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Azacitidine

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https://www.readbyqxmd.com/read/29435332/more-is-less-less-is-more-or-does-it-really-matter-the-curious-case-of-impact-of-azacitidine-administration-schedules-on-outcomes-in-patients-with-myelodysplastic-syndromes
#1
Rory M Shallis, Amer M Zeidan
Myelodysplastic syndromes (MDS) encompass a diverse group of hematologic disorders characterized by ineffective and malignant hematopoiesis, peripheral cytopenias and significantly increased risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine induce meaningful clinical responses in a significant subset of patients with MDS. Though never compared directly with decitabine, only azacitidine has improved overall survival (OS) compared to conventional care in a randomized trial in patients with higher-risk MDS...
2018: BMC Hematology
https://www.readbyqxmd.com/read/29435331/systematic-review-of-azacitidine-regimens-in-myelodysplastic-syndrome-and-acute-myeloid-leukemia
#2
Roman M Shapiro, Alejandro Lazo-Langner
Background: 5-Azacitidine administered as a 7-day dosing regimen (7-0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5-0-0) or 7-day with a weekend break (5-2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5-0-0, 5-2-2, and 7-0-0 regimens in MDS and AML. Methods: A systematic review was conducted using MEDLINE, EMBASE and CENTRAL...
2018: BMC Hematology
https://www.readbyqxmd.com/read/29427211/treatment-with-5-azacitidine-delay-growth-of-glioblastoma-xenografts-a-potential-new-treatment-approach-for-glioblastomas
#3
Tobias Kratzsch, Susanne Antje Kuhn, Andreas Joedicke, Uwe Karsten Hanisch, Peter Vajkoczy, Jens Hoffmann, Iduna Fichtner
PURPOSE: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. The epigenetically active ribonucleoside analog 5-azacitidine is a new therapy option that changes tumor cell chromatin, which is frequently modified by methylation and deacetylation in malignant gliomas. METHODS: In vitro, we analyzed cell viability, cell apoptosis, and migration of human GBM cells. In vivo, we established subcutaneous and intracerebral GBM mouse models originating from U87MG, U373MG, and primary GBM cells as well as one patient-derived xenograft...
February 9, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29389832/treatment-with-azacitidine-in-the-context-of-palliative-care-for-a-patient-with-acute-myeloid-leukemia-complicating-fanconi-anemia-with-biallelic-fancd1-brca-2-mutations
#4
Aurélie Berot, Claire Pluchart
No abstract text is available yet for this article.
January 31, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29383443/establishment-and-validation-of-a%C3%A2-novel-risk-model-for-estimating-time-to-first-treatment-in-120-patients-with-chronic-myelomonocytic-leukaemia
#5
Florian Huemer, Lukas Weiss, Viktoria Faber, Daniel Neureiter, Alexander Egle, Klaus Geissler, Daniela Voskova, Armin Zebisch, Sonja Burgstaller, Angelika Pichler, Reinhard Stauder, Wolfgang Sperr, Alois Lang, Michael Pfeilstöcker, Sigrid Machherndl-Spandl, Margarete Stampfl, Richard Greil, Lisa Pleyer
Chronic myelomonocytic leukaemia is a rare disease and data on the treatment are often extrapolated from myelodysplastic syndrome studies. Although several scores exist for the prognosis of overall survival in chronic myelomonocytic leukaemia, so far there is no designated score for the prediction of the time to first treatment. We tested clinical parameters and cytogenetic information for their ability to predict the time to first treatment in our single center cohort of 55 unselected consecutive chronic myelomonocytic leukaemia patients...
