ABSTRACT
We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P=0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P=0.18), and for grades III-IV was 2.6% vs 11.6% (P=0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P=0.002) and extensive 5% vs 23.6% (P=0.01). OS was 74% vs 76% for BM vs PBSCs (P=0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P=0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P=0.005) respectively. In multivariate analysis, aGvHD II-IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1-5.6, P=0.02) and aGvHD III-IV (HR 8.3 CI 3.4-20.2, P<0.001) proved to be independent negative predictors of survival. In conclusion, BM as a source of cells and ATG-based regimens should be standard because of higher GvHD incidence with PBSCs, although the latter combining with ATG in the conditioning regimen could be an option in selected high-risk patients.
Subject(s)
Anemia, Aplastic/therapy , Antilymphocyte Serum/administration & dosage , HLA Antigens , Siblings , Stem Cell Transplantation , Acute Disease , Adolescent , Adult , Aged , Allografts , Anemia, Aplastic/mortality , Child , Child, Preschool , Disease-Free Survival , Female , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Latin America , Male , Middle Aged , Survival RateABSTRACT
There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.
Subject(s)
Cocaine-Related Disorders/psychology , Excitatory Amino Acid Agents/metabolism , Excitatory Amino Acid Agents/therapeutic use , Animals , Ceftriaxone/therapeutic use , Central Nervous System Stimulants/pharmacology , Cocaine/metabolism , Cocaine/pharmacology , Cocaine-Related Disorders/drug therapy , Comorbidity , Dendritic Spines/drug effects , Excitatory Amino Acid Agents/pharmacokinetics , Extinction, Psychological/drug effects , Glutamic Acid/metabolism , Male , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Self Administration/methods , Self Administration/psychology , Stress, Psychological/metabolism , Synapses/drug effectsABSTRACT
BACKGROUND: Multiple myeloma (MM) is a monoclonal gammopathy characterized by abnormal proliferation of malignant plasma cells. The median overall survival rate has changed from 2-3 to 5-6 or more years with the introduction of novel agents. Recently CD200 protein has been described as an immunosuppressive protein that confers a poor prognostic factor in several neoplastic diseases, including MM. The purpose of our study was to determine CD200 protein in plasma cells of newly diagnosed patients with MM and in CD3+ lymphocytes of healthy donors. METHODS: 35 newly diagnosed MM patients and 25 healthy donors were studied. For flow cytometry tests, a FacsCalibur device and CellQuestPro software were used. Monoclonal antibodies for CD38 (PeCyC5), CD138 (APC), and CD200 (PE) were used. The statistical analysis was performed with SPSS 19v. Mann-Whitney U test, Kaplan-Meier survival curves with Log-Rank tests were done when indicated. RESULTS: The frequencies of anemia, hypercalcemia, increased in LDH, serum creatinine and b2-microglobulin were 68%, 34%, 20%, 22% and 45% respectively. The treatment consisted in MPT 20 (57%), Thal-Dex 8 (23%), and VAD 7 (20%). Five patients (14%) achieved complete response, 17 (49%) partial response, and 13 (37%) minor response or failure to treatment. CONCLUSION: CD200 is a poor prognostic factor for overall survival in multiple myeloma patients. Bone marrow CD3 lymphocytes from MM patients express CD200 protein in higher proportion than healthy donors.
