---------- Forwarded message ---------- Subject: Selected MEDLINE this past month "myeloproliferative"
1: Br J Haematol. 2005 May;129(3):293-306. Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Harrison C. Department of Haematology, Guy's and St Thomas' Foundation Trust, St Thomas' Hospital, London, UK. Summary The myeloproliferative diseases (MPDs) present several therapeutic challenges in patients of childbearing potential. The most extensive literature exists for patients with essential thrombocythaemia, with over 200 pregnancies reported in retrospective case series. Yet there is conflicting data in relation to predicting pregnancy outcome and optimal management strategy. Pregnancy is less frequently reported for polycythaemia vera and myelofibrosis. There is a need for collaboration to further our knowledge in this field. Here, the literature is reviewed in detail and experience of different therapeutic strategies in pregnancy discussed. There is increasing understanding about the pathogenesis of placental dysfunction in inherited thrombophilia and antiphospholipid antibody syndrome pregnancy outcomes in these conditions parallel those reported for MPDs. Furthermore several large studies have influenced pregnancy management in these conditions and, whilst not directly applicable to MPDs, this data have potential to inform treatment protocols. This data are reviewed and a personal management strategy for pregnancy in MPD proposed. PMID: 15842653 [PubMed - as supplied by publisher] 2: J Pediatr Hematol Oncol. 2005 Apr;27(4):192-6. A basic classification and a comprehensive examination of pediatric myeloproliferative syndromes. Gassas A, Doyle JJ, Weitzman S, Freedman MH, Hitzler JK, Sharathkumar A, Dror Y. >From the Divisions of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Ontario, Canada. Myeloproliferative syndromes (MPSs) are clonal stem cell disorders resulting in excessive proliferation of one or more cell lineages. Since MPSs in children occur much less commonly than adults, one can argue that the biology and the categories of the various pediatric MPSs seem to be different from adults. Furthermore, confusion exists between pediatric MPS and other overlapping conditions, such as myelodysplastic syndrome. The authors' objectives were to develop a classification system with a list of disorders relevant to children and to characterize pediatric cases of MPS that were devised according to this classification. Based on the predominant proliferating cell lineage, the authors established a classification system for childhood MPS. Primary MPS was classified into granulocytic proliferation-chronic myelogenous leukemia (CML); monocytic-juvenile myelomonocytic leukemia (JMML); megakaryocytic-essential thrombocythemia (ET), familial thrombocytosis, transient myeloproliferative disorder of Down syndrome (TMD); erythrocytic-polycythemia vera, familial erythrocytosis; fibroblastic-idiopathic myelofibrosis (IMF); eosinophilic-idiopathic hypereosinophilic syndrome (IHES); and mast cells-mastocytosis. Secondary MPS was classified as non-clonal proliferation (eg, infections, drugs, toxins, autoimmune, non-hematologic neoplasm, and trauma), and these were excluded from the study. Next, the classification system was applied to the patient population at the authors' institution. One hundred two cases with primary MPS were identified between 1970 and 2001. Patients were evaluated for clinical manifestations, blood and bone marrow parameters, cytogenetics, and survival following different treatment modalities. Significant proportions of cases of childhood MPS (60%) were unique to the pediatric population and not seen in adults. The most common disorders were JMML (n = 31), TMD of Down syndrome (n = 30), and CML (n = 30); the other disorders were rare: four cases of ET, two of IMF, two of IHES, two of mastocytosis, and one primary erythrocytosis. In contrast to adults, MPS in children is more frequently treated with hematopoietic stem cell transplantation (HSCT), the only available curative option for most of these diseases. HSCT was particularly successful in the more recent cases due to more advanced techniques for HSCT. The authors found that all the cases could be easily classified. MPS in children is different from adult-type MPS in terms of biology, categories, classification, and prognosis. PMID: 15838389 [PubMed - in process] 3: Cancer Cell. 2005 Apr;7(4):291-3. JAKing up hematopoietic proliferation. Shannon K, Van Etten RA. Department of