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https://www.readbyqxmd.com/read/28229434/preclinical-pharmacokinetics-and-pharmacodynamics-of-pinometostat-epz-5676-a-first-in-class-small-molecule-s-adenosyl-methionine-competitive-inhibitor-of-dot1l
#1
Nigel J Waters
Acute leukemias bearing mixed lineage leukemia (MLL) rearrangements are aggressive diseases characterized by a poor overall prognosis despite multi-agent chemotherapy. Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of DOT1L, to a multi-protein complex resulting in aberrant methylation of histone H3 lysine 79 at MLL target genes, and ultimately enhanced expression of critical genes for hematopoietic differentiation, including HOXA9 and MEIS1, and as such defines the established mechanism for leukemogenesis in MLL-rearrangement (MLL-r) leukemias...
February 22, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28218757/allogeneic-stem-cell-transplantation-for-refractory-acute-myeloid-leukemia-in-pediatric-patients-the-uk-experience
#2
P O'Hare, G Lucchini, M Cummins, P Veys, M Potter, S Lawson, A Vora, R Wynn, A Peniket, K Kirkland, R Pearce, J Perry, P J Amrolia
We report outcomes for 44 children who underwent stem cell transplantation (SCT) for refractory AML in the UK between 2000 and 2012. Median age at SCT was 11.5 years. Twenty-three patients had primary refractory and 21 relapsed refractory AML. Refractory disease was confirmed by cytogenetics/molecular genetics in 24 cases. Median follow-up of the whole cohort is 6.8 years (2.1-14.9 years). Thirty patients (68%) achieved a CR following SCT. Transplant-related mortality at 1 year was 18%. Acute GVHD incidence was 52% (grade ⩾III 19%), chronic 7%...
February 20, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28212370/the-evolution-of-allogeneic-stem-cell-transplant-for-children-and-adolescents-with-acute-myeloid-leukemia
#3
Allyson Flower, Mitchell S Cairo
Survival rates in subsets of pediatric patients who have acute myeloid leukemia (AML) with favorable risk features are now greater than 90%. However, outcomes for patients with high-risk (HR) features remain unacceptably poor. As novel technologies for the identification of HR biomarkers and the detection of residual disease are developed, risk stratification and the application of allogeneic hematopoietic stem cell transplant (HSCT) are evolving. HSCT has been shown to benefit subpopulations of pediatric patients with AML, including those with HR cytogenetic translocations, genetic mutations, and/or residual disease after induction...
January 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28211293/hfe-gene-mutation-and-iron-overload-in-egyptian-pediatric-acute-lymphoblastic-leukemia-survivors-a-single-center-study
#4
Farida H El-Rashedi, Mahmoud A El-Hawy, Sally M El-Hefnawy, Mona M Mohammed
BACKGROUND: Hereditary hemochromatosis gene (HFE) mutations have a role in iron overload in pediatric acute lymphoblastic leukemia (ALL) survivors. We aimed to evaluate the genotype frequency and allelic distribution of the two HFE gene mutations (C282Y and H63D) in a sample of Egyptian pediatric ALL survivors and to detect the impact of these two mutations on their iron profile. PATIENTS AND METHODS: This study was performed on 35 ALL survivors during their follow-up visits to the Hematology and Oncology Unit, Pediatric Department, Menoufia University Hospitals...
February 17, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28209658/relevance-of-id3-tcf3-ccnd3-pathway-mutations-in-pediatric-aggressive-b-cell-lymphoma-treated-according-to-the-nhl-bfm-protocols
#5
Marius Rohde, Bettina R Bonn, Martin Zimmermann, Jonas Lange, Anja Möricke, Wolfram Klapper, Ilske Oschlies, Monika Szczepanowski, Inga Nagel, Martin Schrappe, Markus Loeffler, Reiner Siebert, Alfred Reiter, Birgit Burkhardt
Mature B-cell Non-Hodgkin lymphoma is the most common subtype of Non-Hodgkin lymphoma in childhood and adolescence. B-cell Non-Hodgkin lymphoma are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient hit for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell Non-Hodgkin lymphoma patients...
February 16, 2017: Haematologica
https://www.readbyqxmd.com/read/28207544/tser-polymorphism-is-not-associated-with-risk-of-pediatric-acute-lymphoblastic-leukemia-a-meta-analysis
#6
Zhaohua Qiao, Dan Lou, Li Ruan
BACKGROUND: Accumulating studies have explored the effect of thymidylate synthase enhancer region (TSER) variation on risk of pediatric acute lymphoblastic leukemia (ALL) with controversial results. Therefore, this quantitative meta-analysis was performed to assess synthetically the association of TSER variation with susceptibility to develop pediatric ALL. METHODS: The PubMed, ScienceDirect, Google Scholar, Wanfang Database, and China National Knowledge Infrastructure were systematically retrieved to obtain the published case-control studies about the relationship between TSER variation and pediatric ALL risk...
