UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes (MDS) was evaluated by measuring the in vitro response of primitive (BFU-E) and relatively mature (CFU-E) erythroid progenitors from 12 patients and from eight healthy donors to recombinant human erythropoietin (rhEPO), and by quantifying relationships between circulating EPO levels and progenitor cell frequencies in MDS marrow. Half-maximal growth of MDS CFU-E and BFU-E was detected at a 4-fold higher rhEPO concentration than required by control erythroid progenitors. Nine of the patients evaluated exhibited maximal growth of erythroid colonies at 5- to 20-fold higher than control saturating rhEPO concentrations. Circulating EPO levels in MDS patients were elevated, with a mean value approximately 35-fold higher than that of controls. The frequency of MDS marrow CFU-E and BFU-E was 57 +/- 42% and 18 +/- 9% of the mean control values, respectively. Correlation analysis of the relationships between MDS EPO levels and erythroid progenitors indicated that the anemia in MDS is not attributable to an abnormality in the capacity of EPO to induce the generation of CFU-E, but may be influenced by the BFU-E population, whose severe deficiency results in insufficient influx of EPO-responsive cells. Our findings therefore suggest that treatment of MDS patients with rhEPO may be of limited benefit, since the generation of BFU-E from more primitive ancestors and the initial growth requirements of these cells are not under the regulatory influence of this hormone.
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PMID:In vitro studies of erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes. 223 91

Hexamethylene bisacetamide (HMBA; NSC 95580) is a potent polar-planar differentiating agent of leukemia and solid tumor cell lines in vitro at clinically achievable concentrations. HMBA is currently being studied in patients with myelodysplastic syndrome. Previous phase I trials have demonstrated that HMBA produces hematologic toxicity in morphologically normal bone marrows of patients with solid tumors. Because of concern that HMBA may produce more severe myelotoxicity in patients with myelodysplastic syndrome since these patients have limited hematopoietic reserves, we studied the effects of HMBA on myelodysplastic and normal hematopoietic progenitors in vitro. HMBA concentrations that are optimal for differentiation in vitro (2 to 5 mmol/L) and HMBA concentrations that are being achieved in clinical trials (1 to 2 mmol/L) inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units from all 15 patients with myelodysplastic syndrome and all 4 normal subjects, HMBA did not induce proliferation of myelodysplastic or normal progenitors at any concentration; rather, it produced nearly identical inhibition of normal and myelodysplastic hematopoietic progenitors. HMBA also produced quantitatively similar inhibition of clonogenic leukemic growth of two myeloid leukemia cell lines. For a differentiating agent to be effective, it will likely have to either produce both differentiation and proliferation of abnormal hematopoietic progenitors or show selective inhibitory effects on abnormal as compared with normal progenitors. Although the mechanisms responsible for the antiproliferative effects of HMBA cannot be determined from this study, similar inhibitory effects of HMBA on normal and abnormal hematopoietic progenitors suggest that HMBA may be of limited utility in producing and sustaining elevations of peripheral blood cell counts in patients with myelodysplastic syndrome.
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PMID:Effects of the differentiating agent hexamethylene bisacetamide on normal and myelodysplastic hematopoietic progenitors. 225 Mar 14

We have used the monoclonal antibodies 2A4 (specific for the H subunit of human ferritin) and LO3 (specific for the L subunit) for immunocytochemical detection of ferritin in bone marrow and peripheral blood cells from normal subjects and patients with various haematological disorders. Formalin-fixed slides were stained by the immunoalkaline phosphatase procedure (APAAP). In normal subjects, ferritin could be found only in bone marrow smears and appeared to be largely confined to erythroid precursors and reticuloendothelial cells. The more immature erythroid precursors contained higher concentrations of cellular ferritin. Although evaluation could be only semiquantitative, erythroblast ferritin appeared to be more reactive with the monoclonal 2A4 (15 +/- 7% positive erythroblasts) than with the monoclonal LO3 (6 +/- 5% positive erythroblasts), indicating that H-type ferritin was predominant, particularly in proerythroblasts and basophilic erythroblasts. By contrast, the ferritin present in reticuloendothelial cells appeared to be predominantly of L-type. Patients with iron deficiency showed low levels of positive erythroblast, whereas the reverse was true in patients with transfusional iron overload. Intense positivity for reticuloendothelial cell ferritin was found in patients with anaemia of chronic disease. In myelodysplastic syndromes and acute myeloid leukaemia (AML), ferritin positivity was generally very strong at any stage of erythroblast development, particularly with the monoclonal antibody 2A4. Perls-positive perinuclear granules of ring sideroblasts were not stained, confirming that mitochondrial iron deposition is not in the form of ferritin. In AML and myelodysplastic syndromes with excess of blasts, ferritin could be detected also in immature myeloid cells. These data indicate that: (a) in normal conditions ferritin is mainly expressed in red cell precursors and reticuloendothelial cells, and this is in keeping with the peculiar role of these cells in iron metabolism; (b) abnormal cell ferritin contents can be observed in both iron overload and malignancy.
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PMID:Immunocytochemical detection of ferritin in human bone marrow and peripheral blood cells using monoclonal antibodies specific for the H and L subunit. 226 53