Introducción: el mieloma múltiple (MM) es una gammopatía monoclonal caracterizada por la proliferación anormal de células plasmáticas malignas. La proteína CD200 se ha descrito como una proteína con funciones inmunosupresoras y que es un factor de mal pronóstico en algunas enfermedades malignas, incluyendo al MM. El objetivo de este artículo es determinar la cantidad de proteína CD200 en células plasmáticas de pacientes con MM de reciente diagnóstico y en linfocitos CD3+ de donadores sanos. Métodos: se estudiaron 35 pacientes con diagnóstico reciente de MM y 25 individuos sanos. Se usaron los anticuerpos monoclonales para CD38 (PeCyC5), CD138 (APC), y CD200 (PE). El análisis estadístico fue realizado con el programa SPSS 19v. Se utilizaron las pruebas estadísticas U de Mann Whitney, curvas de supervivencia de Kaplan y Meier y la prueba de log-rank. Resultados: las frecuencias de anemia, hipercalcemia, elevación de DHL, creatinina sérica y beta-2 microglobulina fueron de 68%, 34%, 20%, 22% y 45% respectivamente. El tratamiento administrado fue MPT 20, Tal-Dex 8, y VAD 7. Cinco pacientes lograron respuesta completa, 17 respuesta parcial, y 13 respuesta menor o falla al tratamiento. Conclusiones: el CD200 es un factor de mal pronóstico para supervivencia global en pacientes con mieloma múltiple. Los linfocitos CD3+ de medula ósea de pacientes con MM expresan en mayor proporción CD200 en comparación con sujetos sanos.
Subject(s)
Antigens, CD/metabolism , Biomarkers, Tumor/metabolism , Multiple Myeloma/diagnosis , Adult , Aged , Aged, 80 and over , Bone Marrow Cells/metabolism , Case-Control Studies , Female , Flow Cytometry , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multiple Myeloma/metabolism , Multiple Myeloma/mortality , Plasma Cells/metabolism , Prognosis , Prospective StudiesABSTRACT
El virus H1N1 se caracteriza por producir sobretodo sintomatología respiratoria y presentarse en época invernal o epidemiológica. Presentamos el caso de una paciente que debutó con cuadros convulsivos en mayo, fuera de la poca invernal y requirió cuidados intensivos (AU)
The H1N1 virus is characterized by producing respiratory symptoms mostly in winter or epidemiological time. We report the case of a patient that started with seizures in May, out of the winter, and required intensive care (AU)
Subject(s)
Humans , Female , Child , Encephalitis, Viral/diagnosis , Influenza, Human/complications , Seizures/etiology , /pathogenicity , Risk Factors , Diagnosis, DifferentialABSTRACT
AIM: To describe the morbimortality associated to the development of acute kidney injury (AKI) defined by the pediatric adaptation of the RIFLE criteria in a Pediatric Intensive Care Unit (PICU). DESIGN: A retrospective cohort study was carried out. SETTING: Children admitted to a PICU in a tertiary care hospital. Patients or participants A total of 320 children admitted to a tertiary care hospital PICU during the year 2011. Neonates and renal transplant patients were excluded. Primary endpoints AKI was defined and classified according to the pediatric adaptation to the RIFLE criteria. PICU and hospital stays, use of mechanical ventilation and mortality were used to evaluate morbimortality. RESULTS: A total of 315 children met the inclusion criteria, with a median age of 19 months (range 6-72). Of these patients, 128 presented AKI (73 reached the Risk category and 55 reached the Injury and Failure categories). Children with AKI presented a longer PICU stay (6.0 [4.0-12.5] vs. 3.5 [2.0-7.0] days) and hospital stay (17 [10-32] vs. 10 [7-15] days), and a greater need for mechanical ventilation (61.7 vs. 36.9%). The development of AKI was an independent factor of morbidity, associated with a longer PICU and hospital stay, and with a need for longer mechanical ventilation, with a proportional relationship between increasing morbidity and the severity of AKI. CONCLUSION: The development of AKI in critically ill children is associated with increased morbimortality, which is proportional to the severity of renal injury.
Subject(s)
Acute Kidney Injury/complications , Acute Kidney Injury/mortality , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Intensive Care Units, Pediatric , Male , Patient Admission , Retrospective StudiesABSTRACT
Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine.
