Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0002874 (aplastic anemia)
5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In our previous study, approximately 60% of aplastic anemia (AA) and refractory anemia (RA) patients treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEpo) showed a multilineage response. In this study, we analyzed the long-term follow-up of the multilineage responders (multi-R). In the follow-up analysis of 11 multi-R (6 AA and 5 RA), 10 patients (5 AA and 5 RA) were evaluable. The range of time from the start of treatment to the final contact was 50 to 125 months. Analysis of survival times revealed a significant difference between multi-R and non-multi-R among AA patients given this treatment (P = .016). One AA and 1 RA patient among the multi-R developed acute leukemia. Of 7 living multi-R, 3 AA and 2 RA patients did not need transfusion at final contact. Four of them maintained the target hemoglobin concentration of more than 11 g/dL for quality-of-life benefit. The findings suggested that this result is an important advantage of this treatment.
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PMID:Long-term follow-up of patients with aplastic anemia and refractory anemia responding to combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin. 1241 35

The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with cytopenias leading to serious morbidity plus the additional risk of leukemic transformation. Therapeutic dilemmas exist in MDS because of the disease's multifactorial pathogenetic features, heterogeneous stages, and the patients' generally elderly ages. Underlying the cytopenias and evolutionary potential in MDS are innate stem cell lesions, cellular/cytokine-mediated stromal defects, and immunologic derangements. This article reviews the developing understanding of biologic and molecular lesions in MDS and recently available biospecific drugs that are potentially capable of abrogating these abnormalities. Dr. Peter Greenberg's discussion centers on decision-making approaches for these therapeutic options, considering the patient's clinical factors and risk-based prognostic category. One mechanism underlying the marrow failure present in a portion of MDS patients is immunologic attack on the hemopoietic stem cells. Considerable overlap exists between aplastic anemia, paroxysmal nocturnal hemoglobinuria, and subsets of MDS. Common or intersecting pathophysiologic mechanisms appear to underlie hemopoietic cell destruction and genetic instability, which are characteristic of these diseases. Treatment results and new therapeutic strategies using immune modulation, as well as the role of the immune system in possible mechanisms responsible for genetic instability in MDS, will be the subject of discussion by Dr. Neal Young. A common morphological change found within MDS marrow cells, most sensitively demonstrated by electron microscopy, is the presence of ringed sideroblasts. Such assessment shows that this abnormal mitochondrial iron accumulation is not confined to the refractory anemia with ring sideroblast (RARS) subtype of MDS and may also contribute to numerous underlying MDS pathophysiological processes. Generation of abnormal sideroblast formation appears to be due to malfunction of the mitochondrial respiratory chain, attributable to mutations of mitochondrial DNA, to which aged individuals are most vulnerable. Such dysfunction leads to accumulation of toxic ferric iron in the mitochondrial matrix. Understanding the broad biologic consequences of these derangements is the focus of the discussion by Dr. Norbert Gattermann.
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PMID:Myelodysplastic syndromes. 1244 22

Survivin is a member of the inhibitor of apoptosis protein (IAPs) family and considered to play a pivotal role in oncogenesis. We present the first report of survivin expression profile in myelodysplastic syndrome (MDS). Expression of survivin messenger RNA was evaluated by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in patients with MDS and acute myeloid leukemia (AML). Eleven out of 12 patients with refractory anemia (RA) (91.6%), and all 3 patients with refractory anemia with excess blasts in transformation (RAEBt) (100%), were positive for survivin expression with the majority of cases showing abundant levels of the survivin transcript. On the other hand, expression of survivin was undetectable in the 4 patients with chronic myelomonocytic leukemia (CMMoL). The level and frequency of survivin expression in patients with refractory anemia were compared to those in patients with AML. Out of 12 patients with de novo AML, 5 patients (41.7%) showed detectable levels of survivin expression. Abundant survivin expression in RA was also confirmed by immunohistochemistry. In contrast, survivin was almost absent in two cases with aplastic anemia. We propose that high levels of survivin expression can serve as a reliable diagnostic marker of RA in MDS.
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PMID:Expression of the anti-apoptotic gene survivin in myelodysplastic syndrome. 1246 85

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.
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PMID:Diagnostic significance of serum soluble transferrin receptors in various anemic diseases: the first multi-institutional joint study in Japan. 1261 83

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI)-deficient cells that leads to complement-mediated hemolysis. A somatic mutation in the PIG-A gene involved in GPI biosynthesis causes a deficiency of GPI-anchored proteins. However, it is evident that the clonal expansion of GPI-deficient cells is not caused by only the PIG-A mutation and that other changes should be involved in the development of PNH. Some patients with aplastic anemia (AA) develop PNH. Furthermore, it has been reported that most patients with AA and refractory anemia (RA) who carry HLA-DRB1*15 and show a good response to immunosuppressive therapies have an expanded population of GPI-deficient clones. This finding, together with recent data showing resistance of GPI-deficient cells to cytotoxic cells, suggests that GPI-deficient cells escape immunologic attack and are positively selected in the autoimmune environment. However, GPI-deficient clones found in AA and RA are generally small and do not increase to near-complete dominance. Therefore, 1 or more additional genetic abnormalities that confer the growth phenotype on GPI-deficient cells are probably required for fully developed PNH or so-called florid PNH. The next 10 years should witness the discovery of the molecular mechanisms of immunologic selection and the identification of abnormalities involved in the further clonal expansion of PNH cells.
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PMID:Molecular genetics of paroxysmal nocturnal hemoglobinuria. 1262 44