The nosography of the dyserythropoietic syndromes remains poorly defined in the field of clinical hematology. The prominent pathophysiologic feature lies in the "ineffective erythropoiesis" as expressed by bone marrow erythroid hyperplasia with dysplasia accompanied by a normal or only slightly increased reticulocyte count. Both erythrokinetics and ferrokinetics are impaired, as shown by either slight reduction of the red cell survival or marked increased rate of serum iron transport together with reduced cellular iron utilization. The dyserythropoietic syndromes can be classified as acquired, secondary or congenital. The acquired ones, especially the sideroblastic forms, belonging to the myelodysplastic syndromes, are typical of the elderly whereas the congenital are of childhood. Their treatment is still a matter of controversy. However, the employment of folic acid, Vit. B12, pyridoxine and androgens can be useful in selected cases. In case of severe anemia, blood transfusion are required in association with iron chelating agents. However, some biological molecules, such as erythropoietin, interleukins 3 and 4, hemopoietic growth factors (especially GM-CSF), could represent future prospects of treatment.
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PMID:[Dyserythropoietic syndromes: incidence, diagnosis, therapy]. 229 Oct 9

Ineffective erythropoiesis is an early feature of the myelodysplastic syndromes (MDS), usually accompanying an hypercellular marrow. In a previous study, concentrations of serum erythropoietin (EPO) in MDS have been shown to correlate inversely both with haemoglobin concentration and with % bone marrow erythroblasts. We have measured erythroid production using a radioisotopic technique in 20 patients with MDS. Although haemoglobin concentration shows a weak inverse relationship with serum EPO concentration there is considerable variation in EPO concentration at a given haemoglobin level. There is no correlation between serum EPO and total erythroid production, though there is a weak correlation with effective erythropoiesis. The data suggests that control mechanisms of erythropoiesis in patients with MDS are complex.
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PMID:Serum erythropoietin and erythropoiesis in patients with myelodysplastic syndromes. 230 17

Fourteen children with a primary myelodysplastic syndrome (MDS) were seen at this center over a 10-year period. Six of the patients, including two pairs of siblings, had a monosomy 7 population in their bone marrow. Seven patients had the clinical and laboratory features of "juvenile chronic myeloid leukemia." Three patients could be considered to have either the monosomy 7 syndrome or "juvenile chronic myeloid leukemia," indicating that these two entities are not mutually exclusive. All patients fulfilled the French-American-British (FAB) criteria for a myelodysplastic syndrome. Clonal chromosomal abnormalities were detected in 13 of the 14 patients, and consistently involved either monosomy 7, multiple abnormalities, and/or multiple clones. Hematopoietic progenitor assays of blood and marrow samples obtained from most patients showed abnormal progenitor frequencies, or differentiation patterns in culture (or both), often affecting the erythroid as well as the granulopoietic lineages. In particular, granulopoietic progenitors from four to six patients in the "juvenile chronic myeloid leukemia" category generated predominantly abnormal appearing macrophage colonies. Clinical outcomes were poor with rapid transformation to acute myeloid leukemia in most patients. All treated patients responded poorly to conventional chemotherapy, although in two cases remission was achieved with intensive therapy and allogeneic bone marrow transplantation. Childhood myelodysplasia includes a group of diseases that are clinically heterogeneous, and current terminology is confused and inconsistent. Until a better understanding of the biologic and molecular basis of these diseases is obtained, it is proposed that the use of the FAB categories developed for adult MDS might help to improve diagnostic precision and therapeutic comparisons.
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PMID:Childhood myelodysplasia: suggested classification as myelodysplastic syndromes based on laboratory and clinical findings. 230 81

On cytological bone marrow examination we distinguished between pure sideroblastic anaemia (PSA), which is confined to dyserythropoiesis, and refractory anaemia with ring sideroblasts (RARS), which is characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a follow-up study of 94 patients with AISA diagnosed according to FAB criteria for myelodysplastic syndromes we found a striking difference in the risk of leukaemic transformation between PSA and RARS (5 year cumulative rate 1.9% v. 48%). Overall survival was much better in PSA than in RARS (5 year cumulative chance 69% v. 19%). Infections and haemorrhages were frequent causes of death in RARS but not in PSA. Bone marrow culture studies (CFU-GM) were performed on 10 consecutive patients with PSA and RARS, respectively. RARS patients showed grossly impaired colony growth, typical of the myelodysplastic syndromes. Patients with PSA had persisting colony formation, even if moderately decreased in frequency, with numbers of CFU-GM being inversely correlated with the degree of erythroid hyperplasia in the bone marrow. We conclude that on cytomorphological grounds AISA can be divided into pure (dyserythropoietic) sideroblastic anaemia (PSA) and a true myelodysplastic form (RARS), with both types differing considerably in terms of survival, risk of leukaemic transformation and findings on bone marrow culture (CFU-GM).
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PMID:Two types of acquired idiopathic sideroblastic anaemia (AISA) 227 59