January 30, 2018: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/29370237/increased-separase-activity-and-occurrence-of-centrosome-aberrations-concur-with-transformation-of-mds
#6
Sabrina Ruppenthal, Helga Kleiner, Florian Nolte, Alice Fabarius, Wolf-Karsten Hofmann, Daniel Nowak, Wolfgang Seifarth
ESPL1/separase, a cysteine endopeptidase, is a key player in centrosome duplication and mitotic sister chromatid separation. Aberrant expression and/or altered separase proteolytic activity are associated with centrosome amplification, aneuploidy, tumorigenesis and disease progression. Since centrosome alterations are a common and early detectable feature in patients with myelodysplastic syndrome (MDS) and cytogenetic aberrations play an important role in disease risk stratification, we examined separase activity on single cell level in 67 bone marrow samples obtained from patients with MDS, secondary acute myeloid leukemia (sAML), de novo acute myeloid leukemia (AML) and healthy controls by a flow cytometric separase activity assay...
2018: PloS One
https://www.readbyqxmd.com/read/29348128/pevonedistat-a-first-in-class-nedd8-activating-enzyme-nae-inhibitor-combined-with-azacitidine-in-patients-with-aml
#7
Ronan T Swords, Steven Coutre, Michael B Maris, Joshua F Zeidner, James M Foran, Jose Cruz, Harry P Erba, Jesus G Berdeja, Wayne Tam, Saran Vardhanabhuti, Iwona Pawlikowska-Dobler, Hélène M Faessel, Ajeeta B Dash, Farhad Sedarati, Bruce J Dezube, Douglas V Faller, Michael R Savona
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days...
January 18, 2018: Blood
https://www.readbyqxmd.com/read/29340104/somatic-mutation-dynamics-in-mds-patients-treated-with-azacitidine-indicate-clonal-selection-in-patients-responders
#8
Kamila Polgarova, Karina Vargova, Vojtech Kulvait, Nina Dusilkova, Lubomir Minarik, Zuzana Zemanova, Michal Pesta, Anna Jonasova, Tomas Stopka
Azacitidine (AZA) for higher risk MDS patients is a standard therapy with limited durability. To monitor mutation dynamics during AZA therapy we utilized massive parallel sequencing of 54 genes previously associated with MDS/AML pathogenesis. Serial sampling before and during AZA therapy of 38 patients (reaching median overall survival 24 months (Mo) with 60% clinical responses) identified 116 somatic pathogenic variants with allele frequency (VAF) exceeding 5%. High accuracy of data was achieved via duplicate libraries from myeloid cells and T-cell controls...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339403/a-phase-1-study-of-azacitidine-combined-with-chemotherapy-in-childhood-leukemia-a-report-from-tacl-consortium
#9
Weili Sun, Timothy Triche, Jemily Malvar, Paul Gaynon, Richard Sposto, Xiaojing Yang, Henrique Bittencourt, Andrew E Place, Yoav Messinger, Chris Fraser, Luciano Dalla-Pozza, Bodour Salhia, Peter Jones, Alan S Wayne, Lia Gore, Todd M Cooper, Gangning Liang
Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, chemotherapy resistance, and relapse. DNA methyltransferase inhibitors such as azacitidine and decitabine have been shown to reverse drug resistance and prime leukemia cells to cytotoxic agents in vitro. Here we report the first pediatric phase 1 study using azacitidine in sequence with chemotherapy in patients with relapsed/refractory leukemia. Fourteen patients were enrolled, twelve with acute myeloid leukemia (AML) and two with acute lymphoblastic leukemia (ALL)...
January 16, 2018: Blood
https://www.readbyqxmd.com/read/29339097/safety-and-preliminary-efficacy-of-venetoclax-with-decitabine-or-azacitidine-in-elderly-patients-with-previously-untreated-acute-myeloid-leukaemia-a-non-randomised-open-label-phase-1b-study
#10
Courtney D DiNardo, Keith W Pratz, Anthony Letai, Brian A Jonas, Andrew H Wei, Michael Thirman, Martha Arellano, Mark G Frattini, Hagop Kantarjian, Relja Popovic, Brenda Chyla, Tu Xu, Martin Dunbar, Suresh K Agarwal, Rod Humerickhouse, Mack Mabry, Jalaja Potluri, Marina Konopleva, Daniel A Pollyea
BACKGROUND: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study...