Subject(s)
Central Nervous System Sensitization , Central Nervous System Stimulants/pharmacology , Cocaine/pharmacology , Dopamine/metabolism , Glutamic Acid/metabolism , Nucleus Accumbens/physiology , Stress, Psychological/metabolism , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Exocytosis , Gene Expression , Locomotion/drug effects , Male , Neurons/metabolism , Nucleus Accumbens/metabolism , Protein Transport , Rats , Rats, Wistar , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/genetics , Receptors, AMPA/metabolism , Restraint, PhysicalSubject(s)
Humans , Female , Infant , Anemia, Hemolytic/complications , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic, Congenital/complications , Anemia, Hemolytic, Congenital/diagnosis , Pancytopenia/complications , Pancytopenia/diagnosis , Polymerase Chain Reaction/methods , Polymerase Chain Reaction , Vitamin B 12/therapeutic use , Vitamin B 12 Deficiency/diet therapy , Lethargy/complications , Early Diagnosis , Anemia, Hemolytic/enzymology , Anemia, Hemolytic/therapy , Polymerase Chain Reaction/instrumentation , Vitamin B 12 Deficiency/complications , Vitamin B 12 Deficiency/diagnosisABSTRACT
Objetivos: Evaluar el rendimiento de los biomateriales poliméricos basados en ácido hialurónico y su utilidad en el Sistema Nervioso Central, sirviendo como soporte, para la supervivencia y diferenciación celular. Material y Metodos: Con el fin de evaluar la viabilidad de los soportes poliméricos y acanalados, se realizaron experimetos in vitro e in vivo mediante el implante en corteza cerebral de ratas Wistar. Mediante técnicas inmunocitoquímicas e histológicas se procedió al análisis de la viabilidad de los soportes. Resultados: Tras el cultivo pudimos constatar la viabilidad celular sobre los biomateriales, asi como su potencial utilidad para la regeneración in vivo de estructuras vasculares y neurales. Conclusiones: La posibilidad de regenerar estructuras vasculares y neurales a través del implante de biomateriales basados en ácido hialurónico, constituye un avance en la utilización de biomateriales en el Sistema Nervioso Central (AU)
Objetives: To evaluate the performance of polymeric biomaterials based on hyaluronic acid and their usefulness in the central nervous system as support for cell differentiation and survival. Material and methods: With the purpose of assessing the viability of polymeric cannulated scaffolds, in vitro and in vivo experiments were made involving implantation in the Wistar rate brain cortex. Immunocytochemical and histological techniques were used to analyze scaffold viability. Results: Following culture, cell viability on the biomaterials was confirmed, together with the potential usefulness of the latter for the in vivo regeneration of vascular and neural structures. Conclusions: The possibility of regenerating vascular and neural structures through the implantation of biomaterials based on hyaluronic acid constitutes an advance in the use of biomaterials in the central nervous system (AU)
Subject(s)
Animals , Male , Female , Rats , Biocompatible Materials/therapeutic use , Rats, Wistar/classification , Head Injuries, Penetrating/therapy , Cell Membrane Structures/metabolism , Stem Cells/physiology , Nervous System Physiological Phenomena , Histocytochemistry/methods , Biocompatible Materials/administration & dosage , Biocompatible Materials/metabolism , Head Injuries, Penetrating/rehabilitation , Rats, Wistar/metabolism , Hyaluronic Acid/metabolism , Hyaluronic Acid/therapeutic use , Materials Testing/methods , Microsurgery/methods , Histocytochemistry/veterinary , Histocytochemistry/instrumentationABSTRACT
Mycobacterium tuberculosis is the main aetiologic agent of tuberculosis, a disease of great concern in less-developed regions. Apoptosis is a conspicuous event in macrophages infected in vitro with mycobacteria, a phenomenon also observed in vivo in granulomas of patients with tuberculosis. To determine its significance, it is important to define the mycobacterial moieties involved and how they cause apoptosis. Here we show that the 38-kDa lipoprotein induces macrophage caspase-dependent apoptosis involving TNF-alpha and FasL and, interestingly, with the upregulation of cell-death receptors TNFR1, TNFR2 and Fas. A role for the Toll-like receptor 2 was also demonstrated. In conclusion, the ability to induce apoptosis of host cells is another property of the 38-kDa lipoprotein, a molecule that has focused attention for being an immunodominant antigen that participates in phosphate transport.
