The hematology journal : the official journal of the European Haematology Association最新文献

Purpose: The efficacy of low-dose thalidomide (THAL) plus dexamethasone (DEX) has been evaluated in myeloma. The clinical outcome of patients treated with THAL-DEX was compared with that of a control group treated with conventional chemotherapy (CC).

Experimental design: A total of 120 relapsed/refractory patients to one (52%), or two or more(48%) lines of chemotherapy were treated with THAL 100mg/day (continuous) and DEX 40 mg (days 1-4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. Clinical characteristics were homogeneous in the two groups.

Results: In patients treated after one line of chemotherapy, THAL-DEX significantly improved outcome. Median progression-free survival (PFS) was superior in THAL-DEX group versus CC group (17 months versus 11 months, P = 0.0024). The median survival for THAL-DEX patients has not to been reached, but the probabilities of survival at 3 years were 60% after THAL-DEX and 26% after CC (P = 0.0016). The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy, was similar. In the THAL-DEX group, the medianPFS was 11 months compared to 9 months in the CC group (P = NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL-DEX and CC).

Conclusions: As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.

Transplantation of positively selected, CD34(+) peripheral blood stem cells from alternative donors frequently results in delayed immune reconstitution. A shift towards a type 2 cytokine production might be a major contributing factor. We therefore decided to measure IFN-gamma, IL-2, IL-4, and IL-10 after stimulation of peripheral mononuclear cells with PMA/ionomycin and on a single cell level by intracellular cytokine staining during different stages of immune reconstitution. Immediately after transplantation, secretion of all selected cytokines was substantially diminished, and remained subnormal compared to controls until the end of the first year despite normalizing T-cell levels. IL-2 was predominantly produced by CD4(+)CD45RA(+) naïve, whereas IFN-gamma originated mainly from CD8(+)CD45RO(+) memory T cells. Secretion of IL-2 was correlated with the numbers of naive CD4(+) T cells, whereas IFN-gamma secretion correlated with total CD3(+) T-cell counts. IL-4 and IL-10 were produced by CD4(+) and CD8(+) memory T cells; secretion of these cytokines was low, however, and did not increase during follow-up. Therefore, a shift towards a preferential production of type 2 cytokines could not be observed. Analysis of CD69 upregulation upon stimulation revealed a deficiency in patient T-cell activation, which unexpectedly comprised both naïve and memory T-cell subpopulations. Therefore, we suggest that a defect in T-cell activation intrinsic to the host and not graft-versus-host disease, post-transplant immunosuppression or a shift towards a type 2 cytokine pattern contributes to the impaired production of cytokines post-transplant. Further studies will focus on the elimination of host factors that may adversely affect T-cell function after transplantation.

A baby centrally cyanosed from birth was investigated for a congenital cardiac defect. Echocardiography and angiography revealed patent foramen ovale without any other cardiac abnormality. Congenital methaemoglobinaemia was considered as the methaemoglobin level was 27%, suggesting either Hb M or a deficiency of the NADH-cytochrome b5 reductase (cytb5r) enzyme. Measurement of the cytb5r enzyme activity of this patient indicated a reduced level of 7.3 IU/g Hb (normal range 11.5-26.9 IU/g Hb). Sequencing the DIA 1 gene that encodes cytb5r revealed a novel C403T base change, predicting a proline to serine change at codon 144. This amino-acid change is not located in the enzyme's active site and does not cause loss of function. Instead it results in reduced stability of the enzyme and development of the less severe or Type I form of recessive congenital methaemoglobinaemia. The infant was started on daily ascorbic acid treatment. She has very mild cyanosis and normal growth and developmental parameters on follow-up at 10 months of age.

s-Thalidomide has proven efficacy in multiple myeloma. Although it has both antiangiogenic and pro-apoptotic effects, its primary mode of therapeutic action remains unclear. We have investigated the changes to the expression of genes involved with these cellular processes following culture with s-thalidomide in the U266 MM cell line. Cells were cultured with s-thalidomide (0-1000 microM), and cell parameters, including apoptosis, were assessed on day 3. RNA was extracted from cells cultured for 24 h at the IC(50) concentration of s-thalidomide, and changes to gene expression were investigated by microarray methodologies. A reduction in cell viability was observed in U266 cells cultured with s-thalidomide (IC(50): 362 microM), which were mirrored by significant increases in apoptosis (for example, 200 microM on day 3: 40.3+/-3.1% vs. 3.2+/-0.4% on day 0; P<0.001). There were changes in the expression profile of genes involved in angiogenesis and apoptosis, but the changes were most dramatic in the apoptotic genes. In particular, the expression of I-kappaB kinase was decreased by two-fold, which was associated with a four-fold decrease in NF-kappaB expression. These data correlated with immunoblotting analyses, which showed significant increases in I-kappaB protein levels and decreased NF-kappaB activity. Additionally, the Bax : Bcl-2 ratio was significantly increased. Our data suggest that both angiogenic and apoptotic genes and proteins are affected by s-thalidomide. Additionally, a dramatic decrease in Bcl-2 expression with s-thalidomide suggests a possible enhancement of cytotoxic effect if combined with other cytotoxic agents.

