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Barbui T.,Ospedali Riuniti di Bergamo | Barbui T.,Research Foundation | Finazzi M.C.,Ospedali Riuniti di Bergamo | Finazzi G.,Ospedali Riuniti di Bergamo
Blood Reviews | Year: 2012

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a "high-risk" or "low-risk" category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100. mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available. © 2012 Elsevier Ltd.

Tefferi A.,Mayo Medical School | Barbui T.,Research Foundation
Mayo Clinic Proceedings | Year: 2015

Bone marrow (BM) morphologic features remain the cornerstone of diagnosis in both essential thrombocythemia (ET) and polycythemia vera (PV). In addition, recently discovered mutations, such as JAK2, CALR, and MPL, have proven useful in facilitating the diagnostic process. A JAK2 mutation is expected in PV, and its absence makes the diagnosis unlikely. However, JAK2 mutations also occur in about 60% of patients with ET, which underlines the need for BM examination in distinguishing JAK2-mutated ET from PV when the hemoglobin/hematocrit level is diagnostically equivocal (ie, as in "masked" PV). Most patients with JAK2-unmutated ET express CALR or MPL mutations, with respective estimated incidences of 22% and 3%, while approxmately 15% are wild-type for all 3 mutations (ie, they are triple-negative). As such, CALR first, followed by MPL if CALR is absent, mutation screening is appropriate in the diagnostic work-up of JAK2-unmutated ET but does not replace the need for BM morphologic examination in (1) confirming the diagnosis in triple-negative ET and (2) distinguishing ET from other myeloproliferative neoplasms that share the same mutations, including masked PV and early/prefibrotic myelofibrosis. Young patients (aged <60 years) with ET or PV and no history of thrombosis are conventionally regarded as having "low-risk" disease. First-line treatment in low-risk PV is phlebotomy to achieve a hematocrit target of 45% and low-dose aspirin, and first-line treatment in ET is observation alone in the absence of additional risk factors for arterial thrombosis (ie, JAK2 mutation and cardiovascular risk factors) or low-dose aspirin therapy, once or twice daily, in the presence of one or both of these risk factors, respectively. Cytoreductive therapy is indicated in high-risk (patients aged ≥60 years or a history of thrombosis) PV or ET in the form of hydroxyurea as first-line and interferon alfa or busulfan as second-line drugs of choice. We do not use ruxolitinib in patients with PV unless they have severe pruritus or symptomatic splenomegaly that is proved to be refractory to hydroxyurea, interferon alfa, and busulfan. © 2015 Mayo Foundation for Medical Education and Research.

Barbui T.,Research Foundation | Finazzi G.,Hospital Papa Giovanni XXIII | Falanga A.,Hospital Papa Giovanni XXIII
Blood | Year: 2013

Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a "high risk" or "low risk". Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies. © 2013 by The American Society of Hematology.

Tefferi A.,Mayo Medical School | Barbui T.,Research Foundation
Leukemia | Year: 2013

The World Health Organization (WHO) classification system has recently strengthened the diagnostic criteria for essential thrombocythemia (ET) by lowering the threshold platelet count, underscoring its morphological distinction from early/prefibrotic myelofibrosis (MF) and incorporating molecular markers of clonality. The International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) examined the clinical relevance of this process in 1104 cases of locally diagnosed 'ET' and showed worse overall, leukemia-free and fibrosis-free survival, and a higher risk of bleeding in early/prefibrotic MF (n=180) vs WHO-defined ET (n=891). The risk of thrombosis was similar between the two entities and, in WHO-defined ET, was predicted by thrombosis history, older age, cardiovascular risk factors and JAK2V617F. A prognostic model based on these risk factors identified patient groups in ET with residual risk of thrombosis, despite treatment with conventional therapy. The main objectives of the current perspective are to underscore the prognostic importance of morphological confirmation in the diagnosis of ET and provide management recommendations, in both WHO-defined ET and early/prefibrotic MF, based on observations from the aforementioned IWG-MRT and other studies. In so doing, we are fully cognizant and sympathetic of the fact that some of our recommendations need to be tested in prospective controlled studies. © 2013 Macmillan Publishers Limited. All rights reserved.

Research Foundation | Date: 2010-03-05

The invention provides compositions and methods useful to prepare segmented, negative strand RNA viruses, e.g., orthomyxoviruses such as influenza A viruses, entirely from cloned cDNAs and in the absence of helper virus.

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