Pediatrics and Comprehensive Cancer Center, University of California, San Francisco, California 94143. Mutations that deregulate proliferation and survival pathways have emerged as a common molecular theme in the pathogenesis of myeloproliferative disorders (MPDs). Three studies now report an amino acid substitution in the JAK2 kinase in most patients with polycythemia vera as well as in some cases of essential thrombocythemia and chronic idiopathic myelofibrosis. Functional analysis demonstrates that this mutation confers erythropoietin-independent growth in vitro, deregulates signaling pathways downstream of JAK2, and causes polycythemia in mice. These results open new avenues for diagnosing and classifying patients with these disorders, and identify a new molecular target for drug discovery. PMID: 15837617 [PubMed - in process] 4: Cancer Res. 2005 Apr 15;65(8):3281-9. Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression. Komura E, Tonetti C, Penard-Lacronique V, Chagraoui H, Lacout C, Lecouedic JP, Rameau P, Debili N, Vainchenker W, Giraudier S. Institut National de la Sante et de la Recherche Medicale U362, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France. The release of transforming growth factor-beta1 (TGF-beta1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in murine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-beta1 synthesis is poorly known but seems regulated by nuclear factor kappaB (NF-kappaB). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51's overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-kappaB activation after cytokine deprivation. This activation correlates with a low level of IkappaBalpha. A spontaneous activation of NF-kappaB was also detected in proliferating megakaryocytes and in circulating CD34(+) patient cells. In normal cells, NF-kappaB activation was only detected after cytokine treatment. The expression of an NF-kappaB superrepressor in FKBP51 overexpressing cells and in derived megakaryocytes from CD34(+) of IMF patients revealed that NF-kappaB activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-beta1 secretion. These results highlight the importance of NF-kappaB's activation in the fibrosis development of this disease. They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder. PMID: 15833861 [PubMed - in process] 5: Clin Appl Thromb Hemost. 2005 Apr;11(2):197-201. The Plasma Levels of Prostanoids and Plasminogen Activator Inhibitor-1 in Primary and Secondary Thrombocytosis. Birdane A, Haznedaroglu IC, Bavbek N, Kosar A, Buyukasik Y, Ozcebe O, Dundar SV, Kirazli S. Hacettepe University Medical School Department of Hematology, Ankara, Turkey. SUMMARY: An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of plasminogen activator inhibitor type 1 (PAI-1), the inhibitor of fibrinolysis; and thromboxane A2 and 6-keto-PGF1 alpha, the products of endoperoxides, in 16 patients affected with clonal thrombocytemia as compared with 16 patients with reactive thrombocytosis and 15 normal controls. In the clonal thrombocytemia group, plasma levels of PAI-1 antigen and activity were significantly higher than both reactive thrombocytosis and control group. Plasma levels of 6-keto-PGF1alpha were significantly higher in the clonal thrombocytemia group than the other two groups and also higher in the reactive thrombocytosis group than the control group, which was also significant. This study confirms that arachidonate metabolism is frequently deranged in patients with thrombocytosis and hypofibrinolysis due to increased PAI-1 plasma levels as shown in the clonal thrombocytosis group. This may explain the thrombotic tendency in myeloproliferative disorders. PMID: 15821826 [PubMed - as supplied by publisher] 6: Blood. 2005 Apr 7; [Epub ahead of print] On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense. Kaushansky K. Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA, USA. The chronic myeloproliferative diseases, Polycythemia Vera (PV), Essential Thrombocythemia (ET), Idiopathic Myelofibrosis (IMF) and Chronic Myelogenous Leukemia (CML) represent a spectrum of pathogenetically related disorders of varying clinical manifestations. While the origin of CML has been traced to a dysregulated protein kinase, the product of the bcr/abl oncogene, the molecular basis of PV, ET and IMF, which as a group share more similarities with each other than with CML, has been more recalcitrant to solution. However, a major insight into the molecular basis for the enhanced myeloproliferation and clonal dominance that characterizes these disorders is now upon us; four groups of investigators have recently reported that a single, somatic mutation in the protein tyrosine kinase JAK2 appears responsible for many of the features of PV, ET and IMF, an observation that promises to impact the diagnosis and treatment of patients with these disorders, and to spur additional research into the origins of dysregulated cell growth and function. This perspective provides a historical account of the results leading to this landmark finding, and offers observations on the questions that remain unanswered and the opportunities to advance our diagnosis, prognostication and therapy of these challenging disorders of hematopoietic cell regulation. PMID: 15817681 [PubMed - as supplied by publisher] 7: Br J Haematol. 2005 Apr;129(1):66-71. Gains on 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hybridization study. Al-Assar O, Ul-Hassan A, Brown R, Wilson GA, Hammond DW, Reilly JT. Institute for Cancer Studies, Division of Genomic Medicine, Medical School, University of Sheffield, Sheffield, UK. Ideopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder resulting in bone marrow fibrosis as a consequence of growth factor release from clonal haematopoiesis. Conventional cytogenetic analysis identifies abnormalities in approximately a third of cases at diagnosis, although rarely uncovers unique, primary genetic events. We have used comparative genomic hybridization (CGH) to study 25 IMF cases and have compared the results with conventional cytogenetics. Metaphase cells were available for analysis in 13 cases, of which seven showed an abnormal karyotype. CGH chromosomal profiles showed imbalances in 21 of 25 cases. The most frequent aberrations were gains of 9p (12 cases), 2q (seven cases), 3p (seven cases), chromosome 4 (seven cases), 12q (seven cases), 13q (eight cases). The main losses were at 17q and occurred in six cases. The results for CGH and cytogenetics were matched for one case only. Investigation of IMF by CGH suggests that genomic aberrations are much more common than has been previously indicated by conventional cytogenetic analysis and occur in the majority of cases. Gains of 9p were the most frequent finding, occurring in 50% of patients and suggests that genes on 9p may play a crucial role in the pathogenesis of IMF. PMID: 15801957 [PubMed - in process] 8: Cancer Genet Cytogenet. 2005 Apr 15;158(2):188-91. Inv(1)(p22q25) in chronic myeloproliferative disease: constitutional or clonal defect? Wong KF, Wong WC, Cheuk W. Department of Pathology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong SAR, China. [EMAIL PROTECTED] Pericentric inversion of chromosome 1 is uncommon in chronic myeloproliferative disease. We report the occurrence of an isolated inv(1)(p22q25) in two patients with BCR/ABL-negative chronic myeloproliferative disease. The inv(1) is an acquired clonal abnormality in one patient and a constitutional defect in the other. To our knowledge, this is the first report on the occurrence of inv(1)(p22q25) in hematolymphoid malignancies. PMID: 15796968 [PubMed - in process] 9: J Clin Pathol. 2005 Apr;58(4):406-8. Bone marrow biopsy morbidity: review of 2003. Bain BJ. Department of Haematology, St Mary's Hospital Campus of Imperial College Faculty of Medicine, Praed Street, London W2 1NY, UK. [EMAIL PROTECTED] BACKGROUND: Although some hazards are recognised, in general, bone marrow aspiration and trephine biopsy are thought to be safe procedures. Until recently, no attempt had been made to quantify any attendant risks. For this reason, documentation of adverse events was begun in 2001, under the auspices of the British Society for Haematology. Three consecutive years have now been surveyed, the results for 2003 being presented here and compared with earlier results. METHODS: Members of the British Society of Haematology were requested to document adverse events associated with diagnostic bone marrow aspirates and trephine biopsies between 1 January and 31 December, 2003. Data were collect ed early in 2004. RESULTS: In total, 19,259 procedures were reported from 63 hospitals, 13,147 being combined procedures and 6112 aspirates without a trephine biopsy. Sixteen adverse events were reported, representing 0.08% of total reported procedures. The major adverse event was haemorrhage, which comprised 11 of the 16 adverse events. Although infrequent, adverse events were associated with significant morbidity and three were judged as very serious. The major risk factors for haemorrhage, in order of frequency, were diagnosis of a myeloproliferative disorder, aspirin treatment, other putative platelet dysfunctions, and thrombocytopenia. CONCLUSIONS: Adverse events following trephine biopsies and bone marrow aspirates are rare, but nevertheless can have considerable impact on individual patients. PMID: 15790706 [PubMed - in process] 10: Leukemia. 