Subject(s)
Antigens, Bacterial/metabolism , Apoptosis/immunology , Lipoproteins/metabolism , Macrophages/immunology , Mycobacterium tuberculosis/pathogenicity , Toll-Like Receptor 2/immunology , Tuberculosis/immunology , Cells, Cultured , Fas Ligand Protein/metabolism , Humans , Macrophages/microbiology , Mycobacterium tuberculosis/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolism , Receptors, Tumor Necrosis Factor, Type II/metabolism , Toll-Like Receptor 2/agonists , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation , fas Receptor/metabolismABSTRACT
Several prognostic factors have been recognized in patients with multiple myeloma (MM). Among the most important are: the serum levels of beta2-microglobulin, albumin, and LDH; the labeling index; and an abnormal karyotype. Patients with amyloidosis (AL) have poor prognosis; however, little is known concerning the prognostic significance of AL associated to MM. In 201 consecutive patients with de novo MM, we performed a fat-pad biopsy needle aspiration (FPBNA) that was stained with Congo red. Sixty eight (34%) patients had AL and a poorer prognosis disease: lower performance status, presence of B symptoms, higher LDH and calcium values, and worse response to chemotherapy. Cox regression model for overall survival detected three variables having independent prognostic significance: the presence of AL (RR = 3.4, P < 0.004), serum albumin levels <3.5 g/dl (RR 3.2, p < 0.005), and patients not achieving complete remission or very good partial remission (RR 2.9, p < 0.02). In 28% of patients with de novo MM, FPBNA was useful to detect incidental amyloidosis. During follow-up, 69% of these patients had symptoms of AL. Excluding 16 patients with obvious symptoms of AL at diagnosis, overall survival was worse in patients who developed later symptoms of AL. MM-associated AL represents a poorer prognosis disease even in the absence of symptoms at diagnosis, and this specific association may be considered as an independent high-risk prognostic factor. The routine study of periumbilical fat-pad tissue should be mandatory in all patients with MM.
Subject(s)
Amyloidosis/diagnosis , Amyloidosis/pathology , Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Adipose Tissue/pathology , Adult , Aged , Amyloidosis/blood , Amyloidosis/drug therapy , Antineoplastic Agents/therapeutic use , Biopsy , Disease-Free Survival , Female , Humans , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/drug therapy , Prognosis , Proportional Hazards Models , Regression Analysis , Remission Induction , Risk FactorsABSTRACT
A series of polymeric biomaterials including poly (methyl acrylate) (PMA), chitosan (CHT), poly(ethyl acrylate) (PEA), poly(hydroxyethyl acrylate) (PHEA), and a series of random copolymers containing ethyl acrylate and hydroxyethyl acrylate monomeric units were tested in vitro as culture substrates and compared for their impact on the proliferation and expansion of Schwann cells (SCs). Immunocytochemical staining assay and scanning electron microscopy techniques were applied to perform a quantitative analysis to determine the correct maintenance of the cultured glial cells on the different biomaterials. The results strongly suggest that cell attachment and proliferation is influenced by the substrate's surface chemistry, and that hydrophobic biomaterials based on PMA, PEA, and the copolymers PEA and PHEA in a narrow composition window are suitable substrates to promote cell attachment and proliferation of SCs in vitro.
Subject(s)
Schwann Cells/cytology , Animals , Cell Adhesion , Cell Differentiation , Cell Proliferation , Cell Survival , Cells, Cultured , Rats , Rats, Wistar , Schwann Cells/ultrastructure , Substrate Specificity , Surface Tension , Water/metabolismABSTRACT
Autologous peripheral blood stem cell transplantation is the therapy of choice for the treatment of multiple myeloma (MM) patients younger than 70 years old. Between August 1993 and November 2004, 54 patients with MM were autografted after conditioning with high-dose oral melphalan 140 mg/m(2) in combination with etoposide and carmustine (28 patients) or with high-dose melphalan 200 mg/m(2) I.V. (26 patients). The oral and IV melphalan groups were comparable. There were no significant differences in disease-free survival (DFS) and overall survival (OS) between the groups; however, in patients transplanted in remission, OS and DFS were better in the I.V. melphalan group. Four good-prognostic factors were identified: interval between diagnosis and transplant <18 months, number of prior chemotherapy lines < or =2, remission status (complete or partial), and the use of I.V. melphalan. In conclusion, I.V. melphalan is the therapy of choice for conditioning patients with MM who are in remission.
