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https://www.readbyqxmd.com/read/28819011/tp53-mutations-identify-younger-mantle-cell-lymphoma-patients-who-do-not-benefit-from-intensive-chemoimmunotherapy
#1
Christian W Eskelund, Christina Dahl, Jakob W Hansen, Maj Westman, Arne Kolstad, Lone B Pedersen, Carmen P Montano-Almendras, Simon Husby, Catja Freiburghaus, Sara Ek, Anja Pedersen, Carsten Niemann, Riikka Räty, Peter Brown, Christian H Geisler, Mette K Andersen, Per Guldberg, Mats Jerkeman, Kirsten Grønbæk
Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67>30%); however, in multivariate analyses only TP53 mutations (HR=6...
August 17, 2017: Blood
https://www.readbyqxmd.com/read/28814980/cooperative-effect-of-chidamide-and-chemotherapeutic-drugs-induce-apoptosis-by-dna-damage-accumulation-and-repair-defects-in-acute-myeloid-leukemia-stem-and-progenitor-cells
#2
Yin Li, Yan Wang, Yong Zhou, Jie Li, Kai Chen, Leisi Zhang, Manman Deng, Suqi Deng, Peng Li, Bing Xu
BACKGROUND: Many conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed. RESULTS: We report that a low-dose chidamide, a novel orally active benzamide-type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34(+)CD38(-) KG1α cells, CD34(+)CD38(-) Kasumi cells, and primary refractory or relapsed AML CD34(+) cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28811872/current-and-emerging-treatment-options-for-mantle-cell-lymphoma
#3
REVIEW
Bita Fakhri, Brad Kahl
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with typically aggressive behavior. The genetic signature is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. Asymptomatic newly diagnosed MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Although MCL classically responds to upfront chemotherapy, it remains incurable with standard approaches. For patients in need of frontline therapy, the initial decision is whether to proceed with an intensive treatment strategy or a non-intensive treatment strategy...
August 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28810561/cytotoxic-t-lymphocytes-promote-cytarabine-induced-acute-myeloid-leukemia-cell-apoptosis-via-inhibiting-bcl-2-expression
#4
Rui Deng, Fang-Yi Fan, Hai Yi, Li Fu, Yan Zeng, Yi Wang, Xiao-Juan Miao, Yan-Rong Shuai, Guang-Cui He, Yi Su
Acute myeloid leukemia (AML) remains difficult to cure due to its drug tolerance and refractoriness. Immunotherapy is a growing area of cancer research, which has been applied for the treatment of numerous types of cancer, including leukemia. The present study generated AML cell-specific cytotoxic T lymphocytes (CTLs) in vitro and investigated the effect of combining CTL treatment with one of the most commonly used drugs for the treatment of hematological malignancies, cytarabine, on AML cell apoptosis. Firstly, it was observed that monocyte-depleted peripheral blood lymphocytes from healthy donors could be used to generate large numbers of CD3(+)CD8(+) CTLs through immune stimulation...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28810323/-the-efficacy-and-safety-of-the-patients-of-myelodysplastic-syndromes-refractory-anemia-with-excess-blasts-treated-with-decitabine-alone-or-cag-hag-regimen
#5
Z F Xu, T J Qin, H L Zhang, L W Fang, Y Zhang, L J Pan, N B Hu, S Q Qu, B Li, Z J Xiao
Objective: To observe the clinical efficacy and safety of the patients of myelodysplastic syndromes-refractory anemia with excess blasts (MDS-REAB) treated with decitabine alone or based on low dose cytarabine (Ara-C) regimen CAG/HAG [aclarubrci (ACR) /homoharring-tonine (HHT) +cytarabine+granulocyte colony stimulating factor (G-CSF) ]. Methods: Totally 121 patients with MDS-REAB were retrospectively analyzed, including 59 patients treated with decitabine alone (20 mg·m(-2)·d(-1) for 5 days) , the rest 62 ones treated with low-dose Ara-C-based regimen CAG/HAG...
July 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28804680/treatment-of-older-patients-with-acute-myeloid-leukemia-aml-revised-canadian-consensus-guidelines
#6
REVIEW
Joseph M Brandwein, Nancy Zhu, Rajat Kumar, Brian Leber, Mitchell Sabloff, Irwindeep Sandhu, Jeannine Kassis, Harold J Olney, Mohamed Elemary, Andre C Schuh
The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT)...
