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Paediatric acute leukaemia

Henrik Hasle, Gertjan J L Kaspers
Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation...
October 21, 2016: British Journal of Haematology
Fiona C Brown, Paolo Cifani, Esther Drill, Jie He, Eric Still, Shan Zhong, Sohail Balasubramanian, Dean Pavlick, Bahar Yilmazel, Kristina M Knapp, Todd A Alonzo, Soheil Meshinchi, Richard M Stone, Steven M Kornblau, Guido Marcucci, Alan S Gamis, John C Byrd, Mithat Gonen, Ross L Levine, Alex Kentsis
Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases...
October 21, 2016: British Journal of Haematology
Jeffrey A Magee
No abstract text is available yet for this article.
October 21, 2016: British Journal of Haematology
Luca Trentin, Silvia Bresolin, Emanuela Giarin, Michela Bardini, Valentina Serafin, Benedetta Accordi, Franco Fais, Claudya Tenca, Paola De Lorenzo, Maria Grazia Valsecchi, Giovanni Cazzaniga, Geertruy Te Kronnie, Giuseppe Basso
To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia...
October 4, 2016: Scientific Reports
Edyta Ulińska, Katarzyna Mycko, Elżbieta Sałacińska-Łoś, Agata Pastorczak, Alicja Siwicka, Wojciech Młynarski, Michał Matysiak
AIM OF THE STUDY: To characterise expression of mTOR (mammalian target of rapamycin) in childhood B-cell acute lymphoblastic leukaemia (ALL), and to evaluate a possible link between mTOR and clinical characteristics. MATERIAL AND METHODS: The examined group consisted of 21 consecutive patients, aged 1-18 years, diagnosed with B-cell ALL in 2010, and 10 relapsed B-cell ALL patients diagnosed for the first time between 2009 and 2011, who developed relapse before 2014...
2016: Contemporary Oncology Współczesna Onkologia
Denise Niewerth, Gertjan J L Kaspers, Gerrit Jansen, Johan van Meerloo, Sonja Zweegman, Gaye Jenkins, James A Whitlock, Stephen P Hunger, Xiaomin Lu, Todd A Alonzo, Peter M van de Ven, Terzah M Horton, Jacqueline Cloos
BACKGROUND: Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). METHODS: We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children's Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1) and AML (COG-AAML07P1)...
2016: Journal of Hematology & Oncology
Jennifer E Cohen, Claire E Wakefield, Richard J Cohn
BACKGROUND: Childhood cancer survivors are at a higher risk of developing health conditions such as osteoporosis, and cardiovascular disease than their peers. Health-promoting behaviour, such as consuming a healthy diet, could lessen the impact of these chronic issues, yet the prevalence rate of health-protecting behaviour amongst survivors of childhood cancer is similar to that of the general population. Targeted nutritional interventions may prevent or reduce the incidence of these chronic diseases...
2016: Cochrane Database of Systematic Reviews
Emad Uddin Siddiqui, Sayyeda Ghazala Kazi, Muhammad Irfan Habib, Khalid Mehmood Ahmed Khan, Nukhba Zia
OBJECTIVE: To determine the frequency, site and time to relapse from diagnosis, and to see the relationship of relapse with important prognostic factors. METHODS: The prospective descriptive observational study was conducted at the National Institute of Child Health, Karachi, June 2005 to May 2007, and comprised newly-diagnosed cases of acute lymphoblastic leukaemia. Bone marrow aspiration was done on reappearance of blast cells in peripheral smear and cerebrospinal fluid...
August 2016: JPMA. the Journal of the Pakistan Medical Association
Ming Yu, Salma Al-Dallal, Latifa Al-Haj, Shiraj Panjwani, Akina S McCartney, Sarah M Edwards, Pooja Manjunath, Catherine Walker, Alexander Awgulewitsch, Kathryn E Hentges
The mouse zinc-finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B-cell proto-oncogene, causing leukaemia in mice following retroviral insertions in its promoter region that drive Zfp521 over-expression. Furthermore, ZNF521 is expressed in human haematopoietic cells, and translocations between ZNF521 and PAX5 are associated with paediatric acute lymphoblastic leukaemia. However, the regulatory factors that control Zfp521 expression directly have not been characterised...
August 10, 2016: Genesis: the Journal of Genetics and Development
Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Okuno, Genki Yamato, Yusuke Hara, Yasunobu Nagata, Kenichi Chiba, Hiroko Tanaka, Kiminori Terui, Motohiro Kato, Myoung-Ja Park, Kentaro Ohki, Akira Shimada, Junko Takita, Daisuke Tomizawa, Kazuko Kudo, Hirokazu Arakawa, Souichi Adachi, Takashi Taga, Akio Tawa, Etsuro Ito, Keizo Horibe, Masashi Sanada, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations...
July 29, 2016: British Journal of Haematology
Mohamed E Ateyah, Mona E Hashem, Mohamed Abdelsalam
OBJECTIVE: Acute B lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy worldwide but little is known of its origin. Recently, many studies showed both a high incidence of Epstein-Barr virus (EBV) infection and high levels of CD4(+)CD25(+)Foxp3(+)(Treg cells) in children with B-ALL. In our study, we investigated the possible relationship between EBV infection and the onset of B-ALL, and its relation to expression of CD4(+), CD25(high+)Foxp3+ T regulatory cells...
