Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 28-year-old Japanese woman with suspected essential thrombocythemia (ET) had marked thrombocytosis, mild leukocytosis with normal neutrophil alkaline phosphatase activity, and no anemia. She was monitored without being given any medication. Eleven years later, complete blood counts showed no remarkable changes but some non-lobulated mononuclear megakaryocytes were found in the bone marrow. Cytogenetic analysis revealed deletion of the long arm of chromosome 5 (5q-). Subsequently, hemoglobin and platelet counts decreased gradually, splenomegaly appeared and progressed, after which myelofibrosis developed. Acute leukemia developed 16 years after the first documentation of thrombocytosis. 5q- syndrome is known to be a myelodysplastic syndrome (MDS) with unique clinical features and cases with this syndrome presenting with thrombocytosis of more than 1,000 x 10(9)/L but without anemia are rare. Furthermore, it is noteworthy that in this patient transition to acute leukemia occurred following development of myelofibrosis and marked splenomegaly, which are generally observed in blastic crises resulting from chronic myeloproliferative disorders (CMPD). The patient showed features indicative of CMPD rather than of MDS in spite of presenting with 5q- chromosomal abnormality. This case supports the concept of "mixed myelodysplastic and myeloproliferative syndromes" and suggests the possibility of the appearance of CMPD-like manifestations in 5q- syndrome.
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PMID:5q- syndrome presenting chronic myeloproliferative disorders-like manifestation: a case report. 1081 92

A clinicopathological study was carried out to address the currently still controversial issues of: 1) thrombocythaemias in chronic myeloproliferative disorders (MPDs); 2) Initial, prefibrotic idiopathic myelofibrosis (IMF); 3) discrimination of spurious polycythaemic states or polyglobuly (PG) from polycythaemia vera (PV); 4) unclassifiable MPDs. Based on a synoptical approach which implicates a comparative evaluation of laboratory data and histopathology of the bone marrow, the discriminating efficiency of both diagnostic tools has been emphasized. An elaborate evaluation of histotopography and cytological appearance of megakaryopoiesis is an invaluable aid to distinguish the different subtypes of MPDs which may eventually present with a significant elevation of the platelet count. Prefibrotic IMF is not only associated with a certain set of clinical symptoms (minimal to slight anaemia, splenomegaly, thrombocytosis), but should also be characterized by specific alterations of bone marrow morphology. Moreover, follow-up studies are in keeping with the finding that these patients evolve into typical IMF regarding laboratory parameters and ensuing myelofibrosis. Smokers polycythaemia--PG may be separated from early PV by the significant raise in the red cell mass and also by a few, easily determinable clinical parameters (i.e. EPO level, thrombocytosis, LAP). Both conditions can be distinguished by regarding bone marrow features (megakaryopoiesis, interstitial changes) which exert a distinctive impact. According to our experience the majority of patients categorized as unclassifiable MPDs include cases in which clinical or morphological data are inadequate to permit a more precise diagnosis. Only in a small proportion not a failing methodology, but initial stages of the disease process requires sequential examinations to reach a correct diagnosis.
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PMID:Clinicopathology and histochemistry on bone marrow biopsies in chronic myeloproliferative disorders--a clue to diagnosis and classification. 1131 59