2005 May;19(5):792-8. Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Roche-Lestienne C, Lepers S, Soenen-Cornu V, Kahn JE, Lai JL, Hachulla E, Drupt F, Demarty AL, Roumier AS, Gardembas M, Dib M, Philippe N, Cambier N, Barete S, Libersa C, Bletry O, Hatron PY, Quesnel B, Rose C, Maloum K, Blanchet O, Fenaux P, Prin L, Preudhomme C. [1] 1Institut de Recherche contre le Cancer, Inserm U524, Lille, France [2] 2Laboratoire d'Hematologie A, CHRU, Lille, France. Idiopathic hypereosinophilic syndrome (HES) characterized by unexplained and persistent hypereosinophilia is heterogeneous and comprises several entities: a myeloproliferative form where myeloid lineages are involved with the interstitial chromosome 4q12 deletion leading to fusion between FIP1L1 and PDGFRA genes, the latter acquiring increased tyrosine kinase activity. And a lymphocytic variant, where hypereosinophilia is secondary to a primitive T lymphoid disorder demonstrated by the presence of a circulating T-cell clone. We performed molecular characterization of HES in 35 patients with normal karyotype by conventional cytogenetic analysis. TCRgamma gene rearrangements suggesting T clonality were seen in 11 (31%) patients, and FIP1L1-PDGFRA by RT-PCR in six (17%) of 35 patients, who showed no evidence of T-cell clonality. An elevated serum tryptase level was observed in FIP1L1-PDGFRA-positive patients responding to imatinib, whereas serum IL-5 levels were not elevated in T-cell associated hypereosinophilia. Sequencing FIP1L1-PDGFRA revealed scattered breakpoints in FIP1L1-exons (10-13), whereas breakpoints were restricted to exon 12 of PDGFRA. In the 29 patients without FIP1L1-PDGFRA, no activating mutation of PDGFRA/PDGFRB was detected; however; one patient responded to imatinib. FISH analysis of the 4q12 deletion was concordant with FIP1L1-PDGFRA RT-PCR data. Further investigation of the nature of FIP1L1-PDGFRA affected cells will improve the classification of HES.Leukemia (2005) 19, 792-798. doi:10.1038/sj.leu.2403722 Published online 17 March 2005. PMID: 15772698 [PubMed - in process] 11: Cancer Genet Cytogenet. 2005 Apr 1;158(1):81-3. Translocation (X;20) involving the inactive X chromosome in a patient with myeloproliferative disorder. O'Reilly J, Crawford J, Uzaraga J, Cannell P. Department of Haematology, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6847. [EMAIL PROTECTED] We report a patient with an unclassifiable myeloproliferative disorder and the rare t(X;20)(q13;q13.3) as the sole cytogenetic abnormality. The breakpoint on Xq is consistent with other reports of translocations involving the X chromosome with breakpoints that cluster to Xq13 and association with myeloid disorders. Late replication studies demonstrated the inactive X chromosome was involved in this translocation. The critical event in patients with myeloproliferative disease and deletion of 20q appears to be the loss of tumor suppressor genes. This may also be the mechanism in this patient with a potential cryptic deletion associated with the translocation. Alternatively, spreading of X inactivation into the derivative chromosome 20 provides a second mechanism for the loss of function of tumor suppressor genes on 20q. The finding in this patient of t(X;20) together with three others reported in the literature indicates that this may represent a primary non-random abnormality associated with myeloid malignancy, which may take on clinical significance with the accumulation of more cases. PMID: 15771910 [PubMed - indexed for MEDLINE] 12: Leuk Res. 2005 May;29(5):481-91. Epub 2005 Jan 21. Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders. Fruchtman SM, Petitt RM, Gilbert HS, Fiddler G, Lyne A; Anagrelide Study Group. Mount Sinai Medical Center, New York, NY 10029, USA. Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder (MPD) is surrounded by controversy. Although few doubt the association of thrombocytosis with increased risk for life-threatening events such as thrombosis or hemorrhage, or the association between clonal myeloproliferation and the progression to acute leukemia or myelofibrosis, controversy exists regarding the timing and nature of appropriate therapeutic intervention. Studies have shown that treatment with myelosuppressive agents such as chlorambucil, busulfan, radiophosphorus ((32)P), and hydroxyurea reduces the platelet count. However, investigators have also identified an increased risk of drug-related leukemic transformation. An ideal cytoreductive treatment for long-term use should minimize thrombosis and avoid long-term complications, especially acute leukemia (AL). Anagrelide, an imidazoquinolin, inhibits megakaryopoiesis and more selectively reduces platelet production in humans. A retrospective analysis of an open-label, multicenter, international trial reviewing 3660 anagrelide-treated patients was performed to assess efficacy and long-term safety, specifically potential for increased leukemogenicity. The study included MPD patients with thrombocytosis diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of all patients enrolled, 81% had previously received other myelosuppressive agents; of these, 33% were transferred from the original agent to anagrelide due to toxicity and 31% were transferred because of poor platelet control. Over 45% of patients were symptomatic due to thrombocythemia, most commonly vascular sequelae (25%). Dosage was titrated to achieve a platelet count <600x10(9)L(-1) and ideally between 130 and 450x10(9)L(-1). The safety cohort of 3660 patients, including 2251 with essential thrombocythemia (ET), 462 with polycythemia vera (PV), and 947 with chronic myeloid leukemia (CML) and other MPDs, was analyzed to establish the incidence of leukemic transformation in patients with ET and PV. >From the Safety Population, 12.8% (467/3660) of patients were treated with anagrelide as the sole cytoreductive agent (naive patients). Acute leukemia/myelodysplasia developed in 2.1% of ET patients (47/2251) with a maximum follow-up of 7.1 years. Of the PV patients, 2.8% developed acute leukemia/myelodysplastic syndrome (13/462), with a maximum follow-up of 7.0 years. ET and PV patients who transformed to AL had all been previously exposed to other cytotoxics; there were no ET or PV patients in the study who transformed to AL exposed solely to anagrelide. With maximum follow-up over 7 years, anagrelide achieved platelet control in over 75% of MPD patients and did not increase the conversion to acute leukemia during the treatment duration analyzed. Longer follow-up is required to confirm these important observations regarding the long-term safety of anagrelide. PMID: 15755500 [PubMed - in process] 13: Histol Histopathol. 2005 Apr;20(2):633-44. Standardization of bone marrow features--does it work in hematopathology for histological discrimination of different disease patterns? Thiele J, Kvasnicka HM, Diehl V. Institute of Pathology, University of Cologne, Cologne, Germany. [EMAIL PROTECTED] Standardized bone marrow (BM) features determined by semiquantitative scoring are valuable tools for the recognition and easily reproducible interpretation of histological patterns in hematopathology. This procedure may help to characterize various disease entities, but especially to differentiate chronic myeloproliferative disorders (MPDs) with increased platelet counts from reactive thrombocytosis (RTh). A clear-cut separation of these conditions continues to present a major problem in hematology. Therefore MPDs are a most suitable model to test the diagnostic relevance of this procedure. By regarding the literature and based on archive material that involved BM biopsies of 319 patients, a semiquantitative grading of histological parameters was performed. Standardized features were applied for a stepwise discriminant analysis to establish different sets of variables exerting a diagnostic impact. A distinction into five histological patterns was achieved that showed a correctly predicted group membership of about 94 %. These were consistent with the clinicopathological diagnosis of polycythemia vera, essential thrombocythemia (ET), prefibrotic or early fibrotic chronic idiopathic myelofibrosis (CIMF) and finally RTh. Variables of discriminating potency according to their ranking included megakaryopoiesis (maturation defects, nuclear lobulation, naked and bulbous nuclei, small and giant size), reticulin fibers, erythro- and granulopoiesis (left shifting and quantity) and cellularity. These findings are in keeping with the assumption that characteristic patterns of BM histopathology can be assigned to different subtypes of MDPs mimicking ET. Discrimination between ET and especially early stage CIMF with thrombocythemia is warranted because of significant implications concerning therapeutic strategies, follow-up examinations and survival. Regarding these results, a schematic procedure is proposed to be used for daily routine diagnosis concerning the discrimination of MPDs. PMID: 15736066 [PubMed - in process] 14: J Pathol. 2005 Apr;205(5):548-57. Aberrant expression of transforming growth factor beta-1 (TGF beta-1) per se does not discriminate fibrotic from non-fibrotic chronic myeloproliferative disorders. Bock O, Loch G, Schade U, von Wasielewski R, Schlue J, Kreipe H. Institute of Pathology, Medizinische Hochschule Hannover, 30625 Hannover, Germany. [EMAIL PROTECTED] Transforming growth factor beta-1 (TGF beta-1) is a potent inducer of fibrosis and has been shown to be essential for the development of bone marrow fibrosis in an animal model of idiopathic myelofibrosis (IMF). IMF belongs to the Philadelphia chromosome negative chronic myeloproliferative disorders (Ph(-) CMPD). Megakaryocytes and platelets have been suggested as the major cellular source of TGF beta-1 in IMF. The osteoclastogenesis inhibitory factor osteoprotegerin (OPG) seems to be regulated by TGF beta-1 and substantial involvement of OPG expression in the process of osteosclerosis in IMF has recently been suggested. In order to determine TGF beta-1 expression in IMF and other Ph(-) CMPD, total bone marrow cells as well as laser-microdissected megakaryocytes were quantitatively analysed by real-time RT-PCR. OPG mRNA expression in fibrotic IMF was correlated with TGF beta-1 mRNA expression in a case-specific manner. Both OPG and TGF beta-1 were detected immunohistochemically in order to delineate cellular origin. When total bone marrow cells were investigated, TGF beta-1 mRNA expression was increased in some but not all cases of IMF (n = 21), with highest values in fibrotic cases. Unexpectedly, increased values were also observed in essential thrombocythaemia (ET, n = 11) when compared to non-neoplastic haematopoiesis (n = 38). Megakaryocytes isolated by laser microdissection displayed elevated TGF beta-1 mRNA levels in most of the CMPD samples with no significant differences discernible between fibrotic IMF, polycythaemia vera (PV) and ET. TGF beta-1 protein was predominantly expressed by the myeloid lineage in Ph(-) CMPD and non-neoplastic haematopoiesis, which, however, displayed lower expression. IMF cases with advanced fibrosis concomitantly overexpressed TGF beta-1 and OPG. Immunohistochemically, OPG expression was found in different stromal cells and a subfraction of megakaryocytes. In conclusion, enhanced TGF beta-1 expression occurs in megakaryocytes as well as myeloid cells in Ph(-) CMPD. TGF beta-1 may be necessary, but is not sufficient, to induce bone marrow fibrosis in IMF because non-fibrotic Ph(-) CMPD entities share this feature with IMF and cannot be discriminated from each other on the basis of TGF beta-1 expression. PMID: 15726648 [PubMed - in process] 15: Leuk Res. 2005 Apr;29(4):365-70. Epub 2004 Dec 2. A retrospective analysis of myelodysplastic syndromes with thrombocytosis: reclassification of the cases by WHO proposals. Cabello AI, Collado R, Ruiz MA, Martinez J, Navarro I, Ferrer R, Sosa AM, Carbonell F. Service of Hematology, Consorcio Hospital General Universitario of Valencia, Spain. [EMAIL PROTECTED] Myelodysplastic syndromes (MDS) show occasionally thrombocytosis, common feature of myeloproliferative diseases (MPD), with the overlapping of both disorders. Classically, thrombocytosis has been associated with some MDS subtypes: refractory anaemia with ringed sideroblasts (RARS), 5q- syndrome and those MDS with 3q chromosome rearrangements. The recent WHO classification recognises an unclassifiable MDS/MPD category including some of these disorders. Our aim is to determine the frequency of presentation, subtype classification and chromosome abnormalities of MDS with thrombocytosis diagnosed in our institution. Between 1990 and 2003 we studied 317 SMD patients according to FAB and WHO revised classifications and identified 22 cases presenting thrombocytosis associated with dysplasia, that are analysed in this article. PMID: 15725469 [PubMed - indexed for MEDLINE] 16: Genes Chromosomes Cancer. 