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)

Several paraneoplastic inflammatory conditions, particularly autoimmune diseases, have been described in association with myelodysplastic syndromes (MDS). However, to date, recurrent acute pancreatitis has never been described in association with MDS. A 44-year-old man presented with prolonged fever and fatigue. Aortitis and pericarditis were diagnosed simultaneously with MDS, refractory anemia with excess blast type 2. His erythrocyte sedimentation rate and c-reactive protein were markedly elevated. The vasculitic syndrome responded rapidly to corticosteroids, but soon after tapering of corticosteroids, acute pancreatitis developed. Pain and pancreatic enzymes, however, improved rapidly with escalation of corticosteroid dosage. Multiple attempts at discontinuing the drug resulted in symptomatic flare-ups. Finally, his MDS transformed into acute myeloid leukemia (AML); severe acute pancreatitis closely accompanied. Induction chemotherapy and high-dose corticosteroids, however, controlled both conditions. A subsequent pancreatitis attack with pseudocyst formation occurred, but again was controlled with corticosteroids, although this was followed closely by another relapse of AML. All etiologies for recurrent acute pancreatitis were ruled out. The dramatic response of his pancreatitis attacks to immunosuppression suggested its autoimmune origin, while the close relationship in both the timing and severity of acute pancreatitis and MDS/AML suggested that the autoimmune pancreatitis was a paraneoplastic phenomenon related to MDS.
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PMID:Recurrent steroid-responsive pancreatitis associated with myelodysplastic syndrome and transformations. 1562 95

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by intravascular haemolysis, nocturnal haemoglobinuria, thrombotic events, serious infections and bone marrow failure. This acquired disease, caused by a deficiency of glycosylphosphatidylinositol (GPI) anchored proteins on the haematopoietic cells, is rare in children. We describe 11 Dutch paediatric PNH patients (median age: 12 years, range 9-17 years) diagnosed since 1983, seven cases associated with aplastic anaemia (AA), four with myelodysplastic syndrome (MDS). Presenting symptoms were haemorrhagic diathesis (n = 10), palor/tiredness (n = 8), dark urine (n = 1), fever (n = 1) and serious weight loss (n = 1). Treatment consisted of prednisolone (n = 7), anti-thymocyte globulin (n = 3) and/or androgens (n = 5). Eventually, five patients received a bone marrow transplantation (BMT) (three matched unrelated donors/two matched family donors), of whom four are still alive. PNH, diagnosed by immunophenotypic GPI-linked anchor protein analysis, should be considered in all children with AA or MDS. BMT should be considered as a therapeutic option in every paediatric PNH patient with BM failure.
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PMID:Childhood paroxysmal nocturnal haemoglobinuria (PNH), a report of 11 cases in the Netherlands. 1568 69

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.
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PMID:Farnesyltransferase inhibitors in myelodysplastic syndrome. 1586 70

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to bone marrow failure and peripheral blood cytopenias. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease; it often is discovered accidentally during routine physical examinations or blood tests. The U.S. Food and Drug Administration approved azacitidine (Vidaza, Pharmion Corporation, Boulder, CO) for the treatment of MDS. Prior to the approval of azacitidine, no approved therapies were available for the treatment of MDS. Azacitidine is believed to exert its anticancer effects by induction of hypomethylation and cytotoxicity. In clinical studies, the most common adverse events during treatment with azacitidine included nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection-site erythema, constipation, neutropenia, and ecchymosis. To ensure proper treatment with azacitidine, nurses should have an understanding of dosage and administration guidelines, commonly observed adverse events, monitoring and care of adverse events, and monitoring of laboratory tests. Having a comprehensive understanding of MDS, its underlying disease characteristics, and current treatments will enable oncology nurses to provide optimal patient care.
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PMID:Advances in myelodysplastic syndrome: nursing implications of azacitidine. 1611 8

