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Ruxolitinib

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https://www.readbyqxmd.com/read/29675680/a-randomized-double-blind-phase-2-study-of-ruxolitinib-or-placebo-in-combination-with-capecitabine-in-patients-with-advanced-her2-negative-breast-cancer-and-elevated-c-reactive-protein-a-marker-of-systemic-inflammation
#1
Joyce O'Shaughnessy, Angela DeMichele, Cynthia X Ma, Paul Richards, Denise A Yardley, Gail Shaw Wright, Kevin Kalinsky, Ronald Steis, Sami Diab, Gerard Kennealey, Ryan Geschwindt, Wei Jiang, Hope S Rugo
PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1). METHODS: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine...
April 19, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29665922/-safety-and-effectiveness-of-ruxolitinib-for-treatment-of-myeloproliferative-neoplasm-a-meta-analysis
#2
Zhi-Rui Yang, Hai-Yan Zhu
OBJECTIVE: To evaluate the efficacy and safety of ruxolitinib in treatment of myeloproliferative neoplasm. METHODS: Random clinical trials (~September 30, 2017) were identified from PubMed, Embase, Cochrane Library, Clinical Trials, CBM and Chinese Journal Full-text Database. The quality of RCT was assessed by Cochrane risk bias. Meta analysis was performed with Revman 5.3. RESULTS: Ruxolitinib was efficacious in relieving splenomegaly (RR 49...
April 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29651917/erythematous-skin-lesions-with-necrotic-centers-on-lower-extremities-due-to-the-use-of-ruxolitinib-for-primary-myelofibrosis
#3
Constantin A Dasanu
Ruxolitinib is a small molecule JAK-2 inhibitor approved for the treatment of certain myeloproliferative neoplasms. Ruxolitinib-related skin toxicity is extremely rare. We report herein an unusual erythematous skin eruption with necrotic centers involving lower extremities in a patient with primary myelofibrosis treated with ruxolitinib. Awareness of this unusual skin toxicity with ruxolitinib becomes even more important as JAK-2 inhibition might soon find clinical applications in dermatology.
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29650801/the-role-of-jak2-inhibitors-in-mpn-seven-years-after-approval
#4
Francesco Passamonti, Margherita Maffioli
Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV) and primary myelofibrosis (PMF). Phenotype-driver mutations of JAK2, CALR and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high risk myelofibrosis (MF) and of PV inadequately controlled by or intolerant of hydroxyurea...
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29645296/effects-of-jak1-2-inhibition-on-bone-marrow-stromal-cells-of-myeloproliferative-neoplasm-mpn-patients-and-healthy-individuals
#5
Dimitra Zacharaki, Roshanak Ghazanfari, Hongzhe Li, Hooi Ching Lim, Stefan Scheding
OBJECTIVE: Philadelphia-negative myeloproliferative neoplasms (MPNs) commonly share hyperactive JAK-STAT signaling affecting hematopoietic stem cells (HSC) and their progeny. The JAK1/2 inhibitor Ruxolitinib has remarkable clinical efficacy, including spleen reduction, improvement of constitutional symptoms, and bone marrow (BM) fibrosis reversal. Whether this is due to inhibition of JAK2-mutated HSC only, or whether Ruxolitinib also affects BM stroma is not known. METHODS: This study investigated potential effects of Ruxolitinib on BM mesenchymal stromal cells (MSC), which are not only major regulators of hematopoiesis but also contribute to fibrosis, from 10 healthy donors and 7 JAK2V617F -positive MPN patients...
