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Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/administración & dosificación , Talidomida/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In order to compensate for the paucity of defined tumor antigens (Ag) in non-Hodgkin's lymphomas, a promising approach might be the use of whole tumor cells as a source of tumor Ag to pulse antigen-presenting cells (APC). However, it is not presently known how the tumor cells should be delivered to APC to optimize the cross-presentation of tumor Ag to anti-tumor CD8 T cells. We aimed to compare CD20-opsonized, apoptotic and necrotic human tumor cells for their capacity to induce endocytosis and cross-presentation of tumor-associated Ag by dendritic cells (DC) or macrophages. METHODS: Endocytosis of human tumor-derived material by macrophages or DC was monitored by flow cytometry. We used a previously described influenza model and studied cross-presentation of viral Ag as cellular surrogate tumor-associated Ag by APC after endocytosis of lymphoma B cells treated by inactivated influenza virus. RESULTS: Optimal endocytosis was obtained when tumor cells were opsonized by an anti-CD20 antibody and, as expected, macrophages were more phagocytic than DC. However, Ag from opsonized, apoptotic and live cells, but not from necrotic lymphoma cells, were efficiently cross-presented by DC but not by macrophages. DISCUSSION: We have developed a new model with human primary lymphoma cells to study the cross-presentation of tumor-associated Ag by APC. The results we have obtained support the use of whole lymphoma cells from patients to pulse DC to induce an anti-tumor immune response.
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Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Células Dendríticas/inmunología , Linfoma de Células B/inmunología , Macrófagos/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales de Origen Murino , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Antígenos CD20/inmunología , Antígenos de Neoplasias/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/citología , Células Dendríticas/virología , Humanos , Factores Inmunológicos/farmacología , Activación de Linfocitos/inmunología , Macrófagos/citología , Orthomyxoviridae/inmunología , RituximabRESUMEN
Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin's lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3-120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma.
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Enfermedad de Hodgkin/patología , Nefrosis Lipoidea/fisiopatología , Adolescente , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Citocinas/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , FN-kappa B/fisiología , Nefrosis Lipoidea/tratamiento farmacológico , Nefrosis Lipoidea/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Linfocitos T/patología , Factores de TiempoRESUMEN
We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.
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Antineoplásicos/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Adolescente , Adulto , Factores de Edad , Anciano , Europa (Continente) , Femenino , Humanos , Leucemia Promielocítica Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Thalidomide is effective in multiple myeloma (MM), even in patients who have relapsed after high-dose therapy. A potent graft-versus-myeloma (GVM) effect can be induced against MM after allogeneic stem cell transplantation (allo-SCT). In all, 31 MM patients received thalidomide as a salvage therapy after progression following allo-SCT. The median maximum daily dose of thalidomide was 200 mg (range, 50-600). Thalidomide had to be discontinued in six patients (19%) because of toxicity. In all, nine patients (29%; 95% CI, 13-45) achieved an objective response with thalidomide therapy (six partial and three very good partial responses, VGPR). Five patients developed graft-versus-host disease (GVHD) after thalidomide therapy, including the three patients achieving a VGPR. These data demonstrate that thalidomide is potentially effective in MM patients failing allo-SCT.
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Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/terapia , Terapia Recuperativa/métodos , Talidomida/uso terapéutico , Adulto , Femenino , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Talidomida/administración & dosificación , Talidomida/toxicidad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Promielocítica Aguda/terapia , Terapia Recuperativa , Trasplante de Células Madre , Tretinoina/administración & dosificación , Adulto , Femenino , Humanos , Leucemia Promielocítica Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Trasplante de Células Madre/mortalidad , Tasa de Supervivencia , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Paraneoplastic neurological syndromes are associated with various cancers. Cerebellar and limbic paraneoplastic manifestations are known to be associated with Hodgkin's disease (HD), but reports of diffuse encephalitis associated with HD are very rare. We report a case of acute severe diffuse encephalitis revealing a HD. Clinical presentation, cerebro-spinal fluid modifications and magnetic resonance imagery data are described. The treatment associated specific chemotherapy and plasma exchange. The neurological status improved dramatically within the first days of treatment, with parallel neoplasm regression. This case stresses the fact that encephalopathy can be the first sign of an undiagnosed extra-cerebral neoplasm.
Asunto(s)
Encefalitis/complicaciones , Encefalitis/patología , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/patología , Síndromes Paraneoplásicos/complicaciones , Síndromes Paraneoplásicos/patología , Adolescente , Encéfalo/patología , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: Very few tumoral Ags have yet been isolated in NHL B cells. It is nevertheless possible to use whole tumor cells as a source of tumor Ags. We describe the purification of large numbers of human NHL B cells directly from lymph node or spleen biopsies, and different preparations allowing their use in a clinical setting. METHODS: The purification procedure consists of the negative selection of tumor B cells: cells to be eliminated are opsonized by CD2 Abs, and then coupled to magnetic beads for separation by the Isolex 300 magnetic separator. RESULTS: The mean yield of the purification was 74% for CD19+ cells, with a mean purity of 87%, dependent on the initial fraction of tumor cells in the biopsy. Using this procedure, a large number of purified tumor cells can be recovered from a biopsy in sterile conditions. We also describe treatments of B cells that can enhance their uptake by APCs, a critical step in anti-tumor immunotherapy strategies. Cells were opsonized by rituximab, or induced in apoptosis by irradiation, or necrosis by heating. Cell lysates were directly prepared from purified tumor cells. DISCUSSION: These procedures were reproducible on every lymphoma cell, and treated cells were phagocytosed by APCs. The methodology described here allows the evaluation of the immunological potential of apoptotic, necrotic, opsonized lymphoma cells, or their lysates, in a clinical setting.
Asunto(s)
Linfocitos B/inmunología , Separación Celular/métodos , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Anticuerpos Monoclonales , Anticuerpos Monoclonales de Origen Murino , Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/inmunología , Antígenos de Neoplasias/inmunología , Apoptosis/efectos de la radiación , Biopsia , Humanos , Inmunoterapia/métodos , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Linfoma de Células B/terapia , Linfoma no Hodgkin/terapia , Necrosis , Fagocitosis/inmunología , Rituximab , Bazo/citología , Bazo/inmunología , Fracciones Subcelulares/inmunologíaAsunto(s)
Presentación de Antígeno , Antígenos de Histocompatibilidad Clase II/inmunología , Linfoma de Células B/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Antígenos de Histocompatibilidad Clase II/análisis , Antígenos de Histocompatibilidad Clase II/biosíntesis , Humanos , Linfoma de Células B/diagnósticoRESUMEN
PURPOSE: To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. RESULTS: Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P =.02) and incidence of microgranular M3 variant (P =.04). CONCLUSION: ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Abstract: Bone marrow aplasia observed following ionizing radiation exposure (Total Body Irradiation; gamma dose range: 2-10 Gy) is a result, in particular, of the radiation-induced (RI) apoptosis in hematopoietic stem and progenitor cells (HSPC). We have previously shown in a baboon model of mobilized peripheral blood CD34+ cell irradiation in vitro that RI apoptosis in HSPC was an early event, mostly occurring within the first 24 hours, which involves the CD95 Fas pathway. Apoptosis may be significantly reduced with a combination of 4 cytokines (4F): Stem Cell Factor (SCF), FLT-3 Ligand (FL), thrombopoietin (TPO), and interleukin-3 (IL-3), each at 50 ng x mL(-1) (15% survival versus <3% untreated cells, 24 h post-irradiation at 2.5 Gy). In this study we show that addition of TNF-alpha(800 IU/ml) induces an increase in 4F efficacy in terms of cell survival 24 h after incubation (26% survival after 24 h irradiation exposure at 2.5 Gy) and amplification (k) of CD34+ cells after 6 days in a serum free culture medium (SFM) (kCD34+ = 4.3 and 6.3 respectively for 4F and successive 4F + TNF-a/ 4F treatments). In addition, the 4F combination allows culture on pre-established allogenic irradiated stromal cells in vitro at 4 Gy (kCD34+ = 4.5). Overall this study suggests (i) the potential therapeutic interest for an early administration of anti-apoptotic cytokines with or without hematopoiesis inhibitors (emergency cytokine therapy) and (ii) the feasibility in the accidentally irradiated individual, of autologous cell therapy based on ex vivo expansion in order to perform autograft of residual HSPC collected after the accident.