2017: American Journal of Blood Research
https://www.readbyqxmd.com/read/28802254/tdp1-is-critical-for-the-repair-of-dna-breaks-induced-by-sapacitabine-a-nucleoside-also-targeting-atm-and-brca-deficient-tumors
#7
Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N Rajapakse, Shar-Yin N Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier
2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28791810/cytotoxicity-of-anticancer-drugs-and-pj-34-poly-adp-ribose-polymerase-1-parp-1-inhibitor-on-hl-60-and-jurkat-cells
#8
Maciej Stępnik, Sylwia Spryszyńska, Anna Gorzkiewicz, Magdalena Ferlińska
BACKGROUND: The majority of the clinical trials with poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors were conducted or are ongoing in patients with solid tumors, while trials with leukemia patients are less frequent. Surprisingly scarce data is available on the combinatory effects of PARP inhibitors with DNA damaging antitumor drugs in leukemic cells (primary cells or established lines). OBJECTIVES: The aim of the present study was to assess the effect of PJ-34 (PARP-1 inhibitor) on the cytotoxicity of different antileukemic drugs with different DNA damaging mechanisms and potency (doxorubicin, etoposide, cytarabine and chlorambucil) in human leukemic Jurkat and HL-60 cells...
May 2017: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/28778089/identification-of-volasertib-resistant-mechanism-and-evaluation-of-combination-effects-with-volasertib-and-other-agents-on-acute-myeloid-leukemia
#9
Yoshiya Adachi, Yuichi Ishikawa, Hitoshi Kiyoi
Volasertib, a selective PLK1 inhibitor, was effective for acute myeloid leukemia (AML) patients in clinical trials. However, its efficacy was limited in mono-therapy, and a higher incidence of fatal events was revealed in the combination with low-dose cytarabine. Thus, optimization of combination therapy with volasertib and other agents is necessary for its clinical development, and the predictive factors for response or resistance to volasertib remain largely unknown. In this study, we investigated the resistance mechanism in volasertib-resistant cell lines and the combination effects with other agents, such as azacitidine (AZA), on AML cells...
July 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28771903/fludarabine-cytarabine-g-csf-and-idarubicin-for-children-with-relapsed-aml
#10
Hideki Nakayama, Daisuke Tomizawa, Shiro Tanaka, Shotaro Iwamoto, Akira Shimada, Akiko M Saito, Yuka Yamashita, Hiroshi Moritake, Kiminori Terui, Takashi Taga, Hidemasa Matsuo, Yoshiyuki Kosaka, Katsuyoshi Koh, Hajime Hosoi, Hidemitsu Kurosawa, Keiichi Isoyama, Keizo Horibe, Shuki Mizutani, Souichi Adachi
BACKGROUND: The combination of fludarabine (Flu), high dose cytarabine (Ara-C) and granulocyte-colony stimulating factor (G-CSF) called "FLAG" with anthracyclines has become a standard chemotherapy for refractory acute myeloid leukemia (AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin (IDA) for children prospectively, we planned a multicenter phase II study (AML-R11) by Japanese Pediatric Leukemia/Lymphoma Study Group. METHODS: Patients with AML at the age between 2 and 20 years old, who had the first bone marrow (BM) relapse or induction failure, were enrolled...
August 3, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/28767288/arsenic-trioxide-consolidation-allows-anthracycline-dose-reduction-for-pediatric-patients-with-acute-promyelocytic-leukemia-report-from-the-children-s-oncology-group-phase-iii-historically-controlled-trial-aaml0631
#11
Matthew A Kutny, Todd A Alonzo, Robert B Gerbing, Yi-Cheng Wang, Susana C Raimondi, Betsy A Hirsch, Cecilia H Fu, Soheil Meshinchi, Alan S Gamis, James H Feusner, John J Gregory
Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance...
August 2, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28766544/-ebv-positive-central-nervous-system-lymphoproliferative-disease-associated-with-immunosuppression-after-organ-transplantation-long-term-remission-without-chemotherapy
#12
O A Gavrilina, V V Troitskaya, E E Zvonkov, E N Parovichnikova, G M Galstyan, L S Biryukova, I V Nesterenko, A M Kovrigina, A V Bazhenov, V G Savchenko, V G Savchenko
Primary central nervous system (CNS) lymphomas account for 13-20% of the posttransplant lymphoproliferative disorders (PTLD) and rank among the most aggressive conditions. Reduction of immunosuppressive therapy should be mandatory to treat PTLD, but this is rarely used as the only therapy option. Chemotherapy regimens for PTLD involving the CNS most commonly include high-dose rituximab and high-dose methotrexate and/or cytarabine. The efficiency only of discontinuation of immunosuppressive therapy for PTLD does not exceed 5-10%, but there are no literature data on its efficiency for PTLD involving the CNS...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28765039/jnk1-as-a-signaling-node-in-vdr-braf-induction-of-cell-death-in-aml
#13
Xuening Wang, William K Beute, Jonathan S Harrison, George P Studzinski
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC)...
