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)

Diagnosis of essential thrombocythemia (ET) has been usually established by regarding the criteria of the Polycythemia Vera Study Group. Accordingly, a retrospective clinicopathological study was performed on 120 patients with a follow-up ranging between 5 and 13 years and repeated bone marrow trephine examinations. Following the new WHO classification, at presentation patients revealed three distinctive patterns of bone marrow (BM) features: (true) ET in 43 patients, prefibrotic idiopathic myelofibrosis (IMF) in 50 patients, and early IMF in 27 patients. Heterogeneity of morphological features was associated with correspondingly expressed laboratory data. Contrasting initial and early IMF, patients with true ET displayed an about 80% probability to lack splenomegaly, anemia, and increase in the LDH and LAP values and also failed to show any myeloblasts or erythroblasts on the peripheral blood films. Follow-up examinations including sequential BM biopsies (mean interval 39 +/- 31 months) disclosed that of the 43 patients with true ET only one developed an increase in reticulin. On the other hand, 65 of 77 patients with prefibrotic and early IMF evolved into overt myelofibrosis-osteosclerosis. Moreover, survival analysis demonstrated significant differences in our patients. A neglectable proportion of life loss according to a sex- and age-matched general population was found in true ET (less than 11%) opposed to IMF without or mild fibrosis (range 21% to 32%).
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PMID:Follow-up examinations including sequential bone marrow biopsies in essential thrombocythemia (ET): a retrospective clinicopathological study of 120 patients. 1221 Aug 9

Twenty-five patients with advanced essential thrombocythemia (ET; n = 13) or polycythemia vera (PV; n = 12) received hemopoietic stem cell transplants (HSCT) at the Fred Hutchinson Cancer Research Center. In most cases the indication to perform an HSCT was myelofibrosis with splenomegaly and peripheral blood cytopenias or the development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients were 18-60 (median 43) years old with intervals from diagnosis to HSCT of 8-348 (median 168) months. All but five patients had been treated with cytotoxic agents, and nine patients were splenectomized before transplant. Conditioning was performed with chemotherapy only or chemotherapy plus total body irradiation regimens followed by the infusion of either marrow (n = 19) or peripheral blood stem cells (n = 6) from related (n = 16) or unrelated (n = 9) donors. All evaluable patients showed sustained neutrophil engraftment. Nine patients (seven with AML/MDS, two with myelofibrosis) died of transplant-related complications, and 16 are surviving, 14 of them in continuous unmaintained remission. With a median follow-up of 41 (range 5-116) months after transplant, survival at 3 years is 64%. These data provide evidence that HSCT can be a curative treatment for patients with advanced PV and ET.
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PMID:Curative therapy of advanced essential thrombocythemia or polycythemia vera by hemopoietic stem cell transplantation. 1238 21

Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced phases of polycythemia vera and essential thrombocythemia (post polycythemic and post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal, hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly applicable effective therapy have been described. Clinically, these patients experience progressive marrow replacement by fibrotic tissue, ineffective hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly, extramedullary hematopoiesis, profound constitutional symptoms, and a risk of blastic transformation. Historically, therapies have been targeted at palliating symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens, localized radiotherapy). Stem cell transplantation appears promising, but is often toxic and not broadly applicable due to co-morbidities and age of MMM patients. Non-myeloablative approaches to conditioning may broaden the applicability of stem cell transplantation in MMM, yet results to date are preliminary. Although a definitive molecular abnormality responsible for the pathogenesis of MMM has not been described, much has been learned about the aberrant expression of pro-fibrotic cytokines and the presence of increased angiogenesis in MMM. These pathogenetic insights have led to a series of pilot clinical trials with therapeutic agents targeting aberrantly expressed cytokines (and possibly angiogenesis) including Thalidomide (alone or in combination), Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated the most promise (palliating disease associated cytopenia's), whereas the TNF-alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms. Although these later trials have been helpful in a subset of patients, no agent to date has led to solid complete responses in MMM across the spectrum of disease manifestations. Further insights into the pathogenetic mechanisms responsible for myeloproliferation (aberrant cell signaling pathways, apoptotic resistance, other) are necessary to guide selection and testing of the expanding number of novel anti-neoplastic agents in chronic myeloid disorders and MMM.
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PMID:The therapy of myelofibrosis: targeting pathogenesis. 1243 Sep 41

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/ micro l), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.
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PMID:The forgotten myeloproliferative disorder: myeloid metaplasia. 1277 44

