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PubMed1993

[Ferrokinetics and bone marrow scanning in patients with myelodysplastic syndrome, hypoplastic myelodysplastic syndrome and aplastic anemia].

Ferrokinetic measurement were performed in a total of 48 patients with myelodysplastic syndrome (MDS), 13 with hypoplastic MDS and 25 with aplastic anemia (AA). Forty seven % of patients with hypoplastic MDS progressed to acute leukemia, however none of the patients with AA progressed to acute leukemia. Sixty-nine% of the patients with MDS showed increased erythron transferrin uptake (ETU) caused by ineffective erythropoiesis. On the other hand, 85% of the patients with hypoplastic MDS and all patients with AA showed decreased ETU caused by reduced erythropoiesis. Positive correlation was observed between ETU and the erythroid precursor cells in the bone marrow. Bone marrow scintigraphy utilizing 99mTc-sulphur colloid showed peripheral expansion of active marrow in MDS patients and islands-like distribution in hypoplastic MDS and AA patients. Ferrokinetics and bone marrow scintigraphy demonstrated the difference between typical MDS and hypoplastic MDS. Hypoplastic MDS appears to be a distinct clinicopathologic entity.

Anemia, Aplastic↗
PubMed2000

Apoptosis, bcl-2 expression and p53 accumulation in myelodysplastic syndrome, myelodysplastic-syndrome-derived acute myelogenous leukemia and de novo acute myelogenous leukemia.

Apoptosis and its dysregulation have been implicated in dysplastic and ineffective hematopoiesis and the neoplastic transformation of bone marrow in myelodysplastic syndrome (MDS). To explore the role of apoptosis in hematological disorders, we examined the frequency of apoptotic cells by the in situ end labeling method in bone marrow specimens from 37 patients with MDS [refractory anemia (RA) 10 cases, RA with excess of blasts (RAEB) 27 cases including 12 cases with leukemic transformation], 12 patients with MDS-derived acute myelogenous leukemia (AML) and 13 patients with de novo AML. In addition, we investigated the relationship of apoptosis to the immunohistochemical expression of bcl-2 and p53 in these cases, and the association of apoptosis, bcl-2, and p53 with the leukemic evolution of MDS by examining sequential bone marrow samples of the same patient from the time of initial diagnosis to the time of overt leukemia. The percentage frequency of apoptotic cells was significantly greater in MDS (RA: 9.46 +/- 2.99%, m +/- SD; RAEB: 5. 60 +/- 3.09) as compared with those in MDS-derived AML (0.62 +/- 0. 37), de novo AML (0.28 +/- 0.11) and controls (1.00 +/- 0.59). On the other hand, the cases of RAEB with leukemic transformation exhibited a lower frequency of apoptotic cells and a higher frequency of bcl-2- and p53-positive cells than those without transformation. When the RAEB cases transformed to AML, the frequency of apoptotic cells was significantly reduced (2.96 +/- 1. 54 --> 0.62 +/- 0.37), while the frequencies of bcl-2-positive cells and p53-positive cells were greater (10.88 +/- 3.66 --> 30.54 +/- 7. 14, and 20.21 +/- 6.21 --> 32.34 +/- 14.71, respectively). In contrast to MDS-derived AML, over a half of de novo AML cases showed few p53-positive cells. These findings corroborate the earlier notion that apoptosis may play a substantial role in dysplastic and ineffective hematopoiesis in MDS. It is also suggested that the suppression of apoptosis associated with enhanced bcl-2 expression and p53 accumulation increases the probability of developing leukemia in MDS, and that oncogenetic development might be different between MDS-derived AML and de novo AML.

Adolescent↗
PubMed1995

Myelodysplastic syndrome.