Introduction: There is a growing demand for autologous stem cell transplantation (ASCT) in newly diagnosed patients with multiple myeloma (MM), resulting in an increasing pressure on available hospital beds. In addition, more rational utilization of health resources should induce physicians to attempt therapeutic strategies aiming at reduction of costs. The aim of this study was to explore the feasibility and safety of performing ASCT on an outpatient basis, according to an early discharge method.

Materials and methods: A total of 28 patients affected by MM and in complete or partial remission were selected to receive ASCT on an outpatient basis. In particular, after conditioning with high-dose melphalan and stem cell infusion, patients were programmed to go home and to be rehospitalized in the case of febrile neutropenia or other severe toxicities.

Results: All patients accepted the outpatient-based procedure. Out of 28 patients. 18 (64%) did spend the aplastic phase entirely at home following high-dose chemotherapy and stem cell infusion. A second hospital admission was required in 10 patients (36%). Febrile neutropenia and severe mucositis needing total parenteral nutrition were the most frequent causes of hospitalization. However, there were no documented infections and either fever or mucositis was easily resolved at the time of hematopoietic recovery in all patients.

Conclusion: ASCT on an outpatient basis is feasible and safe in patients with MM. More than 60% of patients are manageable at home, provided that a caregiver is available.

The aim of this study was simultaneously to evaluate the potential influence of cytogenetic, immunophenotypic and cell culture studies in the evolution of the myelodysplastic syndromes (MDS) with particular attention to the value of the two latter features in predicting the outcome of those patients in which karyotypic information is normal or not available. A series of 77 newly diagnosed patients with primary MDS were analyzed. Immunophenotypic studies were carried out by flow cytometry in triple color combinations: CD34/CD33/CD38, CD15/CD34/HLADR and HLADR/CD13/CD45. In all, 63% of patients showed a normal karyotype and 37% showed clonal abnormalities. In immunophenotypic analysis, overall 90% of patients displayed phenotypic aberrations and 60% showed two or more aberrations. In univariate analysis, 10 variables had a significant influence on survival: >10% bone marrow (BM) blast cells, >or=peripheral blood (PB) cytopenias, >2% of BM CD34+ cells, >85% of BM myeloid cells, >7% monocytic cells, <49% of neutrophils, a neutrophil/monocytic cell ratio <7, more than three phenotypic aberrations and >80 colony-forming units for granulocytes and macrophages (CFU-GM)/10(5) plated cells. Only the presence of >or=5% of BM blast cells (P=0.001) and cytogenetic subgroups (P=0.008) showed independent prognostic significance by multivariate analysis. In patients lacking cytogenetic information or in which the karyotype was normal additional markers had an independent prognostic value in multivariate analysis: >or=2 phenotypic aberrations (P=0.001) and >or=2 PB cytopenias (P=0.004). In summary, our results show that in patients in whom the karyotype is normal or where an insufficient amount of mitoses is obtained, immunophenotype could help to establish a prognosis.

Venous thromboembolism is a common problem in cancer patients. It complicates both the surgical management of those with cancer and has been associated with varying risk for the development of clinical thromboembolism in patients receiving chemotherapy. Unfractionated and low-molecular-weight heparin have been validated both in terms of their efficacy and safety, in the prevention of venous thromboembolic disease in cancer patients undergoing surgical intervention and for the primary treatment and secondary prevention of recurrent venous thromboembolism. Beyond their uses in the prevention and treatment of thrombosis, low-molecular-weight heparins have recently been shown to prolong survival in patients with solid tumour malignancy.

This report summarizes current transplant activity in Europe. It is based on the activity survey of the European Group for Blood and Marrow Transplantation (EBMT). Introduced in 1990, the survey captures the annual numbers of hematopoietic stem cell transplantation (HSCT) by indication, donor type and stem cell source from each individual European transplant team. Supplemented by demographical data and economical factors, team density and transplant rates can be calculated, and the impact of economics on HSCT rates can be assessed. As documented in the present analysis, in the year 2002, a total 20 207 HSCT were performed on new patients in Europe by 586 teams in 39 countries: 6915 being allogeneic and 13 292 autologous HSCT. The main indications for allogeneic HSCT were leukemias, lymphoproliferative disorders and non-malignant diseases; main indications for autologous HSCT were lymphoproliferative disorders, solid tumors and leukemias. The main source of stem cells were peripheral blood (96%) for autologous, peripheral blood (62%) and bone marrow (38%) for allogeneic HSCT. On the basis of its completeness, the EBMT activity survey presents a rapid description of the status quo, assessment of trends and determination of factors influencing transplant rates. As such, it provides up-to-date information for patients, treating physicians and health-care officials.