February 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28195091/coagulation-profile-during-induction-chemotherapy-in-childhood-acute-lymphoblastic-leukemia
#7
Shivali Sehgal, Sunita Sharma, Jagdish Chandra, Anita Nangia
CONTEXT: Thromboembolism in children with acute lymphoblastic leukemia (ALL) is most commonly reported after the initiation of antileukemic therapy, indicating a possible interaction of disease and therapy. AIMS: To study the effect of induction chemotherapy on coagulation parameters in pediatric ALL patients. SETTINGS AND DESIGN: Thirty-seven newly diagnosed patients of ALL up to 18 years of age were evaluated along with 30 age- and sex-matched controls...
January 2017: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/28193567/genomic-analysis-of-adult-b-all-identifies-potential-markers-of-shorter-survival
#8
Shiven Patel, Clinton C Mason, Martha J Glenn, Christian N Paxton, Sara T South, Melissa H Cessna, Julie Asch, Erin F Cobain, Dale L Bixby, Lauren B Smith, Shalini Reshmi, Julie M Gastier-Foster, Joshua D Schiffman, Rodney R Miles
B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA)...
February 3, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28193268/adipokines-insulin-resistance-and-adiposity-as-a-predictors-of-metabolic-syndrome-in-child-survivors-of-lymphoma-and-acute-lymphoblastic-leukemia-of-a-developing-country
#9
Lourdes Barbosa-Cortés, Mardia López-Alarcón, Juan Manuel Mejía-Aranguré, Miguel Klünder-Klünder, María Del Carmen Rodríguez-Zepeda, Hugo Rivera-Márquez, Alan de la Vega-Martínez, Jorge Martin-Trejo, Juan Shum-Luis, Karina Solis-Labastida, Enrique López-Aguilar, Guadalupe Matute-González, Roberto Bernaldez-Rios
BACKGROUND: There is a growing body of evidence indicating that pediatric survivors of cancer are at a greater risk of developing metabolic syndrome. This study evaluated some probable predictors of metabolic syndrome (MS), such as leptin and adiponectin concentrations, the leptin/adiponectin ratio, insulin resistance, and adiposity, in a sample of child survivors of lymphoma and leukemia in Mexico City. METHODS: Fifty two children (leukemia n = 26, lymphoma n = 26), who were within the first 5 years after cessation of therapy, were considered as eligible to participate in the study...
February 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28187514/aieop-bfm-consensus-guidelines-2016-for-flow-cytometric-immunophenotyping-of-pediatric-acute-lymphoblastic-leukemia
#10
Michael N Dworzak, Barbara Buldini, Giuseppe Gaipa, Richard Ratei, Ondrej Hrusak, Drorit Luria, Eti Rosenthal, Jean-Pierre Bourquin, Mary Sartor, Angela Schumich, Leonid Karawajew, Ester Mejstrikova, Oscar Maglia, Georg Mann, Wolf-Dieter Ludwig, Andrea Biondi, Martin Schrappe, Giuseppe Basso
Immunophenotyping by flow cytometry (FCM) is a worldwide mainstay in leukemia diagnostics. For concordant multicentric application, however, a gap exists between available classification systems, technologic standardization, and clinical needs. The AIEOP-BFM consortium induced an extensive standardization and validation effort between its nine national reference laboratories collaborating in immunophenotyping of pediatric acute lymphoblastic leukemia (ALL). We elaborated common guidelines which take advantage of the possibilities of multi-color FCM: marker panel requirements, immunological blast gating, in-sample controls, tri-partite antigen expression rating (negative vs...
February 10, 2017: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/28185203/hla-haploidentical-hematopoietic-cell-transplantation-using-clofarabine-and-busulfan-for-refractory-pediatric-hematological-malignancy
#11
Masatoshi Takagi, Yasuyoshi Ishiwata, Yuki Aoki, Satoshi Miyamoto, Akihiro Hoshino, Kazuaki Matsumoto, Akira Nishimura, Mari Tanaka, Masakatsu Yanagimachi, Noriko Mitsuiki, Kohsuke Imai, Hirokazu Kanegane, Michiko Kajiwara, Kanako Takikawa, Tsukasa Mae, Osamu Tomita, Junya Fujimura, Masato Yasuhara, Daisuke Tomizawa, Shuki Mizutani, Tomohiro Morio
Haploidentical hematopoietic cell transplantation (HCT) conditioning with clofarabine and target area under the blood concentration-time curve (AUC)-based busulfan adjustment was performed in three patients with refractory pediatric leukemia. The target AUC for two patients who had already received multiple transplantations was 3600 and 4000 μmol min/L, and that for the patient with Down's syndrome was 3000 μmol min/L. Regimen-related toxicity was well tolerated in all cases. All three maintained cytological remission throughout the follow-up period (between 31 and 167 weeks)...
February 9, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28183295/meta-analysis-of-gene-expression-in-relapsed-childhood-b-acute-lymphoblastic-leukemia
#12
Yock-Ping Chow, Hamidah Alias, Rahman Jamal
BACKGROUND: Relapsed pediatric B-acute lymphoblastic leukemia (B-ALL) remains as the leading cause of cancer death among children. Other than stem cell transplantation and intensified chemotherapy, no other improved treatment strategies have been approved clinically. Gene expression profiling represents a powerful approach to identify potential biomarkers and new therapeutic targets for various diseases including leukemias. However, inadequate sample size in many individual experiments has failed to provide adequate study power to yield translatable findings...