Subject(s)
Melphalan/therapeutic use , Multiple Myeloma/therapy , Peripheral Blood Stem Cell Transplantation/methods , Administration, Oral , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Carmustine/administration & dosage , Carmustine/therapeutic use , Combined Modality Therapy , Disease-Free Survival , Dose-Response Relationship, Drug , Etoposide/administration & dosage , Etoposide/therapeutic use , Female , Humans , Infusions, Intravenous , Male , Melphalan/administration & dosage , Mexico , Middle Aged , Multiple Myeloma/pathology , Remission Induction , Transplantation, Autologous , Treatment OutcomeABSTRACT
The copper content of grape and wine from 16 wine-farms in Italy was studied during the harvest of 2003. The influence of the number of copper applications, the period between the last application and harvest, and the total amount of copper applied was examined. Of the total number of samples analysed, 13% of grape samples and 18% of wine samples exceeded the maximum residue level (MRL). The total amount of copper applied and the number of days between the last application and harvest explained 44% of the concentration of copper in grape. This low correlation may be due to other influencing factors, such as meteorology and the application method. In 2003, conditions were unusually dry and the recommended safety interval for copper application (20 days) was not sufficient to guarantee a residue level in grape below the MRL (20 mg kg(-1)). In order to reduce the probability of copper residues being close to the MRL, a period of 40-50 days between the last application and harvest is suggested. Furthermore, the copper content of grape and wine was not dependent on the pest management strategy of the farm (conventional, integrated or organic). A more important factor influencing copper residue levels may be that copper applications are made in response to the prediction of a disease outbreak rather than being dependent on the pest management strategy in place. No difference in copper content was observed between red and white grape or wine.
Subject(s)
Antifungal Agents/analysis , Copper/analysis , Food Contamination/analysis , Vitis/chemistry , Wine/analysis , Antifungal Agents/adverse effects , Copper/adverse effects , Drug Residues/analysis , Environmental Exposure/adverse effects , Food Handling/methods , Italy , Pest Control/methodsABSTRACT
Between June 2003 and November 2004, we collected mobilized peripheral blood units from 29 patients with non-Hodgkin's lymphoma and multiple myeloma for autologous peripheral blood stem cell transplantation. They received granulocyte colony-stimulating factor (G-CSF) (16 micro g/kg/day) for a total of 5 days. Immediately before and 3 h after the fourth and fifth dose of G-CSF, we performed flow cytometry analysis to quantify: T cells (CD3+CD4+, CD3+CD8+), B cells (CD19+), NK cells (CD3-CD16+CD56+), NKT cells (CD3+CD16+CD56+), type 1 dendritic cells (DC1) (lin-HLA-DR+CD11c+), type 2 dendritic cells (DC2) (lin-HLA-DR+CD123+), regulatory T cells (Tregs) (CD4+CD25+), and activated T cells (CD3+HLA-DR+). All cell subsets were mobilized after G-CSF treatment with the exception of B, NK, and NKT lymphocytes. The median number of Treg cells before and after G-CSF was statistically different (29+/-14.9x10(6)/l vs 70.1+/-46.1x10(6)/l, P<0.02). DCs were mobilized significantly with a 5.9-fold increase in DC2 (15.1+/-30.3x10(6)/l vs 89.8+/-81.0x10(6)/l, P<0.02) and a 2.6-fold increase for DC1 (41+/-42.5x10(6)/l vs 109.5+/-58.0x10(6)/l, P<0.04). Patients received a mean of 3.1+/-1.2x10(7)/kg NK cells, 1.3+/-0.9x10(7)/kg NKT cells, 0.41+/-0.29x10(7)/kg DC1, 0.2+/-0.22x10(7)/kg DC2, and 1.8+/-1.9x10(7)/kg Tregs. In conclusion, intermediate doses of G-CSF induce mobilization of different lymphocyte subsets, with the exception of B, NK, and NKT cells. The mobilization of certain suppressive populations (DC2 and Treg) could be in theory deleterious, at least in patients with cancer.
