The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid ...leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.
Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically ...support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.
Research shows that persons with mild to moderate multiple sclerosis are less physically active than healthy controls even though they would benefit from it. This study focusses on the feasibility ...testing and process evaluation of the pilot study of Activity Matters, a twelve-week web-based program, from Ireland, to increase physical activity in this population.PURPOSEResearch shows that persons with mild to moderate multiple sclerosis are less physically active than healthy controls even though they would benefit from it. This study focusses on the feasibility testing and process evaluation of the pilot study of Activity Matters, a twelve-week web-based program, from Ireland, to increase physical activity in this population.The intervention was adapted to local circumstances in Hamburg, Germany and consists of eleven modules incorporating behavior change techniques. After feasibility had been confirmed, 43 persons with multiple sclerosis participated in a pilot study with a pre-post, single-group intervention design. Qualitative data was collected with questionnaires and semi structured interviews. Physical activity level and stage of change was measured quantitatively.MATERIALS AND METHODSThe intervention was adapted to local circumstances in Hamburg, Germany and consists of eleven modules incorporating behavior change techniques. After feasibility had been confirmed, 43 persons with multiple sclerosis participated in a pilot study with a pre-post, single-group intervention design. Qualitative data was collected with questionnaires and semi structured interviews. Physical activity level and stage of change was measured quantitatively.Participants had a mean age of 49.5 years (SD 9.29) and an average Patient Determined Disease Step Score of 2.2 (SD 1.47). Thirty-six participants answered the follow-up questionnaire. On average 9.8 modules were processed within 13 weeks. Each tool for behavior change was perceived as helpful except the chat group. Physical activity levels increased significantly from pre- to post intervention (p-value 0.042, Cohen's d = 0.35).RESULTSParticipants had a mean age of 49.5 years (SD 9.29) and an average Patient Determined Disease Step Score of 2.2 (SD 1.47). Thirty-six participants answered the follow-up questionnaire. On average 9.8 modules were processed within 13 weeks. Each tool for behavior change was perceived as helpful except the chat group. Physical activity levels increased significantly from pre- to post intervention (p-value 0.042, Cohen's d = 0.35).The results indicate that Activity Matters is feasible and satisfactory and may change activity levels.CONCLUSIONSThe results indicate that Activity Matters is feasible and satisfactory and may change activity levels.
Patients with AML or myelodysplastic syndrome who relapse after allo-SCT have a poor prognosis. In the search for novel treatment strategies for these patients, we conducted a multicenter ...retrospective analysis and identified 22 patients treated with the DNA-methylation inhibitor 5-azacytidine (5-Aza). Patients received a median number of two cycles 5-Aza (range 1-8) at a dose of 100 mg/m(2) over 5 days following relapse. Eighteen patients (82%) also received a median number of two donor lymphocyte infusions (DLI, range 1-5). Sixteen patients (72%) responded to 5-Aza treatment and five patients (23%) achieved a CR. 5-Aza-induced CR lasted for 433 days (median, range 114-769). Median survival and the estimated 2-year survival rate were 144 days and 23%, respectively. Acute GVHD after DLI was seen in six patients (33%) and four of these patients developed chronic GVHD of the skin. There were no treatment-related deaths. Patients who achieved halving of leukocyte counts after the first 5-Aza cycle had a superior median survival of 802 days compared with 135 days (P=0.0025) in all other patients. On univariate analysis, the achievement of this halving of leukocyte counts was identified as a significant predictor of survival.
The past and future evolution of atmospheric composition and climate has been simulated with a version of the Max Planck Institute Earth System Model (MPI-ESM). The system consists of the atmosphere, ...including a detailed representation of tropospheric aerosols, the land surface, and the ocean, including a model of the marine biogeochemistry which interacts with the atmosphere via the dust and sulfur cycles. In addition to the prescribed concentrations of carbon dioxide, ozone and other greenhouse gases, the model is driven by natural forcings (solar irradiance and volcanic aerosol), and by emissions of mineral dust, sea salt, sulfur, black carbon (BC) and particulate organic matter (POM). Transient climate simulations were performed for the twentieth century and extended into the twenty-first century, according to SRES scenario A1B, with two different assumptions on future emissions of carbonaceous aerosols (BC, POM). In the first experiment, BC and POM emissions decrease over Europe and China but increase at lower latitudes (central and South America, Africa, Middle East, India, Southeast Asia). In the second experiment, the BC and POM emissions are frozen at their levels of year 2000. According to these experiments the impact of projected changes in carbonaceaous aerosols on the global mean temperature is negligible, but significant changes are found at low latitudes. This includes a cooling of the surface, enhanced precipitation and runoff, and a wetter surface. These regional changes in surface climate are caused primarily by the atmospheric absorption of sunlight by increasing BC levels and, subsequently, by thermally driven circulations which favour the transport of moisture from the adjacent oceans. The vertical redistribution of solar energy is particularly large during the dry season in central Africa when the anomalous atmospheric heating of up to 60 W m^sup -2^ and a corresponding decrease in surface solar radiation leads to a marked surface cooling, reduced evaporation and a higher level of soil moisture, which persists throughout the year and contributes to the enhancement of precipitation during the wet season.PUBLICATION ABSTRACT
We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts ...of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.
Abstract The fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) can be found in about one quarter of patients with acute myeloid leukemia (AML) Small D. FLT3 mutations: biology and ...treatment. Hematology Am Soc Hematology. Educ. Program 2006;178–84 Review. Patients who carry this mutation have a high risk of relapse even after allogeneic stem cell transplantation Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J 2003;4:41–6; Meshinchi S, Arceci RJ, Sanders JE, Smith FO, Woods WB, Radich JP, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood 2006;108(1):400–1. Recent reports show that Sorafenib, a multikinase inhibitor has significant activity against FLT3-ITD+ blasts in vitro Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007;21(3):439–45. We here report the first clinical case of molecular remission induced by Sorafenib in a patient with FLT3-ITD+ AML and extramedullary disease after allogenic stem cell transplantation.
In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with ...normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.
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