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

This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony-stimulating factor (GM-CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes. Mean production of GM-CSF was much lower than in controls, without significant differences among different subtypes. Mean production of TNF was similar in MDS patients and in controls, but noteworthy differences were observed between patients with RA, RAEB and RAEB-t and patients with RARS and CMML. Growth of bone marrow granulocyte macrophage and erythroid progenitors did not correlate with TNF and GM-CSF production, although in MDS subtypes with higher GM-CSF levels, colony growth was slightly higher than in subtypes with lower GM-CSF production.
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PMID:Producton of tumor necrosis factor and granulocyte colony stimulating factor by bone marrow accessory cells in myelodysplastic patients. 859 33

We performed a retrospective analysis of 143 consecutive patients with myelodysplastic syndrome to study the possible relationship between patient age and cytogenetic findings in this disorder. There were 96 men and 47 women, with a mean age of 63 years. Eighty-six patients were 63 years old and above, and 57 patients were younger than 63 years of age. The distributions of the five FAB subtypes were comparable in both groups of patients, except for a higher percentage of refractory anemia with ringed sideroblasts in older patients. The incidences of cytogenetic abnormalities were similar in the two groups. However, the younger patients tended to have a higher frequency of involvement of chromosomes 5 or 7 than the elderly patients (p < 0.05). The implications of our findings in relation to the biology of myelodysplastic syndrome are discussed.
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PMID:The relationship between age and karyotypic abnormalities in myelodysplastic syndromes. 863 Sep 86

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous clonal bone marrow disorders leading to peripheral cytopenia(s) and hypercellular marrow in the majority of the patients. The morphology of the cell lines is characterized by dysplastic features in some or all cell lines. The FAB classification has divided MDS in five subgroups, namely (1) RA (refractory anemia); (2) RARS (refractory anemia with ring sideroblasts); (3) CMML (chronic myelomonocytic leukemia); (4) RAEB (refractory anemia with excess blasts); and (5) RAEB-T (refractory anemia with excess blasts in transformation). Myelodysplastic syndrome remains primarily a disease of the elderly. With a reported median age of 74.4 years, patients have a chronic relentless course with complication of cytopenias, and a significant number of MDS patients, especially from the RAEB and RAEB-T categories, end up in acute myeloid leukemic transformation. Cytogenetic abnormalities are present in 40-58% of the cases and can provide not only help in diagnosis, but also understanding regarding the clinical course and prognostic aspect. Management of MDS is quite pragmatic and at this stage far from satisfactory. Various modalities have included use of differentiating agents, aggressive chemotherapy, bone marrow transplant and, more recently, significant interest has been generated in the use of hematopoietic growth factors. Differentiating agent trials have been unrewarding so far; chemotherapy trials have resulted in less benefit and more early toxic deaths, especially in the elderly MDS patients where the disease predominates. Bone marrow transplant appears suitable for some patients who are at a younger age. Salvation from this disease is being searched in the proper usage of hematopoietic growth factors and cytokines. There has been concern, however, that usage of growth factors has led to early and enhanced transformation of these patients to frank acute leukemic states. This concept appears to be somewhat refuted by newer controlled trials with GM-CSF and G-CSF, emphasizing that the acute leukemic transformation is the natural course of the disease and is not hastened by growth factor use. Preliminary studies are also suggesting that a combination of growth factors, especially G-CSF and erythropoietin as compared to chemotherapies, could be more beneficial in prolonging the survival of MDS patients who have progressed to the acute leukemic phase. More studies are needed for the understanding of the pathogenetic mechanism(s) in order to facilitate a more suitable and appropriate management strategy for MDS.
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PMID:Myelodysplastic syndromes in the elderly: the role of growth factors in management. 863 15