Although a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells is often detected in patients with aplastic anemia (AA) and refractory anemia (RA), the significance of such cells in the pathophysiology of bone marrow (BM) failure remains obscure. We therefore examined clonality in peripheral blood granulocytes from 118 female patients with AA or myelodysplastic syndrome using the X chromosome inactivation pattern. Clonality, defined as a clonal population accounting for 35% or more of total granulocytes, was confirmed in 22 of 68 (32.4%) AA patients, in 13 of 44 (29.5%) RA patients, in all 4 RA with excess blasts (RAEB) patients, and in 4 patients with PNH. When the frequency of patients with granulocyte clonality was compared with respect to the presence of increased PNH-type cells, the frequency was significantly lower in AA patients with (PNH+; 21.2%) than without (PNH-; 42.9%) increased numbers of PNH-type cells (P =.049). Clonality was absent in granulocytes from the 15 PNH+ RA patients but present in 13 of 29 (44.8%) PNH- RA patients (P =.0013). The absence of clonality in AA and RA patients before treatment was strongly associated with positive response to immunosuppressive therapy (without clonality, 74.4%; with clonality, 33.3%; P =.0031) in all patients as well as in PNH+ patients (without clonality, 96.2%; with clonality, 66.6%, P =.026). These results suggest that AA and RA with a minor population of PNH-type cells are benign types of BM failure with immune pathophysiology that have little relationship to clonal disorders such as RAEB or acute myeloid leukemia.
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PMID:Polyclonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. 1267 78

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7. After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration. She received bone marrow (1.57 x 10(5) cells kg(-1) (patient body weight)) plus cord blood cell (0.3 x 10(7) cells kg(-1) (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.
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PMID:Successful bone marrow plus cord blood stem cell transplantation in a girl who developed myelodysplastic syndrome from hepatitis-associated aplastic anemia treated with long-term immunosuppressants and growth factors. 1285 Aug 17

Voriconazole is a new triazole active orally and parenterally that recently proved effective in the treatment of invasive aspergillosis and in empirical antifungal therapy for persistently febrile neutropenic patients. Limited data are available for pediatric patients. We report our experience with voriconazole in seven children with invasive aspergillosis, i.e., four girls and three boys with a median age of 5 (range 2-13) years affected by acute lymphoblastic leukemia (3), acute myeloid leukemia (2), refractory anemia with excess of blasts (1), and severe aplastic anemia (1). First-line therapy in all patients was liposomal amphotericin B (AmBisome) administered at a dosage of 3-5 mg/kg day. Voriconazole was administered for a median 8 (range 2-15) weeks. Response was complete and partial in two patients, respectively, stable in one, and there was no response (failure) in two. The voriconazole treatment was well tolerated. Four patients died-two of progressive aspergillosis. Three patients are alive and well 6, 5, and 4 months after the diagnosis of aspergillosis. Voriconazole appears to be an effective salvage treatment for invasive aspergillosis in pediatric patients, with good responses in patients who recover from neutropenia or are not relapsing.
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PMID:Voriconazole for invasive aspergillosis in oncohematological patients: a single-center pediatric experience. 1368 Mar 24

Myelodysplastic syndromes (MDS), especially refractory anemia (RA) are very heterogeneous diseases regarding their morphological, biological and clinical features. One important clinical problem is the difficulty of diagnosis. Soluble transferrin receptors (sTfRs) reflect the erythropoietic activity in the bone marrow (BM). To establish whether determination of serum sTfR could be useful for the differential diagnosis between RA and aplastic anemia (AA), we measured the serum sTfR concentrations, BM cellularity and BM erythroblast percentages in 14 untreated AA and 7 untreated RA patients. The serum sTfR levels of the RA patients (820.1 +/- 402.8 ng/ml) were significantly higher than those of the AA patients (491.1 +/- 195.2 ng/ml; p = 0.0207). However, the serum sTfR values of RA and AA patients also overlapped. A new index, the 'sTfR-E index' [the ratio of serum sTfR level (ng/ml) to BM cellularity (%) x BM erythroblasts (%)] is proposed, which is expected to reflect the number of transferrin receptors (TfR) on the cell membrane per BM erythroblast. The sTfR-E index values of the 7 RA patients (0.395 +/- 0.234) were significantly lower than those of the 14 AA patients (2.669 +/- 1.633; p = 0.0003). The sTfR-E index values of AA and RA patients overlapped only marginally. In conclusion, the sTfR-E index may be a useful new diagnostic tool to distinguish between AA and RA patients.
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PMID:Soluble transferrin receptor and its ratio to erythroblasts in bone marrow may be a new diagnostic tool to distinguish between aplastic and refractory anemia. 1503 34

Refractory anemia is a component of each of the myelodysplastic syndromes (MDSs). MDSs are acquired pluripotent stem cell disorders leading to one or more peripheral blood cytopenias with dysplasia in the peripheral blood and bone marrow. MDS and aplastic anemia are sometimes grouped as bone marrow failure disorders because patients present with similar peripheral blood pictures. The bone marrow in MDS is generally hypercellular, due to ineffective hematopoiesis, in contrast to the hypocellular bone marrow of aplastic anemia. MDS is more common in the elderly, differing from aplastic anemia that affects all ages. The characteristics of each of the subgroups of the MDS using the World Health Organization (WHO) classification are described. Cytogenetic analysis provides a useful part of disease diagnosis in this new classification system. There is no successful treatment for MDS other than hematopoietic stem cell transplantation which is usually recommended for patients under age 50. A prognostic scoring system has been developed to help predict the severity of disease and guide treatment. Approximately 10% to 40% of MDS cases terminate in acute leukemia. Current treatment consists mostly of supportive measures; however several new therapies are being explored.
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PMID:Refractory anemia and the myelodysplastic syndromes. 1531 93


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