January 12, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29326802/allogeneic-hematopoietic-stem-cell-transplantation-in-therapy-related-myeloid-neoplasms-t-mn-of-the-adult-monocentric-observational-study-and-review-of-the-literature
#11
Elisabetta Metafuni, Patrizia Chiusolo, Luca Laurenti, Federica Sorà, Sabrina Giammarco, Andrea Bacigalupo, Giuseppe Leone, Simona Sica
Background: Therapy related myeloid neoplasms (t-MN) occur due to direct mutational events of chemotherapeutic agents and radiotherapy. Disease latency, mutational events and prognosis vary with drugs categories. Methods: We describe a cohort of 30 patients, 18 females and 12 males, with median age of 52.5 years (range, 20 to 64), submitted to allogeneic stem cell transplantation (HSCT) in our department between September 1999 and March 2017. Patients had a history of solid tumour in 14 cases, haematological disease in 15 cases and both of them in one case...
2018: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/29312564/azacitidine-combined-with-the-selective-flt3-kinase-inhibitor-crenolanib-disrupts-stromal-protection-and-inhibits-expansion-of-residual-leukemia-initiating-cells-in-flt3-itd-aml-with-concurrent-epigenetic-mutations
#12
Anne-Kathrin Garz, Saskia Wolf, Sonja Grath, Verena Gaidzik, Stefan Habringer, Binje Vick, Martina Rudelius, Christoph Ziegenhain, Sylvia Herold, Marie-Theresa Weickert, Martha Smets, Christian Peschel, Robert A J Oostendorp, Sebastian Bultmann, Irmela Jeremias, Christian Thiede, Konstanze Döhner, Ulrich Keller, Katharina S Götze
Effectively targeting leukemia-initiating cells (LIC) in FLT3 -ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3 -ITD LIC and whether efficacy of this combination depends on co-existing mutations...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29291002/mutations-in-the-dna-methylation-pathway-and-number-of-driver-mutations-predict-response-to-azacitidine-in-myelodysplastic-syndromes
#13
M Teresa Cedena, Inmaculada Rapado, Alejandro Santos-Lozano, Rosa Ayala, Esther Onecha, María Abaigar, Esperanza Such, Fernando Ramos, José Cervera, María Díez-Campelo, Guillermo Sanz, Jesús Hernández Rivas, Alejandro Lucía, Joaquin Martínez-López
We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282890/efficacy-safety-and-pharmacokinetics-of-subcutaneous-azacitidine-in-chinese-patients-with-higher-risk-myelodysplastic-syndromes-results-from-a-multicenter-single-arm-open-label-phase-2-study
#14
Xin Du, Yue-Yun Lai, Zhijian Xiao, Ting Liu, Yu Hu, Aining Sun, Xiao Li, Zhi-Xiang Shen, Jie Jin, Li Yu, Eric Laille, Qian Dong, Stephen Songer, C L Beach
BACKGROUND: Azacitidine safety and efficacy were established in studies of mainly Caucasian patients. Differences in drug metabolism enzymes between Caucasian and East Asian populations prevent extrapolation of drug effects between these groups. This phase 2 study evaluated azacitidine safety, efficacy and pharmacokinetics in patients with higher-risk myelodysplastic syndromes (HR-MDS) in mainland China. METHODS: Patients aged ≥18 years with HR-MDS were to receive subcutaneous azacitidine 75 mg/m2 /day for 7 days per 28-day cycle, for ≥6 cycles...
