Myelodysplastic Syndromes/genetics
15.
Transfus Apher Sci ; 37(2): 145-56, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17983836

ABSTRACT

Damage to the stem cell progenitors caused by the chemotherapy received in patients diagnosed with non-Hodgkin's lymphoma (NHL) may be an important factor limiting progenitor cell mobilization. The aim of the present analysis was to evaluate the effect of the chemotherapy on the different progenitor cell subpopulations obtained in the leukapheresis. For this purpose, a combination of immunophenotype and functional assays has been performed in 26 mobilized peripheral blood (PB) samples from NHL patients and 36 healthy donors. The different progenitor subpopulations analyzed by flow cytometry significantly correlated with the corresponding populations assessed by functional assays in both healthy donors and NHL patients (p<0.05, r>0.5). The number of committed CFU-GM was similar in both groups (p=0.246), but we found significant decrease in the number of BFU-E and more immature progenitors in PB from NHL patients as compared to donors (p<0.05). Moreover, the number of total CFU was significantly lower in NHL patients (p=0.007). Accordingly, CD34+ cells (p=0.018) and CD34+ subpopulations was decreased in NHL patients. Nevertheless, CD90 and CD34 intensity was significantly higher within CD34+ cells from NHL patients as compared to donors. However, although numerically reduced non-committed CD34+ cells are more immature in chemotherapy mobilized NHL patients. In summary, our results show that all NHL hematopoietic progenitors, analyzed by both immunophenotypical and functional approaches, are impaired in leukapheresis products.


Subject(s)
Antigens, CD34/biosynthesis , Hematopoietic Stem Cells/immunology , Leukapheresis/methods , Lymphoma, Non-Hodgkin/blood , Thy-1 Antigens/biosynthesis , Antigens, CD34/analysis , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Donors , Cells, Cultured , Colony-Forming Units Assay , Female , Flow Cytometry , Granulocyte Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Humans , Immunophenotyping , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Reproducibility of Results , Thy-1 Antigens/analysis
16.
MAPFRE med ; 18(3): 180-189, jul.-sept. 2007. ilus, tab
Article in Es | IBECS | ID: ibc-056980

ABSTRACT

Introducción: La insuficiencia arterial crónica de las extremidades inferiores es una enfermedad extremadamente incapacitante y que afecta un 3,5% de los varones mayores de 60 años. En el momento actual, la terapia celular es una alternativa de reciente aplicación que presenta grandes perspectivas en el tratamiento de las isquemias periféricas. El objetivo del presente estudio fue analizar la seguridad y eficacia de las células AC133+ autólogas en promover la revascularización de MMII en pacientes con isquemia crítica de las EEII. Material y Métodos: Se han incluido 3 pacientes con isquemia crítica de las extremidades inferiores que fueron sometidos a movilización de células hematopoyéticas desde la médula osea a la sangre periferica (SP) a través del G-CSF. Posteriormente, los progenitores endoteliales autólogos AC133+, extraídos y seleccionados desde SP mediante el sistema CliniMACS® (Miltenyi Biotec), fueron inyectados intramuscularmente. Se hizo un seguimiento de los pacientes durante 6 meses según el protocolo del estudio, valorándose variables clínicas, funcionales, hemodinámicas, anatómicas y de calidad de vida. Resultados: El proceso de movilización, recolección y infusión de los progenitores endoteliales fue bien tolerado. A lo largo del seguimiento no se ha producido ninguna amputación y hubo mejoría objetiva y subjetiva de algunas de las variables estudiadas. Conclusión: Hasta el momento y con tres enfermos incluidos en el estudio el proceso de administración de las células AC133+ se ha mostrado seguro y sin complicaciones, entretanto hemos de ser prudentes en correlacionar la terapia celular y mejoría clínica. Con la inclusión de nuevos pacientes y su seguimiento a medio plazo seguramente se nos aclarará el efecto clínico de las células AC133+


Introduction: Chronical arterial disease (CAD) is an extremely incapacitating illness which affects 3-5% of the male population above 60 years-old. Actually, cell therapy is an alternative that causes great expectation for the treatment of the peripheral ischemias. The aim of the present study was to analyze the efficiency and security of autologous AC133+ cells on promoting limb revascularization in patients with critical CAD. Material and Methods: Three patients with critical CAD were included and followed up to date. The patients were subjected to mobilization of hematopoietic precursors from the bone marrow to peripheral blood with G-CSF. Later, the autologous endothelial stem cells AC133+, extracted and selected from blood through the CliniMACS® (Miltenyi Biotec) system, were injected intramuscularly. The patients were followed for 6 months as the study’s protocol and clinical, functional, hemodynamic, anatomical and quality of life variables were evaluated. Results: The process of mobilization, collection and infusion of the endothelial stem cells was well tolerated. Through the follow-up there were no amputations and there was objective as well as subjective improvement of some studied variables. Conclusion: So far and with three included patients, the process of administration of the AC133+ cells has shown security and lack of complication, although we have to be cautious on correlating cell therapy with clinical improvement. With the inclusion of new patients and their mid term follow-up we shall clarify the clinical effect of the AC133+ cells