Myelodysplastic syndrome continues to present a formidable clinical challenge. Despite considerable effort, no therapy apart from allogeneic bone marrow transplantation has been shown to prolong survival. Lack of effective therapy for myelodysplastic syndrome is of further concern given recent reports on the high incidence of myelodysplastic syndrome in patients undergoing intensive chemotherapy and radiation therapy for other malignancies. However, significant strides have been made in the past year toward understanding the molecular pathogenesis of some forms of myelodysplastic syndrome, as well as developing new approaches for therapy of myelodysplastic syndrome. This review highlights recent advances in the molecular genetics of myelodysplastic syndrome, including clonality analysis and identification of genes that are causally implicated in the pathogenesis of myelodysplastic syndrome; results from recent clinical trials for therapy of myelodysplastic syndrome using growth factors, chemotherapy or both; and recent literature on therapy-related myelodysplastic syndrome in intensively treated patients.

Antineoplastic Agents↗
PubMed1989

Differentiation induction therapy of myelodysplastic syndromes.

Myelodysplastic syndromes are a heterogenous group of haemopoietic stem cell disorders characterized by dysplastic haematopoiesis and a defective maturation of a slowly expanding or sometimes of a stable population of haemopoietic progenitors. Defective maturation, which may involve one or more of the marrow cell lineages is regarded as the central pathophysiological feature of myelodysplastic syndromes. Patients with myelodysplastic syndromes respond poorly to conventional cytotoxic chemotherapy, frequently developing a prolonged marrow aplasia. The alternative and more appropriate form of therapy is differentiation induction therapy. The results of few preliminary clinical studies in myelodysplastic patients showed that a combination of differentiating agents is superior to single agent differentiation therapy. An extensive pre-clinical screening of the response of fresh cells from myelodysplastic patients in primary culture is needed to establish the optimal doses and conditions for significant synergies between various differentiating agents followed by large controlled randomized clinical trials based on differentiation induction therapy for patients with myelodysplastic syndromes.

Cell Differentiation↗
PubMed1994

An association of polymyalgia rheumatica with myelodysplastic syndromes.

Myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders leading to peripheral cytopenias and a high probability of leukemic transformation. Immunological abnormalities, both humoral and cell mediated immunity, as well as vasculitis, a "lupus-like syndrome," neuropathy, and arthritis have been described in association with myelodysplastic syndromes. We describe 3 cases of polymyalgia rheumatica (PMR) developing within 4 months of detection of cytopenia. The possible association of myelodysplastic syndromes and PMR has not been previously recognized.

Aged↗
PubMed2003

Myelodysplastic syndromes.

Myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders in which there is ineffective hematopoiesis. Affected patients are primarily elderly people, but also at risk are certain subsets of patients who have been exposed to antineoplastic chemotherapy and select patients with primary bone marrow failure syndromes such as Fanconi anemia or aplastic anemia. The diagnosis of myelodysplastic syndrome implies a certain probability of leukemic evolution, but the magnitude of this probability varies greatly among patients. Over the years there have been several diagnostic and prognostic classifications of these disorders in an attempt to achieve diagnostic accuracy that is biologically and clinically meaningful. With the aging of the population and with improved survival among patients with cancer, pathologists are likely to confront myelodysplastic syndromes more frequently in their practice. This review discusses the clinical and pathologic manifestations of this group of disorders, major diagnostic and prognostic classification systems, pathogenesis, and select issues that might be clinically relevant in the future.

Humans↗
PubMed1999

Dental management of a pediatric patient with myelodysplastic syndrome.

Myelodysplastic syndrome in the pediatric population is an extremely rare-hematological disorder. An eleven-year-old girl with a remarkable, past medical history of myelodysplastic syndrome is presented. She was treated for a falling hematocrit and platelet count, with splenectomy as a lifesaving measure. The features of the syndrome and treatment options are described. The clinical protocol for the dental management of the pediatric patient with myelodysplastic syndrome is discussed.

Child↗
PubMed1993

Will cytokines alter the treatment of myelodysplastic syndrome?