December 28, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29249821/aza-ms-a-novel-multiparameter-mass-spectrometry-method-to-determine-the-intracellular-dynamics-of-azacitidine-therapy-in-vivo
#15
A Unnikrishnan, A N Q Vo, R Pickford, M J Raftery, A C Nunez, A Verma, L B Hesson, J E Pimanda
The cytidine analogue, 5-azacytidine (AZA; 5-AZA-cR), is the primary treatment for myelodysplastic syndrome and chronic myelomonocytic leukaemia. However, only ~50% of treated patients will respond to AZA and the drivers of AZA resistance in vivo are poorly understood. To better understand the intracellular dynamics of AZA upon therapy and decipher the molecular basis for AZA resistance, we have developed a novel, multiparameter, quantitative mass spectrometry method (AZA-MS). Using AZA-MS, we have accurately quantified the abundance of the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA and the cytoplasm within the same sample using nanogram quantities of input material...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29242529/decitabine-a-dna-demethylating-agent-promotes-differentiation-via-notch1-signaling-and-alters-immune-related-pathways-in-muscle-invasive-bladder-cancer
#16
Swathi Ramakrishnan, Qiang Hu, Nithya Krishnan, Dan Wang, Evelyn Smit, Victoria Granger, Monika Rak, Kristopher Attwood, Candace Johnson, Carl Morrison, Roberto Pili, Gurkamal Chatta, Khurshid Guru, Geraldine Gueron, Lacey McNally, Jianmin Wang, Anna Woloszynska-Read
Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation...
December 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29241450/azacitidine-improves-clinical-outcomes-in-older-patients-with-acute-myeloid-leukaemia-with-myelodysplasia-related-changes-compared-with-conventional-care-regimens
#17
John F Seymour, Hartmut Döhner, Aleksandra Butrym, Agnieszka Wierzbowska, Dominik Selleslag, Jun Ho Jang, Rajat Kumar, James Cavenagh, Andre C Schuh, Anna Candoni, Christian Récher, Irwindeep Sandhu, Teresa Bernal Del Castillo, Haifa Kathrin Al-Ali, Jose Falantes, Richard M Stone, Mark D Minden, Jerry Weaver, Steve Songer, C L Beach, Hervé Dombret
BACKGROUND: Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia-related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (≥65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC. METHODS: We compared clinical outcomes for patients with AML-MRC treated with azacitidine or conventional care regimens (CCR; induction chemotherapy, low-dose cytarabine, or supportive care only) overall and within patient subgroups defined by cytogenetic risk (intermediate or poor) and age (65-74 years or ≥75 years)...
December 14, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29236331/reduction-of-two-histone-marks-h3k9me3-and-h3k27me3-by-epidrug-induces-neuroendocrine-differentiation-in-prostate-cancer
#18
Eunsohl Lee, Jingcheng Wang, Younghun Jung, Frank C Cackowski, Russell S Taichman
Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5-Azacitidine, 5-Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5-Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells...
December 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29227276/alteration-in-the-cytokine-secretion-pattern-in-t-cells-of-patients-with-cystic-fibrosis-caused-by-dna-methyltransferase-inhibitor-5-azacitidine
#19
E Kvaratskhelia, N Dabrundashvili, M Gagua, E Maisuradze, M Kamkamidze, E Abzianidze
Cystic fibrosis (CF) is the autosomal-recessive disorder caused by mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The Airway inflammation plays a central role in the progression of CF disease. Cystic fibrosis characterized by the overproduction of the pro-inflammatory cytokines and reduced expression of anti-inflammatory cytokines. Although the mechanisms of abnormal cytokine expression is still poorly understood, altered epigenetic regulations in T cells might contribute. In the present study we examined the expression of IFN-γ and IL-10 by CF T cells prior to and following 5-azaC treatment...
November 2017: Georgian Medical News
https://www.readbyqxmd.com/read/29222294/incorporating-novel-approaches-in-the-management-of-mds-beyond-conventional-hypomethylating-agents
#20
REVIEW
Olatoyosi Odenike
In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanucleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients who relapse after, or do not respond to, hypomethylating agent therapy, the outcome is dismal, and new agents and approaches that have the potential to alter the natural history of these diseases are desperately needed...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
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