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Apoptosis/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/efectos de la radiación , Papio/fisiología , Animales , Antígenos CD34/inmunología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Citocinas/farmacología , Depresión Química , Hematopoyesis/efectos de los fármacos , Fenotipo , Irradiación Corporal TotalRESUMEN
Ag presentation via HLA class II molecules in B lymphocytes depends on the coordinated action of HLA-DM, the catalyst of class II-peptide loading, and HLA-DO, a pH-dependent modulator of DM, the expression of which is almost completely restricted to B lymphocytes. The relative expression levels of both class II modulators are critical for the composition of the HLA class II peptide repertoire. The data in this work demonstrate that DO and DM expression are both dependent on the cellular activation status in primary human B lymphocytes. In vivo low-density activated primary human B lymphocytes show a prominent reduction in DO and DM expression when compared with high-density resting primary B lymphocytes. In vitro, reduction of DO and DM expression can be induced by B lymphocyte activation via the B cell receptor or by use of the phorbol ester, PMA. Specific inhibition of protein kinase C resulted in a significant reduction of HLA-DO and is potentially due to protein degradation in lysosomal compartments as the phenomenon is reversed by chloroquine. Thus, the expression of the dedicated HLA class II chaperone DM and its pH-dependent modulator DO is regulated and tightly controlled by the activation status of the B lymphocyte.
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Linfocitos B/inmunología , Antígenos HLA-D/metabolismo , Activación de Linfocitos , Antígenos de Diferenciación de Linfocitos B/análisis , Antígenos de Diferenciación de Linfocitos B/metabolismo , Western Blotting , Células Cultivadas , Cloroquina/farmacología , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunofenotipificación , Indoles/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/fisiología , Células Tumorales CultivadasRESUMEN
Between 50 and 75% of adult patients with de novo acute myeloid leukemia achieve complete remission (CR) but 25 to 40% of them require more than one course of induction chemotherapy to achieve CR. In order to investigate the impact of this situation on the overall outcome of patients we conducted a retrospective analysis of 130 patients, resistant to a single induction course from among three consecutive protocols, using the same induction regimen employed by the BGMT study group. This group of patients has a particularly poor prognosis with relapse and survival rates of 70% and 14% respectively at 5 years. For these patients, being in CR after two induction courses appears to be a major prognostic factor for outcome, since the 5-year Kaplan-Meier survival probability is significantly better (29%, range 17-46) than of those patients with resistant disease (5%, range 2-13). However, results are worse than when complete remission is obtained after a single course. Thus, post remission treatment should have a powerful anti-leukemic effect in preventing relapse. Allogeneic bone marrow transplantation is a preferential strategy in this setting but to be effective this should be performed as early as possible. Furthermore, these results indicate that allogeneic bone marrow transplantation from an alternative donor should be considered in the absence of HLA identical sibling.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Trasplante de Médula Ósea/mortalidad , Femenino , Humanos , Leucemia Mieloide/mortalidad , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Trasplante Homólogo/mortalidad , Resultado del TratamientoRESUMEN
Standardized statistical and graphical methods for analysis of limiting dilution assays are highly desirable to enable investigators to compare and interpret results and conclusions with greater accuracy and precision. According to these requirements, we present in this work a powerful statistical slope test that estimates the fit of the single-hit Poisson model to limiting dilution experiments. This method is readily amenable to a graphical representation. This slope test is obtained by modeling limiting dilution data according to a linear log-log regression model, which is a generalized linear model specially designed for modeling binary data. The result of the statistical slope test can then be graphed to visualize whether the data are compatible or not with the single-hit Poisson model. We demonstrate this statistical test and its graphical representation by using two examples: a real limiting dilution experiment evaluating the growth frequency of IL-2-responsive tumor-infiltrating T cells in a malignant lymph node involved by a B cell non-Hodgkin's lymphoma, and a simulation of a limiting dilution assay corresponding to a theoretical non-single-hit Poisson model, suppressor two-target Poisson model.
