Pericyte coverage of abnormal blood vessels in myelofibrotic bone marrows.

Background And Objectives: Myelofibrotic bone marrow displays abnormal angiogenesis but the pathogenic mechanisms of this are poorly understood. Since pericyte abnormalities are described on solid tumor vessels we studied whether vessel morphology and pericyte coverage in bone marrow samples from patients with myelofibrosis differed from that in samples from controls.

Design And Methods: We assessed the microvascular density (MVD), vessel morphology and pericyte coverage in bone marrows from 19 myelofibrosis patients and nine controls.

The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders.

The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards to phenotype.

The mevalonate pathway as a therapeutic target in the Ph-negative chronic myeloproliferative disorders.

The Ph-negative chronic myeloproliferative disorders (CMPDs) polycythaemia vera, essential thrombocytosis and idiopathic myelofibrosis are acquired stem cell disorders, which pathophysiologically are featured by clonal myeloproliferation and accumulation of myeloid cells, the latter being consequent to decreased apoptosis. Myelofibrosis and neoangiogenesis in the bone marrow and spleen are the histopathological hallmarks of idiopathic myelofibrosis but may develop in the other diseases as well. In patients with myelofibrosis elevated levels of circulating CD34+ cells are highly characteristic being partly explained by a proteolytic bone marrow mileu owing to excessive release of various proteases with ensuing extracellular matrix degradation and constitutive mobilisation of CD34+ cells into the peripheral blood.

B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study.

Context: Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of benefit in GD.

Objective/design: The objective of this prospective, controlled, nonrandomized study was to investigate the effect of RTX in GD.

A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group.

A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used.

A der(18)t(9;18)(p13;p11) and a der(9;18)(p10;q10) in polycythemia vera associated with a hyperproliferative phenotype in transformation to postpolycythemic myelofibrosis.

Chromosomal aberrations in polycythemia vera (PV) are heterogenous and nonrandom. A prognostic predictive value of these aberrations has not been established. The V617F mutation in the JAK2 gene on chromosome 9p24.

[New molecular markers within the chronic myeloproliferative disorders. II: the JAK2 mutation].

The Philadelphia-negative chronic myeloproliferative disorders feature autonomous myeloid hyperproliferation and hypersensitivity to a number of growth factors, which most recently have been shown to be explained by a guanine-to-thymidine mutation in the Janus tyrosine kinase (JAK2) gene, implicating that phenylalanine is substituted with valine in position 617 (V617F mutation). JAK2 is of particular importance to haematopoiesis, since JAK2 proteins are activated mainly by the haematopoietic growth factors. The JAK2 mutation is present in most patients with polycythaemia vera and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis.

[New molecular markers within the chronic myeloproliferative disorders. I: the PRV-1 gene].

PRV-1 is a new molecular marker within the Ph-negative chronic myeloproliferative disorders. PRV-1 is a useful, highly sensitive and specific marker in the differentiation between polycythaemia vera (PV) and secondary erythrocytosis (ET), and seems to identify those PV patients presenting in the early phase of the disease with dominating thrombocytosis and thus a clinical phenotype of ET. These PRV-1 positive ET patients can be regarded as having "masked" PV or, more accurately, as having early PV.

The rationale for B lymphocyte depletion in Graves' disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option.

We have reviewed the immunology of thyroid autoimmunity with special reference to the importance of B lymphocytes (B cells) in thyroidal and extrathyroidal Graves' disease (GD), thus providing a framework for the hypothesis that B cell depletion may be beneficial in GD. Additionally, after reviewing the efficacy and safety in other autoimmune diseases, we propose that treatment with the B cell-depleting agent Rituximab may become a clinically relevant treatment option in selected cases of GD, particularly when complicated with thyroid-associated ophthalmopathy.

A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life.

Background: Conventional interferon-alpha (IFN) is an effective treatment for patients with myeloproliferative disorders. However, many patients discontinue therapy because of side effects.

Methods: In this 24-month, Phase II feasibility study of pegylated interferon alpha-2b (PEG-IFN) treatment, a starting dose of 0.

Statins in the treatment of polycythaemia vera and allied disorders: an antithrombotic and cytoreductive potential?

Thrombohaemorrhagic complications are major clinical problems in the classical chronic Ph-negative myeloproliferative disorders (CMPDs), polycytaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF), contributing significantly to morbidity and mortality. Pathophysiologically these disorders are characterized by clonal myeloproliferation, myeloaccumulation and a propensity to develop myelofibrosis and neoangiogenesis in both the bone marrow and spleen. Based upon in vitro and in vivo studies of the effects of statins (antithrombotic, antiproliferative, proapoptotic and antiangiogenic), this review focuses on the translation of these effects into potential clinical benefits of statin therapy in patients with CMPDs.

Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease which involves opsonization of platelets by autoantibodies directed against different surface glycoproteins, leading to their premature destruction by the reticuloendothelial system. Management of patients with refractory ITP is difficult. Recent studies have shown that rituximab, a chimeric anti-CD20 monoclonal antibody, is useful in the treatment of these patients, with overall response rates of about 50%.

Anagrelide treatment in 52 patients with chronic myeloproliferative diseases.

In this retrospective multi-centre study, we report our experience with anagrelide in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases. Our study included 52 patients (age 20-78 years). The initial anagrelide dose was, in general, 0.

T-lymphocyte subsets, thymic size and breastfeeding in infancy.

We followed the changes in concentration of T-lymphocyte subsets (CD4+ and CD8+ cells) in peripheral blood and thymus size during infancy. Previous studies have found increased thymus size in breastfed infants. The present study analyzed the association between breastfeeding and the number of CD4+ and CD8+ cells.

Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders.

Chronic myeloproliferative disorders (MPD) are characterized by progressive remodelling of bone marrow stroma as evidenced by increased deposition of extracellular matrix proteins, neoangiogenesis and displacement of normal haematopoietic cells by fibrotic tissue. The family of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) serve to facilitate and inhibit matrix degradation processes, respectively. In an attempt to investigate potential markers for bone marrow remodelling processes, we investigated plasma levels of total-, free- and complexed TIMP-1, TIMP-2, MMP-2 and MMP-9 in a patient cohort comprising 17 with myelofibrosis (MF), 17 with polycythaemia vera (PV), 15 with essential thrombocythaemia (ET), 1 with a transitional MPD and 30 controls.

Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis.

Imatinib mesylate targets the adenosine triphosphate (ATP)-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, the platelet-derived growth factor (PDGF) and c-kit. In idiopathic myelofibrosis (IMF) PDGF is considered to be one of the growth factors responsible for the development of bone marrow fibrosis. Recently, it has been shown that imatinib has antifibrogenic effect on bone marrow fibrosis in chronic myelogenous leukemia.

Collagen metabolism and enzymes of the urokinase plasminogen activator system in chronic myeloproliferative disorders: correlation between plasma-soluble urokinase plasminogen activator receptor and serum markers for collagen metabolism.

Extracellular proteolytic enzymes of the urokinase-type plasminogen activator (uPA) system and the family of metalloproteinases (MMPs) catalyse the matrix degradation and remodelling processes characteristic of invasive malignant disorders. In a cohort of 50 patients with chronic myeloproliferative disorders (MPD) serum markers for collagen metabolism were compared to plasma levels of enzymes of the uPA and MMP system. Serum aminoterminal propeptide of type III procollagen (S-PIIINP) (P < 0.

Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan.

Eighty-three patients with various chronic myeloproliferative disorders [polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myelofibrosis (IMF)] were analyzed for the occurrence of acute myeloid leukemia (AML) and myelodysplasia (MDS) during treatment with hydroxyurea (HU) alone or HU following treatment with busulphan (BU). A total of 58 patients (29 PV, 14 ET, 12 IMF, 3 unclassified) had been treated with HU. Thirty-five of these patients had been treated with HU alone whereas 18 patients had received both HU and BU.

Thymic size in preterm neonates: a sonographic study.

Aim: To assess the variation in size of the thymus in vivo in preterm neonates and to identify relations between thymic size and gestational age (GA), birthweight, occurrence of postnatal infections and maternal alcohol and tobacco intake during pregnancy.

Methods: Eighty preterm neonates with a GA between 24 and 36 wk, and a birthweight between 490 and 4110 g were examined between days 0 and 19 after birth. The thymic size was assessed by sonography as a volume estimate, the so-called thymic index (Ti).

SU6668 in idiopathic myelofibrosis--a rational therapeutic approach targeting several tyrosine kinases of importance for the myeloproliferation and the development of bone marrow fibrosis and angiogenesis.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder being featured by progressive accumulation of connective tissue in concert with marked neovascularization (angiogenesis) of the bone marrow. Both fibrogenesis and angiogenesis are considered to develop consequent to the intramedullary release of various growth-promoting factors from rapidly proliferating and dysplastic megakaryocytes. Among these growth factors are platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF).