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)

To guide development of new clinical strategies, a review of recent investigations in the pathobiology of MDS was performed. Articles were identified through a Medline search. Studies, including reviews, are cited in the references. A multistep pathogenesis is proposed. (1) Targeted injury or mutation within hemopoietic stem cells may be followed by an immunologic response adversely affecting progenitor survival. (2) Accelerated proliferation and premature death of marrow cells is amplified by apoptogenic cytokines (TNF-alpha, Fas ligand). (3) Establishment of an abnormal clone associated with telomere shortening. (4) Disease progression associated with loss of tumor suppressor activity. Opportunities for therapeutic interventions are possible at each step. Comparisons between the proposed pathogenesis of MDS and severe aplastic anemia (SAA) are also presented. Leukemia (2000) 14, 2-8.
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PMID:A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for new therapies. 1063 70

We scored absolute numbers of circulating CD34+ cells by a highly sensitive triple-color flow cytometric analysis using CD45 monoclonal antibody, CD34 monoclonal antibody and propidium iodide. Forty-one patients with MDS (RA: 27, RARS: 1, RAEB: 6, RAEB-t: 3,CMML: 4), 12 patients with aplastic anemia (AA) and 36 age-adjusted normal subjects were studied. RA had significantly decreased numbers of cells expressing CD34 (0.21 +/- 0.29 x 10(6)/l) compared with normal subjects (0.81 +/- 0.36 x 10(6)/l)(P < 0.001). This low number of CD34+ cells in RA resembles the case of AA (0.39 +/- 0.73 x 10(6)/l). In light-scatter analysis, the CD34+ cells of RA patients were distributed mainly in low forward scatter (FSC) (lymphocyte region). In contrast, the CD34+ cell counts were extremely high in patients with RAEB (46.54 +/- 71.37 x 10(6)/l) and RAEB-t (57.00 +/- 52.36 x 10(6)/l) (P < 0.001) and the CD34+ cells were observed in high FSC (blast region).CMML patients showed moderately increased numbers of CD34+ cells (3.69 +/- 4.64 x 10(6)/l). Thus, there was a distinct difference in cell size and number of circulating CD34+ cells between RA and RAEB/RAEB-t. In univariate and multivariate analysis, a high CD34+ cell count (> or = 1.0 x 10(6)/l) was a poor prognostic factor. This method allows one to distinguish RA from other MDS subtypes more reliably than by morphology alone and provides early signs of progression to acute leukemia.
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PMID:Absolute number of circulating CD34+ cells is abnormally low in refractory anemias and extremely high in RAEB and RAEB-t; novel pathologic features of myelodysplastic syndromes identified by highly sensitive flow cytometry. 1065 53

Myeloablation and immunosuppression were considered to be the two major roles of the conditioning regimens for allogeneic stem cell transplantation to facilitate engraftment. It has turned out, however, that immunosuppression is more important and myeloablation is not necessary for engraftment. At the same time, it is considered that the major anti-tumor effect of allogeneic stem cell transplantation depends on the graft-versus-leukemia effect, not on the conditioning regimen itself. In patients with CML who relapsed after allogeneic transplantation, for example, infusion of donor lymphocytes can induce a second complete remission. Non-myeloablative stem cell transplantation (NST) was developed in the late 90s based on these theories. Low-dose, less toxic, so-called "non-myeloablative" preparative regimens have been designed not to eradicate the malignancies, but to provide sufficient immunosuppression to allow donor cells to engraft, while the graft-versus-malignancy effects eradicate the tumor. This strategy permits allogeneic transplantation to be used in patients who are not eligible for conventional, often myeloablative, transplantation because of advanced age or organ dysfunction. Non-myeloablative preparative regimens contain purine analogs, such as fludarabine or cladribine. The NST regimen being used at the National Cancer Center Hospital, Tokyo, Japan, consists of cladribine (0.11 mg/kg x 6 days), busulfan (4 mg/kg x 2 days) and rabbit anti-thymocyte globulin (2.5 mg/kg x 4 days). We enrolled 6 patients in this NST protocol so far: 1 with severe aplastic anemia (sibling-PBSCT), 2 with MDS-RA (1 for sibling-PBSCT and 1 for matched uBMT), 1 with AML-CR2 (matched uBMT), 1 with AML-CR3 (sibling-PBSCT), and 1 with relapsed AML (mismatched related PBSCT). All patients achieved engraftment within 14 days with complete donor chimerism. In addition to leukemias, a graft-versus-malignancy effect was also reported in allogeneic NST of solid tumors, such as renal cell carcinoma and malignant melanoma. The long-term efficacy of NST remains to be determined, and further clinical trials are warranted.
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PMID:[Non-myeloablative stem cell transplant]. 1089 4