Asunto(s)
Alergia e Inmunología/estadística & datos numéricos , Distribución de Poisson , Linfocitos T/inmunología , Humanos , Modelos Lineales , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma de Células B/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
1q rearrangement is a remarkably frequent secondary chromosomal change in both non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), where it is associated with tumor progression. To gain insight into 1q rearrangement-associated disease mechanisms, we used fluorescence in situ hybridization (FISH) to search for recurring 1q breaks in 35 lymphoma samples (31 NHL patients and 4 lymphoma-derived cell lines) as well as 22 MM patients with cytogenetically determined 1q abnormalities. Strikingly, dual-color FISH analysis with chromosome 1 centromere and 1q12-specific probes identified constitutive heterochromatin band 1q12 as the single most frequent breakpoint site in both NHL and MM (39% and 89% of 1q breaks, respectively). These rearrangements consistently generated aberrant heterochromatin/euchromatin junctions and gain of 1q12 material. A further 30% of NHL 1q breaks specifically involved two other novel, closely spaced sites (clusters I and II) within a 2.5 Mb region of proximal 1q21 (D1S3620 to D1S3623). A possible association between these sites and NHL subtype was evident; the cluster I rearrangement was frequent in follicular and diffuse large cell lymphoma, whereas the cluster II rearrangement was more frequently observed in diffuse small-cell lymphoma (2/2 marginal zone lymphomas, 1/2 atypical chronic lymphocytic leukemias, and 1 lymphoplasmacytic lymphoma in this series). Candidate oncogenes bordering this interval (BCL9 and AF1Q) were not rearranged in any patient except one (AF1Q). This study provides the first evidence of involvement of 1q12 constitutive heterochromatin in the pathogenesis of NHL and MM and indicates proximal 1q21 to be of specific pathological significance in NHL.
Asunto(s)
Cromosomas Humanos Par 1/genética , Heterocromatina/fisiología , Linfoma de Células B/genética , Mieloma Múltiple/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Sanguíneas/genética , Bandeo Cromosómico , Rotura Cromosómica/genética , Femenino , Heterocromatina/genética , Humanos , Cariotipificación , Linfoma de Células B/etiología , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Mieloma Múltiple/etiología , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas , Secuencias Repetitivas de Ácidos Nucleicos/genética , Eliminación de Secuencia/genética , Telómero/genética , Factores de Transcripción , Translocación Genética/genéticaRESUMEN
Diagnosis of essential thrombocythemia (ET) is controversial and remains mainly an exclusion diagnosis. Endogenous megakaryocyte colony (EMC) formation have been largely evaluated to identify specific criteria for ET, but results are impeded by the lack of medium standardization. We evaluated megakaryocyte (MK) colony formation in a serum-free collagen-based medium, without cytokine and in the presence of various concentrations of thrombopoietin (TPO). Thirty-six bone marrows from patients diagnosed with ET (n = 11), polycythemia vera (PV; n = 12), reactive thrombocytosis (RT; n = 6) and healthy donors (n = 7) were assessed. We demonstrate that 11 out 11 of the ET patients had spontaneous megakaryocyte colony-forming unit (CFU-MK) formation, in contrast to none of the RT patients and healthy donors. MK progenitors from ET patients remained responsive to TPO, because exogenous addition of TPO significantly increased cloning efficiency. Moreover, at low doses of TPO (0.5 ng/ml and 5 ng/ml), the number of positive cultures and mean number of TPO stimulated CFU-MK were significantly higher in cultures of cells from patients with ET than in patients with RT. In summary, we have described a standardized serum-free, collagen-based assay that allows differential diagnosis of ET and RT, according to endogenous CFU-MK formation and sensitivity to TPO.