Anemia in cancer patients undergoing treatment is common and can cause debilitating symptoms such as fatigue and reduced exercise tolerance. The introduction of recombinant human erythropoietin represents a potential improvement in the treatment of this condition. Clinical studies in patients with solid tumors and nonmyeloid hematologic malignancies have convincingly shown an improvement in mean hemoglobin concentration, a reduction in transfusion requirement along with an improvement in quality of life scores, although an effect on survival is less clear. In myeloid disorders such as myelodysplasia, response to single-agent recombinant human erythropoietin is disappointing but significant synergism with granulocyte colony stimulating factor has been demonstrated and different dosing regimens may also improve response. Unfortunately, a significant proportion of patients remain refractory to treatment. Efforts have been made to identify treatable causes of erythropoietin refractoriness, such as functional iron deficiency, and concomitant intravenous iron supplementation does appear to improve response rates. The search for pretreatment factors that predict response has been largely disappointing, although a promising model for myelodysplasia has been developed that awaits large-scale evaluation. Recombinant human erythropoietin is well tolerated, although there were concerns in the late 1990s due to a rising incidence of pure red cell aplasia in chronic renal failure patients treated with subcutaneous Eprex (Ortho Biologics) in Europe. Since potentially contributory manufacturing processes have been identified and corrected, the incidence of this complication has been falling.
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PMID:Epoetin alfa: basic biology and clinical utility in cancer patients. 1633 85

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.
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PMID:Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. 1635 41

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.
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PMID:[Hematological side effects of tyrosine kinase inhibition using imatinib]. 1642 5

Tipifarnib is an oral nonpeptidomimetic farnesyl transferase inhibitor developed to inhibit a variety of farnesylated targets potentially relevant to the therapy of various malignancies. The agent has, thus far, been tested in a wide array of both solid tumors and myeloid malignancies. Phase I trials have demonstrated that tipifarnib is best given in a twice-daily fashion in doses of 600-1200 mg/day to avoid significant neuropathy, fatigue and myelosuppression. Subsequent trials demonstrated that pauses in therapy (with staccato dosing schedules) seem to increase tolerability without a clear decrease in efficacy. Phase II and III trials of tipifarnib as monotherapy for breast, colorectal, lung (both non-small cell and small cell), brain, pancreatic and urothelial cancers have all been disappointing. Combination trials of tipifarnib with cytotoxic, hormonal or biological therapies are ongoing. Tipifarnib has displayed the most interesting activity in the myeloid malignancies of myelodysplastic syndrome, myelofibrosis with myeloid metaplasia and elderly/high-risk acute myeloid leukemia. Overall clinical response rates of approximately 20-30% have been reported in myelodysplastic syndrome and acute myeloid leukemia patients who have few alternative therapeutic options. US FDA approval for tipifarnib awaits results of subsequent Phase III trials of the agent in elderly acute leukemia.
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PMID:Tipifarnib: farnesyl transferase inhibition at a crossroads. 1650 48

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

A 59-year-old man with myelodysplastic syndrome who was hospitalized for evaluation of fever and generalized fatigue had elevated levels of C-reactive protein and pancytopenia. A search for a site of infection and empiric treatment with antibiotics were unsuccessful. Over 5 to 6 weeks right upper quadrant pain and rebound tenderness developed. Sonographic Murphys sign was present. Computed tomography showed thickening of the gallbladder wall, and repeated ultrasonography demonstrated changes consistent with cholecystitis. Open cholecystectomy was performed as an emergency procedure. Macroscopically the resected gallbladder showed an edematous and thickened wall. Histopathologic examination revealed transmural infiltration by atypical mononuclear cells with distinct nuclei. The cells showed immunohistochemical staining for CD15, indicating myeloid lineage. By 10 days after surgery, counts of leukocytes and leukoblasts had markedly increased, reaching 36,700/microL and 76.0%, respectively. The blast crisis was thought to indicate progression from myelodysplastic syndrome to leukemia. The patient died of progressive disease 12 days after surgery. We have described a rare case of acute cholecystitis caused by infiltration of immature myeloid cells to the gallbladder. An acute abdomen complicating hematologic disorders is life-threatening and requires prompt and appropriate treatment.
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PMID:Cholecystitis caused by infiltration of immature myeloid cells: a case report. 1664 35


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