July 29, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28751770/enhancing-venetoclax-activity-in-acute-myeloid-leukemia-by-co-targeting-mcl1
#14
T-C Teh, N-Yn Nguyen, D M Moujalled, D Segal, G Pomilio, S Rijal, A Jabbour, K Cummins, K Lackovic, P Blombery, E Thompson, P G Ekert, G Lessene, S P Glaser, D C S Huang, A W Roberts, M A Guthridge, A H Wei
Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the BCL-2 family of proteins is an attractive option to combat chemoresistance in leukemia. Pre-clinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (e.g. venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase anti-leukemic efficacy in a TP53 dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53...
July 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28728594/implementing-the-efftox-dose-finding-design-in-the-matchpoint-trial
#15
Kristian Brock, Lucinda Billingham, Mhairi Copland, Shamyla Siddique, Mirjana Sirovica, Christina Yap
BACKGROUND: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. METHODS: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes...
July 20, 2017: BMC Medical Research Methodology
https://www.readbyqxmd.com/read/28725988/interim-18-f-fgd-pet-ct-may-not-predict-the-outcome-in-primary-central-nervous-system-lymphoma-patients-treated-with-sequential-treatment-with-methotrexate-and-cytarabine
#16
Jae-Cheol Jo, Dok Hyun Yoon, Shin Kim, Kyoungmin Lee, Eun Hee Kang, Jung Sun Park, Jin-Sook Ryu, Jooryung Huh, Chan-Sik Park, Jong Hoon Kim, Sang Wook Lee, Cheolwon Suh
(18)F-fluoro-2-dexoy-D-glucose-positron emission tomography (PET)/computed tomography (CT) is a useful imaging technique for monitoring the treatment response in lymphoma cases. We investigated the value of interim brain PET/CT (I-PET/CT) for monitoring the response to intensive methotrexate-based chemotherapy in primary central nervous system lymphoma (PCNSL) patients with diffuse large B cell lymphoma (DLBCL). Of the 76 PCNSL patients treated with intensive methotrexate and cytarabine chemotherapy between September 2006 and December 2012, 66 patients with DLBCL were included in this study...
September 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28721010/antiglioma-effects-of-cytarabine-on-leptomeningeal-metastasis-of-high-grade-glioma-by-targeting-the-pi3k-akt-mtor-pathway
#17
Kai-Hong Zhao, Can Zhang, Yue Bai, Yan Li, Xun Kang, Jian-Xin Chen, Kun Yao, Tao Jiang, Xiao-Song Zhong, Wen-Bin Li
Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28718728/a-phase-i-ii-randomized-trial-of-clofarabine-or-fludarabine-added-to-idarubicin-and-cytarabine-for-adults-with-relapsed-or-refractory-acute-myeloid-leukemia
#18
Nicholas J Short, Hagop Kantarjian, Farhad Ravandi, Xuelin Huang, Lianchun Xiao, Guillermo Garcia-Manero, William Plunkett, Varsha Gandhi, Koji Sasaki, Naveen Pemmaraju, Naval G Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Zeev Estrov, Tapan M Kadia, William G Wierda, Courtney D DiNardo, Mark Brandt, Susan M O'Brien, Jorge E Cortes, Elias Jabbour
The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m(2) was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = ...
July 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28717763/burkitt-s-lymphoma-and-b-cell-lymphoma-unclassifiable-with-features-intermediate-between-diffuse-large-b-cell-lymphoma-and-burkitt-s-lymphoma-in-patients-with-hiv-outcomes-in-a-south-african-public-hospital
#19
Gerhard Sissolak, Matthew Seftel, Thomas S Uldrick, Tonya M Esterhuizen, Nooroudien Mohamed, Danie Kotze
PURPOSE: Burkitt's lymphoma (BL) is a common HIV-associated lymphoma in South Africa. B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BL/DLBCL) also occurs in HIV infection. Outcomes of HIV-infected patients with BL or BL/DLBCL in a resource-constrained setting are not defined. METHODS: We performed a retrospective study of HIV-positive patients with BL or BL/DLBCL treated from 2004 to 2012 with curative intent at a publically funded academic medical center in South Africa...
June 2017: Journal of Global Oncology
https://www.readbyqxmd.com/read/28711923/acute-myeloid-leukemia-cells-require-6-phosphogluconate-dehydrogenase-for-cell-growth-and-nadph-dependent-metabolic-reprogramming
#20
Haymanti Bhanot, Ellen L Weisberg, Mamatha M Reddy, Atsushi Nonami, Donna Neuberg, Richard M Stone, Klaus Podar, Ravi Salgia, James D Griffin, Martin Sattler
Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth...
June 28, 2017: Oncotarget
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