Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Marrow transplantation is effective treatment for a number of hematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is successful in the treatment of aplastic anemia with 70-85% long-term survival. It offers 10-30% apparent cures for patients with acute leukemia who have relapsed at least once, and for those with chronic myelocytic leukemia in blast crisis. Although still somewhat controversial, it appears to be the treatment of choice for patients with acute nonlymphoblastic leukemia in first chemotherapy induced remission, and for those with chronic myelogenous leukemia in the chronic phase since approximately 50-60% of these patients experience long-term, disease-free survival. Patients with acute lymphoblastic leukemia grafted in second or subsequent remission may expect a 30% "cure" of their disease. Marrow grafting is the only effective treatment for many patients with inherited immunologic deficiencies and certain genetic storage diseases. Cures of congenital Fanconi's anemia, Blackfan-Diamond anemia, osteopetrosis, paroxysmal nocturnal hemoglobinuria and thalassemia major have been achieved. Marrow transplantation is being explored for the therapy of patients with lymphoma, Hodgkin's disease, preleukemia, multiple myeloma, hairy cell leukemia, small cell lung cancer, testicular cancer, ovarian cancer and neuroblastoma. Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. More recently, marrow transplants from HLA-nonidentical family members and even from unrelated donors have been successfully explored.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Marrow transplantation: the Seattle experience. 391 47

The oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone, CAS 30652-11-0) has been given daily for 3-11 months to 6 transfusion dependent iron loaded patients (myelodysplasia (MDS) 2, Diamond-Blackfan anaemia 1, thalassaemia intermedia 1, thalassaemia major 2). Daily doses of 3 g, 2 x 2 g and 3 x 2 g were administered for the first 2-7 months. Daily doses of 2 x 3 g were also used for periods up to 4 months. Urine iron excretion following 3 g of L1 was found to be related to the number of previous transfusions but not to serum ferritin or the amount of L1 excreted. In each case 24 h urinary iron excretion in response to 3 g L1 ranged from 5-21 mg in MDS, 13-25 mg in a thalassaemia intermedia and a Diamond-Blackfan patient and 16-110 mg in thalassaemia major patients. Further increases of urinary iron were observed in all the patients when the daily dose was increased. Serum ferritin levels have fluctuated but overall have remained unchanged. Biochemical assessment did not show any major abnormalities ascribed to L1 except from subnormal serum zinc levels in two patients and white blood cell absorbate in another. In a separate study we have compared urinary L1 and iron excretions in 7 transfusional iron loaded patients. In all the cases the concentration of L1 was in excess of iron and higher than the level required for 100% iron binding. There was no other apparent correlation between the concentrations of L1 and iron in the urines studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oral iron chelation therapy with deferiprone. Monitoring of biochemical, drug and iron excretion changes. 789 73

Injection of 10(6) immortalized, but non-leukemic, granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent FDC-P1 cells into GM-CSF transgenic hybrid mice with elevated GM-CSF levels led to death within three months with elevated blast cell numbers in the blood, massive organ infiltration by blast cells, and associated anemia and thrombocytopenia. No disease developed within this period in littermate mice injected with 10(6) FDC-P1 cells. All moribund transgenic recipients contained transformed FDC-P1 cells able to produce rapidly-growing transplanted leukemias in syngeneic normal DBA/2 recipients. The leukemias appeared to arise in the primary recipients by independent transformation events. The transformed cells from different mice differed in their in vitro growth characteristics, their ability to produce GM-CSF or multipotential CSF, and in the nature of the transplanted tumors derived from the primary cells. While all primary recipients at death contained fully transformed leukemic cells, the bulk of the large population of FDC-P1 cells appeared either to be untransformed or to have altered characteristics not yet representing full transformation. If the FDC-P1 engrafted model has some validity for myelodysplasia, the results suggest that sustained CSF administration to myelodysplastic patients possessing abnormal, potentially preleukemic, granulocyte-macrophage populations may increase the risk of death either from accumulated pretransformed or from fully transformed leukemic cells.
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PMID:Leukemic transformation of immortalized FDC-P1 cells engrafted in GM-CSF transgenic mice. 850 82

Hematopoietic stem-cell transplantation (HSCT) is an effective mode of therapy in pediatrics for the treatment of both malignant and non-malignant disorders. We compared the course of children transplanted with unrelated umbilical cord blood (UCB) to those transplanted with allogeneic sibling bone marrow (BM) for bone marrow failure syndromes. Thirteen patients with a median age of 6.3 years were transplanted for the following diseases between April 1992 and November 1997: myelodysplastic syndromes, aplastic anemia, Diamond-Blackfan anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, osteopetrosis and dyskeratosis congenita. The stem cell source was BM in ten patients and UCB in three. We retrospectively examined the conditioning regimens, stem cell source and dose, days to engraftment, survival and complication rate to see whether there was a significant advantage in using one source over the other. The median time to an absolute neutrophil count > 500 per microL was 25 days for UCB patients and 16 days for BM patients. The median time to a platelet count > 20,000 per microL was 55 days for UCB patients and 22 days for BM patients. The 100-day mortality was 66% in UCB patients and 20% in BM patients. The overall mortality rates were 66% and 40%, respectively. Three patients died prior to engraftment. Seven patients (54%) were still alive as of May 1999 with a median follow-up of 1574 days post-transplant. The patients transplanted with BM had faster engraftment and lower rates of graft-versus-host disease, 100-day mortality and overall mortality. HLA-matched sibling BM is preferred as a source but transplantation using unrelated UCB is still an option in treating pediatric bone marrow failure syndromes.
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PMID:Hematopoietic stem-cell transplantation using unrelated cord-blood versus matched sibling marrow in pediatric bone marrow failure syndrome: one center's experience. 1056 77

Parasitologic confirmation of cutaneous leishmaniasis is obligatory before chemotherapy can be considered. Direct microscopic examination of scrapings taken from indurated borders of ulcers has been routinely used as primary method of diagnosis. In this report we compared the sensitivity of examination of dermal scrapings taken from the bottoms of ulcers (BDS) with that of dermal scrapings taken from indurated active margins of lesions (MDS) in a total of 115 patients. The sensitivities of the microscopic examination were 90.4 and 78.3% for BDS and MDS samples, respectively. When the PCR method was used with a group of 40 patients, we also observed a higher sensitivity when BDS samples were examined (80.8% in BDS samples versus 57.7% in MDS samples). The improvement of the diagnostic sensitivity in the BDS samples appears to be related to the higher parasite load and more easily detectable morphology of amastigotes in the centers of the ulcers. Other parasitologic diagnostic methods, such as culture and histopathologic examination of biopsies, are less sensitive (67.5 and 64.3%, respectively). Aspirate culture, however, was shown to be the most sensitive method for the diagnosis of patients with chronic ulcers. When microscopic examinations of both MDS and BDS samples are combined, the sensitivity of diagnosis may rise up to 94%. We therefore recommend this method as a primary routine procedure for diagnosis of cutaneous leishmaniasis.
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PMID:Diagnosis of cutaneous leishmaniasis in Colombia: the sampling site within lesions influences the sensitivity of parasitologic diagnosis. 1101

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

We have used a novel method to conduct non-myeloablative stem cell transplantation (NST), making the following changes in previous methods: Use of the cheapest conditioning drugs, tailored number of apheresis sessions in the donors, elimination of ganciclovir and IgG, outpatient conduction when possible, diminished number of transfusions of blood products and diminished number of donor lymphocyte infusions. With this method, we have prospectively conducted 70 allografts in patients with different diseases: Chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplasia, thalassemia major, relapsed Hodgkins disease, Blackfan-Diamond syndrome and aplastic anemia. In them, the median granulocyte recovery time to 0.5 x 10(9)/L was 11 d, whereas the median platelet recovery time to 20 x 10(9)/L was 12 d. Twenty patients did not need red blood cell transfusions and 17 did not need platelet transfusions. In 55 individuals (78%), the procedure could be completed fully on an outpatient basis. Follow-up times range between 30 and 800 d.: Four patients failed to engraft and recovered endogenous hemopoiesis; 16 patients (23%) developed acute graft versus-host disease (GVHD) whereas 28 (49%) developed chronic GVHD. Thirty two patients (47%) have died: 21 with a relapsing disease and seven as a result of GVHD; the median post-trasplant survival (SV) was 420 d., whereas the 12-mo. SV was 42%. The 100-day mortality was 3.8% and the transplant-related mortality was 14.2%. The median cost of the allografts was 18,000.00 US dollars. This method could be particularly adequate in developing countries, where very few individuals can afford the cost of a conventional bone marrow transplantation procedure.
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PMID:Allogeneic stem cell transplantation using non-myeloablative conditioning regimens: results of the Mexican approach. 1243 Aug 85

New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte-mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.
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PMID:Marrow failure. 1556 90

The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leukemias. It is becoming more apparent that progression of myelodysplastic syndromes and myeloproliferative diseases to acute myelogenous leukemia is the result of defects in progenitor cell maturation. The MPC of bone marrow was analyzed in mice using a cell culture assay for measuring the relative frequency of proliferative myeloid progenitors. Response to the cytokines SCF, IL-3, and GM-CSF was determined by this assay for the leukemic mouse strain BXH-2 and ten other inbred mouse strains. Significant differences were found to exist among ten inbred mouse strains in the nature of their MPC in bone marrow, indicating the presence of genetic polymorphisms responsible for the divergence. The SWR/J and FVB/J strains show consistently low frequencies of myeloid progenitors, while the DBA/2J and SJL/J inbred strains show consistently high frequencies of myeloid progenitors within the bone marrow compartment. In addition, in silico linkage disequilibrium analysis was conducted to identify possible chromosomal regions responsible for the phenotypic variation. Given the importance of this cell compartment in leukemia progression and the soon to be released genomic sequence of 15 mouse strains, these differences may provide a valuable tool for research into leukemia.
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PMID:Analysis of expansion of myeloid progenitors in mice to identify leukemic susceptibility genes. 1689 42

Glucocorticoids (GCs) are known for their clinically useful effects in immunologic and inflammatory disorders. Although there is a huge volume of knowledge concerning the cellular and molecular effects of GCs, statements regarding their effects in multiple diseases at variable doses are not clear-cut owing to pharmacogenetic differences. The main actions of GCs in hematologic disorders have been related to their differentiation-inducing and apoptosis-inducing effects, but modification of several steps of the hematopoietic and/or immune pathway has also been reported. In our clinic, mega-dose methylprednisolone (MDMP) has been successfully used for treatment of different hematologic diseases, such as leukemias, bone marrow failure in aplastic anemia, hypoplastic anemia, myelodysplastic syndrome, neutropenia, autoimmune diseases, and in some congenital hereditary diseases. Both clinical and experimental studies in our department revealed that MDMP was more effective than conventional dose steroids. It is interesting that MDMP can be curative in some congenital hereditary diseases such as Diamond-Blackfan syndrome. However, more research is required to clarify their roles in biology, physiology, and molecular genetics.
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PMID:Comparison of megadose methylprednisolone versus conventional dose prednisolone in hematologic disorders. 1741 60


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