Clinical features, as well as morphology, immunophenotype and cytogenetics were retrospectively studied in 20 patients with an original diagnosis of erythroleukaemia (EL) reclassified according to the FAB criteria. Fifteen patients had de novo EL, five patients had therapy-related EL. Myelodysplasia preceded the onset of EL in eight cases and myelodysplastic features involving multiple haemopoietic lineages were observed at leukaemia presentation in all cases. Immunologic findings confirmed multilineage involvement, showing sub-population of cells expressing platelet-associated markers in more than 50% of cases tested and the presence of a myelomonocytic component, besides glycophorin A-positive cells. Cytogenetically, major karyotype aberrations (MAKA), defined by the presence of three or more aberrant events in the same clone, were observed in 14 cases, minor karyotype aberrations (MIKA) were observed in four cases and normal karyotype in two cases. No differences in the cytological-cytogenetic picture of our patients with de novo EL, and with therapy-related EL were found suggesting that aetiological factors and/or pathogenetic mechanisms common to EL and secondary leukaemia may exist. All patients with MAKA had leftward shift of erythropoiesis with proerythroblasts and basophilic erythroblasts usually representing more than 50% of all erythroid cells. In patients with MIKA or normal karyotype, maturatio of erythroid cells, though morphologically abnormal, was quantitatively preserved and early erythroblasts never exceeded 25% of erythroid cells. Clinically, the haemoglobin level at presentation, as well as in the proportion of patients achieving complete remission after chemotherapy, appeared to be lower in the maturation arrest-MAKA group as compared to the preserved maturation-MIKA/normal karyotype group. Median survival was shorter in the former group (3.5 months) than in the latter (median 13 months). Morphologic-immunologic-cytogenetic studies thus allow for the identification of two distinct cytogenetic-clinicopathological types of EL.
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PMID:Morphologic, immunologic and cytogenetic studies in erythroleukaemia: evidence for multilineage involvement and identification of two distinct cytogenetic-clinicopathological types. 238 68

The haematopoietic microenvironment or stroma plays a decisive role for the proliferation and differentiation of haemopoietic cells. We studied if bone marrow cells from patients with myelodysplastic syndromes (MDS) and acute nonlymphocytic leukaemias (ANLL) are altered in their ability to form adherent stromal layer with active haemopoiesis in the Dexter liquid culture. Bone marrow cells were obtained from 24 normal volunteers, 28 patients with ANLL in different stages of the disease and 9 patients with MDS. There are no differences between the stromal layers of patients with ANLL in complete remission and those of normal volunteers after two weeks of cultivation. However, bone marrow cells from patients with ANLL before treatment and from patients in relapse formed a poor adherent stromal layer in most cases. In 6 of 9 cases we found the normal stromal grade of bone marrow cells from patients with MDS. There were qualitative differences in the nonadherent cell population between normal and ANLL patients in complete remission. In most cases we found morphologically recognizable erythroid cells after two-weeks Dexter liquid culture of bone marrow cells from patients with ANLL in complete remission, which were not seen with normal volunteers. This could be an indication of harmful effects on the balance of haematopoiesis caused by previous infiltration with leukaemic cells or/and high-dose chemotherapy.
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PMID:Bone marrow stromal culture from patients with myelodysplastic syndromes and patients at different stages of acute nonlymphocytic leukaemia. 247 21

Regulation of haemopoiesis in the marrow of patients with myelodysplastic syndromes (MDS) was evaluated by assaying (1) the production of haemopoietic regulators acting upon multipotent and committed progenitors by MDS marrow cells, and (2) the responsiveness of MDS marrow progenitors to stimulation with granulocyte colony-stimulating factor (G-CSF). The levels of multipotent progenitor cell colony-stimulating activity (CFU-GEMMCSA) in 7 d bone marrow-conditioned medium (BMCM) from MDS patients were markedly reduced as compared to controls. MDS BMCM also exhibited reduced levels of burst-promoting activity (BPA) for primitive erythroid (BFU-E) progenitors. Both CFU-GEMMCSA and BPA detected in BMCM were completely neutralized by antibodies directed against interleukin-3. MDS BMCM exhibited markedly reduced levels of murine-active CSA. This activity was partially neutralized by anti-CSF-1 antibodies. Levels of regulators in BMCM of refractory anaemia (RA), sideroblastic anaemia. RA with excess blasts, and chronic myelomonocyte leukaemia were virtually the same. CFU-GEMM and BFU-E growth in MDS marrow (n = 9) was markedly reduced. A 5-fold saturating dose of G-CSF induced an approximately 2-fold increase in CFU-GEMM in four of eight MDS and a 1.5-fold increase of BFU-E in five of nine MDS, but not in control (n = 5) marrow cell cultures. Impaired haemopoiesis in MDS marrow may be related to abnormalities both in regulator production by marrow accessory cells and in regulator responsiveness of multipotent and committed progenitors.
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PMID:Regulatory abnormalities in the marrow of patients with myelodysplastic syndromes. 247 8

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