Subject(s)
Dendritic Cells , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization , Lymphocytes , Lymphoma, Non-Hodgkin , Multiple Myeloma , Adult , Aged , Antigens, Differentiation/metabolism , Cell Fractionation/methods , Dendritic Cells/pathology , Female , Filgrastim , Humans , Lymphocytes/pathology , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Multiple Myeloma/therapy , Peripheral Blood Stem Cell Transplantation/methods , Recombinant Proteins , Transplantation, AutologousABSTRACT
To analyze the relationship between the cellular composition of peripheral blood allografts and clinical outcome, we performed a prospective study in 45 adult patients who underwent allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from a histocompatibility leukocyte antigen identical sibling donor for different hematological malignancies. The dose of CD34+, CD3+, CD4+, CD8+, and CD19+ lymphocytes, natural killer (NK) cells, natural killer T (NKT) cells, type 1 and type 2 dendritic cells (DC1 and DC2), as well as regulatory T (Treg) lymphocytes was analyzed. All patients were conditioned with busulphan and cyclophosphamide (BuCy2) +/- VP-16 and received a short course of methotrexate and cyclosporin-A as graft-versus-host disease (GVHD) prophylaxis. Acute GVHD (aGVHD) was present in 9 of 43 (21%) patients, and chronic GVHD (cGVHD) developed in 18 of 39 (46%) patients. There was a significantly higher incidence of aGVHD in patients receiving more than 6x10(6)/kg CD34+ cells. In univariate analysis, variables associated with better survival were as follows: a dose of less than 1.5x10(7)/kg NKT cells and less than 1.7x10(6)/kg DC2 for disease-free survival (DFS), and a dose of less than 3x10(7)/kg NK cells, less than 1.5x10(7)/kg NKT cells, less than 3x10(6)/kg DC1, and less than 1.7x10(6)/kg DC2 for overall survival (OS). In the Cox regression analysis, the dose of NKT cells was the only variable associated with better DFS, while the doses of NK, NKT, and CD34+ cells (less than 8x10(6)/kg) were associated with better OS. In conclusion, different circulating cell populations, other than CD34+ cells, are also of relevance in predicting the clinical outcome after allogeneic peripheral blood HSCT.
Subject(s)
Dendritic Cells/metabolism , Granulocyte Colony-Stimulating Factor/metabolism , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Killer Cells, Natural/cytology , Adolescent , Adult , Antigens, CD19/biosynthesis , Antigens, CD34/biosynthesis , CD3 Complex/biosynthesis , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Child , Female , Graft vs Host Disease/therapy , Humans , Killer Cells, Natural/metabolism , Male , Middle Aged , Prospective Studies , T-Lymphocytes, Regulatory/metabolism , Transplantation Conditioning/methods , Transplantation, HomologousABSTRACT
Using a reduced-intensity stem cell transplantation (RIST) schedule, 24 patients with Philadelphia (Ph1) (+) chronic myelogenous leukemia (CML) in first chronic phase (CP) were prospectively allografted in four Latin American countries: México, Brazil, Colombia and Venezuela, using HLA-identical siblings as donors. The median age of the patients was 41 years (range 10-71 years); there were eight females. Patients received a median of 4.4 x 10(6)/kg CD34 cells. The median time to achieve above 0.5 x 10(9)/l granulocytes was 12 days, range 0-41 days, and the median time to achieve above 20 x 10(9)/l platelets was also 12 days, range 0-45 days. In all, 22 patients are alive 81-830 (median 497) days after RIST. The 830-day probability of survival is 92%, and the median survival has not been reached, being beyond 830 days. A total of 11 patients (46%) developed acute graft-versus-host disease (GVHD), and seven of 23 (30%) developed chronic GVHD. Two patients died 43 and 210 days after RIST, one as a result of sepsis and the other of chronic GVHD. The 100-day mortality was 4.4%, and transplant-related mortality was 8%. RIST for patients with CML in CP appears to be an adequate therapeutic option.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Stem Cell Transplantation/methods , Adolescent , Adult , Aged , Antigens, CD34/biosynthesis , Benzamides , Blood Component Removal , Child , Female , Graft vs Host Disease/therapy , Humans , Imatinib Mesylate , Male , Middle Aged , Prospective Studies , Time Factors , Transplantation Conditioning , Treatment OutcomeABSTRACT