A clinicopathological study was performed to define initial-prefibrotic precursor stages of idiopathic (primary) myelofibrosis (IMF) by presenting laboratory and histological bone marrow features. Contrary to the usually accepted diagnostic requirements for IMF, including bone marrow fibrosis and a leukoerythroblastic blood picture, we found that 80 patients did not completely comply with these criteria. In particular, this cohort displayed no increase in the reticulin-collagen fiber content of the bone marrow at onset. Therefore, these cases were occasionally regarded as unclassifiable chronic myeloproliferative disorders (MPDs), or presumptively as essential thrombocythemia (ET). Patients were characterized by a certain set of clinical parameters comprising a borderline to slight leukocytosis and therapy-refractory anemia, minimal to modest splenomegaly, and often an elevated platelet count. Peripheral blood films revealed, only very sparsely, tear drop cells and a few erythroid and myeloid precursors, but no definite leukoerythroblastic reaction. Bone marrow histopathology was consistent with an increase in cellularity and a prominent left-shifted neutrophil granulopoiesis. Erythropoiesis disclosed a slight reduction with small to medium-sized islets. Megakaryopoiesis was the most prominent diagnostic hallmark to distinguish initial-prefibrotic IMF from the allied subtypes of MPDs. This cell lineage was not only characterized by a conspicuous growth and abnormal clustering, but also by a pronounced deviation from nuclear-cytoplasmic differentiation (dysplastic appearance). Cytological anomalies were compatible with a large variety of size and shape, ranging from giant- to atypical micromegakaryocytes with compact and bulky, cloud-like nuclei, due to a coarse lobulation and a frequent occurrence of naked (denuded) nuclei. Follow-up examinations, including sequential trephine biopsies in 22 patients, revealed a transition into myelofibrosis accompanied by laboratory findings in keeping with manifest IMF. In conclusion, morphological and clinical parameters have been validated by this study, which are consistent with a set of diagnostic criteria to recognize initial or prefibrotic precursor stages of IMF.
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PMID:Clinical and morphological criteria for the diagnosis of prefibrotic idiopathic (primary) myelofibrosis. 1132 Sep 1

Therapy-related changes of the bone marrow fiber content remain a controversial issue in hematopathology. This conflict of opinion firstly depends on difficulties to determine the quantity of fibers exactly (semiquantitative grading, morphometry, reference to cellularity). Secondly, the appropriate selection of patients with specific monotherapies including hydroxyurea (HU) and interferon-alpha (IFN) seems to present some problems. Finally, assessment of myelofibrosis is further biased by the different endpoints of sequential examinations. The latter shortcoming can be improved upon by the calculation of the myelofibrosis progression/regression index which describes the ratio between difference of fiber density and observation time. Using strictly defined therapeutic regimens and intervals between sequential trephine biopsies a stimulating effect of IFN administration on bone marrow fibrosis in Ph1+-chronic myelogenous leukemia (CML) has been found. This result is comparable with the failure of this agent to improve myelofibrosis (and splenomegaly) in a considerable number of patients with allied subtypes of chronic myeloproliferative disorders. This is in contrast to the effect HU exerts which is a more fibrolytic or even stabilizing influence on bone marrow fibrosis. This phenomenon is readily demonstrable by the assessment of dynamic features (myelofibrosis progression index). In addition, patients showing a rapid progression of myelofibrosis during IFN and HU treatment of Ph1+-CML are generally associated with a poor risk outcome and a significant worsening of survival.
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PMID:Comparative effects of interferon and hydroxyurea on bone marrow fibrosis in chronic myelogenous leukemia. 1169 40

Polycythemia vera (PV), one of the chronic myeloproliferative disorders (MPD), is characterized by predominant erythroid proliferation and secondary platelet proliferation, and by progression from a proliferative stage to a metastatic phase and finally a malignant phase. These characteristics expose patients to increased risk for thrombohemorrhagic complications, myeloid metaplasia, myelofibrosis, and acute leukemic conversion irrespective of treatments. Currently, there are three agents-hydroxyurea (HU), interferon-alfa (IFN-alpha), and anagrelide-that differ in mechanisms of action and in treating specific phenotypic manifestations of PV, suggesting a potential role for combination therapy. They also differ widely in side effects profiles and severity. Because of the differing risks for long-term complications associated with these agents, age is an important variable in selecting treatments. Patients at high risk for thrombohemorrhagic complications all require cytoreduction, as do patients at intermediate risk who are not effectively managed by phlebotomy and low-dose aspirin. In younger patients, the safest and most effective combination treatment appears to be anagrelide plus IFN-alpha, while in older patients anagrelide plus hydroxyurea may be effective. HU is used sparingly in younger patients because of the long-term increased risk of mutagenicity and possibly leukemogenesis. IFN-alpha is particularly indicated for patients with myeloid metaplasia evidenced by splenomegaly. Anagrelide, which acts on the mature megakaryocyte to prevent platelet budding, is uniquely efficacious in the control of platelet counts.
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PMID:Modern treatment strategies in polycythemia vera. 1268 79