The human erythropoietin receptor (EpoR) gene has been cloned and characterized. Very few EpoR genetic abnormalities have been reported so far. Polycythemia vera (PV) is characterized by low/normal serum erythropoietin (Epo) levels with proposed Epo hypersensitivity. Myelodysplastic syndromes (MDS) are characterized by refractory anemia with variable serum Epo levels. Several reports have suggested EpoR abnormalities in both types of stem cell disorders. We analyzed DNA obtained from peripheral blood mononuclear cells of seven healthy controls, 20 patients with myeloproliferative disorders (MPD, 11 patients with PV, five agnogenic myeloid metaplasia with myelofibrosis, four essential thrombocytosis) and eight patients with refractory anemia with ringed sideroblasts (RARS), an MDS variant. The DNA was digested with four restriction enzymes (BamHI, Bgl II, Sacl and HindIII), followed by Southern blot, using a 32P radiolabeled probe, containing 1.5 kb of the human EpoR cDNA. All 20 MPD patients and seven out of the eight MDS patients demonstrated a restriction pattern which was identical to the seven normal controls, as well as to the erythroid cell line K562, and also consistent with the expected restriction map, for all four enzymes tested. One RARS patient had a normal pattern with three enzymes but a different one with HindIII. The HindIII 12 kb large band was replaced by a faint 12 kb band and a new (about 9 kb) band appeared. The EpoR restriction map and the normal pattern obtained with the other three enzymes suggest that this patient has a 3 kb upstream deletion in one allelic EpoR gene. The same molecular pattern was detected in the patient's sister, who suffers from anemia with mild bone marrow (BM) dyserythropoiesis and plasmacytosis. Northern blot analysis showed that the patient's BM RNA carried normal EpoR message. This familial pattern may represent polymorphism. However, the patient's very high serum Epo level, her resistance to treatment with recombinant Epo, and the abnormally low growth rate of in vitro erythroid cultures, suggesting poor response to Epo in this MDS patient as well as the hematological abnormalities in her sister, support the speculation that the different EpoR gene might serve as a genetic predisposing marker and potentially could be involved (probably via post-transcriptional mechanisms and by an interaction with other factors or cytokines) in the pathogenesis. Our data suggest that the EpoR is intact in MPD and in most patients with RARS. One RARS patient had a familial different genetic structure, which could represent polymorphism. However, we can speculate also that it might be involved in the pathogenesis of the disease.
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PMID:Analysis of the erythropoietin receptor gene in patients with myeloproliferative and myelodysplastic syndromes. 870 17

We retrospectively reviewed 62 MDS patients (15 RA, 3 RARS, 10 CMML, 20 RAEB, 14 RAEBT) to clarify the current problems in their management. Median survival of RA and RARS patients was 67.9 months and significantly longer than that of CMML, RAEB, or RAEB-T patients with median survivals of 16.1, 16.8, and 9.5 months, respectively. Karyotypic abnormalities were observed in 58% of the patients examined. Forty-two patients died, 16 (38%) of leukemic transformation and 21(50%) of bone marrow failure. While most of the RAEB-T patients of all ages and all the RAEB patients diagnosed below 60 years of age died of transformation, 70% of the older RAEB patients died of infection. Prognosis after transformation was poor and 12 patients died within two months. These results indicate that management after transformation and treatment against infection in RAEB patients with advanced age are crucial to improve the prognosis in MDS.
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PMID:Prognostic implications in myelodysplastic syndromes: A review of 62 cases. 917 14