April 12, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29643232/increased-neutrophil-extracellular-trap-formation-promotes-thrombosis-in-myeloproliferative-neoplasms
#6
Ofir Wolach, Rob S Sellar, Kimberly Martinod, Deya Cherpokova, Marie McConkey, Ryan J Chappell, Alexander J Silver, Dylan Adams, Cecilia A Castellano, Rebekka K Schneider, Robert F Padera, Daniel J DeAngelo, Martha Wadleigh, David P Steensma, Ilene Galinsky, Richard M Stone, Giulio Genovese, Steven A McCarroll, Bozenna Iliadou, Christina Hultman, Donna Neuberg, Ann Mullally, Denisa D Wagner, Benjamin L Ebert
Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29627078/the-roles-of-jak2-in-dna-damage-and-repair-in-the-myeloproliferative-neoplasms-opportunities-for-targeted-therapy
#7
REVIEW
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29624703/epidemiology-outcome-and-risk-factors-for-infectious-complications-in-myelofibrosis-patients-receiving-ruxolitinib-a-multicenter-study-on-446-patients
#8
Nicola Polverelli, Giuseppe A Palumbo, Gianni Binotto, Elisabetta Abruzzese, Giulia Benevolo, Micaela Bergamaschi, Alessia Tieghi, Massimiliano Bonifacio, Massimo Breccia, Lucia Catani, Mario Tiribelli, Mariella D'Adda, Nicola Sgherza, Alessandro Isidori, Francesco Cavazzini, Bruno Martino, Roberto Latagliata, Monica Crugnola, Florian Heidel, Costanza Bosi, Adalberto Ibatici, Francesco Soci, Domenico Penna, Luigi Scaffidi, Franco Aversa, Roberto M Lemoli, Umberto Vitolo, Antonio Cuneo, Domenico Russo, Michele Cavo, Nicola Vianelli, Francesca Palandri
Infections represent one of the major concerns regarding the utilization of ruxolitinib (RUX) in patients with myelofibrosis. With the aim to investigate epidemiology, outcome and risk factors for infections in RUX-exposed patients, we collected clinical and laboratory data of 446 myelofibrosis patients treated with RUX between June 2011 and November 2016 in 23 European Hematology Centers. After a median RUX exposure of 23.5 months (range, 1-56), 123 patients (28%) experienced 161 infectious events (grades 3-4 32%, fatal 9%), for an incidence rate of 17 cases per 100 pts/y...
April 6, 2018: Hematological Oncology
https://www.readbyqxmd.com/read/29622655/repurposing-tofacitinib-as-an-anti-myeloma-therapeutic-to-reverse-growth-promoting-effects-of-the-bone-marrow-microenvironment
#9
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
https://www.readbyqxmd.com/read/29616317/outcomes-of-patients-with-myelofibrosis-treated-with-compassionate-use-pacritinib-a-sponsor-independent-international-study
#10
J Mascarenhas, E Virtgaym, M Stal, H Blacklock, A T Gerds, R Mesa, P Ganly, D Snyder, I Tabbara, D Tremblay, E Moshier
Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients...
April 3, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29597187/combination-therapy-with-ruxolitinib-and-hydroxyurea-for-the-treatment-of-myeloid-predominant-leukocytosis-in-a-patient-with-myelofibrosis
#11
Giovanni Caocci, Silvia Ghiani, Cristina Mocci, Giorgio La Nasa
No abstract text is available yet for this article.
March 29, 2018: Acta Haematologica
https://www.readbyqxmd.com/read/29565699/jak2-v617f-mutation-in-plasma-cell-free-dna-preceding-clinically-overt-myelofibrosis-implications-for-early-diagnosis
#12
Michael Y Choi, Shumei Kato, Huan-You Wang, Jonathan H Lin, Richard B Lanman, Razelle Kurzrock
A 52 year-old man with Erdheim-Chester Disease (ECD) (a non-Lanherhans polyostotic sclerosing histiocytosis) had next-generation sequencing (NGS) performed as part of his diagnostic workup. In addition to the tissue BRAF V600E mutation that is found in over 50% of ECD cases, he was also found to have a JAK2 V617F alteration in cell-free circulating tumor DNA (ctDNA) (liquid biopsy). The latter was thought to be an "incidental" finding, perhaps due to clonal hematopoiesis (though this usually occurs in older individuals), as his blood counts were normal and he had no splenomegaly...