Myelodysplastic syndrome is a frustrating disorder, which until recently lacked effective treatment. Patients usually succumb to infection, bleeding complications, or progression to acute leukemia. Recombinant cytokines such as granulocyte macrophage-colony stimulating factor, granulocyte-colony stimulating factor, interleukin-3, and erythropoietin have been used to ameliorate the cytopenias associated with this disease. Small clinical trials in myelodysplastic syndrome patients, using cytokines with myeloid activity (G-CSF, GMCSF, IL-3), have shown consistent elevations in the white blood cell counts with little success in elevating hemoglobin or platelets. Erythropoietin is able to increase the hemoglobin in a small group of myelodysplastic syndrome patients. Future trials using combinations of these cytokines may lead to multilineage effects.

Animals↗
PubMed2005

Telomerase activity in myelodysplastic syndromes.

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral cytopenias. Telomeres are thought to be critical in maintaining normal hematopoiesis. In this study, we assessed telomere dynamics in order to obtain further insight into the pathogenesis of MDS. We studied telomerase activity (TA) in mononuclear cells from peripheral blood (PB) and bone marrow (BM) from patients with myelodysplastic syndrome (MDS; n=24), acute myeloid leukemia (AML; n=14), chronic myeloid leukemia (CML; n=12) and 11 normal controls using a polymerase chain reaction-based telomeric repeat amplification assay. Telomerase activities (mean+/-S.D.) were found as 0.199+/-0.09, 0.414+/-0.55, 0.253+/-0.26 and 0.181+/-0.05 pg/ml in PB mononuclear cells, respectively (P>0.05). Comparison of TA of BM mononuclear cells from 19 MDS patients versus 10 BM samples from normal controls revealed no significant difference (P=0.3). There was no correlation between the levels of TA and clinical and prognostic parameters of the patients with MDS, such as degree of anemia, platelet counts on presentation, gender, presence of organomegaly, bone marrow fibrosis and BM blast percentages. Patients who had higher TA had significantly inferior survival compared with patients who had lower TA (P=0.005). Consistent with previous data, our results suggest that in patients with MDS, telomerase activity might be insufficient to compensate for the telomere shortening. Furthermore, TA might be prognostically important in patients with MDS. Measurements of enzymatic activity in association with telomere length studies may help to understand the prognostic role of telomere dynamics in patients with myelodysplastic syndromes more reliably.

Adult↗
PubMed2003

Hemopoietic cell transplantation for myelodysplastic syndromes.

Myelodysplastic syndromes are clonal stem cell disorders, and allogeneic hemopoietic cell transplantation (HCT) is the only therapy with curative potential. Among patients with less-advanced myelodysplastic syndromes, 3-year survivals of 65% to 75% are achievable with human leukocyte antigen (HLA)-identical related and HLA-matched unrelated donors. The probability of relapse is less than 5%. Among patients with advanced disease (> or = 5% marrow blasts), 35% to 45% and 25% to 30%, respectively, are surviving in remission after transplantation from related or unrelated donors. The incidence of post-transplant relapse is 10% to 35%. Criteria of the International Prognostic Scoring System, originally developed for nontransplanted patients, also predict relapse and survival after HCT. Refined conditioning regimens have permitted successful HCT even in patients in their seventh decade of life. Results with a regimen using a combination of busulfan (targeted to predetermined plasma levels) and cyclophosphamide are particularly encouraging. Improved survival with transplants from unrelated volunteer donors reflects selection of donors on the basis of high-resolution (allele-level) HLA typing. Nevertheless, transplant-related morbidity and mortality, including graft-versus-host disease, remain challenges that need to be addressed with innovative approaches. Some patients who achieve a chemotherapy-induced complete remission may also benefit from autologous HCT.

Age Factors↗
PubMed2002

Important features of myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are characterized by peripheral cytopenias in combination with a hyperplastic bone marrow. During the last 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndromes. The classification according to the World Health Organization (WHO) includes mainly morphological criteria and is supplemented by the International Prognostic Scoring System (IPSS) which takes cytogenetical changes into consideration when determining the prognosis of MDS. Also MDS after radiotherapy, chemotherapy or chemical exposure must be distinguished from primary MDS. The underlying mechanisms in primary MDS have not yet been established but it is a multistep alteration to the hematopoietic stem cells that include genes involved in cell cycle control, mitotic checkpoints as well as growth factor receptors, secondary signal proteins and transcription factors which gives the cell a growth advantage over its normal counterpart.