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.
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PMID:Chronic myeloproliferative disorders. 1463 83

Contrasting the circulating CD34+ hematopoietic progenitor cells (HPCs) in chronic myeloproliferative disorders (CMPDs), scant knowledge is available regarding their quantity in the bone marrow (BM). Therefore, a clinicopathological study was performed on trephine biopsies in 575 patients with CMPDs focused on chronic idiopathic myelofibrosis (CIMF). A comparison with 25 healthy subjects revealed no significant differences in the numbers of HPCs (6 +/- 3/mm2) in polycythemia vera, essential thrombocythemia and advanced fibro-osteosclerotic stages of CIMF. Pre-fibrotic and early-stage CIMF displayed 16 +/- 11 precursors per mm2 BM. Sequential biopsies in this disorder showed a decline in HPCs (10 +/- 6/mm2) with evolving myelofibrosis-myeloid metaplasia (MMM), while in terminal stages acceleration generated an increase (24 +/- 25/mm2). A significant association between the quantity of HPCs and the development of myelofibrosis, splenomegaly, and anemia as well as an increase in peripheral blasts was recognizable in CIMF. Moreover, in all subtypes of CMPDs, a favorable prognosis was significantly associated with a higher number of HPCs in the BM. In conclusion, enhanced inflow of precursors from the BM with subsequent trapping, self-renewal and mobilization by the spleen is assumed to indicate a progressive generalization and worsening of the outcome. This putative pathomechanism is significantly associated with the evolution of MMM.
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PMID:Bone marrow CD34+ progenitor cells in Philadelphia chromosome-negative chronic myeloproliferative disorders--a clinicopathological study on 575 patients. 1601 8

Idiopathic myelofibrosis is a type of chronic myeloproliferative disorders characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis, in various degrees of bone marrow fibrosis and extramedullary hematopoiesis. In this paper, the biological characters and pathogenesis of idiopathic myelofibrosis such as mutation of tyrosine kinase receptor, mutation of GABA transporter 1, JAK2 mutation and c-MPl mutation, as well as other pathogenesis related with idiopathic myelofibrosis were reviewed.
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PMID:[New insight into pathogenesis of idiopathic myelofibrosis--review]. 1808 95

An activating mutation of Janus kinase 2 (JAK2-V617F) was previously described in chronic myeloproliferative disorders (MPD). In previously published studies, the frequency of the JAK2-V617F mutation was determined to be 80-90 % for patients with polycythemia vera (PV) and 40-70 % for essential thrombocythemia (ET). In this study, we analyzed the relationship between the JAK2-V617F mutation and clinical-hematological parameters in Turkish patients with MPD and compared these findings with published studies from other geographic regions. A total of 148 patients were studied; of which, 70 were diagnosed with PV and 78 with ET. The mutation status of JAK2 was determined using a tetra-primer polymerase chain reaction. We found that 80 % of the PV group and 42 % of the ET group were positive for the JAK2-V617F mutation. When all patients were analyzed, the levels of white blood cells, hemoglobin and splenomegaly were significantly different in patients with the JAK2-V617F mutation (p < 0.05). To our knowledge, this study is the first to evaluate the relationship between MPD and JAK2-V617F in Turkish patients. The JAK2-V617F mutation is frequently detected in the Turkish patients with MPD, and especially in patients with PV. Hence, it would be useful to include JAK2 mutation screening in the initial evaluation of patients suspected to have MPD.
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PMID:Evaluation of the JAK2-V617F gene mutation in Turkish patients with essential thrombocythemia and polycythemia vera. 2272 88


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