We prospectively conducted a quantitative and phenotypic analysis of T, B, natural killer (NK), NKT, type 1 and 2 dendritic cells (DC), and regulatory T cells, before and after mobilization with intermediate doses of granulocyte colony-stimulating factor (G-CSF) (16 microg/kg per day). Between November, 2003, and December, 2004, we collected stem cells from 25 HLA identical sibling donors for allogeneic hematopoietic stem cell transplantation. Before mobilization and 3 h after the fourth and fifth doses of G-CSF, blood samples were taken for blood counts and flow cytometry. The median number of regulatory T cells before and after G-CSF was statistically different (69 +/- 41 x 10(6)/L versus 161 +/- 159 x 10(6)/L, p < 0.01). We observed a 1.7-fold increase in NK and NKT cells (p < 0.009 and p < 0.02, respectively). DC were mobilized with a 11.5-fold increase in type 2 (p < 0.004) and a 8.5-fold increase in type 1 DC (p < 0.003). The patients received a mean of: 2.2 x 10(7)/kg +/- 1.4 x 10(7)/kg of NK cells, 0.95 x 10(7)/kg +/- 0.81 x 107/kg of NKT cells, 0.43 x 107/kg +/- 0.53 x 10(7)/kg of type 1 DC, 0.3 v 10(7)/kg +/- 0.45 x 10(7)/kg of type 2 DC and 1.4 x 10(7)/kg +/- 1.2 x 10(7)/kg of regulatory T cells. Using intermediate doses of G-CSF, we have demonstrated the mobilization of different lymphocyte subsets, in particular regulatory T cells and DC, which can be expanded later and used in the treatment of cancer and autoimmune diseases.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Transplantation/methods , Dendritic Cells/immunology , Granulocyte Colony-Stimulating Factor/pharmacology , Lymphocyte Activation , Lymphocytes/immunology , Receptors, Interleukin-2/analysis , Stem Cells/cytology , Adult , Antigens, CD/analysis , Blood Component Removal/methods , Female , Hematopoietic Stem Cell Mobilization/methods , Humans , Living Donors , Male , Middle Aged , Recombinant Proteins , SiblingsABSTRACT
Reduced intensity conditioning (RIC) have allowed the application of transplantation to older patients and to patients with underlying medical problems. Between October, 1999, and June, 2003, 61 patients with acute leukemia or chronic myeloid leukemia received allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings. Thirty-four were conditioned with myeloablative protocols and twenty-seven with RIC regimens. The patients in the myeloablative group were younger (29 vs. 37 years; p < 0.0003), most of them were transplanted in complete remission (74% vs. 59%; p < 0.03), had a shorter interval between diagnosis and HSCT (12 vs. 21 months; p < 0.02) and a greater proportion belonged to standard-risk prognosis (68% vs. 48%; p < 0.1). The median times to neutrophil, platelet and red blood cell engraftment for the myeloablative and RIC groups were 14 versus 11 days (p < 0.009), 17 versus 9 days (p < 0.0001), and 19 versus 12 days (p < 0.007), respectively. Transfusion requirements were lower in the RIC group. Severe mucositis was present in 32% and 7%, respectively (p < 0.01). The proportion of patients having acute graft versus-disease (GVHD), chronic GVHD, and infections was the same, as well as early and late mortality, disease-free survival, and overall survival. Analyzing all the patients together, three factors significantly influenced overall survival: standard risk patients, complete remission at transplant, and the absence of severe acute GVHD. In conclusion, our data suggest that even in high-risk patients, RIC transplantation seems to be as useful as ablative HSCT.