Chromosome Aberrations↗
PubMed2001

Altered self-reactive antibody repertoires are a general feature of patients with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is characterized by an acquired clonal disorder of haematopoietic progenitor cells that results in inhibition of normal haematopoiesis and contributes to the development of haematological malignancies. Autoimmune syndromes may occur in MDS, but they are not a major clinical feature of the disease. In the present study, we have analysed the global antibody repertoires of IgM and IgG in plasma of 10 patients with MDS toward self- and non-self-antigens by quantitative immunoblotting. Myelodysplastic syndrome patients included in this study did not exhibit autoimmune symptoms nor secondary haematological neoplastic disease. Data were compared by means of multiparametric statistical analysis. We demonstrate that the antibody repertoires of self-reactive IgM and IgG of patients with MDS exhibit significantly altered patterns of reactivity, as compared to those of healthy individuals. In contrast, reactivity patterns of IgM in plasma of patients and of healthy controls toward non-self-antigens were similar, whereas reactivity patterns of IgG of patients and healthy subjects toward non-self-antigens were discriminated by multiparametric statistical analysis. These observations indicate that a broad disturbance of self-recognition mechanisms is a general feature of patients with MDS. A failure in the regulation of self-reactivity may contribute to the pathogenesis of MDS.

Adult↗
PubMed2005

CD34/CD117 positivity in assessment of prognosis in children with myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders that are characterized by morphology identifying dysplastic changes in one or more cell lineages, peripheral blood cytopenias and a propensity to evolve into secondary acute myeloid leukemia (AML). CD34 is commonly expressed in all types of childhood leukemias, whereas CD117 is a reliable and specific marker to detect leukemia cells committed to myeloid lineage. Co-expression of CD34/CD117 may strongly suggest the diagnosis of AML (Rytting ME. Pediatric myelodysplastic syndromes. Curr hematol Rep 2004;3(3):173-7. May; Uçkan D, Hiçsönmez G, Yetgin S, Gürgey A, Cetin M, Karaağaoğlu E, et al. CD34/CD117 co-expression in childhood acute leukemia. Leukemia Res 2000;24:201-6.). We describe the case of a 22 month-old-girl with MDS and Down syndrome who was presented with severe anemia and thrombocytosis at diagnosis, transformed into AML-M7. In our patient, CD34 and CD117 markers were positive on the blast cells of the BM 6 months before the chemotherapy decision. As the disease progressed, CD34/117 co-existence was increased and MDS transformed into AML. As a result, an increase in CD34 and CD117 positivity of the BM blast cells may be associated with a higher risk of leukemic transformation.

Antigens, CD34↗
PubMed1999

Concurrent inflammatory bowel disease and myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) may be associated with inflammatory bowel disease (IBD). We characterized the clinical features and outcomes of patients with concurrent IBD and MDS. Using a diagnostic index, we identified all patients with both IBD and MDS at our center between 1976 and 1997. We also calculated an incidence rate of MDS in IBD using population-based data from Olmsted County, Minnesota, between 1950 and 1993. Among approximately 15,000 IBD patients seen, 25 (approximately 0.17%) were diagnosed with MDS. Fourteen had Crohn's disease and 11 had ulcerative colitis. The median age at diagnosis of IBD, particularly Crohn's disease, was higher than expected. Median age at diagnosis of MDS was typical. All but one ulcerative colitis patient was diagnosed before the diagnosis of MDS, while one-half of Crohn's disease patients were diagnosed with both ailments simultaneously. Five patients who had been diagnosed with IBD first were persistently anemic for at least 1 year prior to diagnosis of MDS. Two Crohn's disease patients had received purine analogs in the past. Median follow-up after MDS diagnosis was 1 year. Seven patients died, including two who progressed to acute myeloid leukemia. The incidence rate of MDS in IBD based on Olmsted County data was 0 cases per 100,000 person-years (95% CI, 0-55.2). The seemingly high frequency of myelodysplastic syndromes in a large referral-based group of patients with IBD suggests an association; however, an increased risk of MDS was not observed in a small regional cohort of IBD patients. Patients with MDS are diagnosed with concurrent IBD at an age older than expected. Simultaneous diagnoses were made in one-half of Crohn's disease patients. MDS should be considered in the differential diagnosis of anemia in IBD patients.

Aged↗
PubMed1999

Malignancy: Current Clinical Practice: Current Therapeutic Options in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are characterized initially by ineffective hematopoiesis and subsequently the frequent development of acute myelogenous leukemias (AML). During the last 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndromes. Risk-adapted treatment strategies were established due to the high median age (60-75 years) of MDS-patients and the individual history of the disease (number of cytopenias, cytogenetical changes, transfusion requirements). The use of allogeneic bone marrow transplantation for MDS patients currently offers the only potentially curative treatment, but this treatment modality is not available for the most of the "typical" MDS-patients aged >60 years. Based on in-vitro findings analyzing the potential of several agents to differentiate or to stimulate hematopoietic progenitor cells a number of therapeutic options were evaluated in clinical trials: hematopoietic growth factors (e.g. erythropoietin, G-CSF), differentiation inducers (e.g. retinoids), or cytoprotective substances (amifostine). The role of immunsuppressive agents (antithymocyte globulin, cyclosporine A) either alone or in combination is being actively investigated. Using intensive cytotoxic treatment in patients with advanced MDS or AML after MDS complete remission rates comparable with those known from the treatment of de novo AML were reported. The therapy related toxicity (early death rate <10%) was reduced by using G-CSF given prior ("Priming") and/or after the cytotoxic treatment.

Journal Article↗
PubMed1998

Myelodysplastic syndrome associated with Griscelli syndrome.

Myelodysplastic syndrome (MDS) in children has been reported to be associated with various constitutional anomalies; however, it has not been described previously in patients with Griscelli syndrome (GS). In this report, we present a case with GS and refractory anemia with an excess of blasts. We believe that careful evaluation of peripheral blood and bone marrow could increase the number of patients who are found to have GS-associated MDS.

Hepatomegaly↗
PubMed1991

Myelodysplastic syndrome with myelofibrosis: myelodysplastic syndrome as a major primary disorder for acute myelofibrosis.

Seven cases of myelodysplastic syndrome with myelofibrosis, which is defined using the following criteria: (1) pancytopenia with less than 5% blasts in the peripheral blood; (2) minimal or no splenomegaly; (3) myelofibrosis with cellular marrow; (4) absence of diffuse proliferation of blasts in the bone marrow; and (5) presence of myelodysplastic features of bone marrow or peripheral blood cells, are presented. They were in the range of 52-82 years old and consisted of 3 males and 4 females. Six out of 7 cases developed into acute leukaemia after 5 to 8 months from the onset and died from between 2 weeks to 8 months from the evolution to leukaemia. The type of leukaemia was acute myeloblastic in 3 patients, and acute myelo-megakaryoblastic in 3 patients. Another patient died of severe hepatic injury after 5 months from the onset of the disease. These findings revealed that the complication of myelofibrosis in the patients with myelodysplastic syndrome was an indicative sign of rapid progression to overt leukaemia or otherwise poor prognosis for survival. In addition myelodysplastic syndrome is thought to be major primary disorder for acute myelofibrosis. Myelodysplastic syndrome with myelofibrosis is closely associated with the neoplastic proliferation of megakaryoblasts in a considerable number of patients.

Acute Disease↗
PubMed2005

Lack of mutations of the human telomerase RNA gene (hTERC) in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS), considered a pre-leukemic state, has recently been categorized as a subset of bone marrow failure syndromes. Unlike other subtypes of bone marrow failure syndromes, such as aplastic anemia or dyskeratosis congenita, little is known about genetic alterations of human telomerase in MDS, despite the fact that immune cells from patients with MDS frequently exhibit telomere attrition.

Adult↗