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Células Madre Hematopoyéticas/patología , Megacariocitos/patología , Trombocitemia Esencial/diagnóstico , Trombocitosis/diagnóstico , Trombopoyetina/farmacología , Médula Ósea/patología , Colágeno , Ensayo de Unidades Formadoras de Colonias , Medio de Cultivo Libre de Suero , Diagnóstico Diferencial , Resistencia a Medicamentos , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Masculino , Megacariocitos/efectos de los fármacos , Policitemia Vera/patología , Trombocitemia Esencial/patología , Trombocitosis/patologíaAsunto(s)
Trasplante de Médula Ósea , Busulfano/uso terapéutico , Ciclofosfamida/uso terapéutico , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de RemisiónRESUMEN
Non-myeloablative allogeneic stem cell transplantation has been reported to induce sustained complete remission even in advanced diseases (acute leukemia, lymphomas). The tolerance of this procedure allows treatment of poor candidates to conventional allogeneic transplantation with persisting or relapsing myeloma patients. Twelve patients previously treated with at least VAD regimen and autologous transplantation were included. All patients had a serum beta2 microglobuline >3 mg/l at diagnosis. The conditioning regimen consisted of fludarabine 25 mg/m/day x 5, antithymoglobulin 2.5 mg/kg/day x 5, busulphan 2 mg/kg/day x 2; the transplant was peripheral stem cells (except one) from an HLA-matched sibling and was followed by cyclosporin for 45 to 90 days. This treatment results in a well-tolerated procedure (no mucositis, duration of aplasia <7 days). A dramatic graft anti-myeloma effect is documented even in progressive disease (11/12 PR + CR, 4/12 CR). However, five patients underwent CMV disease, one died of CMV encephalitis (UPN 3) and delayed severe GVHD occurred in four patients. Our data suggest that a better survival could be achieved when patients are transplanted with a controlled disease. In high risk patients, we now propose a non-myeloablative transplantation in addition to the conventional and intensive chemotherapy as first-line of treatment.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Persona de Mediana Edad , Mieloma Múltiple/sangre , Proyectos Piloto , Terapia Recuperativa , Acondicionamiento Pretrasplante , Trasplante Autólogo , Trasplante HomólogoRESUMEN
This work aims to demonstrate that CD4(+)CD56(+) malignancies arise from transformed cells of the lymphoid-related plasmacytoid dendritic cell (pDC) subset. The analysis of malignant cells from 7 patients shows that in all cases, like pDCs, leukemic cells are negative for lineage markers CD3, CD19, CD13, CD33, and CD11c but express high levels of interleukin-3 receptor alpha chain (IL-3Ralpha), HLA-DR, and CD45RA. Tumor cells produce interferon-alpha in response to influenza virus, while upon maturation with IL-3 they become a powerful inducer of naive CD4(+) T-cell proliferation and promote their T-helper 2 polarization. As pDCs, leukemic cells also express pre-Talpha and lambda-like 14.1 transcripts, arguing in favor of a lymphoid origin. In addition, malignant cells express significant levels of CD56 and granzyme B. Overall, those observations suggest that CD4(+)CD56(+) leukemic cells could represent the malignant counterpart of pDCs, both of which are closely related to B, T, and NK cells.