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Nikolai A Podoltsev, Maximilian Stahl, Amer M Zeidan, Steven D Gore
More than half of the patients with acute myeloid leukaemia (AML) are older than 60years. The treatment outcomes in this group remain poor with a median overall survival of <1year. Selecting initial treatment for these patients involves an assessment of 'fitness' for induction chemotherapy. This is done based on patient and disease-related characteristics which help to estimate treatment-related mortality and chance of complete remission with induction chemotherapy. If the risk of treatment-related mortality is high and/or the likelihood of a patient achieving a complete remission is low, lower-intensity treatment (low-dose cytarabine, decitabine and azacitidine) should be discussed...
October 8, 2016: Blood Reviews
G L Uy, E J Duncavage, G S Chang, M A Jacoby, C A Miller, J Shao, S Heath, K Elliott, T Reinick, R S Fulton, C C Fronick, M O'Laughlin, L Ganel, C N Abboud, A F Cashen, J F DiPersio, R K Wilson, D C Link, J S Welch, T J Ley, T A Graubert, P Westervelt, M J Walter
Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (i...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Beejal R Ganti, Bernard L Marini, Jerod Nagel, Dale Bixby, Anthony J Perissinotti
PURPOSE: This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients. METHODS: This was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis...
October 14, 2016: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
M Shao, X P Lyu, Q K Yang, W T Zhu, J Song, Y K Kong, J Wang, L Sun, F Wang
Objective: To investigate the impact of promoter CpG island methylation on ABO mRNA expression in leukemia. Methods: 25 cases of leukemia and 20 cases of normal control were studied, and the leukemia cell lines K562、HL-60 and Jurkat were treated with different concentrations of decitabine. PCR-SSP was used to identify ABO genotype, RQ-PCR for ABO mRNA expression and bisulfite sequencing PCR for DNA methylation status. Results: ① The methylation of ABO promoter in acute myeloid leukemia patients (10 cases) and acute lymphoblastic leukemia patients (10 cases) were 53...
September 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Zheng Zhang, Chun-Kang Chang, Qi He, Juan Guo, Ying Tao, Ling-Yun Wu, Feng Xu, Dong Wu, Li-Yu Zhou, Ji-Ying Su, Lu-Xi Song, Chao Xiao, Xiao Li
Decitabine is an effective therapy for patients with lower risk myelodysplastic syndrome (MDS). However, the mechanisms of decitabine's therapeutic effect are not well established. Forty-four lower risk MDS patients received decitabine therapy. 59.1% patients achieved treatment response, and 53.8% patients who were RBC/platelet-dependent cast off the transfusion burden. The median overall survival (OS) was 19.0 months after decitabine treatment. Moreover, polarization toward type 1 in the CD8 + subset was enhanced, and a significantly increased expression of the PD-1, PD-L1, and PD-1/STAT1 ratio was observed in these lower risk MDS...
August 11, 2016: Leukemia & Lymphoma
Xiao Huang, Guiqing Kong, Yan Li, Weiwei Zhu, Haixiao Xu, Xiaohua Zhang, Jiankui Li, Lipeng Wang, Zhongwen Zhang, Yaru Wu, Xiangyong Liu, Xiaozhi Wang
Decitabine (5-aza-2'-deoxycytidine, DAC) and 5-azacitidine (Aza), an inhibitor of DNA methyltransferases, possess a wide range of anti-metabolic and anti-cancer activities. This study examined the effects of DAC and Aza on inflammatory and oxidative injuries, as well as on glycocalyx and MAPK signaling pathways, in a LPS-stimulated ARDS mouse model. Results of ELISA revealed that DAC and Aza significantly inhibited the production of TNF-α and IL-1β and prevented LPS-induced elevation of myeloperoxidase and malondialdehyde levels in serum...
September 26, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Cheol-Hun Son, Hong-Rae Lee, Eun-Kyoung Koh, Dong-Yeok Shin, Jae-Ho Bae, Kwangmo Yang, You-Soo Park
Decitabine has been found to have anti-metabolic and anti-tumor activities in various tumor cells. Recently, the use of decitabine in combination with other conventional therapies reportedly resulted in improved anti-tumor activity against various tumors. Ionizing radiation (IR) is widely used as a cancer treatment. Decitabine and IR improve immunogenicity and susceptibility of tumor cells to immune cells by up-regulating the expression of various molecules such as major histocompatibility complex (MHC) class I; natural-killer group 2, member D (NKG2D) ligands; and co-stimulatory molecules...