July 25, 2016: Journal of Clinical Pathology
Alenka Smid, Natasa Karas-Kuzelicki, Janez Jazbec, Irena Mlinaric-Rascan
Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR)...
2016: Scientific Reports
Kshitij Joshi, Harsha Panchal, Sonia Parikh, Gaurang Modi, Avinash Talele, Asha Anand, Urmila Uparkar, Nitin Joshi, Itesh Khatawani
The author describes paediatric case of relapsed acute lymphoblastic leukaemia (ALL) presented as aleukemic leukaemia cutis (ALC). A 2 year old child was admitted in tertiary oncology centre. He suffered from pre B cell ALL with absent Philadelphia chromosome. This patient received multiagent induction chemotherapy as per Berlin-Frankfurt-Munster (BFM) protocol for ALL. He achieved remission after 28 days of treatment. Subsequently he presented with multiple skin lesions in the form of multiple small erythematous violaceous macules, papules, plaques and nodules on face, chest and back regions...
June 2016: Indian Journal of Hematology & Blood Transfusion
Yuhki Koga, Utako Oba, Wakako Kato, Hiroaki Ono, Kentaro Nakashima, Hidetoshi Takada
We report a patient with non-Down syndrome AML, also known as AMKL, with monosomy 7, who was also obese and had a hearing impairment and mental retardation. Non-myeloablative bone marrow transplantation was performed successfully after the patient received less aggressive azacitidine treatment, without the usual intensive induction chemotherapy regimen for AML.
September 2016: Pediatric Transplantation
Claire Edwin, Joanne Dean, Laura Bonnett, Kate Phillips, Russell Keenan
Composition of tumour immune cell infiltrates correlates with response to treatment and overall survival (OS) in several cancer settings. We retrospectively examined immune cells present in diagnostic bone marrow aspirates from paediatric patients with B-cell acute lymphoblastic leukaemia. Our analysis identified a sub-group (∼30% of patients) with >2.37% CD20 and >6.05% CD7 expression, which had 100% OS, and a sub-group (∼30% of patients) with ≤2.37% CD20 and ≤6.05% CD7 expression at increased risk of treatment failure (66...
October 2016: Pediatric Blood & Cancer
Heiko-Manuel Teltschik, Frank Heinzelmann, Bernd Gruhn, Tobias Feuchtinger, Patrick Schlegel, Michael Schumm, Bernhard Kremens, Ingo Müller, Martin Ebinger, Carl Philipp Schwarze, Hellmut Ottinger, Daniel Zips, Rupert Handgretinger, Peter Lang
Graft failure is a life-threatening complication after allogeneic haematopoietic stem cell transplantation (HSCT). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias (n = 14) and non-malignant diseases (n = 5) who experienced graft failure after previous HSCT from matched (n = 3) or haploidentical donors (n = 16) between 2003 and 2012. After total nodal irradiation (TNI)-based reconditioning combined with fludarabine, thiotepa and anti-T cell serotherapy, all patients received T cell-depleted peripheral blood stem cell grafts from a second, haploidentical donor...
October 2016: British Journal of Haematology
Madara Kreile, Linda Piekuse, Dmitrijs Rots, Zane Dobele, Zhanna Kovalova, Baiba Lace
INTRODUCTION: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. MATERIAL AND METHODS: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands...
June 1, 2016: Archives of Medical Science: AMS
Henrik Lilljebjörn, Rasmus Henningsson, Axel Hyrenius-Wittsten, Linda Olsson, Christina Orsmark-Pietras, Sofia von Palffy, Maria Askmyr, Marianne Rissler, Martin Schrappe, Gunnar Cario, Anders Castor, Cornelis J H Pronk, Mikael Behrendtz, Felix Mitelman, Bertil Johansson, Kajsa Paulsson, Anna K Andersson, Magnus Fontes, Thoas Fioretos
Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations...
2016: Nature Communications
Elizabeth G Salazar, Yimei Li, Brian T Fisher, Susan R Rheingold, Julie Fitzgerald, Alix E Seif, Yuan-Shung Huang, Rochelle Bagatell, Richard Aplenc
Although inferior outcomes of children with Down syndrome (DS) and acute lymphoid leukaemia (ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System (PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS-ALL (2·8%). In a multivariate model, DS was associated with increased risk of cardiovascular (odds ratio [OR] 2·0, 95% confidence interval [CI] 1·6-2·7), respiratory (OR 2·1, 95% CI: 1·6-2·9), neurologic (OR 3·4, 95% CI 1·9-6·2), and hepatic (OR 1·4, 95% CI 1·0-1·9) dysfunction and sepsis (OR 1·8, 95% CI: 1·4-2·4)...
August 2016: British Journal of Haematology
Siew Mei Yap, Peter MacEneaney, Clodagh Ryan, Orna O'Toole
A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms...
2016: BMJ Case Reports
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