Apoptosis of hematopoietic progenitor cells is increased in myelodysplastic syndromes (MDS). We have studied Fas (CD95/Apo-1) antigen expression in 27 MDS patients (RARS 4, RA 3, RAEB 13; RAEB-t 3, CMML 4) and three AML secondary to MDS. We found that the Fas antigen was not expressed on normal bone marrow (BM) CD34+, CD14+, or glycophorin+ cells, and only slightly on CD33+ cells. Patients with MDS had upregulation of Fas expression on total bone marrow nuclear cells (BMMC) (t-test, P = 0.04), CD34+ (P = 0.013), CD33+ (P = 0.04), and glycophorin+ (P = 0.032) BM cells compared to controls. Fas expression did not correlate to the FAB subtype, the Bournemouth score, or to peripheral cytopenias. However, Fas expression intensity on CD34+ cells negatively correlated to the BM blasts number (Spearman, P = 0.01) suggesting that leukemic blasts cells lose Fas antigen expression with progression of myelodysplasia. Using both proliferation assays in liquid cultures and clonogenic progenitor assays in the presence of an agonist anti-Fas MoAb (CH11), we showed that the Fas protein was functional in some patients. Dose-dependent inhibition of DNA synthesis was observed in three out of seven patients studied. CFU-GM and BFU-E colonies suppression in some patients suggested that Fas can induce apoptosis in myeloid and erythroid BM progenitors of MDS patients. The TUNEL technique on BM smears gave a mean of 12.6% +/- 2.5 of bone marrow apoptotic cells in five controls. Patients with MDS had increased bone marrow apoptosis (mean 39% +/- 5.7, t-test, P = 0.012). Four out of 15 (26%) patients studied with a sensitive radiolabeled DNA ladder technique had typical DNA ladders indicative of advanced stages of apoptosis. Massive BM suicide was observed in patients with RA (2/2) and RAEB (8/11), whereas apoptosis rates were normal or low in patients with RAEB-t (3/3) or secondary AMLs (3/3). Moreover, high rates of apoptosis correlated to low Bournemouth score (Spearman, P = 0.01). No statistical correlation could be found between Fas expression and apoptosis rates. Our results confirm the importance of programmed cell death in MDS. The Fas antigen is clearly upregulated on BM cells, but its role in the pathophysiology of apoptosis in myelodysplasia is still unclear, indicating that many factors positively or negatively interfere with the Fas-mediated pathway of apoptosis in vivo and in vitro.
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PMID:Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. 917 38

By application of morphological and ultrastructural methods for identification of apoptosis, we analyzed the incidence of morphologically evident apoptosis in the bone marrow of 30 patients with myelodysplastic syndrome (MDS), and in the bone marrow of 12 healthy individuals. According to FAB classification, out of 30 patients, eight (26.6%) had refractory anemia, three (10%) had refractory anemia with ringed sideroblasts, 14 (46.6%) had refractory anemia with excess of blasts and two (6.8%) had refractory anemia with excess of blasts in transformation. Three patients (10%) had chronic myelomonocytic leukemia. Cells in apoptosis were examined on semithin slides and expressed as the apoptotic index (AI) (percent counted on at least 1000 cells). An overall increase in apoptosis in patients with MDS was found (median AI in patients vs controls, 3.13% vs 1.05%, P < 0.01 by Mann-Whitney U test). Also, negative correlation between AI and white blood cell count was found (linear r= -0.53, or Spearman rank R= -0.52, both P < 0.01). In patients with evident karyotype changes AI was not higher than in patients with normal karyotype. This suggests that discrete alterations in apoptosis are present even in karyotypically 'normal' clones. Our results strongly support the hypothesis that apoptosis has a role in ineffective hematopoiesis and may be a mechanism responsible for the paradox of hypercellular bone marrow and peripheral blood pancytopenia in MDS.
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PMID:Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment. 918 Feb 88

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5' CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5' CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.
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PMID:Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. 926 57

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/microL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16, 000 to 110,000/microL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses </=200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.
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PMID:Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. 1153 40

Previous studies have shown that approximately 40% of patients with myelodysplastic syndrome (MDS) and anaemia respond to treatment with human recombinant granulocyte-CSF (G-CSF) plus erythropoietin (epo). The present study was designed to investigate pre-treatment variables for their ability to predict erythroid responses to this treatment. 98 patients with MDS (30 RA, 31 RARS, 32 RAEB, five RAEB-t) were treated with a combination of G-CSF (0.3-3.0 microg/kg/d, s.c.) and epo (60-300 U/kg/d, s.c.) for at least 10 weeks. Minimum criteria for erythroid response was a 100% reduction of red blood cell (RBC) transfusion need or an increase in haemoglobin level of > or = 1.5 g/dl. 35 patients (36%) showed responses to treatment. Medium duration of response was 11-24 months. In multivariate analysis, serum erythropoietin levels and initial RBC-transfusion need retained high statistical significance (P < 0.01). Using pre-treatment serum epo levels as a ternary variable (< 100, 100-500 or > 500 U/l) and RBC transfusion need as a binary variable (< 2 or > or = 2 units per month), the analysis provided a predictive score for erythroid response. This score divided patients into three groups: one group with a high probability of erythroid responses (74%), one intermediate group (23%) and one group with poor responses to treatment (7%). This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS, both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospective trials.
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PMID:Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. 937 52


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