September 27, 2016: Scientific Reports
L Fransecky, M Neumann, S Heesch, C Schlee, J Ortiz-Tanchez, S Heller, M Mossner, S Schwartz, L H Mochmann, K Isaakidis, L Bastian, U R Kees, T Herold, K Spiekermann, N Gökbuget, C D Baldus
BACKGROUND: GATA3 is pivotal for the development of T lymphocytes. While its effects in later stages of T cell differentiation are well recognized, the role of GATA3 in the generation of early T cell precursors (ETP) has only recently been explored. As aberrant GATA3 mRNA expression has been linked to cancerogenesis, we investigated the role of GATA3 in early T cell precursor acute lymphoblastic leukemia (ETP-ALL). METHODS: We analyzed GATA3 mRNA expression by RT-PCR (n = 182) in adult patients with T-ALL...
2016: Journal of Hematology & Oncology
Amer M Zeidan, Amy J Davidoff, Jessica B Long, Xin Hu, Rong Wang, Xiaomei Ma, Cary P Gross, Gregory A Abel, Scott F Huntington, Nikolai A Podoltsev, Uno Hajime, Thomas Prebet, Steven D Gore
The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan-Meier methods and used multivariate Cox proportional hazards models to adjust for covariates...
September 21, 2016: British Journal of Haematology
Simone Jueliger, John Lyons, Sara Cannito, Illar Pata, Pille Pata, Marianna Shkolnaya, Oriana Lo Re, Marion Peyrou, Francesc Villarroya, Valerio Pazienza, Francesca Rappa, Francesco Cappello, Mohammad Azab, Pietro Taverna, Manlio Vinciguerra
Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine...
August 11, 2016: Epigenetics: Official Journal of the DNA Methylation Society
W Blum, B L Sanford, R Klisovic, D J DeAngelo, G Uy, B L Powell, W Stock, M R Baer, J E Kolitz, E S Wang, E Hoke, K Mrózek, J Kohlschmidt, C D Bloomfield, S Geyer, G Marcucci, R M Stone, R A Larson
In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1...
October 7, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Valeria Lucarini, Carla Buccione, Giovanna Ziccheddu, Francesca Peschiaroli, Paola Sestili, Rossella Puglisi, Gianfranco Mattia, Cristiana Zanetti, Isabella Parolini, Laura Bracci, Iole Macchia, Alessandra Rossi, Maria Teresa D'Urso, Daniele Macchia, Massimo Spada, Adele De Ninno, Annamaria Gerardino, Pamela Mozetic, Marcella Trombetta, Alberto Rainer, Luca Businaro, Giovanna Schiavoni, Fabrizio Mattei
Resistance to Type I IFN (IFN-I)-induced anti-neoplastic effects has been reported in many tumors and arise, in part, from epigenetic silencing of IFN-stimulated genes by DNA methylation. We hypothesized that restoration of IFN-stimulated genes by co-administration of the demethylating drug 5-Aza-2'-Deoxycitidine (Decitabine; DAC) may enhance the susceptibility to IFN-I-mediated anti-tumoral effects in melanoma. We show that combined administration of IFN-I and DAC significantly inhibits the growth of murine and human melanoma cells, both in vitro and in vivo...
September 10, 2016: Journal of Investigative Dermatology
Haixia Zhou, Changcheng Zheng, Xiaoyu Zhu, Baolin Tang, Juan Tong, Xuhan Zhang, Lei Zhang, Huilan Liu, Zimin Sun
No clinical studies have investigated the role of decitabine as a part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL in patients in NR status. The aim of this study was to identify the potential benefits of decitabine as a prior therapy before salvaged unrelated UCBT for refractory or relapsed childhood AL. Eight consecutive patients with childhood refractory/relapsed AL were enrolled in our study between 2013 and 2014. All patients were in NR status before the time of transplant and had features associated with poor outcomes, such as CNSL, MDS-AML, high WBC count at diagnosis, and hypodiploid status (FLT3+/ITD+)...
September 12, 2016: Pediatric Transplantation
Evanguelos Xylinas, Melanie R Hassler, Dazhong Zhuang, Martin Krzywinski, Zeynep Erdem, Brian D Robinson, Olivier Elemento, Thomas Clozel, Shahrokh F Shariat
Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients...