While this study is larger than previous investigations and includes workers with a wide range of exposures to benzene, the estimates of risk, as measured by statistical confidence intervals, are still fairly broad, and would benefit from the larger numbers that could be provided by continued follow-up of this population. Nevertheless, the study confirms earlier findings of increased risk for ANLL and aplastic anemia among benzene-exposed workers, provides the first substantial evidence that MDS is linked to benzene exposure, and provides evidence that benzene increases risk for ANLL/MDS at lower levels of exposure than had previously been demonstrated. Currently we are evaluating the potential for extending the follow-up of workers included in this study. A new study would include expanded data collection for cases of hematopoietic malignancy and related disorders and for an appropriate control series.
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PMID:Benzene and lymphohematopoietic malignancies in China. 1108 48

The development of myelodysplastic syndrome/acute myeloblastic leukaemia (MDS/AML) has been reported in patients with aplastic anaemia (AA) after administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). Similarly, patients with severe congenital neutropenia (SCN) have an increased risk of developing MDS/AML after treatment with rhG-CSF. Point mutations in the G-CSF receptor gene are found in about 20% of SCN patients who are predisposed to MDS/AML. We investigated the occurrence of mutations in the G-CSF receptor in eight patients with AA who developed MDS/AML. No mutations were detected around the cytoplasmic domain of the gene in our patients, indicating that the mechanisms of clonal evolution to MDS/AML in patients with AA might be different from those with SCN.
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PMID:Absence of mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene in patients with myelodysplastic syndrome/acute myeloblastic leukaemia occurring after treatment of aplastic anaemia with G-CSF. 1112 17

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.
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PMID:Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. 1131 87

It is often difficult to distinguish hypoplastic myelodysplastic syndrome (h-MDS) from acquired aplastic anaemia (AA), because of the considerable clinical, cytological and histological similarities between these two disorders. The distinction between AA and h-MDS is important because there is a higher risk of progression to acute leukaemia in patients with h-MDS compared with AA. Recent studies suggest that tumour necrosis factor-alpha (TNF-alpha) plays an important role in the development of AA. In order to determine the potential importance of TNF-alpha in the differential diagnosis of hypoplastic bone marrow (BM) disorders, we examined whether analysis ofTNF-receptor expression could be used as a tool to differentiate AA from h-MDS. Flow cytometric analysis revealed that BM stem cells (CD34+) from AA patients have markedly greater TNF receptor (R) 1 and TNFR2 expression than those from patients with MDS and h-MDS. We suggest that the BM stem cells with a high expression of TNFR in patients with AA may be potently sensitive to TNF-alpha stimulation of differentiation. Thus, we propose that quantification of TNFR expression in BM stem cellsmay be a useful method to distinguish AA from h-MDS.
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PMID:Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the tumour necrosis factor receptor. 1210 Jan 46

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

In order to investigate the significance of apoptosis and proliferation rates in differential diagnosis, evaluating curative effect and leukemia transformation in myelodysplastic syndromes, apoptosis index (AI) and proliferating index (PI) were assayed in marrow smears from 60 cases of MDS, 30 AML, 21 chronic aplastic anemia (CAA), 16 hemolytic anemia, 15 megaloblastic anemia and 30 normal controls. The apoptotic cells were assayed with TUNEL technique and proliferating cell nuclear antigen (PCNA) by immunohistochemical method in situ. The results showed that average AI in marrow smears from 39 cases with MDS prior therapy was (11.2 +/- 8.8)% and PI was (17.3 +/- 8.7)%, significant differences were observed in MDS group and normal control group, as well as in AML, CAA, megaloblastic anemia and hemolytic anemia groups. Hypoplastic MDS can be distinguished from CAA by AI and PI. Clinical therapy induced significant alteration of AI and PI in MDS, AML and CAA. After therapy of MDS, the AI dropped from (11.2 +/- 8.8)% to (6.6 +/- 0.7)%. It was concluded that examination of AI and PI of marrow cells in situ may provide valuable prognostic information, also can contribute to evaluate therapeutic effectiveness.
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PMID:[Significance of in situ identification of apoptosis and proliferation rates in diagnosis of myelodysplastic syndromes]. 1251 42

We assessed the prognostic importance of the platelet count 100 days post transplant of 107 consecutive patients receiving ablative allogeneic bone marrow transplant (BMT) between 7/96 and 12/00 who survived at least 100 days. Diagnoses included AML (n=36), chronic myelogenous leukemia (n=27), NHL (n=14), ALL (n=16), MDS (n=9), aplastic anemia (n=3), and one Hodgkin's disease and myelofibrosis each. In total, 64% were in remission or in chronic phase or had aplastic anemia (good risk), and 36% had active disease at the time of transplant (bad risk). In all, 70% were matched sibling transplants and 30% were matched unrelated donor transplants. The mean follow-up for the patients remaining alive is 48 months. Survival was powerfully influenced by the 100-day platelet count: 4-year survival was 19% for patients with a platelet count <30 x 10(9)/l; 41% for patients with a platelet count of 30-50; and 72% for those with a platelet count >50 (P<0.001; log-rank test). In a multivariable analysis, the most powerful risk factors for mortality after allogeneic BMT were low 100-day platelet count (P<0.001) and bad risk disease (P=0.009). We conclude that the platelet count 100 days post transplant is a powerful predictor of overall survival.
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PMID:Prognostic importance of the platelet count 100 days post allogeneic bone marrow transplant. 1468 14


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