Subject(s)
Humans , Ischemia/therapy , Peripheral Vascular Diseases/therapy , Cell- and Tissue-Based Therapy/methods , Lower Extremity/physiopathology , Angiogenesis Inducing Agents/therapeutic use
17.
Cytotherapy ; 9(1): 14-22, 2007.
Article in English | MEDLINE | ID: mdl-17354099

ABSTRACT

BACKGROUND: The aim of this study was to identify circulating endothelial progenitor cells (EPC) with colony-forming capacity and compare them with the monocytic-macrophage lineage. METHODS: Forty-two healthy donors were analyzed. EPC were cultured with VEGF and b-FGF. Sequential studies were performed on days +7 (colonies) +21 and +35. Monocytic cells were cultured using the same conditions as EPC until day +21 or alternatively by adding IGF. RESULTS: The number of EPC colonies was higher in BM than in mobilized or steady-state PB. Using EPC medium, monocytic cells formed cord-like structures but no colonies. However, colonies grew when IGF was added to the medium. By immunocytochemistry, colonies showed CD45, CD31 and lysozyme but no vWF. Colonies were CD4+, CD13+dim, CD14+, CD15++, CD16-/+dim, CD31+dim, CD33+dim, CD45+, CD105-/+dim, lysozyme+ and VE-cadherin+, and constantly negative for CD34, CD133 and KDR, when flow cytometry was used. The immunophenotype of pre-cultured and cultured monocytes was similar to that described for EPC. DISCUSSION: Our results suggest that the so-called 'EPC' obtained at 7 days of culture belong to the monocyte-macrophage lineage, as they share immunophenotypic and molecular features.


Subject(s)
Endothelial Cells/cytology , Monocytes/cytology , Stem Cells/cytology , Adult , Antigens, CD/analysis , Biomarkers/analysis , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Fibroblast Growth Factor 2/pharmacology , Flow Cytometry , Gene Expression/drug effects , Humans , Immunohistochemistry , Male , Monocytes/drug effects , Monocytes/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/drug effects , Stem Cells/metabolism , Time Factors , Vascular Endothelial Growth Factor A/pharmacology , von Willebrand Factor/analysis , von Willebrand Factor/genetics
18.
Cytotherapy ; 9(1): 99-102, 2007.
Article in English | MEDLINE | ID: mdl-17354105

ABSTRACT

We present a patient with critical limb ischemia who was successfully treated with the injection of autologous peripheral blood (PB) CD133+ purified stem cells (SC) into the gastrocnemius muscle. No serious adverse events related to G-CSF administration, mononuclear cells harvest or CD133+ SC administration was observed. After 17 months of follow-up, our patient has experienced limb salvage, symptomatic relief and functional improvement. Moreover, we have observed the appearance of flow in the right posterior tibial artery that was absent before the procedure. To our knowledge, this is the first case of critical limb ischemia treated with PB CD133+ SC.


Subject(s)
Antigens, CD/metabolism , Endothelial Cells/transplantation , Extremities/blood supply , Glycoproteins/metabolism , Ischemia/surgery , Peptides/metabolism , Stem Cell Transplantation/methods , AC133 Antigen , Aged , Endothelial Cells/metabolism , Follow-Up Studies , Humans , Male , Treatment Outcome
20.
Biol Blood Marrow Transplant ; 12(9): 936-41, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16920559

ABSTRACT

Acute graft-versus-host disease (aGVHD) remains one of the most severe complications after allogeneic transplantation; in particular, the presence of gut involvement has been related to increased mortality and poorer response. The use of systemic steroids remains the standard for first-line treatment despite its severe secondary effects. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with low absorption, thereby avoiding many of the deleterious side effects associated with systemic steroids. In the present study we analyzed the efficacy of BDP in a series of 26 patients who were diagnosed with grade 1 and 2 gastrointestinal aGVHD. Twenty patients (77%) responded to BDP treatment, 17 (65.5%) reached complete remission (CR), and 3 (11.5%) showed partial response. Among those patients who reached CR, 5 relapsed, although 1 of them reached second CR after a second course of BDP; therefore, 13 (50%) of the 26 patients did not require systemic steroids to treat gastrointestinal aGVHD. CR rates in those showing gastrointestinal symptoms were 68% for patients with persistent nausea, 50% for those with vomiting, and 54% for those with diarrhea (P=.2). No patient included in the study developed any symptom related to adrenal axis suppression. Thirteen patients (50%) developed >or=1 infectious episode during the first 100 days after transplantation. Transplant-related mortality was 0% at 100 days, and overall transplant-related mortality was 30%, with only 2 patients dying due to infectious complications. Therefore, our study shows that monotherapy with oral BDP is an effective initial therapeutic approach for mild to moderate intestinal GVHD, which avoids complications related to systemic steroids.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Beclomethasone/administration & dosage , Gastrointestinal Diseases/drug therapy , Graft vs Host Disease/drug therapy , Hematologic Neoplasms/therapy , Administration, Oral , Adolescent , Adult , Aged , Anti-Inflammatory Agents/adverse effects , Beclomethasone/adverse effects , Disease-Free Survival , Female , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/mortality , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Time Factors
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