2005 May;43(1):37-44. Interpretation of submicroscopic deletions of the BCR or ABL gene should not depend on extra signal-FISH: problems in interpretation of submicroscopic deletion of the BCR or ABL gene with extra signal-FISH. Kim YR, Cho HI, Yoon SS, Park S, Kim BK, Lee YK, Chun H, Kim HC, Lee DS. Department of Laboratory Medicine, Cheju National University College of Medicine, Jeju, Korea. Several groups have demonstrated that a submicroscopic gene deletion in Ph+ chronic myelogenous leukemia (CML) is associated with a poor prognosis and reduced response to treatment. To assess the variation between detection methods in the interpretation of a submicroscopic gene deletion, we performed an extra signal (ES)-FISH BCR/ABL and double-FISH (D-FISH) BCR/ABL on frozen bone marrow cells from 79 patients with CML (63 in the chronic phase, 6 in the accelerated phase, and 10 in blast crisis) and 30 patients with a BCR/ABL-negative myeloproliferative disorder as determined by RT-PCR. The normal cutoff values were 0.22% for ES-FISH and 0.25% for D-FISH. The cutoff values for false-positive signals from a juxtaposition of the BCR and ABL gene were 11% in ES-FISH and 13% in D-FISH. Of the 14 patients who showed an ABL gene deletion by ES-FISH, 5 had an ABL deletion only, 5 had both a BCR and an ABL deletion, but 4 proved to have a classic BCR/ABL rearrangement without a submicroscopic deletion, as determined by D-FISH. Discrepant results between ES- and D-FISH were observed in 12 of the 79 patients (15.8%), and the main causes of a discrepancy were a false-positive ABL deletion (4 of 12, 33%), a variant Philadelphia chromosome (3 of 12, 25%), an inversion of derivative chromosome 9 at the very breakpoint of the ABL gene (9q32) (1 of 12, 8.3%), a cryptic variant Ph chromosome (1 of 12, 8.3%), and a marker chromosome (1 of 12, 8.3%). Although there was no significant difference in the sensitivity for the detection of the fusion signal between ES- and D-FISH, ES-FISH showed a high percentage of cells with false-positive fusion signals (1 orange, 1 green, 1 yellow), which makes it difficult to interpret the submicroscopic ABL deletion. In conclusion, an interpretation of the submicroscopic deletions of the BCR or ABL gene should not depend on ES-FISH. Copyright 2005 Wiley-Liss, Inc. PMID: 15723338 [PubMed - in process] 17: Ann Hematol. 2005 Apr;84(4):250-7. Epub 2005 Feb 4. Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information. Bacher U, Haferlach T, Kern W, Hiddemann W, Schnittger S, Schoch C. Laboratory for Leukemia Diagnostics, Department for Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany, [EMAIL PROTECTED] In chronic myeloproliferative disorders other than CML (CMPD) recurrent cytogenetic abnormalities occur, but specific patterns of chromosomal aberrations in the specific entities have so far not been detected. Thus, the value of conventional cytogenetics in the routine diagnostic setting of CMPD remains to be clarified. We performed a cytogenetic study on 409 patients with different CMPD [polycythemia vera, essential thrombocytosis (ET), idiopathic osteomyelofibrosis, chronic myelomonocytic leukemia (proliferative subtype), idiopathic hypereosinophilic syndrome (HES), myeloproliferative syndrome (unclassifiable)] and on 102 patients with suspected CMPD. Cytogenetic abnormalities occurred in different frequencies ranging from 3 to 40% depending on the subtype, and showed some specific differences with respect to their type. The highest frequency and the most complex pattern of clonal aberrations were observed in idiopathic osteomyelofibrosis. However, clonal aberrations were also found in 10% of patients with suspected CMPD establishing the diagnosis of a malignant disease. In conclusion, cytogenetics are essential in the routine diagnostic setting of CMPD or cases suspicious for CMPD. In ET and in HES the aberration rate was only 3 and 7%, respectively. Thus, cytogenetics can be omitted. However, in some of these cases molecular procedures should be integrated into the routine diagnostic process. PMID: 15692838 [PubMed - in process] 18: Blood. 2005 May 1;105(9):3743-5. Epub 2005 Jan 4. Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells. Larghero J, Gervais N, Cassinat B, Rain JD, Schlageter MH, Padua RA, Chomienne C, Rousselot P. Service Clinique des Maladies du Sang, Hopital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10. [EMAIL PROTECTED] Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV. PMID: 15632209 [PubMed - in process] Main web page http://members.aol.com/mpdsupport/ ------------------------ Yahoo! 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