September 2, 2016: Biomolecules
Hazem E Hassan, Jean-Arnaud Keita, Lawrence Narayan, Sean M Brady, Richard Frederick, Samuel Carlson, Karen C Glass, Senthil Natesan, Thomm Buttolph, Tamer E Fandy
Curcumin and its analogs exhibited antileukemic activity either as single agent or in combination therapy. Dimethoxycurcumin (DMC) is a more metabolically stable curcumin analog that was shown to induce the expression of promoter-methylated genes without reversing DNA methylation. Accordingly, co-treatment with DMC and DNA methyltransferase (DNMT) inhibitors could hypothetically enhance the re-expression of promoter-methylated tumor suppressor genes. In this study, we investigated the cytotoxic effects and epigenetic changes associated with the combination of DMC and the DNMT inhibitor decitabine (DAC) in primary leukemia samples and cell lines...
September 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Cristina Riccadonna, Céline Yacoub Maroun, Romain Vuillefroy de Silly, Margaux Boehler, Marta Calvo Tardón, Simone Jueliger, Pietro Taverna, Leticia Barba, Eliana Marinari, Serena Pellegatta, Esen Yonca Bassoy, Denis Martinvalet, Pierre-Yves Dietrich, Paul R Walker
Malignant gliomas are aggressive brain tumours with very poor prognosis. The majority of glioma cells are differentiated (glioma-differentiated cells: GDCs), whereas the smaller population (glioma-initiating cells, GICs) is undifferentiated and resistant to conventional therapies. Therefore, to better target this pool of heterogeneous cells, a combination of diverse therapeutic approaches is envisaged. Here we investigated whether the immunosensitising properties of the hypomethylating agent decitabine can be extended to GICs...
2016: PloS One
Yang Cao, Guo-Qiang Qiu, Hao-Qing Wu, Zhi-Lin Wang, Yan Lin, Wei Wu, Xiao-Bao Xie, Wei-Ying Gu
The present study investigated the interactions between decitabine (DAC) and bortezomib (BTZ) in RPMI 8226 multiple myeloma (MM) cells. Cells were exposed to DAC alone and in combination with BTZ for 48 h. A Cell Counting Kit‑8 assay was performed to assess the rate of proliferation inhibition in the cells. Cell apoptosis was investigated by Annexin V-fluorescein isothiocyanate and propidium iodide staining. Flow cytometry was used to detect the different cell cycle stages. Western blotting was performed to analyze the protein expression levels of poly(ADP‑ribose) polymerase 1 (PARP‑1), caspase‑3, ‑9 and DNA (cytosine‑5‑)‑methyltransferase 1 (DNMT1)...
October 2016: Molecular Medicine Reports
Xin-Yan Xie, Zong-Hong Shao, Rong Fu, Li-Juan Li, Hua-Quan Wang, Hui Liu, Yi-Hao Wang, Wei Zhang, Jing-Lian Tao
OBJECTIVE: To investigate the expression pattern of HOXA9 in myelodysplastic syndrome (MDS) patients and its relation with clinical characteristics and treatment response. METHODS: The mRNA and protein expression levels of HOXA9 in bone marrow cells from 33 cases of MDS, 12 cases of AML, 20 cases of ITP and 18 normal controls were detected by real-time guautitative PCR(RT-PCR) and flow cytometry, respectively. RESULTS: The percentage of HOXA9(+)/CD34(+) and HOXA9(+)/CD34(+)CD38(-) in MDS patients were significantly higher than that in control group (P<0...
August 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Yu Jing, Xiangshu Jin, Lixin Wang, Liping Dou, Quanshun Wang, Yushi Yao, Shimei Lian, Jihao Zhou, Haiyan Zhu, Zilong Yao, Lijun Gao, Lili Wang, Yonghui Li, Xuefeng Bai, Meiyun Fang, Li Yu
In this study, we first initiated a multicenter, single-arm, phase-II clinical trial using decitabine (DAC) (20mg/m2 for five days) based chemotherapy, followed by haploidentical lymphocyte infusion (HLI) that was applied as induction therapy for elderly patients with AML. Furthermore, the role of HLI infusion was explored in a mouse model. The clinical trial included 29 elderly patients (median age: 64, range 57-77) with AML. Sixteen cases achieved complete remission (CR) and 9 cases achieved partial remission (PR) after the first treatment cycle...
August 10, 2016: Oncotarget
Yanchun Pan, Takuji Daito, Yo Sasaki, Yong Hee Chung, Xiaoyun Xing, Santhi Pondugula, S Joshua Swamidass, Ting Wang, Albert H Kim, Hiroko Yano
Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression...
2016: Scientific Reports
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