March 22, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29562644/understanding-splenomegaly-in-myelofibrosis-association-with-molecular-pathogenesis
#13
REVIEW
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen...
March 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29550629/steroid-refractory-chronic-graft-versus-host-disease-cost-effectiveness-analysis
#14
Fevzi F Yalniz, Mohammad H Murad, Stephanie J Lee, Steven Z Pavletic, Nandita Khera, Nilay D Shah, Shahrukh K Hashmi
Given the increasing incidence of cGVHD and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost effectiveness analysis (CEA) for the frequently utilized agents in SR-cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis (ECP), pomalidomide and methotrexate...
March 14, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29546543/maldi-imaging-facilitates-new-topical-drug-development-process-by-determining-quantitative-skin-distribution-profiles
#15
David Bonnel, Raphaël Legouffe, André H Eriksson, Rasmus W Mortensen, Fabien Pamelard, Jonathan Stauber, Kim T Nielsen
Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration...
March 15, 2018: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/29544547/long-term-effects-of-ruxolitinib-versus-best-available-therapy-on-bone-marrow-fibrosis-in-patients-with-myelofibrosis
#16
Hans Michael Kvasnicka, Jürgen Thiele, Carlos E Bueso-Ramos, William Sun, Jorge Cortes, Hagop M Kantarjian, Srdan Verstovsek
BACKGROUND: Myelofibrosis (MF) is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, and progressive bone marrow (BM) fibrosis. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been shown to improve splenomegaly, symptom burden, and overall survival in patients with intermediate-2 or high-risk MF compared with placebo or best available therapy (BAT). METHODS: The effects of ruxolitinib therapy for up to 66 months on BM morphology in 68 patients with advanced MF with variable BM fibrosis grade were compared with those in 192 matching patients treated with BAT...
March 15, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29522138/pacritinib-vs-best-available-therapy-including-ruxolitinib-in-patients-with-myelofibrosis-a-randomized-clinical-trial
#17
John Mascarenhas, Ronald Hoffman, Moshe Talpaz, Aaron T Gerds, Brady Stein, Vikas Gupta, Anita Szoke, Mark Drummond, Alexander Pristupa, Tanya Granston, Robert Daly, Suliman Al-Fayoumi, Jennifer A Callahan, Jack W Singer, Jason Gotlib, Catriona Jamieson, Claire Harrison, Ruben Mesa, Srdan Verstovsek
Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib. Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia. Design, Setting, and Participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis...
March 8, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29515770/ruxolitinib-significantly-enhances-in-vitro-apoptosis-in-hodgkin-lymphoma-and-primary-mediastinal-b-cell-lymphoma-and-survival-in-a-lymphoma-xenograft-murine-model
#18
Sanghoon Lee, Tishi Shah, Changhong Yin, Jessica Hochberg, Janet Ayello, Erin Morris, Carmella van de Ven, Mitchell S Cairo
Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation...
February 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29515238/philadelphia-chromosome-negative-classical-myeloproliferative-neoplasms-revised-management-recommendations-from-european-leukemianet
#19
REVIEW
Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi, Francesco Passamonti, Richard T Silver, Ronald Hoffman, Srdan Verstovsek, Ruben Mesa, Jean-Jacques Kiladjian, Rȕdiger Hehlmann, Andreas Reiter, Francisco Cervantes, Claire Harrison, Mary Frances Mc Mullin, Hans Carl Hasselbalch, Steffen Koschmieder, Monia Marchetti, Andrea Bacigalupo, Guido Finazzi, Nicolaus Kroeger, Martin Griesshammer, Gunnar Birgegard, Giovanni Barosi
This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development...
February 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29508628/drug-associated-pulmonary-arterial-hypertension
#20
Michael McGee, Nicholas Whitehead, Jennifer Martin, Nicholas Collins
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension...
March 6, 2018: Clinical Toxicology
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