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

Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder and is one of the four major myeloproliferative disorders, which include essential thrombocythemia (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML). Patients may be asymptomatic at the early stages, but later progress to marrow fibrosis, splenomegaly with pancytopenia leading to anemia, and other constitutional symptoms. Most of the care available is supportive and only palliates the constitutional symptoms. Prognosis for these patients is dependent on karyotype, hemoglobin count, and age. Stem cell transplantation is the only curative therapy, which results in eradication of the stem cell clone, with the cessation of extramedullary hematopoiesis and resolution of marrow fibrosis and its sequelae. Stem cell replacement therapy using either autologous or allogeneic stem cells has been attempted in small populations of patients with variable benefit. A nonmyeloablative approach has shown promise in a very small number of patients, but additional investigation is required for the ideal management of these patients.
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PMID:Transplant strategies for idiopathic myelofibrosis. 1519 May 20

A 52-year-old previously healthy woman was admitted to our hospital for status epilepticus in November 1999. She had not taken oral contraceptives. After treatment with intravenous diazepam and phenytoin, she did not develop seizures anymore. When she became alert, there was a mild left hemiparesis. Lumbar puncture showed an opening pressure of 145 mm H2O, and the cerebrospinal fluid was acellular. Cranial MR imaging demonstrated thrombosis of the superior sagittal sinus and fresh infarction in the right frontal lobe. Plasma fibrinogen, fibrin degradation product, and prothrombin fragment 1 + 2 levels were elevated. Proteins S and C activities and anti-thrombin III levels were within the normal range. Lupus anticoagulant and anti-cardiolipin antibody were negative. She was treated with continuous heparin infusion for ten days and with oral warfarin thereafter. Six months after the first admission, platelet count became more than 400 x 10(3)/microliter. In July 2002, she developed slowly progressive monoplegia of the left arm. Cranial MR imaging demonstrated patent superior sagittal sinus, fresh infarction in the right parietal lobe, and old small infarction in the right corona radiata. The patient was maintained on warfarin and 100 mg of aspirin thereafter. In September 2002, platelet count was 737 x 10(3)/microliter. Bone marrow examination showed increased megakaryopoiesis with normal erythroid and myeloid series and no chromosomal aberrations. Serum C-reactive protein and iron levels were in the normal range. An abdominal ultrasound demonstrated mild splenomegaly. Thus, we made a diagnosis of essential thrombocythemia (ET). ET causes thrombotic events in the course of the disease at a rate of 7% per year. Cerebral infarction is not uncommon, but occurrence of cerebral sinus thrombosis has been rarely reported. Recently, several cases have been reported in which cerebral infarction was the first manifestation of ET even with platelet counts lower than 600 x 10(3)/microliter. To our knowledge, there have been no reported cases of ET presenting with cerebral venous sinus thrombosis. Platelet count should be monitored in the patients with venous sinus thrombosis of undetermined etiology.
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PMID:[Superior sagittal sinus thrombosis as first manifestation of essential thrombocythemia]. 1519 36

Essential thrombocythemia (ET) and chronic myelogenous leukemia (CML) usually present with distinctive features. Citing experience with cases that overlap, the Polycythemia Vera Study Group recommends that negative tests for the Philadelphia chromosome be obtained before diagnosing ET. We describe two young women presenting with features absolutely typical for ET, including extreme thrombocytosis, no leukocytosis, no basophilia, no peripheral immature cells, and no splenomegaly. Severe thrombotic complications ensued: multiple cerebrovascular thromboemboli, pulmonary emboli, and miscarriage in one and myocardial infarction in the other. By 4 years, both developed leukocytosis, extreme basophilia, and circulating blasts, typical of accelerated CML. Cytogenetic studies were then performed, revealing the Philadelphia chromosome. Imatinib produced rapid clearing of blasts and basophils, but one woman later succumbed after allogeneic bone marrow transplant and the other has not achieved a major cytogenetic response. We conclude that CML can present in identical fashion as ET. The mandate for routine Philadelphia chromosome testing is magnified by the availability of targeted therapy and its greater efficacy in early stage disease.
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PMID:Every case of essential thrombocythemia should be tested for the Philadelphia chromosome. 1560 81

We describe the case of a 45-year-old male smoker who presented with an acute anterior wall myocardial infarction and a platelet count on admission of 1030000/mm3. Emergent coronary angiography revealead left anterior wall akinesia caused by a spontaneously resolved thrombosis of the left anterior descending artery with residual stenosis. Primary percutaneous coronary angioplasty and stenting were performed. Postangioplasty course was uneventful. He was diagnosed with essential thrombocythemia based on the findings of marked thrombocytosis of 1,030,000/mm3, splenomegaly and numerous clumping giant megakaryocytes on bone marrow biopsy. In addition to standard therapy with aspirin, heparin, betablocking agent, ACE-inhibitor and statine he received additional anti-platelet therapy with Clopidogrel. Cytoreductive therapy was not necessary.
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PMID:[Exercise-induced left arm pain and thrombocytosis]. 1588 26

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


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