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Brady L Stein, Stephen T Oh, Dmitriy Berenzon, Gabriela S Hobbs, Marina Kremyanskaya, Raajit K Rampal, Camille N Abboud, Kenneth Adler, Mark L Heaney, Elias J Jabbour, Rami S Komrokji, Alison R Moliterno, Ellen K Ritchie, Lawrence Rice, John Mascarenhas, Ronald Hoffman
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis...
November 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Andrzej Mital, Witold Prejzner, Renata Świątkowska-Stodulska, Andrzej Hellmann
INTRODUCTION: The aim of this study was to verify if PV patients with and without avWS differ in terms of their baseline clinical parameters. MATERIAL AND METHODS: The study included 142 consecutive patients with PV. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters...
October 2015: Thrombosis Research
Animesh Pardanani, Claire Harrison, Jorge E Cortes, Francisco Cervantes, Ruben A Mesa, Donald Milligan, Tamás Masszi, Elena Mishchenko, Eric Jourdan, Alessandro M Vannucchi, Mark W Drummond, Mindaugas Jurgutis, Kazimierz Kuliczkowski, Emanuil Gheorghita, Francesco Passamonti, Frank Neumann, Abhay Patki, Guozhi Gao, Ayalew Tefferi
IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF...
August 2015: JAMA Oncology
A Pardanani, A Tefferi, C Jamieson, N Y Gabrail, C Lebedinsky, G Gao, F Liu, C Xu, H Cao, M Talpaz
In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed...
August 7, 2015: Blood Cancer Journal
Ayalew Tefferi, Animesh Pardanani
Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) constitute the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by mutually exclusive Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; respective frequencies of these mutations are approximately 95%, 0%, and 0% in PV, 60%, 20%, and 3% in ET, and 60%, 25%, and 7% in PMF. These mutations might be accompanied by other mutations that are less specific to myeloproliferative neoplasms but are prognostically relevant, such as additional sex combs-like 1 (ASXL1)...
April 2015: JAMA Oncology
Alessandro M Vannucchi, Jean Jacques Kiladjian, Martin Griesshammer, Tamas Masszi, Simon Durrant, Francesco Passamonti, Claire N Harrison, Fabrizio Pane, Pierre Zachee, Ruben Mesa, Shui He, Mark M Jones, William Garrett, Jingjin Li, Ulrich Pirron, Dany Habr, Srdan Verstovsek
BACKGROUND: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. METHODS: We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients)...
January 29, 2015: New England Journal of Medicine
Rodolphe Besancenot, Damien Roos-Weil, Carole Tonetti, Hadjer Abdelouahab, Catherine Lacout, Florence Pasquier, Christophe Willekens, Philippe Rameau, Yann Lecluse, Jean-Baptiste Micol, Stefan N Constantinescu, William Vainchenker, Eric Solary, Stéphane Giraudier
Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL...
September 25, 2014: Blood
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