February 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28182004/tenovin-6-impairs-autophagy-by-inhibiting-autophagic-flux
#13
Hongfeng Yuan, Brandon Tan, Shou-Jiang Gao
Tenovin-6 has attracted significant interest because it activates p53 and inhibits sirtuins. It has anti-neoplastic effects on multiple hematopoietic malignancies and solid tumors in both in vitro and in vivo studies. Tenovin-6 was recently shown to impair the autophagy pathway in chronic lymphocytic leukemia cells and pediatric soft tissue sarcoma cells. However, whether tenovin-6 has a general inhibitory effect on autophagy and whether there is any involvement with SIRT1 and p53, both of which are regulators of the autophagy pathway, remain unclear...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28179213/juvenile-myelomonocytic-leukemia-in-turkey-a-retrospective-analysis-of-65-patients
#14
Özlem Tüfekçi, Ülker Koçak, Zühre Kaya, İdil Yenicesu, Canan Albayrak, Davut Albayrak, Şebnem Yılmaz Bengoa, Türkan Patıroğlu, Musa Karakükçü, Ekrem Ünal, Elif Ünal İnce, Talia İleri, Mehmet Ertem, Tiraje Celkan, Gül Nihal Özdemir, Nazan Sarper, Dilek Kaçar, Neşe Yaralı, Namık Yaşar Özbek, Alphan Küpesiz, Tuba Karapınar, Canan Vergin, Ümran Çalışkan, Hüseyin Tokgöz, Melike Sezgin Evim, Birol Baytan, Adalet Meral Güneş, Deniz Yılmaz Karapınar, Serap Karaman, Vedat Uygun, Gülsun Karasu, Mehmet Akif Yeşilipek, Ahmet Koç, Erol Erduran, Berna Atabay, Haldun Öniz, Hale Ören
OBJECTIVE: To define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey, in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course and treatment strategies. MATERIALS AND METHODS: Data including clinical and labarotory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled into the study...
February 9, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/28179212/association-between-n363s-and-bcli-polymorphisms-of-the-glucocorticoid-receptor-gene-nr3c1-and-glucocorticoid-side-effects-during-childhood-acute-lymphoblastic-leukemia-treatment
#15
Meriç Kaymak Cihan, Halil Gürhan Karabulut, Nüket Yürür Kutlay, Hatice Ilgın Ruhi, Ajlan Tükün, Lale Olcay
OBJECTIVE: Glucocorticoids (GCs) are the key drugs for the treatment of pediatric acute lymphoblastic leukemia (ALL). Herein, investigation of the relationship between the N363S and BclI polymorphisms of the GC receptor gene (NR3C1) and the side effects of GCs during pediatric ALL therapy was aimed. MATERIALS AND METHODS: N363S and BclI polymorphisms were analyzed in 49 patients with ALL treated between 2000 and 2012. Control group consisted 46 patients with benign disorders...
February 9, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/28174417/amkl-chimeric-transcription-factors-are-potent-inducers-of-leukemia
#16
J Dang, S Nance, J Ma, J Cheng, M P Walsh, P Vogel, J Easton, G Song, M Rusch, A L Gedman, C Koss, J R Downing, T A Gruber
Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathologic including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI, and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2 which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models...
February 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28174375/-characteristics-of-adolescent-and-young-adult-cancer
#17
Keizo Horibe
In adolescent and young adult(AYA)population, cancer is the leading cause of death due to illness with the lowest mortality rate as well as children, and national measures for cancer was left behind. Leukemia, lymphomas, brain tumors, thyroid cancer, ovarian cancer, cervical cancer, breast cancer, testicular cancer and bone and soft tissue sarcomas account for majority of the cancers in this age group. There has been no significant improvement in AYA patients in contrast to other age groups. AYA patients with cancer are under growing independency, starting in life to the community, and reproductive age...
January 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28171800/epigenetic-drug-combination-overcomes-osteoblast-induced-chemoprotection-in-pediatric-acute-lymphoid-leukemia
#18
Anthony Quagliano, Anilkumar Gopalakrishnapillai, Sonali P Barwe
Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts...
January 27, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28161117/new-drugs-for-rare-diseases-in-children
#19
Klaus Rose
PURPOSE: United States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children's health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed...
February 1, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28157215/identification-of-a-genetically-defined-ultra-high-risk-group-in-relapsed-pediatric-t-lymphoblastic-leukemia
#20
P Richter-Pechańska, J B Kunz, J Hof, M Zimmermann, T Rausch, O R Bandapalli, E Orlova, G Scapinello, J C Sagi, M Stanulla, M Schrappe, G Cario, R Kirschner-Schwabe, C Eckert, V Benes, J O Korbel, M U Muckenthaler, A E Kulozik
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0...
February 3, 2017: Blood Cancer Journal
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